HEMATOLOGY REFERENCE LIST

Index



Hematopoiesis: regulation and disorders thereof
  1. Varmus and Lowell. Cancer genes and hematopoiesis. Blood 1994;83:5
  2. Baron et al. The embryonic origins of erythropoiesis in mammals. Blood 2012;119:4828
  3. Shivdasani and Orkin. The transcriptional control of hematopoiesis. Blood 1996;87:4025
  4. Phillips et al. The genetic program of hematopoietic stem cells. Science 2000;288:1635
  5. Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 2015;125: 2605
  6. Boulais and Frenette. Making sense of hematopoietic stem cell niches. Blood 2015;125:2621
  7. Calvi and Link. The hematopoietic stem cell niche in homeostasis and disease. Blood 2015;126:2443
  8. Sluvkin I. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells. Blood 2013;122:4035
  9. Lessard and Sauvageau.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423:255
  10. Möröy et al. From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation. Blood 2015;126:2561
  11. Shizuru et al. Hematopoietic Stem and Progenitor Cells: Clinical and Preclinical Regeneration of the Hematolymphoid System.  Ann Rev Med 2005;56:509
  12. Khan et al. Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 2016;351:176
  13. Notta et al. Isolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment. Science 2011;333:218
  14. Notta et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 2016;351:139
  15. Catlin et al. The replication rate of human hematopoietic stem cells in vivo. Blood 2011; 117:4460 (Estimate that HSCs replicate on average once every 40 weeks)
  16. Méndez-Ferrer et al. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008;452: 442
  17. Papayannopoulou and Scadden.Stem cell ecology and stem cells in motion. Blood 2008;111:3923
  18. Fares et al. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 2014;345:1509 (Small molecules that stimulate expansion of human hematopoietic stem cells)
  19. Samokhvalov et al. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 2007;446:1056
  20. Chen et al. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 2016;530:223
  21. Adolfsson et al. Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential: A Revised Road Map for Adult Blood Lineage Commitment. Cell 2005;121:295
  22. O'Connell et al. MicroRNA function in myeloid biology. Blood 2011;118:2960
  23. Luo et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell 2015;16:426
  24. Thomson et al. embryonic stem cell lines derived from human blastocysts.  Science 1998;282:1145
  25. Kaufman et al. Hematopoietic colony-forming cells derived from human embryonic stem cells. PNAS 2001;98:10716
  26. Fogg et al. A Clonogenic Bone Marrow Progenitor Specific for Macrophages and Dendritic Cells. Science 2006;311:83
  27. Tam et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nature Medicine 2006;12:793
  28. Semenza G. Oxygen sensing, homeostasis, and disease. NEJM 2011;365:537
  29. Yvan-Charvet et al. ATP-Binding Cassette Transporters and HDL Suppress Hematopoietic Stem Cell Proliferation. Science 2010;328:1689 (Removal of cholesterol from membrane rafts by HDL suppresses growth factor signaling)
  30. Ito et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science 2016;354:1156 (With editorial)
  31. Heidt et al. Chronic variable stress activates hematopoietic stem cells. Nat Med 2014;20:754 (With editorial)
  32. Kopp et al. The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology 2005:20:349
  33. Méndez-Ferrer et a. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466:829
  34. Mendelson and Frenette. Hematopoietic stem cell niche maintanance during homeostasis and regeneration. Nat Med 2014;20:833
  35. Hattangadi et al. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 2011;118:6258
  36. Deutsch and Tomer. Megakaryocyte development and platelet production. Br J Haematol 2006;134:453
  37. Bianchi et al. Genomic landscape of megakaryopoiesis and platelet function defects. Blood 2016;127:1249
  38. Bruns et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 2014;20:1315 (with editorial)
  39. Zhao et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 2014;20:1321 (with editorial)
  40. Junt et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 2007;317:1767 (with movies)
  41. Nishimura et al. IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J Cell Biol 2015;209:453 (Alternative mechanism for rapid platelet release in inflammatory states)
  42. Kaushansky K. Determinants of platelet number and regulation of thrombopoiesis. Hematology 2009; 147
  43. Lisman et al. The circulating platelet count is not dictated by the liver, but may be determined in part by the bone marrow: analyses from human liver and stem cell transplantations. J Thromb Haemost 2012;10:1624
  44. Schwertz et al. Anucleate platelets generate progeny. Blood 2010;115:3801 (Thrombopoiesis may continue after platelets enter the bloodstream)
  45. Gieger et al. New gene functions in megakaryopoiesis and platelet formation. Nature 2011;480:201
  46. Bluteau et al. Developmental changes in human megakaryopoiesis. J Thromb Haemost 2013;11:1730
  47. Nijnik et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 2007;447: 686
  48. Rossi et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007;447:725
  49. Cobaleda et al. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 2007;449:473
  50. Vo and Daley. De novo generation of HSCs from somatic and pluripotent stem cell sources. Blood 2015;125:2641
  51. Bell and Bhandoola. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 2008;452:764 (see also the accompanying editorial)
  52. Wada et al. Adult T-cell progenitors retain myeloid potential. Nature 2008;452:768 (see also the accompanying editorial)
  53. Akala et al. Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors. Nature 2008;453:228
  54. Landsdorp P. Telomeres, stem cells, and hematology. Blood 2008;111:1759
  55. Geissmann et al. Development of Monocytes, Macrophages, and Dendritic Cells. Science 2010;327:5966
  56. de Bruin et al. Impact of interferon-γ on hematopoiesis. Blood 2014;124:2479


Bone marrow biopsy
  1. Malempati et al. Videos in clinical medicine: Bone marrow aspiration and biopsy. NEJM 2009; 361:e28
  2. Bain B.  Bone marrow biopsy morbidity and mortality.  Br J Haematol 2003;121:949
  3. Eikelboom J. Bone marrow biopsy in thrombocytopenic or anticoagulated patients. Br J Haematol 2005;129:562
  4. Hot et al. Yield of Bone Marrow Examination in Diagnosing the Source of Fever of Unknown Origin. Arch Intern Med 2009;169:2018 (Diagnostic yield 24%; presence of thrombocytopenia or anemia increased diagnostic yield)

Biology and clinical use of cytokines and hematopoetic growth factors

General

  1. Metcalf D. Hematopoietic cytokines. Blood 2008;111:485
  2. Kaushansky K. Lineage-Specific Hematopoietic Growth Factors. NEJM 2006;354:2034
  3. Rollins BJ. Chemokines. Blood 1997;90:909
  4. Bennett et al. Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project. Br J Haematol 2006;135:642 (with editorial)

G-CSF

  1. Anderlini and Champlin. Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges. Blood 2008;111:1767
  2. Hirsch et al. Effects of granulocyte-colony stimulating factor on chromosome aneuploidy and replication asynchrony in healthy peripheral blood stem cell donors. Blood 2011;118:2602 (No evidence that G-CSF, as given to stem cell donors, causes chromosomal instability)
  3. Hercus et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 2009;114:1289
  4. Hartmann et al. Granulocyte colony-stimulating factor in severe chemotherapy-induced febrile neutropenia. NEJM 1997;336:1776
  5. Clark et al. Colony-Stimulating Factors for Chemotherapy-Induced Febrile Neutropenia: A Meta-Analysis of Randomized Controlled Trials. J Clin Oncol 2005;23:4198
  6. Sung et al. Meta-analysis: Effect of Prophylactic Hematopoietic Colony-Stimulating Factors on Mortality and Outcomes of Infection. Ann Intern Med 2007;147:400 (They reduce infection rate but have little effect on survival)
  7. Weiss et al. Granulocyte colony-stimulating factor to prevent the progression of systemic nonresponsiveness in systemic inflammatory response syndrome and sepsis. Blood 1999;93:425
  8. Beekman and Touw. G-CSF and its receptor in myeloid malignancy. Blood 2010;115:5131 (Reviews evidence linking G-CSF administration and leukemogenesis)
  9. Relling et al.  Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment.  Blood 2003;101:3862
  10. Park et al. NF-kB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nature Med 2007;13:62 (GM-CSF may promote metastasis)
  11. Ringdén et al. Treatment With Granulocyte Colony-Stimulating Factor After Allogeneic Bone Marrow Transplantation for Acute Leukemia Increases the Risk of Graft-Versus-Host Disease and Death: A Study From the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.  J Clin Oncol 2004;22:416
  12. Socie et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 2007;109:2794 (G-CSF administration increased risk of MDS/AML by about 2)

Erythropoietin and erythropoietic drugs

  1. Rizzo et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010116:4045
  2. Henry et al.  Epoetin Alfa.Clinical Evolution of a Pleiotropic Cytokine. Arch Intern Med 2004;164:262
  3. Tam et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nature Medicine 2006;12:793
  4. Goodnough et al. Erythropoietin, iron, and erythropoiesis. Blood 2000;96:823
  5. Minamishima and Kaelin. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science 2010;329:407 (Drugs that inhibit prolyl hydroxylase could restore physiologic EPO production in renal failure)
  6. Arcasoy M. The non-haematopoietic biological effects of erythropoietin. Br J Haematol 2008;141:14
  7. Fehr et al. Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia. Kidney Int 2004;66:1206
  8. Unger et al. Erythropoiesis-stimulating agents - time for a reevaluation (editorial). NEJM 2010;362:189
  9. Besarab et al. The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin.  NEJM 1998; 339:584 (Raising hemoglobin to normal levels associated with increased mortality in dialysis patients with CHF or ischemic heart disease)
  10. Remuzzi and Ingelfinger.  Correction of anemia - payoffs and problems (editorial). NEJM 2006;355:2144 (Normalization of hemoglobin level in uremia with EPO does not lead to improved cardiovascular outcomes)
  11. Phrommintikul et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007;369:381 (Target hemoglobin above 12 grams associated with higher mortality)
  12. Corwin et al. Efficacy and safety of epoetin alfa in critically ill patients. NEJM 2007;357:965 (EPO did not reduce transfusion requirements; it may have reduced mortality in trauma patients, but caused increased risk of thrombosis. With editorial)
  13. Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia. JAMA 2008;299:914 (Increased VTE and mortality risk in patients receiving ESAs)
  14. Heinze et al. Mortality in renal transplant recipients given erythropoietins to increase haemoglobin concentration: cohort study. BMJ 2009;339:b4018 (Mortality increased in ESA recipients with Hgb > 12.5)
  15. Pfeffer et al. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. NEJM 2009;361:2019 (Giving darbepoetin to attain a target Hgb of 13 did not reduce risk of death or cardiovascular events, increased stroke risk)
  16. Rizzo et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood 2008;111:25
  17. Palmer et al. Meta-analysis: Erythropoiesis-Stimulating Agents in Patients With Chronic Kidney Disease. Ann Intern Med 2010;153:23 (Targeting Hgb>12 increases risk for stroke, hypertension and vascular device thrombosis, and "probably" for death and cardiovascular events)
  18. Clement et al. The Impact of Selecting a High Hemoglobin Target Level on Health-Related Quality of Life for Patients With Chronic Kidney Disease. A systematic review and meta-analysis. Arch Intern Med 2009;169:1104 ("Targeting hemoglobin levels above 12 grams leads to small and not clinically meaningful improvements in QOL")
  19. Solomon et al. Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes. NEJM 2010;363:1146 (Dose escalation in poor responders to darbepoetin associated with increased risk of cardiovascular events or death)
  20. Collister et al. The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2016;164:472 (Targeting higher Hb does not improve quality of life)
  21. Wang et al. Association Between Changes in CMS Reimbursement Policy and Drug Labels for Erythrocyte-Stimulating Agents With Outcomes for Older Patients Undergoing Hemodialysis Covered by Fee-for-Service Medicare. JAMA Int Med 2016;176:1818 (More conservative dosing of ESAs resulted in reduced stroke risk, modest increase in transfusion rate; black patients had significant reduction in cardiace events and death; with editorial)
  22. Skali et al. Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa. The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Experience. Circulation 2011;124:2903 (2-fold increased incidence of stroke in patients given darbepoetin)
  23. Gabrilove et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times weekly dosing. J Clin Oncol 2001;19:2875
  24. Talving et al. Erythropoiesis Stimulating Agent Administration Improves Survival After Severe Traumatic Brain Injury: A Matched Case Control Study. Ann Surg 2010; 251:1 (Retrospective study)
  25. Ghali et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation 2008;117:526 (No improvement in function or quality of life)
  26. Swedberg et al. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. NEJM 2013;368:1210 (No improvement in outcomes)
  27. Kansagara et al. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159:746
  28. Auerbach et al. Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Related Anemia: A Multicenter, Open-Label, Randomized Trial.  J Clin Oncol 2004;22:1301
  29. Henke et al.  Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255 (Possible adverse effect of Epo treatment on disease control)
  30. Casadevall et al. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial.  Blood 2004;104:321 (Treatment was expensive, and did not improve quality of life)
  31. Österborg et al. Impact of epoetin-ß on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study. Br J Haematol 2005;129:1365 (no effect on survival vs placebo)
  32. Musto et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol 2005;128:204
  33. Bohlius et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373:1532 (ESA treatment increased mortality during treatment and decreased overall survival)
  34. Jaspers et al. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial. Blood 2014;124:33 (EPO started one month after HSCT hastens RBC recovery and reduces transfusion requirements)
  35. Casadevall N et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. NEJM 2002;346:469
  36. Bennett et al. Pure Red-Cell Aplasia and Epoetin Therapy.  NEJM 2004;351:1403
  37. Stead et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood 2006;108:1830

Thrombopoietin and thrombopoietic drugs

  1. de Sauvage et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 1994;369:533  (discovery and characterization of thrombopoietin)
  2. Grozovsky et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015;21:47 (Aging platelets lose sialic acid, then bind to hepatic receptor that promotes TPO production)
  3. Kuter and Begley:  Recombinant human thrombopoeitin: basic biology and evaluation of clinical studies.  Blood 2002:100:3457
  4. Kuter D. New thrombopoietic growth factors. Blood 2007;109:4607
  5. Andemariam et al. Novel thrombopoietic agents. Hematology 2007;106
  6. Ellis et al.  Recombinant human interleukin-11 and bacterial infection in patients with haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomized trial. Lancet 2003;361:275

Aplastic anemia and related disorders

General; biology & pathophysiology

  1. Young NS Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology 2013:76
  2. Calado and Young. Telomere diseases. NEJM 2009;361:2353
  3. Marsh J. Making Therapeutic Decisions in Adults with Aplastic Anemia. Hematology 2006;78-85
  4. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood 2016;128:337
  5. Afable et al. Clonal evolution in aplastic anemia. Hematology 2011:90
  6. Yoshizato et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. NEJM 2015;373:35 (About half of patients have evidence of clonal hematopoiesis; biased mutation set consistent with Darwinian selection in marrow, correlated with outcome)
  7. Yamaguchi et al. Mutations in TERT, the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia. NEJM 2005;352:1413
  8. Calado and Young. Telomere maintenance and human bone marrow failure. Blood 2008;111:4446
  9. Scheinberg et al. Association of Telomere Length of Peripheral Blood Leukocytes With Hematopoietic Relapse, Malignant Transformation, and Survival in Severe Aplastic Anemia. JAMA 2010;304:1358 (Shorter telomeres predicted risk of relapse, clonal evolution and overall survival)
  10. Dumitriu et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. Blood 2015;125:706
  11. Jerez et al. STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients. Blood 2013;122:2453 (LGL clones with STAT3 mutations may cause marrow failure in some patients with AA and MDS)
  12. Dunn et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999;131:401
  13. Sugimori et al. Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood 2006;107:1308z
  14. Baumelou et al. Epidemiology of aplastic anemia in France. Blood 1990; 75:1646
  15. Marsh et al. The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood 1990; 76:1748
  16. Nosticò and Young. Gamma-interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994;120:463
  17. Brown et al. Hepatitis-associated aplastic anemia. NEJM 1997;336:1059
  18. Dainiak et al. The Hematologist and Radiation Casualties.Hematology 2003:473-496
  19. Parry et al. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 2011;117:5607

Treatment of aplastic anemia

  1. Guinan EC. Diagnosis and management of aplastic anemia. Hematology 2011:76
  2. Bacigalupo A. How I treat acquired aplastic anemia. Blood 2017;129:1428
  3. Young et al. A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases. Blood 1988; 72:1861
  4. Frickhofen et al.  Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia.  Blood 2003;101:1236
  5. Brodsky et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med 2001;135:477
  6. Scheinberg et al. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol 2006;133:606 (no benefit from adding mycophenolate)
  7. Scheinberg et al. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol 2006;133:622 (30% response rate in patients who were refractory to horse ATG or who relapsed after treatment)
  8. Scheinberg et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. NEJM 2011;365:430 (Horse ATG superior)
  9. Marsh et al. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood 2012;119:5391 (Response rates and OS lower than achieved with horse ATG)
  10. Teramura et al. Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood 2007;110:1756
  11. Brodsky et al. High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood 2010;115:2136 (88% overall survival, 58% event-free survival at 10 years)
  12. DeZern et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases. Medicine 2011;90:89
  13. Tichelli et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood 2011;117:4434 (OS at 6 years 76%; no survival benefit from adding G-CSF but fewer infections)
  14. Marsh and Kulasekararaj. Management of the refractory aplastic anemia patient: what are the options? Hematology 2013:87
  15. Socié et al. Malignant tumors occurring after treatment of aplastic anemia. NEJM 1993;329:1152
  16. Scheinberg et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood 2012;119:345 (Best results in relapsed and refractory patients; ATG preferable for treatment-naive patients)
  17. Olnes et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. NEJM 2012;367:11 (44% of patients had a hematologic response; minimal toxicity)
  18. Desmond et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014;123:1818 (40% OR rate)
  19. Townsley et al. Danazol treatment for telomere diseases. NEJM 2016;374:1922 (Drug was effective in reducing rate of telomere attrition - almost all patients had telomere elongation - and improving hematopoietic function; with editorial)

Aplastic anemia: stem cell transplantation

Pure red cell aplasia

  1. Means RT. Pure red cell aplasia. Blood 2016;128:2504
  2. Lacy et al. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities. Blood 1996;87:3000
  3. Sloand et al. Successful Treatment of Pure Red-Cell Aplasia with an Anti–Interleukin-2 Receptor Antibody (Daclizumab). Ann Intern Med 2006;144:181
  4. Macdougall et al. A Peptide-Based Erythropoietin-Receptor Agonist for Pure Red-Cell Aplasia. NEJM 2009;361:1848
  5. Thompson and Steensma. Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience. Br J Haematol 2006;135:405
  6. Young and Brown.  Parvovirus B-19.  NEJM 2004;350:586
  7. Potter et al. Variation of Erythroid and Myeloid Precursors in the Marrow and Peripheral Blood of Volunteer Subjects Infected with Human Parvovirus (B19).  J Clin Invest 1987;79.1486

Inherited marrow failure syndromes

  1. Townsley et al. Bone marrow failure and the telomeropathies. Blood 2014;124:2775
  2. Narla and Ebert. Ribosomopathies: human disorders of ribosome function. Blood 2010;115:3196 (Mutations involved in several marrow failure syndromes)
  3. De Keersmaecker et al. Ribosomopathies and the paradox of cellular hypo- to hyperproliferation. Blood 2015;125:1377
  4. Ruggero and Shimamura. Marrow failure: a window in to ribosome biology. Blood 2014;124:2784
  5. Alter B. Diagnosis, genetics and management of inherited bone marrow failure syndromes. Hematology 2007;29
  6. Longerich et al. Stress and DNA repair biology of the Fanconi anemia pathway. Blood 2014;124:2812
  7. Soulier J. Fanconi Anemia. Hematology 2011:492
  8. Garaycoechea and Patel. Why does the bone marrow fail in Fanconi anemia? Blood 2014;123:26
  9. D'Andrea A. Susceptibiity pathways in Fanconi's anemia and breast cancer. NEJM 2010;362:1909
  10. Kutler et al.  A 20-year perspective on the International Fanconi Anemia Registry (IFAR).  Blood 2003;101:1249
  11. Peffault de Latour and Soulier. How I treat MDS and AML in Fanconi anemia. Blood 2016;127:2971
  12. Ball S. Diamond Blackfan anemia. Hematology 2011:487
  13. Flygare and Karlsson. Diamond-Blackfan anemia: erythropoiesis lost in translation. Blood 2007;109:3152
  14. Vlachos and Muir. How I treat Diamond-Blackfan anemia. Blood 2010;116:3715
  15. Orfali et al. Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Br J Haematol 2004;125:243
  16. Campagnoli et al. Molecular basis of Diamond-Blackfan anemia: new findings from the Italian registry and a review of the literature. Haematologica 2004;89:480
  17. Farrar et al. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood 2008;112:1582
  18. Ludwig et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med 2014;20:748 (with editorial)
  19. Vlachos et al. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood 2012;119:3815 (5.4-fold increased cancer risk; risk of MDS increased 287-fold)
  20. Gagne et al. Pearson marrow pancreas syndrome in patients suspected to have Diamond-Blackfan anemia. Blood 2014;124:437
  21. Wong et al. Defective ribosome assembly in Schwachman-Diamond syndrome. Blood 2011;118:4305
  22. Dokal I. Dyskeratosis Congenita. Hematology 2011:480

Other inherited anemias

  1. Donker et al. Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis. Blood 2014;123:3873
  2. Schmitz-Abe et al. Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. Blood 2015;126:2734 (Mild anemia, dominant inheritance)

Pathophysiology and diagnosis of anemia; red cell biology
  1. Sankaran and Weiss. Anemia: progress in molecular mechanisms and therapies. Nat Med 2015;21:221
  2. Beutler and Waalen. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;107:1747
  3. Kassenbaum et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615 (About one-third of the people in the world are anemic; iron deficiency most common)
  4. Bain B. Diagnosis from the blood smear. NEJM 2005;353:498
  5. Higgins and Mahadevan. Physiological and pathologica population dynamics of circulating human red blood cells. PNAS 2010;107:20587 (See also an editorial in the NEJM)
  6. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood 2008;112:3927
  7. Hsia C. Respiratory function of hemoglobin. NEJM 1998;338:239
  8. Semenza G. Oxygen sensing, homeostasis, and disease. NEJM 2011;365:537
  9. Mohandas and Gallagher. Red cell membrane: past, present, and future. Blood 2008;112:3939
  10. Roy and Enns. Iron homeostasis: new tales from the crypt. Blood 2000;96:4020
  11. Pasini et al. In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood 2006;108:791
  12. DeLoughery T. Microcytic anemia. NEJM 2014;371:1324
  13. Tefferi A.  Anemia in adults: a contemporary approach to diagnosis.  Mayo Clin Proc 2003;78:1274
  14. Ershler et al. Serum erythropoietin and aging: a longtitudinal analysis. J Am Geriatr Soc 2005;53:1360
  15. Tefferi et al. How to Interpret and Pursue an Abnormal Complete Blood Cell Count in Adults. Mayo Clin Proc 2005;80:923
  16. Rosse WF. Dr. Ham's test revisited. Blood 1991; 78:547
  17. Beguin et al. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 1993;81:1067
  18. Waalen et al. Haemoglobin and ferritin concentrations in men and women: cross sectional study. BMJ 2002;325:137
  19. Price E. Aging and erythopoiesis: Current state of knowledge. BCMD 2008;41:158
  20. Guralnik et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:2263
  21. Ershler et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc 2005;53:1360
  22. Ferruci et al. Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol 2007;136:849
  23. Culleton et al. Impact of anemia on hospitalization and mortality in older adults. Blood 2006;107:3841    (Lowest mortality with Hgb 13-15 in women, 14-17 in men)
  24. Steensma and Tefferi. Anemia in the Elderly: How Should We Define It, When Does It Matter, and What Can Be Done? Mayo Clin Proc 2007;82:958
  25. Riva et al. Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study. Haematologica 2009;94:22
  26. Patel et al. Racial variation in the relationship of anemia with mortality and mobility disability among older adults. Blood 2007;109:4663 (Anemia increased risk of disability and death by 2-3 fold in older white patients, but not in black patients)
  27. Jacob et al. Postural Pseudoanemia: Posture-Dependent Change in Hematocrit. Mayo Clin Proc 2005;80:611   (average 4-point drop in Hct going from standing to recumbent position)
  28. Beutler and West. Hematologic differences between African-Americans and whites: the roles of iron deficiency and -thalassemia on hemoglobin levels and mean corpuscular volume. Blood 2005;106:740  ("normal" hemoglobin levels lower in African-Americans)
  29. Zakai et al. A Prospective Study of Anemia Status, Hemoglobin Concentration, and Mortality in an Elderly Cohort.  Arch Intern Med 2005;165:2214 (Lower and higher hematocrits associated with increased mortality)
  30. Kosiborod et al. Anemia and Outcomes in Patients With Heart Failure. A Study From the National Heart Care Project. Arch Intern Med 2005;165:2237 (Higher mortality in anemic patients with CHF largely a function of underlying comorbid disease)
  31. Ble et al. Renal Function, Erythropoietin, and Anemia of Older Persons. The InCHIANTI Study. Arch Intern Med 2005;165:2222   (CrCl less than 30 associated with low EPO levels and anemia in individuals >65)
  32. Ferrucci et al. Low Testosterone Levels and the Risk of Anemia in Older Men and Women. Arch Intern Med 2006;166:1380
  33. Wu et al. Preoperative Hematocrit Levels and Postoperative Outcomes in Older Patients Undergoing Noncardiac Surgery. JAMA 2007;297:2481
  34. Patel et al. Red Blood Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults. Arch Intern Med 2009;169:515 (Higher RDW associated with increased risk of death)
  35. Perlstein et al. Red Blood Cell Distribution Width and Mortality Risk in a Community-Based Prospective Cohort. Arch Intern Med 2009;169:588
  36. Socolovsky M. Exploring the erythroblastic island. Nat Med 2013;19:399 (Role of macrophages in regulating erythropoiesis in health & disease)
  37. Ramos et al. Macrophages support pathologic erythropoiesis in polycythemia vera and β-thalassemia. Nat Med 2013;19:437
  38. Chow et al. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 2013;19:429
  39. Sankaran et al. A functional element necessary for hemoglobin swtiching. NEJM 2011;365:807 (with editorial)
  40. Perkins et al. Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants. Blood 2016;127:1856 (KLF1 variants associated with thalassemias, HPFH, PK deficiency, nonspherocytic hemolytic anemias, congenital dyserythropoietic anemias)
  41. Coulon et al. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia. Nat Med 2011;17:1456 (Possible alternative to EPO treatment)

Hemolytic anemias

General

  1. Schaer et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013;121:1276
  2. Brodsky RA. Complement in hemolytic anemia. Blood 2015;126:1259 (PNH, aHUS, cold agglutinin disease)

Autoimmune

  1. Hoffman P. Immune hemolytic anemia - selected topics.  Hematology 2009;80
  2. Lechner and Jäger. How I treat autoimmune hemolytic anemia in adults. Blood 2010;116:1831
  3. Liesveld et al. Variability of the erythropoietic response in autoimmune hemolytic anemia: analysis of 109 cases. Blood 1987; 69:820
  4. Barcellini et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 2014;124:2930 (Suggests rituximab preferable to splenectomy as second-line treatment)
  5. Petz L. A physician's guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol 2004;124:712
  6. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008;141:149
  7. Dierickx et al. The role of rituximab in adults with warm antibody autoimmune hemolytic anemia. Blood 2015;125:3223
  8. Birgens et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol 2013;163:393 (Rate and duration of remissions superior in rituximab arm)
  9. Barcellini et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood 2012;119:3691 (100 mg weekly x 4 doses, 100% response rate in warm AIHA)
  10. Gómez-Almaguer et al. Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood 2010;116:4783
  11. Crowther et al. Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. Blood 2011;118:4036
  12. Norton and Roberts. Management of Evans syndrome. Br J Haematol 2006;132:125
  13. Michel et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009;114:3167 (50% had associated autoimmune, lymphoproliferative or immunodeficiency disease)
  14. Seif et al. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood 2010; 115:2142 (> 5% double-negative T cells in peripheral blood a strong predictor of ALPS)
  15. Dowdell et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010;115:5164
  16. Bride et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood 2016;127:17 (Pediatric study, patients had multilineage immune cytopenia due to ALPS, CVID, Evans syndrome or SLE)
  17. Ratnasingam et al. Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv 2016;1:31 (Bortezomib effective in a variety of autoimmune conditions including AIHA, acquired factor VIII inhibitor, and TTP)
  18. Rother et al. The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin. A Novel Mechanism of Human Disease. JAMA 2005;293:1653
  19. Petz L.  Immune hemolysis associated with transplantation.  Semin Hematol 2005;42:145
  20. Chiao et al. Risk of Immune Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia Among 120 908 US Veterans With Hepatitis C Virus Infection. Arch Intern Med 2009;169:357
  21. Cappellini M. Coagulation in the pathophysiology of hemolytic anemias. Hematology 2007;74
  22. Wooley et al. Post-Babesiosis Warm Autoimmune Hemolytic Anemia. NEJM 2017;376:939 (6/18 asplenic patients with Babesiosis developed AIHA 2-4 weeks after diagnosis of infection)

Cold agglutinin disease

  1. Swiecicki et al. Cold agglutinin disease. Blood 2013;122:1114
  2. Gertz MA. Management of cold haemolytic syndrome. Br J Haematol 2007;138:422
  3. Berentsen et al.  Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients.  Blood 2004;103:2925
  4. Berentsen S. How I manage cold agglutinin disease. Br J Haematol 2011;153:309
  5. Berentsen et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood 2010;116:3180
  6. Shi et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood 2014;123:4015

Drug-induced hemolytic anemia

  1. Garratty G. Drug-induced immune hemolytic anemia. Hematology 2009:73
  2. Fellay et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010; 464:405 (Inosine triphosphatase deficiency protects against ribavirin-induced hemolysis)

Hemolysis due to infection

  1. Haldar and Mohandas. Malaria, erythrocytic infection, and anemia. Hematology 2009:87

Red cell enzyme deficiencies

  1. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood 2008;111:16
  2. van Wijk and van Solinge. The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis. Blood 2005;106:4034
  3. Cocco et al. Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency. Blood 1998;91:706
  4. Pamba et al. Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase–deficient children receiving dapsone. Blood 2012;120:4123
  5. Zanella et al. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol 2005;130:11
  6. Ayi et al. Pyruvate kinase deficiency and malaria. NEJM 2008;358:1805 (Mutant PK alleles protect against malaria)
  7. Zanella et al. Hereditary pyrimidine 5'-nucleotidase deficiency: from genetics to clinical manifestations. Br J Haematol 2006;133:113
  8. Beutler E. PGK deficiency. Br J Haematol 2007;136:3 (Phosphoglycerate kinase deficiency)

Membrane disorders

  1. Gallagher P. Red Cell Membrane Disorders. Hematology 2005:13-18
  2. An and Mohandas. Disorders of red cell membrane. Br J Haematol 2008;141:367
  3. Perrotta et al Hereditary spherocytosis. Lancet 2008;372:1411
  4. Eber and Lux. Hereditary Spherocytosis—Defects in Proteins That Connect the Membrane Skeleton to the Lipid Bilayer. Semin Hematol 2004; 41:118-141
  5. Bolton-Maggs et al.  Guidelines for the diagnosis and management of hereditary spherocytosis. Br J Haematol 2004;126:455
  6. Gallagher P. Hereditary Elliptocytosis: Spectrin and Protein 4.1R. Semin Hematol 2004; 41:142-164
  7. Delaunay J. The Hereditary Stomatocytoses: Genetic Disorders of the Red Cell Membrane Permeability to Monovalent Cations. Semin Hematol 2004; 41:165-172
  8. Rapetti-Mauss et al. A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood 2015;126:1273
  9. Glogowska et al. Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood 2015;126:1281

PNH

  1. Brodsky R. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804
  2. Parker CJ. Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy. Hematology 2011;21
  3. Townsley and Young. Blood consult: paroxysmal nocturnal hemoglobinuria and its complications. Blood 2013;122:2795
  4. Hillmen et al. Natural history of paroxysmal nocturnal hemoglobinuria. NEJM 1995;333:1253
  5. de Latour et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008;112:3099
  6. Schrezenmeier et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014;99:922
  7. Socié et al. Paroxsmal nocturnal hemoglobinria: long-term follow-up and prognostic factors. Lancet 1996;348:573
  8. Rosse and Ware. The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood 1995;86:3277
  9. Parker et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005;106:3699
  10. Dunn et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999;131:401
  11. Hall et al. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).  Blood 2003;102:3587
  12. Ziakas et al. Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview. J Thromb Haemost 2007;5:642
  13. van Bijnen et al. Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria. J Thromb Haemost 2012;10:1
  14. Hill et al. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121:4985
  15. Parker C. Eculizumab for paroxysmal nocturnal hemoglobinuria. Lancet 2009;373:759
  16. Hillmen et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. NEJM 2006;355:1233 (About half of recipients became transfusion-independent)
  17. Hillmen et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007;110:4123 (85% reduction in rate of thromboembolism)
  18. Brodsky et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840 (51% of patients became transfusion independent, QOL improved)
  19. Kelly et al. Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria. NEJM 2015;373:1032
  20. Nishimura et al. Genetic variants in C5 and poor response to eculizumab. NEJM 2014;370:632
  21. Peffault de Latour et al. Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125:775 (CH50 activity is a good measure of complement blockade)
  22. Lin et al. Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 2015;126:891 (C3 mediated RBC destruction can cause persistent hemolysis in eculizumab-treated patients)

Hemoglobinopathies and thalassemias

General, pathophysiology

  1. Thein SL. Genetic association studies in β-hemoglobinopathies. Hematology 2013:354
  2. Zhang et al. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 2016;127:801
  3. Manwani and Frenette. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 2013;122:3892
  4. Telen M. Role of adhesion molecules and vascular endothelium in the pathogenesis of sickle cell disease. Hematology 2007:84
  5. Kuypers F. Membrane lipid alterations in hemoglobinopathies. Hematology 2007:68
  6. May et al. Hemoglobin Variants and Disease Manifestations in Severe Falciparum Malaria. JAMA 2007;297:2220
  7. Penman et al. Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. PNAS 2009; 106:21242
  8. Sankaran et al. Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A. Science 2008;322:1839 (potential target for reactivation of HbF)
  9. Sankaran et al. A functional element necessary for hemoglobin swtiching. NEJM 2011;365:807 (with editorial)
  10. Akinsheye et al. Fetal hemoglobin in sickle cell anemia. Blood 2011;117:19
  11. Steinberg et al. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014;123:481 (HbF concentration in individual cells varies, overall HbF concentration not predictive of protection from sickling)
  12. Bunn et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 2010;116:687
  13. Vincent et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 2013;122:1853
  14. Allen et al. Methemoglobinemia and ascorbate deficiency in hemoglobin E β thalassemia: metabolic and clinical implications. Blood 2012;120:2939 (Elevated methemoglobin levels in Hb E are common, may improve with ascorbate treatment)
  15. Bauer et al. An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. Science 2013;342:253 (Potential target for treatment of thalassemias and hemoglobinopathies; with editorial)
  16. Dussiot et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med 2014;20:398 (with editorial)
  17. Suragani et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 2014;20:408 (with editorial)
  18. Whelihan et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost 2016;14:1941

Complications

  1. Miller et al. Prediction of adverse outcomes in children with sickle cell disease. NEJM 2000;342:83
  2. Steinberg M. Predicting clinical severity in sickle cell anaemia. Br J Haematol 2005;129:465
  3. Reiter et al.  Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease.  Nature Medicine 2002;8:1383 (See also comment on this paper)
  4. Kato et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006;107:2279
  5. Ataga and Key. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology 2007;91
  6. Ataga et al. β-Thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol 2007;139:3
  7. van Beers et al. Sickle cell disease-related organ damage occurs irrespective of pain rate: implications for clinical practice. Haematologica 2008;93:757 (includes a protocol for screening sickle cell patients for end-organ damage)
  8. Platt et al. Influence of sickle hemoglobinopathies on growth and development. NEJM 1984; 311:7
  9. Almeida and Roberts. Bone involvement in sickle cell disease.  Br J Haematol 2005;129:482
  10. Platt et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. NEJM 1994;330:1639
  11. Quinn et al. Improved survival of children and adolescents with sickle cell disease. Blood 2010; 115:3447 (Increased mortality rate associated with transition from pediatric to adult care)
  12. Gladwin and Vichinsky. Pulmonary complications of sickle cell disease. NEJM 2008;359:2254
  13. Castro et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. Blood 1994;84:643
  14. Vichinsky et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 1997;89:1787
  15. Vichinsky et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. NEJM 2000;342:1855 (Fat embolism relatively common in patients > 20 yrs)
  16. Gordeuk et al. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood 2016;127:820
  17. Dessap et al. Pulmonary Hypertension and Cor Pulmonale during Severe Acute Chest Syndrome in Sickle Cell Disease. Am J Respir Crit Care Med 2008; 177:646 (Markers of pulmonary hypertension and right heart failure correlate with outcome in chest crisis)
  18. Gladwin et al.  Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.  NEJM 2004;350:886
  19. Machado and Gladwin. Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haematol 2005;129:449
  20. Klings et al. Abnormal Pulmonary Function in Adults with Sickle Cell Anemia. Am J Resp Crit Care Med 2006;173:1264 (90% of patients had abnormal PFTs)
  21. Field and DeBaun. Asthma and sickle cell disease: two distinct diseases or part of the same process? Hematology 2009;45
  22. Strouse et al. Severe pandemic H1N1 and seasonal influenza in children and young adults with sickle cell disease. Blood 2010;116:3431
  23. DeBaun and Kirkham. Central nervous system complications and management in sickle cell disease. Blood 2016;127:829
  24. Kassim et al. How I treat and manage strokes in sickle cell disease. Blood 2015;125:3401
  25. Adams et al.  Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. NEJM 1998;339:5
  26. Verduzco and Nathan. Sickle cell disease and stroke. Blood 2009;114:5117
  27. Vichinsky et al. Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adults With Sickle Cell Anemia. JAMA 2010;303:1823 (Adults with sickle disease had poorer cognitive performance than controls; worse scores associated with more severe anemia and older age)
  28. Naik et al. Venous thromboembolism incidence in the Cooperative Study of Sickle Cell Disease. J Thromb Haemost 2014;12:2010 (High incidence of VTE in SS disease, higher mortality rates in patients with VTE)
  29. Smith-Whitley et al.  Epidemiology of human parvovirus B19 in children with sickle cell disease.  Blood 2004;103:422
  30. Falk and Hood. The heart in sickle cell anemia. Arch Intern Med 1982; 142:1680
  31. Sharpe and Thein. How I treat renal complications in sickle cell disease. Blood 2014;123: 3720
  32. Smith-Whitley K. Reproductive issues in sickle cell disease. Blood 2014;124:3538
  33. Oteng-Ntim et al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood 2015;125:3316

Treatment of sickle cell disease

  1. Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 2016;127:810
  2. Hoban et al. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 2016;127:839
  3. Xu et al. Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing. Science 2011;334:993
  4. Ribeil et al. Gene therapy in a patient with sickle cell disease. NEJM 2017;376:848
  5. Wong et al. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014;124:3850
  6. Ware R. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 2010;115:5300
  7. Ataga K. Novel therapies in sickle cell disease. Hematology 2009: 54
  8. Manwani and Frenette. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Hematology 2013:362
  9. Ataga et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. NEJM 2017;376:429 (More than 60% reduction in pain crises with administration of this antibody to P-selectin; with editorial)
  10. Almeida et al. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood 2015;126:711 (Mouse study suggesting HU can reduce inflammatory response to heomolysis by acting as nitric oxide donor)
  11. Vichinsky et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. NEJM 1995;333:206
  12. Howard et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013; 381:930 (Perioperative transfusion to Hb 10 and Hb @ <60% associated with fewer complications)
  13. DeBaun et al. Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia. NEJM 2014;371:699 (Keeping Hb S < 30% reduces stroke risn in high risk children)
  14. Detterich et al. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood 2014;126:703
  15. Malinowski et al. Prophylactic transfusion for pregnant women with sickle cell disease: a systematic review and meta-analysis. Blood 2015;126:2424 (Prophylactic transfusion beneficial in pregnancy)
  16. Wiles and Howard. Role of hydroxycarbamide in prevention of complications in patients with sickle cell disease. Ther Clin Risk Manag 2009; 5:745 (Hydroxycarbamide = hydroxyurea)
  17. Brawley et al. National Institutes of Health Consensus Development Conference Statement: Hydroxyurea Treatment for Sickle Cell Disease. Ann Intern Med 2008;148:932
  18. Smith et al. Daily Assessment of Pain in Adults with Sickle Cell Disease. Ann Intern Med 2008;148:94 (Chronic pain is very common in sickle disease and is often undertreated)
  19. Solomon L. Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void. Blood 2008;111:997
  20. Ballas et al. Sickle cell pain: a critical reappraisal. Blood 2012;120:3647
  21. Ataga et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 2008;111:3991 (Drug appeared to decrease rate of hemolysis)
  22. Telen et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 2015;125:2656 (Drug blocks selectin-mediated cell adhesion; 83% reduction in IV opioid use)
  23. Heeney et al. A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events. NEJM 2016;374:625 (No apparent benefit)
  24. Koshy et al. Surgery and anesthesia in sickle cell disease. Blood 1995;86:3676
  25. Swerdlow PS. Red Cell Exchange in Sickle Cell Disease. Hematology 2006;48-53
  26. Griffin et al. High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. NEJM 1994;330:733
  27. Bakanay et al. Mortality in sickle cell patients on hydroxyurea therapy.  Blood 2005;105:545
  28. Voskaridou et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 2010;115:2354 (HU dramatically reduced complications and increased 10 year survival by 20%)
  29. Castro et al. Hydroxycarbamide treatment in sickle cell disease: estimates of possible leukaemia risk and of hospitalization survival benefit. Br J Haematol 2014;167:687 (No increased risk of leukemia, survival benefit with huse of HU)
  30. Saunthararajah et al. Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 2003;102:3871
  31. Morris et al. Arginine Therapy. A New Treatment for Pulmonary Hypertension in Sickle Cell Disease? Am J Resp Crit Care Med 2003; 168:63
  32. Gladwin et al. Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis. JAMA 2011;305:893 (No apparent benefit)
  33. Bernaudin et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 2007;110:2749
  34. Gardner et al. How we treat sickle hepatopathy and liver transplantation in adults. Blood 2014;123:2302
  35. Anele et al. How I treat priapism. Blood 2015;125:3551

Sickle cell trait

  1. Austin et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007; 110:908 (2-fold increased risk of VTE in sickle trait)
  2. Folsom et al. Prospective study of sickle cell trait and venous thromboembolism incidence. J Thromb Haemost 2014;13:2 (2-fold increase in PE risk, no increase in DVT risk)
  3. Naik et al. Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans. JAMA 2014;312:2115 (OR for CKD 1.57 in individuals with sickle trait)
  4. Nelson et al. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. NEJM 2016;375:435 (SS trait associated with 1.54 x higher risk of rhabdomyolysis but not death)
  5. Liem et al. Association among sickle cell trait, fitness, and cardiovascular risk factors in CARDIA. Blood 2017;129:723 (Sickle trait not associated with decreased fitness, hypertension, diabetes or metabolic syndrome)
  6. Lacy et al. Association of Sickle Cell Trait With Hemoglobin A1c in African Americans. JAMA 2017;317:507 (A1c underestimates glycemia in sickle trait)

Thalassemia and related hemoglobinopathies

  1. Higgs et al. Thalassemia. Lancet 2012;379:373
  2. Rachmilewitz and Giardina. How I treat thalassemia. Blood 2011;118:3479
  3. Rund and Rachmilewitz. ß-Thalassemia.  NEJM 2005;353:1135
  4. Piel and Weatherall. The α-Thalassemias. NEJM 2014;371:1908
  5. Songdej et al. An international registry of survivors with Hb Bart's hydrops fetalis syndrome. Blood 2017;129:1251 (A few patients survive to adulthood)
  6. Borgna-Pignatti C. Modern treatment of thalassemia intermedia. Br J Haematol 2007;138:291
  7. Musallam et al. Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia. Blood 2012;119:364 (Higher HbF associated with less morbidity)
  8. Cavazzana-Calvo et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 2010;467:318
  9. Mettananda et al. α-Globin as a molecular target in the treatment of β-thalassemia. Blood 2015;125:3694
  10. Modell et al. Survival in beta-thalassaemia major in the UK: data from the UK thalassaemia register. Lancet 2000;355:2051
  11. Cunningham et al.  Complications of beta-thalassemia major in North America. Blood 2004;104:39
  12. Taher et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood 2010;115:1886 (Evaluates the roles of transfusion, chlelation and hydroxyurea therapy)
  13. Oliveri and Brittenham. Iron-chelating therapy and the treatment of thalassemias. Blood 1997;89:739
  14. Pennell et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia. Blood 2010;115:2364
  15. Kwiatkowski et al. Chelation use and iron burden in North American and British thalassemia patients: a report from the Thalassemia Longitudinal Cohort. Blood 2012;119:2746 (Increasing use of oral chelators likely contributes to lower iron burden)
  16. Tanno et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nature Medicine 2007;13:1096
  17. Taher et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood 2012;120:970
  18. Pasricha et al. Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with β-thalassemia major: a longitudinal study. Blood 2013;122:124
  19. Fucharoen and Viprakasit. Hb H disease: clinical course and disease modifiers. Hematology 2009: 26
  20. Vichinsky E. Alpha thalassemia major—new mutations, intrauterine management, and outcomes. Hematology 2009;35
  21. Chen et al. Genetic and clinical features of hemoglobin H disease in Chinese patients. NEJM 2000;343:544
  22. Chui et al.  Hemoglobin H disease: not necessarily a benign disorder.  Blood 2003;101:791
  23. Lal et al. Heterogeneity of hemoglobin H disease in childhood. NEJM 2011;364:710
  24. Vichinsky E. Hemoglobin E syndromes. Hematology 2007;74
  25. Olivieri et al. Studies in haemoglobin E beta-thalassemia (Br J Haematol 2008;141:388
  26. Premawardhena et al. Haemoglobin E ß-thalassaemia in Sri Lanka. Lancet 2005;366:1467
  27. Allen et al. Adaptation to anemia in hemoglobin E-β thalassemia. Blood 2010;116:5368 (Right-shifted oxygen dissociation curve)
Other
  1. Ash-Bernal et al.  Acquired methemoblobinemia.  A retrospective series of 138 cases at 2 teaching hospitals. Medicine 2004;83:265
  2. Kane et al. Benzocaine-Induced Methemoglobinemia Based on the Mayo Clinic Experience From 28 478 Transesophageal Echocardiograms. Arch Intern Med 2007;167:1977
  3. Steensma et al.  Acquired a-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies.  Blood 2005;105:443
  4. Jauréguiberry et al. Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins. Blood 2014;124: 167


B-12 and folate deficiency; nutritional anemias
  1. Bunn HF. Vitamin B12 and pernicious anemia - the dawn of molecular medicine. NEJM 2014;370:773
  2. Carmel et al. Update on Cobalamin, Folate, and Homocysteine Hematology 2003:62-81.
  3. Carmel R. How I treat cobalmin (vitamin B12) deficiency. Blood 2008;112:2214
  4. Toh et al. Pernicious anemia. N Engl J Med 1997;337:1441
  5. Solomon L. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing.  Blood 2005;105:978
  6. Chanarin and Metz. Diagnosis of cobalmin deficiency: the old and the new. Br J Haematol 1997;97:695
  7. Chang and Cook. Spurious elevations of vitamin B12 with pernicious anemia. NEJM 2012;366:1742
  8. Carmel and Agrawal. Failure of cobalmin assays in pernicious anemia. NEJM 2012;367:385
  9. den Elzen et al. Vitamin B12 and Folate and the Risk of Anemia in Old Age. The Leiden 85-Plus Study . Arch Intern Med 2008;2238 (anemia in pts over 85 associated with folate deficiency rather than B-12 deficiency)
  10. Kuzminski et al. Effective treatment of cobalmin deficiency with oral cobalmin. Blood 1998;92:1191
  11. Quinlivan et al.  Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 2002;359:227
  12. Ting et al. Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin. Arch Intern Med 2006;166:1975
  13. Todd and Erber. Acquired and inherited disorders of cobalmin and folate in children.  Br J Haematol 2006;134:125
  14. Halfdanarson et al. Hematologic manifestations of celiac disease. Blood 2007;109:412 (B-12, folate, iron deficiency)
  15. Bailey and Ayling. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. PNAS 2009; 106: 15424 (Utility of high dose folate supplementation limited by slow metabolism in some people)
  16. Lam et al. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. JAMA 2013;310:2435
  17. Clemens TL. Vitamin B12 deficiency and bone health. NEJM 2014;371:963
  18. Hesdorffer and Longo. Drug-induced megaloblastic anemia. NEJM 2015;373:1649

Iron deficiency, metabolism, overload

Iron metabolism

  1. Camaschella C. Iron-deficiency anemia. NEJM 2015;372:1832
  2. Drakesmith and Prentice. Hepcidin and the iron-infection axis. Science 2012;338:768
  3. Ganz and Nemeth. The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders. Hematology 2011: 538
  4. Andrews NC. Closing the iron gate. NEJM 2012;366:376
  5. Finberg KE. Unraveling mechanisms regulating systemic iron homeostasis. Hematology 2011:532
  6. Meynard et al. The liver: conductor of systemic iron balance. Blood 2014;123:168
  7. Nemeth et al. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science 2004;306:2090
  8. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425
  9. Girelli et al Hepcidin in the diagnosis of iron disorders. Blood 2016;127;2809
  10. Ganz et al. Immunoassay for serum hepcidin. Blood 2008;112:4292
  11. Kautz and Nemeth. Molecular liasons between erythropoiesis and iron metabolism. Blood 2014;124:479
  12. Kautz et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014;46:678 (May mediate the suppression of hepcidin production in patients with erythroid hyperplasia)
  13. Du et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008;320:1088 (This protease responsible for suppressing hepcidin expression in iron deficiency)
  14. Tanaka et al. A genome-wide association analysis of serum iron concentrations. Blood 2010;115:94 (Polymorphisms of TMPRSS6 - see above reference - correlated strongly with serum iron, hemoglobin, MCV)
  15. Shi et al. A cytosolic iron chaperone that delivers iron to ferritin. Science 2008;320:1207
  16. De Domenico et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Nat Acad Sci USA 2005;102:8955
  17. Cazzola M. Genetic disorders of iron overload and the novel "ferroportin disease".  Haematologica 2003;88:721
  18. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005;106:3710
  19. Mastrogiannaki et al. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 2013;122:885
  20. Barber and Elde. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 2014;346:1362 (Transferrin variants have evolved to better compete with bacterial iron-binding proteins; with editorial)
Iron deficiency
  1. Conrad and Crosby. The natural history of iron deficiency induced by phlebotomy. Blood 1962; 20:173
  2. Goodnough et al. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010;116:4754
  3. Barron et al. A bone marrow report of absent stainable iron is not diagnostic of iron deficiency. Ann Hematol 2001;80:166
  4. Zimmerman and Hurrell. Nutritional iron deficiency. Lancet 2007;370:511
  5. Hershko and Camaschella. How I treat unexplained refractory iron deficiency anemia. Blood 2014;123:326 (Ddx includes H pylori, celiac dz, autoimmune gastritis, genetic disorders)
  6. Kumpf and Holland. Parenteral iron dextran therapy. DICP 1990;24:162
  7. Auerbach et al. Clinical update: intravenous iron for anaemia. Lancet 2007;369:1502
  8. Avni et al. The safety of intravenous iron preparations. Systematic review and meta-analysis. Mayo Clin Proc 2015;90:12
  9. Krayenbuehl et al. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood 2011;118:3222 (Most benefit in women with ferritin levels <15; see also this editorial)
  10. Rampton et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica 2014;99:16771
  11. Wang et al. Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. JAMA 2015;314:2062 (Anaphylaxis least common with iron sucrose, most common with iron dextran; see also a critique of this study)
  12. Halfdanarson et al. Hematologic manifestations of celiac disease. Blood 2007;109:412
  13. Anker et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. NEJM 2009;361:2436 (with editorial)
  14. Finberg et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008;40:569
  15. Khalafallah et al. Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial. Lancet Haematol 2016;3: e415 (Preemptive single dose of IV iron after surgery hastened recovery of Hb, decreased transfusion requirements, shortened hospital stay, lowered infection rate)
Hereditary hemochromatosis
  1. Fleming and Ponka. Iron overload in human disease. NEJM 2012;366:348
  2. Pietrangelo A.  Hereditary Hemochromatosis — A New Look at an Old Disease.  NEJM 2004;350:2383
  3. Bomford A.  Genetics of haemochromatosis.  Lancet 2002;360:1673
  4. Adams and Barton. How I treat hemochromatosis. Blood 2010;116:317
  5. Zumerle et al. Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype. Blood 2014;123:3646
  6. Wood et al. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008;111:4456
  7. Beutler et al. The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000;133:329
  8. Beutler et al.  Penetrance of 845G*A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211
  9. Allen et al. Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis. NEJM 2008;358:221 (28% of male C282Y homozygotes, but only 1% of females, developed clinical iron overload)
  10. McLaren and Gordeuk. Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology 2009;195
  11. U.S. Preventive Services Task Force. Screening for hemochromatosis: Recommendation statement. Ann Intern Med 2006;145:204 (Screening asymptomatic patients for hemochromatosis not recommended)
  12. Qaseem et al. Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians. Ann Intern Med 2005;143:517
  13. Schmitt et al. Screening Primary Care Patients for Hereditary Hemochromatosis with Transferrin Saturation and Serum Ferritin Level: Systematic Review for the American College of Physicians. Ann Intern Med 2005;143:522
  14. Morrison et al.  Serum Ferritin Level Predicts Advanced Hepatic Fibrosis among U.S. Patients with Phenotypic Hemochromatosis.  Ann Intern Med 2003;138:627
  15. Waalen et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008;111:3373 (40% of people with ferritin > 1000 had inherited hemochromatosis)
  16. Fischer and Harmatz. Non-invasive assessment of tissue iron overload. Hematology 2009;215
  17. Brissot and de Bels. Current Approaches to the Management of Hemochromatosis. Hematology 2006;36-41

Other causes of iron overload; chelation therapy

  1. Harris et al. Serum Ferritin and Transferrin Saturation in Asians and Pacific Islanders. Arch Intern Med 2007;167:722
  2. Camaschella C. Treating iron overload. NEJM 2013;368:2325
  3. Lok et al. Iron overload in the Asian community. Blood 2009;114:20
  4. Adams et al. Hemochromatosis and iron-overload screening in a racially diverse population. NEJM 2005;352:1769 (Iron overload in non-whites is usually not caused by HFE mutations)
  5. Wood JC. Impact of iron assessment by MRI. Hematology 2011:443
  6. Gandon et al.  Non-invasive assessment of hepatic iron stores by MRI.  Lancet 2004;363:357
  7. Fischer and Harmatz. Non-invasive assessment of tissue iron overload. Hematology 2009;215
  8. Adamkiewicz et al. Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury. Blood 2009; 114:4632 (Ferritin < 1500 typically not associated with clinical sequelae; ferritin > 3000 associated with liver injury)
  9. Schafer et al. Clinical consequences of acquired transfusional iron overload in adults. NEJM 1981; 304:319
  10. Hoffbrand et al. How I treat transfusional iron overload. Blood 2012;120:3657
  11. Brittenham GM. Iron-chelating therapy for transfusional iron overload. NEJM 2011;364:146
  12. Taher et al. Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia. Br J Haematol 2015;168:284 (Suggests treatment when ferritin > 800, stopping when ferritin < 300, dose escalation when ferritin > 2000)
  13. Pullarkat V. Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye? Blood 2009;114:5251 (Suggests that chelation may decrease infection risk, delay leukemic transformation and improve stem cell transplant outcomes)
  14. Kwiatkowski JL. Real-world use of iron chelators. Hematology 2011:451
  15. Jensen et al. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood 2003;101:91
  16. Franchini et al. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood 2000;95:2776
  17. Cohen et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone.  Blood 2003;102:1583
  18. Chan et al. Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease. Br J Haematol 2006;133:198
  19. Borgna-Pignatti et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 2006;107:3733
  20. Pennell et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006;107:3738
  21. Nisbet-Brown et al.  Effectiveness and safety of ICL670 in iron-loaded patients with thalassemia: a randomised, double-bline, placebo-controlled, dose-escalation trial.  Lancet 2003;361:1597
  22. Cappellini et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with -thalassemia. Blood 2006;107:3455
  23. Vichinsky et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501
  24. Chirnomas et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood 2009;114:4009 (Poor responders had lower drug bioavailability)
  25. Pennell et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia. Blood 2010;115:2364
  26. Wood et al. The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood 2010;116:537 (Chelation effective in patients wth mild to moderate, but not severe, iron overload)
  27. Cappellini et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood 2011;118:884
  28. Pennell et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA). Blood 2014;123:1447 (Both drugs similarly effective)
  29. Lee et al. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial. Blood 2010;116:2448
  30. List et al. Deferasirox Reduces Serum Ferritin and Labile Plasma Iron in RBC Transfusion–Dependent Patients With Myelodysplastic Syndrome. J Clin Oncol 2012;30:2134
  31. Aydinok et al. Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload. Blood 2015;125:3868
  32. Neufeld et al. A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. Blood 2012;119:3263 (Well-tolerated and effective oral chelator)
  33. Fernandes et al. A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major. Blood 2016;128:1555
  34. Cohen et al. Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major. Blood 2008;111:583
  35. Leitch and Vickars. Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron? Hematology 2009;664
  36. Kremastinos and Farmakis. Iron overload cardiomyopathy in clinical practice. Circulation 2011;124:2253

Anemia of chronic disease and other anemias
  1. Weiss and Goodnough.  Anemia of chronic disease.  NEJM 2005;352:1011
  2. Sramek et al.  Anemia with impaired erythropoietin response in diabetic patients. Arch Intern Med. 2005;165:466
  3. Ble et al. Renal Function, Erythropoietin, and Anemia of Older Persons. The InCHIANTI Study. Arch Intern Med 2005;165:2222 (CrCl less than 30 associated with low EPO levels and anemia in individuals >65)
  4. Tomosugi et al. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood 2006;108:1381    (Accumulation of hepcidin in the blood in renal failure may limit iron availability)
  5. Song et al. Down-regulation of hepcidin resulting from long-term treatment with an anti–IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 2010;116:3627 (Evidence that IL-6 induces hepcidin production in this condition)
  6. van Eijk et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood 2014;124:2643 (Hepcidin inhibitor raised serum iron levels vs placebo)
  7. Semba et al. The Impact of Anemia on Energy and Physical Functioning in Individuals With AIDS. Arch Intern Med 2005;165:2229
  8. Perlstein et al. Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation. Blood 2011;117:2800
  9. Orfali et al. Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Br J Haematol 2004;125:243
  10. Iolascon et al. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood 2013;122:2162
  11. Heimpel et al. Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation. Blood 2006;107:334
  12. Heimpel et al.  Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation.  Blood 2003;102:4576
  13. Fleming MD. Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation. Hematology 2011:525
  14. Papadaki et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-antibody therapy. Blood 2002;100:474
  15. Tang and Katz. Anemia in chronic heart failure: Prevalence, etiology, clinical correlates, and treatment options. Circulation 2006;113:2454
  16. van der Meer et al. Levels of Hematopoiesis Inhibitor N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Partially Explain the Occurrence of Anemia in Heart Failure. Circulation 2005;112:1743 (An inhibitor of hematopoiesis normally degraded by ACE accumulates in heart failure and is associated with anemia)
  17. Vanasse et al. A polymorphism in the leptin gene promoter is associated with anemia in patients with HIV disease. Blood 2011;118:5401
  18. Lesheim-Rubinow et al. Association of angiotensin-converting enzyme inhibitor therapy initiation with a reduction in hemoglobin levels in patients without renal failure. Mayo Clin Proc 2012;87:1189
  19. Achebe and Gafter-Gvilli. How I treat anemia in pregnancy: iron, cobalamin, and folate. Blood 2017;129:940

Transfusion Medicine

General

  1. Carson et al. Red blood cell transfusion: A clinical practice guideline from the AABB. Ann Intern Med 2012;157:49
  2. Reid M. Transfusion in the age of molecular diagnostics. Hematology 2009;171
  3. Goodnough et al.  Transfusion medicine.  Hematology 2004:457 (variant CJD, TRALI, recombinant VIIa)
  4. Klein et al. Red cell transfusion in clinical practice. Lancet 2007;370:415
  5. Ortega et al. Transfusion of red cells. NEJM 2016;374:e12 (With video)
  6. Vanderlinde et al.  Autologous transfusion. BMJ 2002;324:772
  7. Alter and Klein. The hazards of blood transfusion in historical perspective. Blood 2008;112:2617
  8. Cserti and Dzik. The ABO blood group system and Plasmodium falciparum malaria. Blood 2007;110:2250 (Genetic pressure from malaria may have influenced origin and distribution of ABO types)
  9. Anstee D. The relationship between blood groups and disease. Blood 2010;115:4635
  10. Carson et al. Outcomes Using Lower vs Higher Hemoglobin Thresholds for Red Blood Cell Transfusion. JAMA 2013;309:83
  11. Carson et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. NEJM 2011;365:2453 (No advantage to transfusing for Hb <10 vs Hb <8 or for symptoms of anemia)
  12. Murphy et al. Liberal or Restrictive Transfusion after Cardiac Surgery. NEJM 2015;372:997 (No advantage to transfusing for Hb < 7.5 vs Hb < 9 with regard to morbidity or cost; with editorial)
  13. Hebert et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. NEJM 1999;340:409
  14. Villanueva et al. Transfusion strategies for acute upper gastrointestinal bleeding. NEJM 2013; 368:11 (Survival better with a restrictive transfusion strategy; with editorial)
  15. Etchason et al. The cost effectiveness of preoperative autologous blood donations. NEJM 1995;332:719
  16. Koch et al. Duration of red-cell storage and complications after cardiac surgery. NEJM 2008;358:1229 (Older blood - over 14 days in storage - associated with more complications)
  17. Marik and Sibbald. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993;269:3024
  18. Lacroix et al. Age of Transfused Blood in Critically Ill Adults. NEJM 2015;372:1410 (No difference in 90-day mortality with "fresh" vs standard-issue RBC)
  19. Steiner et al. Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery. NEJM 2015;372:1419 (No apparent benefit to "fresh" RBC)
  20. Alexander et al. Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis. Blood 2016;127:400 ("Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates")
  21. Halmin et al. Length of Storage of Red Blood Cells and Patient Survival After Blood Transfusion: A Binational Cohort Study. Ann Int Med 2017;166:248 (No association between storage duration and mortality)
  22. Raghavan and Marik. Anemia, Allogenic Blood Transfusion, and Immunomodulation in the Critically Ill. Chest 2005;127:295
  23. Lacroix et al. Transfusion Strategies for Patients in Pediatric Intensive Care Units. NEJM 2007;356:1609 (No advantage to keeping Hgb above 9.5 vs 7)
  24. Holst et al. Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. NEJM 2014;371:1381 (No improvement in outcomes with RBC transfusion threshold of 9 grams vs 7 grams)
  25. Petz L. A physician's guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol 2004;124:712
  26. Hess J. Blood and coagulation support in trauma care. Hematology 2007:187
  27. Murthi et al. Transfusion medicine in trauma patients: an update. Exp Rev Hematol 2011;4:527
  28. Hunt et al. A practical guideline for the haematological management of major haemorrhage. Br J Haematol 2015;171:788
  29. Holcomb et al. Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma. The PROPPR Randomized Clinical Trial. JAMA 2015;313:471 (1:1:1 ratio associated with less fatal bleeding, no difference in overall mortality)
  30. Hardy et al. Massive transfusion and coagulopathy: pathyphysiology and implications for clinical management.  Can J Anesth 2006;53:S40
  31. Khorana et al. Blood Transfusions, Thrombosis, and Mortality in Hospitalized Patients With Cancer. Arch Intern Med 2008;168:2377 (RBC and platelet transfusions associated with higher risk of venous and arterial thrombosis)
  32. Vamvakas and Blajchman. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood 2009;113:3406
  33. Jelkman and Lundby. Blood doping and its detection. Blood 2011;118:2395
  34. Chapuy et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;33:1545
Non-infectious transfusion reactions
  1. Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion 1990; 30:583
  2. Bordin et al. Biologic effects of leukocytes present in transfused cellular blood products. Blood 1994;84:1703
  3. Heddle et al. The role of the plasma from platelet concentrates in transfusion reactions. NEJM 1994;331:625
  4. Silliman et al. Transfusion-related acute lung injury (TRALI): Current concepts and misconceptions. Blood Rev 2009; 23:245
  5. Shaz et al. Transfusion-related acute lung injjry: from bedside to bench and back. Blood 2011;117:1463
  6. Vlaar and Juffermans. Transfusion-related acute lung injury: a clinical review. Lancet 2013;382:984
  7. Greinacher et al. Characterization of the human neutrophil alloantigen-3a. Nature Med 2010;16:45 (Characterization of the most important antigen responsible for TRALI)
  8. Storch et al. Spotlight on pathogenesis of TRALI: HNA-3a (CTL2) antibodies. Blood 2014;124:1868
  9. Kopko et al. Transfusion-Related Acute Lung Injury. Report of a Clinical Look-Back Investigation. JAMA 2002;287:1968 (TRALI often underdiagnosed)
  10. Gajic O. Transfusion-related Acute Lung Injury in the Critically Ill: Prospective Nested Case-Control Study. Am J Respir Crit Care Med 2007;176:886
  11. Vlaar et al. The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study. Blood 2010; 117:4218 (2.4% incidence, 13% mortality; HLA and neutrophil antibodies in transfused blood products most important risk factor)
  12. Toy et al. Transfusion-related acute lung injury: incidence and risk factors. Blood 2012;119:1757 (Plasma from female donors 4.5 x more likely to cause TRALI)
  13. Schroeder M.  Transfusion-associated graft-versus-host disease. Br J Haematol 2002;117:265
  14. Koplovic et al. A systematic review of transfusion-associated graft-versus-host disease. Blood 2015;126:406
  15. Edgren et al. Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study. Lancet 2007;369:1724 (No detectable increase in cancer risk in recipients)
  16. Castillo et al. Association between red blood cell transfusions and development of non-Hodgkin lymphoma: a meta-analysis of observational studies. Blood 2010;116:2897 (Increased risk of NHL, particularly CLL/SLL)
Infectious complications of transfusion
  1. Blajchman et al.  The continuing risk of transfusion-transmitted infections.  NEJM 2006;355:1303
  2. Hillyer et al. Bacterial Contamination of Blood Components: Risks, Strategies, and Regulation: Joint ASH and AABB Educational Session in Transfusion Medicine. Hematology 2003:575-589
  3. Herwaldt et al. Transfusion-associated Babesiosis in the United States: a description of cases. Ann Intern Med 2011;155:509
  4. Stramer et al.  Detection of HIV-1 and HCV Infections among Antibody-Negative Blood Donors by Nucleic Acid–Amplification Testing  NEJM 2004;351:760
  5. Ljungman P.  Risk of cytomegalovirus transmission by blood products to immunocompromised patients and means for reduction. Br J Haematol 2004;125:107
  6. Pealer et al.  Transmission of West Nile virus through blood transfusion in the United States in 2002.  NEJM 2003;349:1236
  7. Ludlam and Turner. Managing the risk of transmission of variant Creutzfeldt Jakob disease by blood products. Br J Haematol 2006;132:13
  8. Ludlam et al. Clinical perspectives of emerging pathogens in bleeding disorders. Lancet 2006;367:202
  9. Hladik et al. Transmission of human herpesvirus 8 by blood transfusion.  NEJM 2006;355:1331
Fresh frozen plasma
  1. Stanworth S. The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology 2007:179
  2. Puetz J. Fresh frozen plasma: the most commonly prescribed hemostatic agent. J Thromb Haemost 2013;11:1794 (Summarizes the limited evidence for benefit from FFP infusion in coagulopathic patients)
  3. Key and Negrier. Coagulation factor concentrates: past, present and future. Lancet 2007;370:439
  4. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  British Committee for Standards in Haematology, Blood Transfusion Task Force. Br J Haematol 2004;126:11
  5. Stansworth et al. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;126:139
  6. Dara et al. Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy.  Crit Care Med 2005; 33:2667 (higher incidence of acute lung injury, no survival benefit with prophylactic FFP transfusion to non-bleeding pts)
  7. Chowdhury et al. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004;125:69
  8. Ho et al. Are we giving enough coagulation factors during major trauma resuscitation?  Am J Surg 2005;190:479
  9. Holland and Brooks. Toward Rational Fresh Frozen Plasma Transfusion. The Effect of Plasma Transfusion on Coagulation Test Results. Am J Clin Pathol 2006;126:133 (Useful data on amount of FFP needed to correct a prolonged INR; little benefit to giving FFP when INR < 1.7)
  10. Abdel-Wahab et al. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006;46:1279 (FFP transfusion ineffective for INR <1.9)
  11. Rashidi and Tahhan. Fresh frozen plasma dosing for warfarin reversal: a practical formula. Mayo Clin Proc 2013;88:244
  12. Youssef et al. Role of Fresh Frozen Plasma Infusion in Correction of Coagulopathy of Chronic Liver Disease: A Dual Phase Study. Am J Gastroenterol 2003;98:1391 (FFP in doses up to 6 U rarely corrects coagulopathy in liver disease)
  13. Jia et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single-institution propensity-adjusted cohort study. Lancet Haematol 2016;3:e139 (No evidence of benefit, higher RBC transfusion need in FFP-treated patients; with editorial)
  14. Müller et al. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost 2015;13:989 (12 ml/kg FFP raised clotting factor levels by 10-12% but did no enhance thrombin generation in non-bleeding critically ill patients with a long INR)

Prothrombin complex concentrate and rVIIa

  1. Roberts et al. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104:3858
  2. Dentali et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011;106:429
  3. Colomina et al. Perioperative use of prothrombin complex concentrates. Minerva Anestesiol 2012;78:358
  4. Grottke et al. Thrombin Generation Capacity of Prothrombin Complex Concentrate in an In Vitro Dilutional Model. PLOS One 2013;8:e64100 (Variable pro- and anti-coagulant properties of different PCCs)

Cryoprecipitate

  1. Levy and Goodnough. How I use fibrinogen replacement therapy in acquired bleeding. Blood 2015;125:1387
  2. Stanworth S. The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology 2007:179
  3. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  British Committee for Standards in Haematology, Blood Transfusion Task Force. Br J Haematol 2004;126:11
Platelet transfusion
  1. Kaufman et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015;162:205 (10K threshold for post-chemo patients, 20K prior to central line placment, 50K prior to LP or general surgery)
  2. Heddle et al. A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 2009;113:1564 (trial stopped early; more severe bleeding in low-dose arm)
  3. Metcalfe P. Platelet antigens and antibody detection. Vox Sang 2004;87 (suppl 1):S82
  4. Hoffmeister et al.  The Clearance Mechanism of Chilled Blood Platelets. Cell 2003;112:87
  5. Hoffmeister et al.  Glycosylation restores survival of chilled blood platelets.  Science 2003;301:1531
  6. Delaflor-Weiss and Mintz. The evaluation and management of platelet refractoriness and alloimmunization. Transfus Med Rev 2000;14:180
  7. Stanworth et al. Platelet refractoriness – practical approaches and ongoing dilemmas in patient management. Br J Haematol 2015;171:297
  8. Slichter et al. Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood 2005;105:4106
  9. Speiss et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion 2004;44:1143
  10. Lieberman et al. Platelet transfusions for critically ill patients with thrombocytopenia. Blood 2014;123:1146 (Little data to support giving platelets prophylactically to non-bleeding patients)
  11. Goel et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015;125:1470 (Platelet transfusion deleterious in TTP and HIT, not ITP)
  12. Bishop et al. Clinical factors influencing the efficacy of pooled platelet transfusion. Blood 1988; 71:383
  13. Rebulla et al. The threshold for prophylactic platelet transfusion in adults with acute myeloid leukemia. NEJM 1997;337:1870
  14. Slichter et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. NEJM 2010;362:600 (Lower doses led to decreased total platelets given per patient, with no increase in bleeding)
  15. Stanworth et al. A No-Prophylaxis Platelet-Transfusion Strategy for Hematologic Cancers. NEJM 2013;368:1771 (No prophylaxis → more bleeding)
  16. Wandt et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet 2012;380:1309 (No prophylaxis → more bleeding in AML patients but not in autologous SCT patients)
  17. Baharoglu et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016;387:2605 (Worse outcomes with platelet transfusion in this setting; with editorial)
  18. Schiffer et al. High-dose intravenous gammaglobulin in alloimmunized platelet transfusion recipients. Blood 1984; 64:937
  19. Christie et al. Vancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia. Blood 1990; 75:518
  20. TRAP Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. NEJM 1997;337:1861
  21. Seftel et al.  Universal prestorage leukoreduction in Canada decreases platelet alloimmunization and refractoriness.  Blood 2004;103:333
Granulocyte transfusion
  1. Bishton and Chopra. The role of granulocyte transfusions in neutropenic patients. Br J Haematol 2004;127:501
  2. Price et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone–treated donors in neutropenic patients with infection. Blood 2015;126:2153 (No overall benefit of granulocyte transfusion found, although patients getting higher doses tended to have better outcomes)
Plasma exchange & Apheresis
  1. Schwartz et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis. J Clin Apheresis 2013;28:145 (Lengthy, comprehensive review)
  2. Blum and Porcu. Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome. Semin Thrombos Hemost 2007;33: 350
IVIG
  1. Knezevic-Maramica and Kruskall. Intravenous immune globulins: an update for clinicians. Transfusion 2003;43:1460
  2. Kaveri et al. The antiinflammatory IgG. NEJM 2008;359:307 (a specific fraction of IVIG has potent antiinflammatory properties)
  3. Raanani et al. Immunoglobulin Prophylaxis in Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis. J Clin Oncol 2008; (Epub) (No evidence of benefit)
  4. Anthony et al. Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway. Nautre 2011; 475:110
  5. Amman et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood 2016;127:200 (3x higher risk of MI or stroke following IVIG treatment; 1% increase in absolute risk of severe thromboembolism in patients treated for a year)

Blood substitutes

  1. Natanson et al. Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death. A Meta-analysis. JAMA 2008;299:2304


The spleen: function and pathology; splenectomy
  1. Schaffner et al. The hypersplenic spleen. A contractile reservoir of granulocytes and platelets. Arch Intern Med 1985;145:651
  2. Grover et al. Does this patient have splenomegaly? JAMA 1993;270:2218
  3. Rubin and Schaffner. Care of the asplenic patient. NEJM 2014;371:349
  4. Ianitto and Tripodo. How I diagnose and treat splenic lymphomas. Blood 2011;117:2585 (DDx of massive splenomegaly)
  5. British Committee for Standards in Haematology Clinical Haematology Task Force. Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen.  BMJ 1996;312:430
  6. Halfdanarson et al. Hematologic manifestations of celiac disease. Blood 2007;109:412 (Celiac disease as a cause of hyposplenism)
  7. Schilling et al. Delayed adverse vascular events after splenectomy in hereditary spherocytosis. J Thromb Haemost 2008; 6:1289 (7-fold increase in risk of arterial events, 3-fold increase in risk for venous thrombosis)
  8. Crary and Buchanan. Vascular complications after splenectomy for hematologic disorders. Blood 2009;114:2861
  9. Di Sabatino et al. Post-splenectomy and hyposplenic states. Lancet 2011;378:86
  10. Thomsen et al. Risk for Hospital Contact With Infection in Patients With Splenectomy. A Population-Based Cohort Study. Ann Intern Med 2009; 151:546 (4.6-fold increased risk for infection in first year after splenectomy, 2.5-fold increased risk thereafter; risk highest in those splenectomized for hematologic disorders)
  11. Adriani et al. Bacterial Meningitis in Adults After Splenectomy and Hyposplenic States. Mayo Clin Proc 2013;88:571 (Increased risk for pneumococcal meningitis; vaccination partially protective)
  12. Boyle et al. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 2013;121:4782
  13. Swirski et al.Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites. Science 2009;325:612 (Splenic monocytes play an importrant role in repairing ischemic myocardium)
  14. Bolze et al. Ribosomal Protein SA Haploinsufficiency in Humans with Isolated Congenital Asplenia. Science 2013;340:976
  15. Kang et al. An extracorporeal blood cleansing-device for sepsis therapy. Nat Med 2014;20:1211 (An "artificial spleen")

Coagulation: biology and clinical and laboratory evaluation

General

  1. Furie B. Pathogenesis of thrombosis. Hematology 2009;255
  2. Dahlbäck B. Blood coagulation. Lancet 2000;355:1627
  3. Weisel and Litvinov Mechanisms of fibrin polymerization and clinical implications. Blood 2013;121:1712
  4. Wagner and Frenette. The vessel wall and its interactions. Blood 2008;111:5271
  5. Lynch and Ludlam. Plasma microparticles and vascular disorders. Br J Haematol 2007;137:36
  6. Swystun and Liaw. The role of leukocytes in thrombosis. Blood 2016;128:753
  7. Borissoff et al. The hemostatic system as a modulator of atherosclerosis. NEJM 2011;364:1746
  8. Renné et al. In vivo roles of factor XII. Blood 2012;120:4296
  9. Ivanov et al. Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood 2017;129:1527
  10. Long et al. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016;14:427
  11. Manon-Jensen et al. Collagen-mediated hemostasis. J Thromb Haemost 2016;14:438
  12. Attard et al. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013;11:1850
  13. Antoniak and Mackman. Multiple roles of the coagulation protease cascade during virus infection. Blood 2014;123:2605
  14. Griffin et al. Activated protein C: biased for translation. Blood 2015;125:2898 (Describes the cytoprotective role of APC and potential therapeutic benefit of engineered APC variants)
  15. Gu et al. Regulation of thrombosis and vascular function by protein methionine oxidation. Blood 2015;125:3851
  16. Nieman M. Protease-activated receptors in hemostasis. Blood 2016;128:169
  17. Posma et al. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016;14:1908
  18. Flaumenhaft and Furie. Vascular thiol isomerases. Blood 2016;128:893

 

Thrombin generation

  1. Butenas et al. "Normal" thrombin generation. Blood 1999;94:2169
  2. Furie and Furie. Mechanisms of thrombus formation. NEJM 2008;359:938
  3. Harris et al. Coagulation tests: a primer for clinical chemists. Clin Lab News 2012:38
  4. Bates and Weitz. Coagulation assays. Circulation 2005;112;e53
  5. Kamal et al. How to Interpret and Pursue an Abnormal Prothrombin Time, Activated Partial Thromboplastin Time, and Bleeding Time in Adults. Mayo Clin Proc 2007;82:864
  6. Zürcher et al. Stability of coagulation assays performed in plasma from citrated whole blood transported at ambient temperature. Thromb Haemost 2008;99:416
  7. Verhovsek et al. Laboratory testing for fibrinogen abmormalities.Am J Hematol 2008;83:928
  8. Lane et al. Directing Thrombin.  Blood 2005;106:2605
  9. Hogan et al. Mouse models of coagulation. Thromb Haemost 2002;87:563  (Summary of mouse knockout models)
  10. Colman and Schmaier. Contact system: a vascular biology mediator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997;90:3819
  11. Kravtsov et al. Factor XI contributes to thrombin generation in the absence of factor XII. Blood 2009;114:452
  12. Andrew et al. Maturation of the hemostatic system during childhood. Blood 1992;80:1998
  13. Attard et al. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013;11:1850
  14. Shearer and Newman. Metabolism and cell biology of vitamin K. Thromb Haemost 2008;100:530
  15. Presnell and Stafford.  The vitamin K-dependent carboxylase.  Thrombos Haemst 2002;87:937
  16. Sunnerhagen et al. Structure of the Ca2+-free GLA domain sheds light on membrane binding of blood coagulation factors. Nature Struct Biol 1995;2:504
  17. Hansson and Stenflo. Post-translational modifications in proteins involved in blood coagulation. J Thromb Haemost 2005;3:2633
  18. Emsley et al. Structure and function of factor XI. Blood 2010;115:2569
  19. de Maat and Mass. Factor XII: form determines function. J Thromb Haemost 2016;14:1498

Platelets & von Willebrand factor

  1. George JN. Platelets. Lancet 2000;355:1531
  2. Bye et al. Platelet signaling: a complex interplay between inhibitory and activatory networks. J Thromb Haemost 2016;14:918
  3. Simon et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 2014;123:e37
  4. Beck et al. Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition. Blood 2017;129:e1 (With editorial)
  5. Schubert et al. A tour through the transcriptional landscape of platelets. Blood 2014;124:493
  6. Leslie M. Beyond clotting: the powers of platelets. Science 2010;328:562
  7. Morrell et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014;123: 2759
  8. Randi and Laffan. Von Willebrand factor and angiogenesis: basic and applied issues. J Thromb Haemost 2017;15:13 (Reviews evidence linking VWD and angiodysplasia)
  9. Wu et al. Platelets and von Willebrand factor in atherogenesis. Blood 2017;129:1415
  10. Grozovsky et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015;21:47 (Aging platelets lose sialic acid, then bind to hepatic receptor that promotes TPO production)
  11. Heemskerk et al. Platelet activation and blood coagulation. Thromb Haemost 2002;88:186
  12. Jackson S. The growing complexity of platelet aggregation. Blood 2007;109:5087
  13. Edelstein et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013;19:1609
  14. Hayward et al. Development of North American Consensus Guidelines for Medical Laboratories That Perform and Interpret Platelet Function Testing Using Light Transmission Aggregometry. Am J Clin Pathol 2010; 134:955
  15. Min and Abrans. Regulation of platelet plug formation by phosphoinositide metabolism. Blood 2013;122:1358
  16. Lynch and Ludlam. Plasma microparticles and vascular disorders. Br J Haematol 2007;137:36
  17. Biolard et al. Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production. Science 2010;327:580 (With editorial)
  18. Gawaz and Vogel. Platelets in tissue repair: control of apoptosis and interactions with regenerative cells. Blood 2013;122:2550
  19. Jackson and Schoenwaelder. Procoagulant platelets: are they necrotic? Blood 2010;116:2011
  20. McMorran et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science 2012;338:1348
  21. Nachman and Rafii. Platelets, Petechiae, and Preservation of the Vascular Wall. NEJM 2008;359:1261
  22. Shattil and Newman. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004;104:1606
  23. Springer TA. von Willebrand factor, Jedi knight of the bloodstream. Blood 104;124:1412
  24. Lenting et al. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015;125:2019
  25. Shim et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008;111:651 (Platelets enhance VWF cleavage by ADAMTS-13)
  26. Zhang et al. Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor. Science 2009;324:1330
  27. Crawley et al. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 2011;118:3212
  28. Gilbert et al. Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine. Blood 2015;126:1237 (Soluble fibrin enhances f VIII binding to platelets more effectively than PS; with editorial)
  29. Agbani et al. Coordinated Membrane Ballooning and Procoagulant Spreading in Human Platelets. Circulation 2015;132:1414 (Supplementary material includes some interesting movies of platelets in action)

Fibrinolysis; D-dimer

  1. Cesarman-Maus and Hajjar. Molecular mechanisms of fibrinolysis. Br J Haematol 2005;129:307
  2. Williams EC. Plasma alpha 2-antiplasmin activity. Role in the evaluation and management of fibrinolytic states and other bleeding disorders. Arch Intern Med 1989;149:1769
  3. Ågren et al. Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis. J Thromb Haemost 2006;4:201
  4. Adam et al. D-dimer antigen: current concepts and future prospects. Blood 2009;113:2878
  5. Koracevic G. Pragmatic classification of the causes of high D-dimer. Am J Emerg Med 2009;27:1016.e5

Regulation of coagulation

  1. De Caterina et al. General mechanisms and targets of anticoagulants (Section 1). Thromb Haemost 2013;109:569 (Review of physiologic and pharmacologic anticoagulants)
  2. Mosnier et al. The cytoprotective protein C pathway. Blood 2007;109:3161
  3. Danese et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010;115:1121
  4. Cheng et al. Activated protein C inhibits tissue plasminogen activator–induced brain hemorrhage. Nature Med 2006;12:1278
  5. Cines et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998;91:3527
  6. Pluvinet et al. CD40: an upstream master switch for endothelial cell activation uncovered by RNAi-coupled transcriptional profiling. Blood 2008;112:3624
  7. Lwaleed and Bass.  Tissue factor pathway inhibitor: structure, biology and involvement in disease.  J Pathol 2005
  8. Massberg et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010;16:887 (Neutrophil proteases promote clotting by degrading TFPI)
  9. Morrissey et al. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012;119:5972
  10. Pozzi et al. β2-Glycoprotein I binds to thrombin and selectively inhibits the enzyme procoagulant functions. J Thromb Haemost 2013;11:1093
  11. Wood et al. Biology of tissue factor pathway inhibitor. Blood 2014;123:2934

Diagnosis of bleeding disorders; screening tests

  1. Mauer et al. Impact of sex, age, race, ethnicity and aspirin use on bleeding symptoms in healthy adults. J Thromb Haemost 2011;9:100 (Menorrhagia, epistaxis, bruising, and several other bleeding symptoms common in healthy people)
  2. Simeoni et al. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders. Blood 2016;127:2791 (with editorial)
  3. Appel et al. Age dependency of coagulation parameters during childhood and puberty. J Thromb Haemost 2012;10:2254
  4. Hayward C. Diagnosis and Management of Mild Bleeding Disorders. Hematology 2005:423-428
  5. Boender et al. A diagnostic approach to mild bleeding disorders. J Thromb Haemost 2016;14:1507
  6. Šrámek et al. Usefulness of patient interview in bleeding disorders. Arch Intern Med 1995;155:1409
  7. Eckman et al. Screening for the risk for bleeding or thrombosis. Ann Intern Med 2003;138:W-15 ("For nonsurgical and surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing has no benefit in assessment of bleeding risk")
  8. Chee et al. Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures : British Committee for Standards in Haematology. Br J Haematol 2008;140:496 ("Patients with a negative bleeding history do not require routine coagulation screening prior to surgery")
  9. Carpenter et al. Evaluating for suspected child abuse: conditions that predispose to bleeding. Pediatrics 2013;131:e1357
  10. Kitchens CS. To bleed or not to bleed? is that the question for the PTT?. J Thromb Haemost 2005;3:2607 ("A prolonged PTT is not strongly predictive of hemorrhage nor does a normal PTT provide shelter against hemorrhagic risk")
  11. Le et al. The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relation to other monitoring methods. Ann Intern Med 1994;120:552
  12. Hirsh and Poller. The international normalized ratio. A guide to understanding and correcting its problems. Arch Intern Med 1994;154:282
  13. Barton and Poon. Coagulation testing of Hickman catheter blood in patients with acute leukemia. Arch Intern Med 1986; 146:2165
  14. Michelson A.  Platelet function testing in cardiovascular disease.  Circulation 2004;110:e489
  15. Harker and Schlichter. The bleeding time as a screening test for evaluation of platelet function. NEJM 1972; 287:155
  16. Lind S. The bleeding time does not predict surgical bleeding. Blood 1991;77:2547
  17. Quiroga et al.  Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients.  J Thromb Haemost 2004;2:892
  18. Harrison P. The role of PFA-100® testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3
  19. Haubelt et al. Variables influencing Platelet Function Analyzer-100TM closure times in healthy individuals. Br J Haematol 2005;130:759
  20. Kolev and Longstaff. Bleeding related to disturbed fibrinolysis. Br J Haem 2016;175:12
  21. Trapani L. Thromboelastography: current applications, future directions. Open J Anesth 2013;3:23
  22. Karon BS. Why is everyone so excited about thromboelastography (TEG)? Clin Chim Acta 2014;436:143
  23. Nogami K. The utility of thromboelastography in inherited and acquired bleeding disorders. Br J Haem 2016;174:503
  24. Levi and Hunt. A critical appraisal of point-of-care coagulation testing in critically ill patients. J Thromb Haemost 2015;13:1960 (TEG and ROTEM)
  25. Lordkipanidzé et al. Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay. Blood 2014;123:e11
  26. Mumford et al. A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders. Thromb Haemost 2015;114:14
  27. Wong et al. Development of Consensus Guidelines for Anticardiolipin and Lupus Anticoagulant Testing. Semin Hematol 2005;31:39
  28. Amdo and Welker.  An approach to the diagnosis and treatment of cryofibrinogenemia.  Am J Med 2004;116:332
  29. DeLoughery T. Critical care clotting catastrophes. Crit Care Clin 2005; 21:531
  30. Bain B. Diagnosis from the blood smear. NEJM 2005;353:498
  31. Abrich et al. Risk factors for recurrent spontaneous epistaxis. Mayo Clin Proc 2014;89:1636

Congenital disorders of coagulation

General

  1. Rick et al. Congenital Bleeding Disorders. Hematology 2003:559-574
  2. Peyvandi et al. Genetic sequence analysis of inherited bleeding disorders. Blood 2013;122:3423
  3. Martin and Key. How I treat patients with inherited bleeding disorders who need anticoagulant therapy. Blood 2016;128:178
Hemophilia
  1. Josephson N. The hemophilias and their clinical management. Hematology 2013:261
  2. Everett et al. Murine factor VIII is synthesized in endothelial cells. Blood 2014;123:3697
  3. Fahs et al. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 2014;123:3706
  4. Escobar and Sallah. Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis. J Thromb Haemost 2013;11:1449
  5. Fogarty PF. Biologic rationale for new drugs in the bleeding disorder pipeline. Hematology 2011:397
  6. Ragni MV. The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders. Hematology 2013:44
  7. Pruthi R. Hemophilia: A Practical Approach to Genetic Testing. Mayo Clin Proc 2005;80:1485
  8. Furie et al. A practical guide to the evaluation and treatment of hemophilia. Blood 1994;84:3
  9. Peyvandi et al. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost 2016;14:248 (Conventional factor VIII assays may underestimate factor activity after treatment with some clotting factor products)
  10. Boylan et al. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations. J Thromb Haemost 2015;13:1036 (Patients with hemophilia A phenotype should have VWF evaluation)
  11. Nathwani et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. NEJM 2011;365:2357
  12. Nathwani et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. NEJM 2014;371:1994
  13. Sehgal et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 2015;21:492 (In animal models)
  14. Raffini and Manno Modern management of hemophilic arthropathy. Br J Haematol 2007;136:777
  15. Valentino L. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010;8:1895
  16. Tagariello et al. Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009;114:779 (3-fold higher rate of arthroplasty in hemophilia A vs B)
  17. Manco-Johnson et al. Prophylaxis versis episodic treatment to prevent joint disease in boys with severe hemophilia. NEJM 2007;357:535
  18. Fischer et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013;122:1129 ("the incremental benefits of high-dose prophylaxis appear limited")
  19. Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015;125:2038
  20. Rodriguez-Merchan E.  Orthopaedic surgery in persons with haemophilia.  Thromb Haemost 2003;89:34
  21. DeBiasi et al. The impact of a very high purity factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs. Blood 1991; 78:1919
  22. Soucie et al.  Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors.  Blood 2004;103:2467
  23. Srivastava A.  Dose and response in haemophilia – optimization of factor replacement therapy. Br J Haematol 2004;127:12 (currently recommended doses of clotting factor may be excessive)
  24. Hazendonk et al. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications. J Thromb Haemost 2016;14:468
  25. Powell et al. Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B. NEJM 2013;369:2313 (Prophylaxis with this long-acting derivative of Factor IX substantially reduced bleeding rates)
  26. Collins et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124:3880 (Weekly prophylaxis lowered bleeding rates, improved QOL)
  27. Santogostino et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127:1761 (Weekly and q14 day prophylaxis schedules effective; mean trough levels 20% and 12% respectively)
  28. Mahlangu et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014;123:317
  29. Young et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost 2015;13:967 (Twice weekly prophylaxis; 46% had no bleeding episodes while on treatment)
  30. Shapiro et al. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost 2014;12:1788 (Higher VWF levels allow less frequent dosing; 5-day interval effective in many cases)
  31. Konkle et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015;126:1078 (1.5x extended half-life. Twice-weekly prophylaxis reduced bleed rate vs standard Rx, no inhibitors found)
  32. Mahlangu et al. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood 2016;128:630
  33. Uchida et al. A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects. Blood 2016;127:1633 (Antibody binds to both factor IXa and factor X, shortens clotting times and enhances thrombin generation with half-life > 4 weeks)
  34. Shima et al. Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. NEJM 2016;374:2044 (With editorial)
  35. Inwood et al. The use and safety of ibuprofen in the hemophiliac. Blood 1983; 61:709
  36. Pipe et al. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016;128:2007 (Half-life of VWF is limiting factor for half life of extended half-life FVIII products)
  37. Tsoukaset al. Evaluation of the efficacy and safety of etoricoxib in the treatment of hemophilic arthropathy. Blood 2006;107:1785
  38. Ludlam et al. Clinical perspectives of emerging pathogens in bleeding disorders. Lancet 2006;367:202 (emerging pathogens that may be transmitted via factor concentrate)
  39. Plug et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006;4:510
  40. Darby et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110:815
  41. Posthouwer et al. Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study. Blood 2007; 109:3667
  42. Mannucci et al. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009;114:5256
  43. Kamphuisen and ten Cate. Cardiovascular risk in patients with hemophilia. Blood 2014;123:1297
  44. Plug et al. Bleeding in carriers of hemophilia.  Blood 2006;108:52
Inhibitors in Hemophilia
  1. Astermark J. FVIII inhibitors: pathogenesis and avoidance. Blood 2015;125:2045
  2. Lollar P.  Pathogenic antibodies to coagulation factors.  Part one: factor VIII and factor IX.  J Thromb Haemost 2004;2:1082
  3. Lavigne-Lissalde et al. Anti-factor VIII antibodies. Thromb Haemost 2005;94:760
  4. Batsuli et al. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors. Blood 2016;128:2055 (Inhibitors that are weakly inhibitory in a Bethesda assay but can accelerate FVIII clearance)
  5. Cannavò et al. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A. Blood 2017;129:1245 (Antibodies present in untreated hemophilia patients predict subsequent inhibitor development)
  6. Kempton and White. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009;113:11
  7. Leissinger et al. How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors. Blood 2015;126:153
  8. Kempton and Meeks. Toward optimal therapy for inhibitors in hemophilia. Blood 2014;124:3365
  9. Young et al. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives. Blood 2013;121:1944 (Use of TEG in assessing response to bypass agents in hemophiliacs with inhibitors)
  10. Gouw et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012;119:2922
  11. Eckhardt et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 2013;122:1954
  12. Gouw et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013;121:4046 (High dose factor replacement increases risk, prophylactic treatment decreases it)
  13. Castaman and Fijnvandraat. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood 2014;124:2333 (Lifelong risk of inhibitor development in mild HA, increasing in parallel with factor exposure; risk also dependent on type of mutation)
  14. Callaghan and Fogarty. What is the Evidence for the Use of Immunomodulatory Agents to Eradicate Inhibitory Antibodies in Patients with Severe Hemophilia A Who Have Previously Failed to Respond to Immune Tolerance Induction? Hematology 2011:405
  15. Kruse-Jarres R. Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A. Hematology 2011:407
  16. Scott et al. Progress toward inducing immunologic tolerance to factor VIII. Blood 2013;121:4449
  17. Lim et al. Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors. J Thromb Haemost 2014;12:897 (9/9 patients had eradication of inhibitors with mean response time of 95 days)
  18. Leissinger et al. Rituximab for treatment of inhibitors in haemophilia A. A Phase II study. Thromb Haemost 2014;112:445 (Modest efficacy as single-agent treatment)
  19. Franchini and Lippi. How I treat acquired factor VIII inhibitors. Blood 2008;112:250
  20. McMillan C et al. The natural history of factor VIII:c inhibitors in patients with hemophilia A. Blood 1988; 71:344
  21. Lacroix-Desmazes et al. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 1999;5:1044
  22. Goudemand et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood 2006;107:46 (2 to 3-fold higher risk of inhibitor development with use of recombinant factor VIII vs plasma-derived factor)
  23. Gouw et al. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007;109:4648
  24. Gouw et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007;109:4693 (No evidence that use of recombinant vs plasma-derived factors, or switching products, increases risk of inhibitor development)
  25. Collins et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood 2014;124:3389 (Risk factors for inhibitor development: brand of factor, FVIII genotype, ethnicity, intensive treatment episodes)
  26. Calvez et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood 2014;124:3398
  27. Peyvandi et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. NEJM 2016;374:2054 (VWF-containing plasma-derived concentrate caused less inhibitor development than recombinant VIII; with editorial)
  28. Shima et al. Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. NEJM 2016;374:2044 (Antibody effective in patients with and without inhibitors. With editorial)
  29. Roberts et al. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104:3858
  30. Abshire and Kenet. Recombinant factor VIIa: review of efficacy, dosing requirements, and safety in patients with congenital and acquired factor VIII and IX inhibitors.  J Thromb Haemost 2004;2:899
  31. Lentz et al. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa. J Thromb Haemost 2014;12:1244
  32. Leissinger et al. Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors. NEJM 2011;365:1684
  33. Hay et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006;133:591
  34. Lillicrap D. The Role of Immunomodulation in the Management of Factor VIII Inhibitors. Hematology 2006;421
  35. Antun et al. Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 2015;13:1980 (Treatment with immunosuppressive drugs associated with higher rate of inhibitor recurrence)
  36. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007;138:305
von Willebrand Disease: Biology, Genetics, Diagnosis
  1. Laffan et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014;167:453
  2. Leebeek and Eikenboom. Von Willebrand's disease. NEJM 2016;375:2067
  3. Lenting et al. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015;125:2019
  4. Lippok et al. von Willebrand factor is dimerized by protein disulfide isomerase. Blood 2016;127:1183
  5. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Hematology 2013:254
  6. Sadler E. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology 2009: 106
  7. De Meyer et al. von Willebrand factor to the rescue. Blood 2009;113:5049
  8. Mendolicchio and Ruggeri. New Perspectives on von Willebrand Factor Functions in Hemostasis and Thrombosis. Semin Hematol 2005;42:5
  9. Sadler et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006;4:2103
  10. Roberts et al. Rapid discrimination of the phenotypic variants of von Willebrand disease. Blood 2016;127:2472
  11. Flood et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016;127:2481 (Poor correlation between VWF level and bleeding score; most patients with mild VWF deficiency did not have VWF sequence variants)
  12. Valentijn and Eikenboom. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemst 2013;11:581
  13. Kanaji et al. Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost 2012;1646 (Endothelial cell VWF sufficient for normal hemostasis in mice)
  14. De Jong and Eikenboom. Developments in the diagnostic procedures for von Willebrand disease. J Thromb Haemost 2016;14:449
  15. Sadler and Rodeghiero. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005;3:775
  16. Quiroga et al. Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. J Thromb Haemost 2014;12:1238 (3-fold increase in rate of VWD diagnosis when VWF blood level cutoff raised from 30 to 40%; commentary emphasizes role of bleeding score in making treatment decisions)
  17. Bowman et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008;6:2062
  18. Federici et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood 2014;123:4037
  19. Goodeve A. The genetic basis of von Willebrand disease. Blood Rev 2010;24:123
  20. Pruthi R. A Practical Approach to Genetic Testing for von Willebrand Disease. Mayo Clin Proc 2006;81:679
  21. Schneppenheim and Budde. Phenotypic and Genotypic Diagnosis of von Willebrand Disease: A 2004 Update. Semin Hematol 2005;42:15
  22. Sanders et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014;12:1066 (VWF levels increase with aging in type I VWD but not in type 2 VWD; bleeding risk increases with age more in type 2 than type 1)
  23. Rodeghiero et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2005;3:2619
  24. Tosetto et al. Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach. Blood 2008;111:3998
  25. Ng et al. Diagnostic approach to von Willebrand disease. Blood 2015;125:2029
  26. Sadler E. Von Willebrand disease type 1: a diagnosis in search of a disease.  Blood 2003;101:2089
  27. Haberichter et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival.  Blood 2006;108:3344.
  28. Haberichter et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD). Blood 2008;111:4979
  29. Sanders et al. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015;125:3006 (41% of individuals thought to have type 3 VWD had circulating VWF propeptide, indicating that they actually have severe type 1 disease)
  30. Goodeve et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007;109:112
  31. James et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007;109:145
  32. Gallinaro et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008;111:3570
  33. James et al. Alloantibodies in von Willebrand disease. Blood 2013;122:636 (Acquired inhibitors develop in 5-10% of patients with type 3 VWD)
  34. Sanders et al. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost 2013;11:845
  35. Seaman et al. Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register. J Thromb Haemost 2015;13:1999 (Yes)
  36. Franchini and Mannucci. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost 2014;112:427
  37. Othman et al. Platelet type von Willebrand disease and registry report: communication from the SSC of the ISTH. J Thromb Haemost 2016;14:411

von Willebrand Disease & Women's Health

  1. Kujovich J.  von Willebrand disease and pregnancy.  J Thromb Haemost 2005;3:246
  2. Lee and Abdul-Kadir. von Willebrand Disease and Women’s Health. Semin Hematol 2005;42:42
  3. Lak et al. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000;111:1236
  4. Lethagen et al. Distribution of von Willebrand factor levels in young women with and without bleeding symptoms. Influence of ABO blood group and promoter haplotypes. Thromb Haemost 2008;99:1013 (Low VWF activity found in about 10% of young women with bleeding sx, vs 1.4% of controls. Blood type O strongly associated with low VWF levels)

von Willebrand Disease: Treatment

  1. Rodeghiero et al. How I treat von Willebrand disease. Blood 2009;114:1158
  2. Mannucci P. Treatment of von Willebrand disease.  NEJM 2004;351:683
  3. Rodeghiero et al. Optimizing treatment of von Willebrand disease by using phenotypic and molecular data. Hematology 2009: 113
  4. Tosetto and Castaman. How I treat type 2 variant forms of von Willebrand disease. Blood 2015;125:907
  5. Ruggeri et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP. Blood 1982; 59:1272
  6. Denis et al. Clearance of von Willebrand factor. Thromb Haemost 2008;99:271
  7. Federici et al.  Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study.  Blood 2004;103:2032
  8. Castaman et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008;111:3531

Inherited platelet function disorders

  1. Bianchi et al. Genomic landscape of megakaryopoiesis and platelet function defects. Blood 2016;127:1249
  2. Lentaigne et al. Inherited platelet disorders: toward DNA-based diagnosis. Blood 2016;127:2814
  3. Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology 2013:268
  4. Bolton-Maggs et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006;135:603
  5. Dovlatova N. Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders. Br J Haematol 2015;170:150
  6. Lambert MP. What to do when you suspect an inherited platelet disorder. Hematology 2011:377
  7. Cattaneo M. Inherited platelet-based bleeding disorders.  J Thromb Haemost 2003;1:1628
  8. Nurden and Nurden. Congenital disorders associated with platelet dysfunction. Thromb Haemost 2008;99:253
  9. Mumford et al. A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders. Thromb Haemost 2015;114:14
  10. Kunicki and Nugent. The genetics of normal platelet reactivity. Blood 2010;116:2627
  11. Dawood et al. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. Blood 2012:120:5041
  12. Rao AK.  Inherited defects in platelet signaling mechanisms.  J Thromb Haemost 2003;1:671
  13. Lopez et al. Bernard-Soulier syndrome. Blood 1998;91:4397
  14. Sandrock-Lang et al. Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations. Thromb Haemost 2015;113:782
  15. Kuijpers et al. Natural history and early diagnosis of LAD-1/variant syndrome. Blood 2007;109:3529 (Defect in integrin signaling leading to platelet dysfunction and severe bleeding, as well as neutrophil dysfunction)
  16. Gunay-Aygun et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood 2010;116:4990
  17. Gunay-Aygun et al. NEBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules. Nat Genet 2011;43:732
  18. Monteferrario et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. NEJM 2014;370:245
  19. Noris et al. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 2014;99:1387
  20. Civaschi et al. Analysis of 65 pregnancies in 34 women with five different forms of inherited platelet function disorders. Br J Haematol 2015;170:559 (Severe bleeding occurred in Glanzmann's but not storage pool defects or aspirin-like defects)

Other Inherited Bleeding Disorders

  1. Palla et al. Rare bleeding disorders: diagnosis and treatment. Blood 2015;125:2052
  2. Mumford et al. Guideline for the diagnosis and management of the rare coagulation disorders. A United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014;167:304
  3. Bolton-Maggs P. Factor XI deficiency—resolving the enigma? Hematology 2009: 97
  4. Asakai et al. Factor XI deficiency in Ashkenazi Jews in Israel. NEJM 1991; 325:153
  5. O'Connell N. Factor XI deficiency. Semin Hematol 2004; 41(suppl 1):76-81
  6. Pike et al. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood2015;126:397 (An assay that predicts bleeding tendency in F XI deficient patients)
  7. Preis et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017;129:1210
  8. Mannucci et al.  Recessively inherited coagulation disorders.  Blood 2004; 104:1243
  9. Peyvandi et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thrombos Haemost 2012;10:615
  10. Acharya et al.  Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.  J Thromb Haemost 2004;2:248
  11. Tie et al. Characterization of vitamin K–dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood 2016;127:1847 (High dose vit K corrected coag defect, but not associated skeletal and vascular defects caused by lack of matrix Gla protein)
  12. Bouchard et al. Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency. Blood 2015;125:3647
  13. Nagler et al. Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review. Thromb Haemost 2016;116:722 (Increased VTE risk due to decreased thrombin scavenging? Replacement therapy may decrease risk)
  14. Casini et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015;125:553 (By age 50, 19% had major bleeding and 30% had a thrombotic event)
  15. Casini et al. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015;13:909
  16. Peyvandi et al. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006;4:1634
  17. Bornikova et al. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011;9:1687
  18. Cunningham et al. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002;126:499
  19. Mariani et al. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency.  Thromb Haemost 2005;93:481
  20. Benlakhal et al. A retrospective analysis of 157 surgical procedures performed without replacement therapy in 83 unrelated factor VII-deficient patients. J Thromb Haemost 2011;9:1149 (Individuals with f VII levels >10% do not routinely need prophylactic replacement therapy for major surgery)
  21. Lovejoy et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood 2006;108:57
  22. Inbal et al. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 2012;119:5111
  23. Iwaki et al. Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans. J Thromb Haemost 2011;9:1200
  24. Dargaud et al. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood 2015;125:1497
  25. Burley et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood 2016;128:1879
  26. Geisthoff et al. How to manage patients with hereditatry haemorrhagic telangiectasia. Br J Haematol 2015;171:443
  27. Dupuis-Girod et al. Hereditary hemorrhagic telangiectasia: from molecular biology to patient care. J Thromb Haemost 2010;8:1447
  28. Sabba C. A rare and misdiagnosed bleeding disorder: hereditary hemorrhagic telangiectasia. J Thromb Haemost 2005;3:2201
  29. Iyer et al. Effect of Center Volume on Outcomes in Hospitalized Patients With Hereditary Hemorrhagic Telangiectasia. Mayo Clin Proc 2016;91:1753 (Includes data on complication rates in over 9000 hospitalizations for HHT)
  30. Bose et al. Bevacizumab in Hereditary Hemorrhagic Telangiectasia (letter). NEJM 2009; 360:2143
  31. Dupuis-Girod et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatiic vascular malformations and high cardiac output. JAMA 2012;307:948
  32. Dupuis-Gerod et al. Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia.A Randomized Clinical Trial. JAMA 2016;316:934 (No apparent benefit from this treatment)
  33. Whitehead et al. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia A Randomized Clinical Trial. JAMA 2016;316:943 (Neither bevacizumab or tranexamic acid reduced bleeding vs placebo)
  34. Lebrin et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010; 16:420
  35. Lyle et al. Pulmonary hypertension in hereditary hemorrhagic telangiectasia. Chest 2016;149:362
  36. De Paepe and Malfait. Bleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders. Br J Haematol 2004;127:491
  37. Parapia and Jackson. Ehlers-Danlos syndrome – a historical review. Br J Haematol 2008;141:32
  38. Ong et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010;376:1476


Thrombocytopenic disorders

General

  1. Kaushansky K. Thrombopoietin. NEJM 1998;339:746
  2. Kaushansky K. Historical review: megakaryopoiesis and thrombopoiesis. Blood 2008;111:981
  3. Cines et al.  Congenital and acqquired thrombocytopenia.  Hematology 2004:390
  4. Eto and Kunishima. Linkage between the mechanisms of thrombocytopenia and thrombopoiesis. Blood 2016;127:1234
  5. Segal et al. Accuracy of platelet counting haematology analysers in severe thrombocytopenia and potential impact on platelet transfusion. Br J Haematol 2005;128:520
  6. Tefferi et al. How to Interpret and Pursue an Abnormal Complete Blood Cell Count in Adults. Mayo Clin Proc 2005;80:923
  7. Warkentin T. Drug-induced immune-mediated thrombocytopenia - from purpura to thrombosis. (Editorial) NEJM 2007;356:891
  8. Bizarro N. EDTA-dependent pseudothrombocytopenia: A clinical and epidemiological study of 112 cases, with 10-year follow-up. Am J Hematol 1995;50:103
  9. Stasi et al. Long-Term Outcome of Otherwise Healthy Individuals with Incidentally Discovered Borderline Thrombocytopenia. PLoS Med 3(3): e24. doi:10.1371/journal.pmed.0030024 (Patients with platelet counts between 100K and 150K had 12% probability of developing an autoimmune disorder within 10 years; 85% of autoimmune disorders occurred in women)
Inherited thrombocytopenias
  1. Bianchi et al. Genomic landscape of megakaryopoiesis and platelet function defects. Blood 2016;127:1249
  2. Favier and Raslova. Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias. Br J Haematol 2015;170:626
  3. Drachman J. Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood 2004;103:390
  4. Balduni et al. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 2013;11:1006
  5. Balduini et al.  Inherited thrombocytopenias: from genes to therapy.  Haematologica 2002;87:860
  6. Imai et al.  Clinical course of patients with WASP gene mutations. Blood 2004;103:456. (Wiskott-Aldrich syndrome)
  7. Bosticardo et al. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 2009;113:6288
  8. Burns et al.  Mechanisms of WASp-mediated hematologic and immunologic disease. Blood 2004;104:3454  (Wiskott-Aldrich syndrome)
  9. Albert et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment optiions. Blood 2010;115:3231
  10. Lopez et al. Bernard-Soulier syndrome. Blood 1998;91:4397
  11. Sivapalaratnam et al. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood 2017;129:520
  12. Kunicki and Newman. The molecular immunology of human platelet proteins. Blood 1992;80:1386
  13. Bolton-Maggs et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006;135:603
  14. Noris et al. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. Blood 2014;124 (6):e4
  15. Manchev et al. A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene. Blood 2014;124:2554 (Severe thrombocytopenia with bleeding, recessive inheritance)
  16. Bottega et al. ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. Blood 2015;125:869 (A relatively common, dominantly inherited form of mild macrothrombocytopenial; mutation in α-actinin1 gene)
  17. Pecci et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood 2010;116:5832 (11/12 patients responded)
  18. Gerrits et al. Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia. Blood 2015;126:1367 (
ITP
  1. Neunert et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190
  2. Neunert C. Current management of immune thrombocytopenia. Hematology 2013:276
  3. Provan et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168
  4. Liebman and Pullarkat. Diagnosis and management of immune thrombocytopenia in the era of thrombopoietin mimetics. Hematology 2011:384
  5. Cooper and Bussel.  The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol 2006;133:364
  6. Cines et al. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511
  7. Cines and Blanchette. Immune thrombocytopenic purpura. NEJM 2002;346:995
  8. Segal and Powe.  Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost 2006;4:2377  (About 10 cases/100,000)
  9. Moulis et al. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 2014;124:3308 (Incidence 2.9/100K/yr; severe bleeding rare but more common in older people)
  10. Aledort et al. Prospective Screening of 205 Patients With ITP, Including Diagnosis, Serological Markers, and the Relationship Between Platelet Counts, Endogenous Thrombopoietin, and Circulating Antithrombopoietin Antibodies. Am J Hematol 2004;76:205 (Normal thrombopoietin levels in most patients with ITP; 5% incidence of thrombotic or ischemic events)
  11. Neylon et al.  Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003;122:966
  12. Cohen et al. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000;160:1630 (5 year mortality 2.2% for those under 40, 48% for those over 60)
  13. Neunert et al. Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review. J Thromb Haemost 2015;13:457
  14. Page et al. The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP. Br J Haematol 2007; 138:245
  15. Neunert et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood 2008;112:4003 (severe bleeding uncommon at diagnosis and rarely begins within 4 weeks after diagnosis)
  16. Psaila et al. Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases. Blood 2009;114:4777 (0.19% to 0.78% incidence; children with severe thrombocytopenia plus head trauma or hematuria at greatest risk)
  17. Neunert et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood 2013;121:4457 ("ITP is a benign condition for most affected children and that major hemorrhage, even with prolonged severe thrombocytopenia, is rare")
  18. Hill and Newland. Fatigue in immune thrombocytopenia. Br J Haematol 2015;170:141
  19. Rizvi et al. United Kingdom immune thrombocytopenia registry: retrospective evaluation of bone marrow fibrosis in adult patients with primary immune thrombocytopenia and correlation with clinical findings. Br J Haematol 2015;169:590 (25% of TPO-RA naive patients had increased reticulin fibrosis in marrow)
  20. Heitink-Pollé et al. Clinical and laboratory predictors of chronic immune thrombocytopenia in children: a systematic review and meta-analysis. Blood 2014;124:3295 (Older age, insidious onset, no preceding infection, mild bleeding, and higher platelet count predict chronic ITP; IVIG may protect against it)
  21. Grimaldi-Bensouda et al. A case-control study to assess the risk of immune thrombocytopenia associated with vaccines. Blood 2012;120:4938 (Exposure to vaccines not associated with development of ITP in adults)
  22. Sarpatwari et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica 2010;95:1167
  23. Severinsen et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danis population-based cohort study. Brit J Haematol 2011;153:260 (Estimated 2-fold increased VTE risk in ITP)
  24. Ruggeri et al. Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors. J Thromb Haemost 2014;12:1266
  25. Mahevas et al. Association of sarcoidosis and immune thrombocytopenia. Presentation and outcome in a series of 20 patients. Medicine 2011;90:269
  26. Cines and Bussel.  How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005;106:2244
  27. Stasi and Povan.  Management of immune thrombocytopenic purpura in adults.  Mayo Clin Proc 2004;79:504
  28. Ghanima et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood 2012;120:960
  29. George J.  Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost 2006;4:1664
  30. Cuker and Neunert. How I treat refractory immune thrombocytopenia. Blood 2016;128:1547
  31. Mahévas et al. Characteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia. Blood 2016;128:1625 (70% response rate to immunosuppression + TPO receptor agonist)
  32. Gernsheimer et al. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. NEJM 1989; 320:974
  33. Sigaram et al. Intravenous immunoglobulin ameliorates ITP via activating Fcg receptors on dendritic cells. Nat Med 2006;12:688
  34. Mazzucconi et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 2007;109:1401
  35. Wei et al. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood 2016;127:296 (Initial response rates better with dex, sustained response rates similar; dex better tolerated)
  36. Zaja et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010;115:2755 (63% vs 36% sustained response rate)
  37. Gudbrandsdottir et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood 2013;121:1976 (R+D gave higher response rates, more durable remissions than D alone)
  38. Kojouri et al. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004;104:2623
  39. Keidar et al.  Analysis of outcome of laparoscopic splenectomy for idiopathic thrombocytopenic purpura by platelet count. Am J Hematol 2005;80:95 (more complications when platelets <20K)
  40. Boyle et al. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 2013;121:4782
  41. Vesely et al.  Management of Adult Patients with Persistent Idiopathic Thrombocytopenic Purpura Following Splenectomy. Ann Intern Med 2004;140:112
  42. Godeau et al. Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin. Blood 1993;82:1415
  43. Law et al. High-dose intravenous immune globulin and the response to splenectomy in patients with idiopathic thrombocytopenic purpura. NEJM 1997;336:1494
  44. Scaradavou et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997;89:2689
  45. Despotovic et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy. Transfusion 2011 (epub)
  46. Robak et al. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia. Blood 2012;120:3670
  47. Cheng et al.  Initial tratment of immune thrombocytopenic purpura with high-dose dexamethasone.  NEJM 2003;349:831
  48. Godeau et al. Intravenous immunoglobulin or high-dose methylprednisolone with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002;359:23
  49. Spahr and Rodgers. Treatment of immune-mediated thrombocytopenia purpura with concurrent intravenous immunoglobulin and platelet transfusion: A retrospective review of 40 patients. Am J Hematol 2008; 83:122
  50. Figueroa et al. Combination chemotherapy in refractory immune thrombocytopenic purpura. N Engl J Med 1993;328:1226
  51. Boruchov et al. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 2007;110:3526 (IVIG, steroids, vincristine, IV anti-D induction plus danazol, azathioprine maintenance)
  52. Arnold et al. Combination immunosuoppressant therapy for aptients with chronic refractory immune thrombocytopenic purpura. Blood 2010;115:29 (Mycophenolate, azathioprine and cyclosporine combination produced over 70% CR rate, median duration of CR 24 mo)
  53. Choi et al. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood 2015;126:500 (60% 6-mo OR rate, little toxicity)
  54. Stasi et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001;98:952
  55. Cooper et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004;125:232
  56. McMillan and Durette. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104:956
  57. Shanafelt et al.  Rituximab for immune cytopenias in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome.  Mayo Clin Proc 2003;78:1340
  58. Gómez-Almaguer et al. Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood 2010;116:4783
  59. Arnold et al. Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura. Ann Intern Med 2007;146:25   (62.5% response rate, 2.9% death rate in uncontrolled trials)
  60. Godeau et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood 2008;112:999 (40% had good response, over half avoided splenectomy)
  61. Stasi et al. Response to B-cell–depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007;110:2924
  62. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008;141:149
  63. Patel et al. Outcomes 5 years after response to rutixumab therapy in children and adults with immune thrombocytopenia. Blood 2012;119:5989 (21% of adults with initial CR to rituximab remained in remission without further treatment after 5 years; no significant toxicity observed)
  64. Gómez-Almaguer et al. High response rate to low-dose rituximab plus high-dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia. Eur J Haematol 2013 (ePub)
  65. Mahévas et al. B cell depletion in ummune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest 2013;123:432 (Rituximab treatment may promote development of long-lived platelet-reactive plasma cells)
  66. Khellaf et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014;124:3228 (61% initial response rate, 39% sustained responses, relatively low toxicity)
  67. Audia et al Preferential splenic CD8+ T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia. Blood 2013;122:2477
  68. Nazi et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013;122:1946 (Ab response to vaccination decreased for at least 6 mo after rituximab treatment)
  69. Rodrigo and Gooneratne. Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review. J Thromb Haemost 2013;11:1946
  70. Michel et al.  Does Helicobater pylori initiate or perpetuate immune thrombocytopenic purpura? Blood 2004;103:890  (It apparently did not in this series)
  71. Sato et al. Effect of Helicobacter pylori Eradication on Platelet Recovery in Patients With Chronic Idiopathic Thrombocytopenic Purpura.  Arch Intern Med 2004;164:1904
  72. Emilia et al. Helicobacter pylori infection and chronic immune thrombocytopenic purpura: long-term results of bacterium eradication and association with bacterium virulence profiles. Blood 2007;110:3833 (51% of ITP patients had H pylori infection; 68% had improvement in ITP upon eradication of infection)
  73. Stasi et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009; 113:1231 (about a third of patients improve after treatment for H pylori, but response rates vary widely in different countries)
  74. Cortelazzo et al. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 1991; 77:31
  75. Portieleje et al. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001;97:2549
  76. Nørgaard et al. Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood 2011;117:3514
  77. Webert et al.  A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003;102:4306
  78. Lostau et al. Effect of pregnancy on the course of immune thrombocytopenia: a retrospective study of 118 pregnancies in 82 women. Br J Haematol 2014;166:929
  79. Michel et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine 2004;83:254
  80. Norton and Roberts. Management of Evans syndrome. Br J Haematol 2006;132:125

Thrombopoietic drugs in ITP and other thrombocytopenias

  1. Imbach and Crowther. Thrombopoietin-Receptor Agonists for Primary Immune Thrombocytopenia. NEJM 2011;365:734
  2. Newland et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol 2006;135:547 (Romiplostim)
  3. Bussel et al. AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP. NEJM 2006;355:1672 (Romiplostim)
  4. Kuter et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371:395
  5. Kuter et al. Romiplostim or standard of care in patients with immune thrombocytopenia. NEJM 2010;363:1889 (Romiplistim treatment associated with higher response rate, fewer complications, higher quality of life)
  6. Bussel et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161
  7. Khellaf et al. Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program. Blood 2011;118:4338
  8. Newland et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol 2016;172:262 (About 30% of responding patients able to stop drug without recurrent severe thrombocytopenia)
  9. Kuter et al. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 2009;114:3748
  10. Ghanima et al. Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica 2014;99:937 (Grade 2 or 3 fibrosis found in about 20% of patients treated > 2 yrs)
  11. Kantarjian et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood 2010;116:3163 (Uncertain benefit)
  12. Bussel et al. Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura. NEJM 2007;357:2237
  13. Bussel et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:641
  14. Cheng et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011;377:393
  15. Saleh et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood 2013;121:537
  16. Gómez-Almaguer et al. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood 2014;123:3906 (12 month RFS 67% after 4 days of dex followed by 4 week course of eltrombopag)
  17. Pecci et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood 2010;116:5832 (11/12 patients responded)
  18. McHutchison et al. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. NEJM 2007;357:2227
  19. Afdhal et al. Eltrombopag Increases Platelet Numbers in Thrombocytopenic Patients With HCV Infection and Cirrhosis, Allowing for Effective Antiviral Therapy. Gastroenterology 2014;146:442 (Higher platelet counts, higher incidence of liver decompensation and thrombosis in eltrombopag-treated patients)
  20. Moussa and Mowafy. Preoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis. J Gastroenterol Hepatol 2013;28:335 (33/35 patients had plts 70K with no bleeding or thrombosis)
  21. Olnes et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. NEJM 2012;367:11 (44% of patients had a hematologic response; minimal toxicity)
  22. Afdhal et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. NEJM 2012;367:716 (Treatment reduced need for platelet transfusion but increased risk of portal vein thrombosis)
  23. González-Porras et al. Use of eltrombopag after romiplostim in primary immune thrombocytopenia. Br J Haematol 2015;169:111 (80% response rate)
  24. Bussel et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood 2014;123:3887
  25. Zhou et al. A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP. Blood 2015;125:1541 (Addition of rhTPO improved CR rate but not relapse rate)
  26. Liu et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood 2016;128:852 (TPO agonists may reduce rate of platelet destruction in addition to promoting production)
Heparin-induced thrombocytopenia
  1. Linkins et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e495S
  2. Greinacher A. Heparin-induced thrombocytopenia. NEJM 2015;373:252
  3. Kelton and Warkentin. Heparin-induced thrombocytopenia: a historical perspective. Blood 2008;112:2607
  4. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost 2016;116:813
  5. Cuker and Cines. How I treat heparin-induced thrombocytopenia. Blood 2012;119:2209
  6. Aljabri et al. Cost-effectiveness of anticoagulants for suspected heparin-induced thrombocytopenia in the United States. Blood 2016;128:3043 (Fondaparinux more cost-effective than argatroban or bivalirudin)
  7. Cuker A. Management of the multiple phases of heparin-induced thrombocytopenia. Thromb Haemost 2016;116:835
  8. Selleng and Selleng. Heparin-induced thrombocytopenia in cardiac surgery and critically ill patients. Thromb Haemost 2016;116:843
  9. Warkentin and Anderson. How I treat patients with a history of heparin-induced thrombocytopenia. Blood 2016;128:348
  10. Lo et al. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007;82:1037 (Specificity of SRA for HIT)
  11. Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: An epidemic of overdiagnosis. Thromb Haemost 2011;106:993
  12. Chan et al. The Role for Optical Density in Heparin-Induced Thrombocytopenia: A Cohort Study. Chest 2015;148:55 (HIT ELISA OD cutoff of >1.0 had much better specificity and as good sensitivity as a cutoff of >0.4; with editorial)
  13. Nagler et al. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2016;127:546
  14. Oliveira et al. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med 2008;168:94 (36% incidence of thrombocytopenia - not all due to HIT - with heparin Rx for > 4d; increased risk of death, thrombotic and hemorrhagic events in affected pts)
  15. Greinacher et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005;94:132
  16. Girolami et al.  The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003;101:2955
  17. Warkentin et al. Heparin-Induced Thrombocytopenia in Medical Surgical Critical Illness. Chest 2013;144:848 (LMWH associated with less seroconversion than UFH, and lower rate of clinical events in seropositive patients than UFH)
  18. McGowan et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood 2016;127:1954 (Routine use of LMWH rather than UFH decreased incidence of HIT by 79% and incidence of HITT by 91%)
  19. Lubenow et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010;115:1797 (HIT antibodies more common after major than minor surgery, and more common with UFH than LMWH)
  20. Warkentin et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. NEJM 1995;332:1330
  21. Prandoni et al. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study . Blood 2005;106:3049
  22. Falvo et al. Heparin-associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost 2011;9:1761 (Higher risk of HIT in patients treated with unfractionated heparin vs LMWH)
  23. Greinacher et al. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007;5:1666 (HIT ELISA test for IgG antibodies 99% sensitive for HIT, but only about 50% specific)
  24. Warkentin et al. Prevalence and Risk of Preexisting Heparin-Induced Thrombocytopenia Antibodies in Patients With Acute VTE. Chest 2011; 140:366 (Positive SRA assay predicts rapid-onset HIT; positive EIA with negative SRA does not)
  25. Warkentin et al. Studies of the immune response in heparin-induced thrombocytopenia. Blood 2009;113:4963
  26. Prechel et al. Activation of platelets by heparin-induced thrombocytopenia antibodies in the serotonin release assay is not dependent on the presence of heparin. J Thromb Haemst 2005;3:21 (Antibodies may cause disease in the absence of heparin)
  27. Padmanabhan et al. Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis. Blood 2015;125:155 (A subset of HIT antibodies recognize PF4 bound to platelet chondroitin sulfate; possible explanation for "delayed HIT")
  28. Cines et al. Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia. Blood Adv 2016;1:62
  29. Greinacher et al. The temporal profile of the anti-PF4/heparin immune response. Blood 2009;113:4970 (rapid onset - 4-14 days - and spontaneous disappearance of IgG antibodies to heparin-PF4 in absence of prior heparin exposure is common pattern)
  30. Khandelwal et al. The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21), Blood 2016;128:1789
  31. Warkentin et al. Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005;106:3791
  32. Bito et al. Mechanical prophylaxis is a heparin-independent risk for anti–platelet factor 4/heparin antibody formation after orthopedic surgery. Blood 2016;127:1036
  33. Warkentin and Kelton. Temporal aspects of heparin-induced thrombocytopenia. NEJM 2001;344:1286
  34. Warkentin et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006;108:2937
  35. Warkentin et al. An Improved Definition of Immune Heparin-Induced Thrombocytopenia in Postoperative Orthopedic Patients. Arch Intern Med 2003;163:2518
  36. Lo et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759
  37. Cuker et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012;120:4160 ("A low probability 4Ts score appears to be a robust means of excluding HIT")
  38. Linkins et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood 2015;126:597 (4Ts score <4, negative rapid immunoassay → no HIT)
  39. Raschke et al. Improving Clinical Interpretation of the Anti-Platelet Factor 4/Heparin Enzyme-Linked Immunosorbent Assay for the Diagnosis of Heparin-Induced Thrombocytopenia Through the Use of Receiver Operating Characteristic Analysis, Stratum-Specific Likelihood Ratios, and Bayes Theorem. Chest 2013;144:1269 (SRA considered unneccessary if ELISA OD < 0.6 or > 2.0)
  40. Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost 2015 (Epub)
  41. Trehel-Tursis et al. Clinical and Biologic Features of Patients Suspected or Confirmed to Have Heparin-Induced Thrombocytopenia in a Cardiothoracic Surgical ICU. Chest 2012;142:815 (False positive results with heparin-induced platelet aggregation assay vs SRA. With editorial)
  42. Rauova et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005;105:131
  43. Kelton et al. Nonheparin anticoagulants for heparin-induced thrombocytopenia. NEJM 2013;368:737
  44. Joseph et al. Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost 2014;12:1044
  45. Lewis et al. Effects of Argatroban Therapy, Demographic Variables, and Platelet Count on Thrombotic Risks in Heparin- Induced Thrombocytopenia. Chest 2006;129:1407
  46. Levine et al. Argatroban Therapy in Heparin-Induced Thrombocytopenia With Hepatic Dysfunction. Chest 2006;129:1167
  47. Keyl et al. Argatroban pharmacokinetics and pharmacodynamics in critically ill cardiac surgical patients with suspected heparin-induced thrombocytopenia. Thromb Haemost 2016;115:1081 (Drug half-life markedly increased in critically ill cardiac pts)
  48. Efird and Kockler. Fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia. Ann Pharmacother 2006;40:1383
  49. Kang et al. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score–matched study. Blood 2015;125:924 (Retrospective study; fondaparinux associated with similar bleeding rates and somewhat lower thrombosis rates than alternative therapies)
  50. Dhakal et al. New Oral Anticoagulants for the Management of Heparin Induced Thrombocytopenia: A Focused Literature Review. Cardiovasc Hematol Agents Med Chem. 2015;13:87 (DOACs appear to be effective therapy for HIT)
  51. Shatzel et al. Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases. Thromb Haemost 2016;116:397
  52. Selleng et al. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation. Blood 2008;112:4024 (safe to give limited course of UFH if functional assay for heparin Ab negative)
  53. Warkentin et al. A Spontaneous Prothrombotic Disorder Resembling Heparin-induced Thrombocytopenia. Am J Med 2008;121:632
  54. Warkentin et al. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood 2014;123:3651
  55. Warkentin et al. Anti-PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis. J Thromb Haemost 2013;11:253 (Risk of graft occlusion in SRA-negative patients)
  56. Welsby et al. The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery. J Thromb Haemost 2017;15:57 (No impact of positive antibody test on thrombosis or survival)
  57. Warkentin and Sheppard. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin. Blood 2014;123:2485 (1/20 patients developed recurrent HIT; 8/20 seroconverted)

Thrombocytopenia in pregnancy

  1. Gernsheimer et al. How I treat thrombocytopenia in pregnancy. Blood 2012;121:38
  2. Lescale et al. Antiplatelet antibody testing in thrombocytopenic pregnant women. AJOG 1996;174:1014 (Gestational thrombocytopenia often associated with high levels of platelet-associated immunoglobulin)
  3. Parnas et al. Moderate to severe thrombocytopenia during pregnancy. Eur J Obstet Gynecol Reprod Biol 2006
  4. Webert et al.  A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003;102:4306
  5. Sun et al. Corticosteroids compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in pregnancy. Blood 2016;128:1329 (Many did not need treatment, IVIG and steroids produced similar good outcomes in this retrospective study)
  6. Vesely et al. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Transfusion 2004;44:1149
  7. Martin et al. Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955-2006. AJOG 2008;199:98
  8. Moatti-Cohen et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012;119:5888

Post-transfusion purpura; neonatal alloimmune purpura

  1. Abramson et al.  Post-transfusion purpura: immunologic aspects and therapy.  NEJM 1974;291:1163
  2. Kickler et al. Studies on the pathophysiology of posttransfusion purpura. Blood 1986; 68:347
  3. Ghevaert et al. Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers. Blood 2012;122:313
  4. Winkelhorst et al. Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood 2017;129:1538

Drug-induced immune thrombocytopenia

  1. George and Aster. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology 2009;153
  2. Bougie et al. Mechanism of quinine-dependent monoclonal antibody binding to platelet glycoprotein IIb/IIIa. Blood 2015;126:2146 (Drug binds to antibody, increasing its affinity for platelet antigen)
  3. Reese et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010;116:2127
  4. Arnold et al. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013;11:169 (Drugs most likely: quinine, quinidine, TMP/sulfa, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin, suramin, abciximab, tirofiban and eptifibatide)
  5. Aster and Bougie. Current concepts: drug-induced immune thrombocytopenia. NEJM 2007;357:580
  6. Warkentin T. Drug-induced immune-mediated thrombocytopenia - from purpura to thrombosis. (Editorial) NEJM 2007;356:891
  7. George et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 1998;129:886
  8. Bougie et al. Patients with quinine-induced immune thrombocytopenia have both "drug-dependent" and "drug-specific" antibodies. Blood 2006;108:922
  9. Liles et al. Diversity and severity of adverse reactions to quinine: A systematic review. Am J Hematol 2016 (Epub) (20% of reactions to quinine-containing beverages, lifethreatening multisystem illness common)
  10. Von Drygalski et al. Vancomycin-mediated immune thrombocytopenia. NEJM 2007; 356:904
  11. Aster et al. Thrombocytopenia associated with the use of GPIIb/IIIa inhibitors: position paper of the ISTH working group on thrombocytopenia and GPIIb/IIIa inhibitors. J Thromb Haemost 2006;4:678
  12. Greinacher et al. Megakaryocyte impairment by eptifibatide-induced antibodies causes prolonged thrombocytopenia. Blood 2009;114:1250
  13. Wu et al. High Frequency of Linezolid-Associated Thrombocytopenia and Anemia among Patients with End-Stage Renal Disease. Clin Infect Dis 2006;42:66
  14. Cuker et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 2011;118:6299 (Delayed presentation, severe thrombocytopenia, responsive to standard treatment, prolonged remission)
  15. Bakchoul et al. Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies. J Thromb Haemost 2016;14:1685

Other acquired thrombocytopenias

  1. Stasi et al. Long-Term Outcome of Otherwise Healthy Individuals with Incidentally Discovered Borderline Thrombocytopenia. PLoS Med 3(3): e24. doi:10.1371/journal.pmed.0030024 (Patients with platelet counts between 100K and 150K had 12% probability of developing an autoimmune disorder within 10 years; 85% of autoimmune disorders occurred in women)
  2. Saito et al. Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels. Br J Haem 2016;175:246
  3. Warkentin et al. Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome. Hematology 2003:497-519
  4. Claushuis et al. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood 2016;127:3062
  5. Drews and Weinberger. Thrombocytopenic disorders in critically ill patients. Am J Respir Crit Care Med 2000;162:347
  6. Cole et al. Ineffective platelet production in thrombocytopenic human immunodeficiency virus-infected patients. Blood 1998;91:3239
  7. Greinacher and Selleng. How I evaluate and treat thrombocytopenia in the intesive care unit. Blood 2016;128:3032
  8. Alhamdi et al. Histone-associated thrombocytopenia in patients who are critically ill. JAMA 2016;315:817
  9. Lill et al. Pathogenesis of Thrombocytopenia in Cyanotic Congenital Heart Disease.  Am J Cardiol 2006;98:254
  10. Ando et al. New insights into the thrombopoietic status of patients on dialysis through the evaluation of megakaryocytopoiesis in bone marrow and of endogenous thrombopoietin levels. Blood 2001;97:915
  11. Kiaii et al. Use of electron-beam sterilized hemodialysis membranes and risk of thrombocytopenia. JAMA 2011;306:1679
  12. Rajan et al. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol 2005;129:818
  13. McHutchison et al. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. NEJM 2007;357:2227
  14. Chiao et al. Risk of Immune Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia Among 120 908 US Veterans With Hepatitis C Virus Infection. Arch Intern Med 2009;169:357
  15. Bat et al. Thrombopoietic status of patients on hemodialysis. Br J Haematol 2016;172:954 (Higher TPO levels and increased proportion of immature platelets in dialysis patients suggest shortened platelet lifespan)

TTP and related disorders

TTP

  1. Crawley and Scully. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology 2013:292
  2. George and Nester. Syndromes of thrombotic microangiopathy. NEJM 2014;371:654
  3. Scully et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost 2017;15:312 (DDX of TMA)
  4. Bendapudi et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol 2017;4:e157 (Link to score)
  5. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010;116:4060
  6. Sayani and Abrams. How I treat refractory thrombotic thrombocytopenic purpura. Blood 2015;125:3860
  7. Sadler JE. Thrombotic Thrombocytopenic Purpura: A Moving Target. Hematology 2006;415
  8. Veyradier and Meyer.  Thrombotic thrombocytopenic purpura and its diagnosis. J Thromb Haemost 2005;3:2420
  9. Mariotte et al. Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy. Lancet Haematol 2016;3:e237 (Many patients with severe ADAMTS13 deficiency and TTP had non-autoimmune disease associated with infection, cancer, transplantation, drugs, HIV; high incidence of inherited deficiency in OB cases)
  10. Imanirad et al. A case series of atypical presentations of thrombotic thrombocytopenic purpura. J Clin Apheresis 2012;27:221
  11. Joly et al. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy. Lancet Haematol 2016;3:e537 (< 10% of children with TMA have severe ADAMTS-13 deficiency; about a third of those have congenital deficiency)
  12. Bessman J. Red blood cell fragmentation. Am J Clin Pathol 1988; 90:268
  13. Grall et al. Thrombotic thrombocytopenic purpura misdiagnosed as autoimmune cytopenia: Causes of diagnostic errors and consequence on outcome. Experience of the French thrombotic microangiopathies reference centre. Am J Hematol 2017;92:381
  14. Le Besnerais et al. Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura. J Thromb Haemost 2016;14:1917
  15. Rock et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. NEJM 1991; 325:393
  16. Hayward et al. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Intern Med 1994;154:982
  17. Lim et al. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood 2015;125:1526
  18. Scully et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011;118:1746 (Quicker response, lower relapse rate, no apparent complications with rituximab vs hist. controls)
  19. Fakhouri et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005;106:1932
  20. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008;141:149
  21. Westwood et al. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. J Thromb Haemost 2013;11:481
  22. Page et al. Rituximab reduces risk for relapse in patients with thrombotic thrombocytopenic purpura. Blood 2016;127:3092 (With editorial)
  23. Hie et al. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood 2014;124:204 (Rituximab given to patients with persistently low ADAMTS13 levels)
  24. Tersteeg et al. Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy. Circulation 2014;129:1320 (Proposes that thrombolytic agents may be useful in treatment of TTP; with editorial)
  25. Peyvandi et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. NEJM 2016;374:511 (Anti-VWF nanobody induced faster resolution of TTP, with some increase in bleeding; see also subsequent letter to editor)
  26. Patriquin et al. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haem 2016;173:779 (5/6 patients had CR)
  27. Ratnasingam et al. Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv 2016;1:31 (Bortezomib effective in a variety of autoimmune conditions including AIHA, acquired factor VIII inhibitor, and TTP)
  28. Vesely et al. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Transfusion 2004;44:1149
  29. Jiang et al. Pregancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood 2014;123:1674
  30. Martin et al. Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955-2006. AJOG 2008;199:98
  31. Scully et al. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood 2014;124:211 (TTP presenting during pregnancy is often due to previously undiagnosed congenital ADAMTS13 deficiency)
  32. Crowther et al. Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Intern Med 1996;125:294
  33. Moatti-Cohen et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012;119:5888
  34. Deford et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood 2013;122:2023
  35. Zafrani et al. Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity. J Thromb Haemost 2015;13:380 (25% of patients in this retrospective series required renal replacement Rx)

ADAMTS-13

  1. Sadler E. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008;112:11
  2. Furlan et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. NEJM 1998;339:1578.
  3. Tsai and Lian. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. NEJM 1998;339:1585
  4. Bendapudi et al. Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative. Brit J Haem 2015 (Epub). (TMA without severe ADAMTS13 deficiency associated with DIC, drug-associated TMA, transplant-related TMA, did not seem to benefit from plasma exchange)
  5. Hassan et al. The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry. Brit J Haem 2015;171:830
  6. Banno et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 2006;107:3161 (In mice)
  7. Feys et al. Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus). Blood 2010;116:2005
  8. Raife et al. Severe deficiency of VWF-cleaving protease (ADAMTS13) activity defines a distinct population of thrombotic microangiopathy patients. Transfusion 2004;44:146
  9. Hovinga et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010;115:1500 (Low ADAMTS13 activity associated with higher relapse rate; some patients did not relapse despite persistently low levels)
  10. Rieger et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005;106:1262  (ELISA assay for ADAMTS-13 antibodies)
  11. Zheng et al. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.  Blood 2004;103:4043
  12. Böhm et al. The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 2005;129:644
  13. Coppo et al. Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura. Br J Haematol 2006;132:66
  14. Starke et al. The clinical utility of ADAMTS13 activity, antigen and autoantibody assays in thrombotic thrombocytopenic purpura. Br J Haematol 2007;136:649
  15. Jin et al. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse. Brit J Haematol 2008;141:651 (Low ADAMTS13 level, younger age associated with higher relapse rate)
  16. Page et al. Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura (letter). Blood 2016;128:2175 (Levels may fluctuate dramatically during remission without clinical relapse)
  17. Mannucci and Peyvandi. TTP and ADAMTS13: when is testing appropriate? Hematology 2007:121
  18. Fakhouri et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005;106:1932
  19. Nolasco et al. Hemolytic uremic syndrome–associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 2005;106:4199
  20. Chauhan et al. The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis. Blood 2008;111:3452. (VWF mediates thrombocytopenia in ADAMTS-13 deficiency but not endotoxemia)
  21. Sonneveld et al. Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. Blood 2015;126:2739
  22. Maino et al. Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis. J Thromb Haemost 2015;13:1396 (Very low ADAMTS13 levels associated with high risk of MI)
  23. Uemura et al. Comprehensive analysis of ADAMTS-13 in patients with liver cirrhosis. Thromb Haemost 2008;99:1019

HUS

  1. George and Nester. Syndromes of thrombotic microangiopathy. NEJM 2014;371:654
  2. Lizewski and Atkinson. Too Much of a Good Thing at the Site of Tissue Injury: The Instructive Example of the Complement System Predisposing to Thrombotic Microangiopathy. Hematology 2011: 9
  3. Conway EM. HUS and the case for complement. Blood 2015;126:2085
  4. Phillips et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost 2016;14:175 (Platelet count and creatinine not adequate to distinguish aHUS from TTP; complelement mutation analysis recommended in TMA patients with ADAMTS13 > 10%)
  5. Pennington H. Escherichia coli 0157. Lancet 2010;376:1428
  6. Tarr et al. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005;365:1073
  7. Su and Brandt. Escherichia coli O157:H7 infection in humans. Ann Intern Med 1995;123:698
  8. Garg et al.  Long-term renal prognosis of diarrhea-associated hemolytic-uremic syndrome.  JAMA 2003;290:1360
  9. Lapeyraque et al. Eculizumab in severe Shiga-toxin-associated HUS (letter). NEJM 2011;364:2561
  10. Nitschke et al. Association Between Azithromycin Therapy and Duration of Bacterial Shedding Among Patients With Shiga Toxin–Producing Enteroaggregative Escherichia coli O104:H4. JAMA 2012;307:1046 (Antibiotic treatment associated with lower frequency of long-term bacterial carriage)
  11. Caprioli et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108:1267
  12. Kavanagh and Goodship. Atypical Hemolytic Uremic Syndrome, Genetic Basis, and Clinical Manifestations. Hematology 2011;15
  13. Noris and Remuzzi. Atypical hemolytic-uremic syndrome. NEJM 2009;361:1676
  14. Cataland and Wu. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 2014;123:2478
  15. Loirat et al. Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010;36:673
  16. Fang et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008;111:624
  17. Fakhouri et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood 2008;112:4542 (Mutations found in 4/11 patients)
  18. Frémeaux-Bacchi et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112:4948
  19. Roumenina et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 2009;114:2837
  20. Delvaeye et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. NEJM 2009;361:345
  21. Roumenina et al. A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood 2012;119:4182
  22. Legendre et al. Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic–Uremic Syndrome. NEJM 2013;368:2169
  23. Cofiell et al. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood 2015;125:3253
  24. Noris et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 2014;124:1715 (In vitro complement deposition assays correlated with treatment response, could be used to titrate drug dose)
  25. Cataland et al. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood 2014;123: 3733
  26. Feng et al. Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood 2013;122:1487 (Found concomitant with complement gene mutations in many patients)

Other thrombotic microangiopathies

  1. George and Nester. Syndromes of thrombotic microangiopathy. NEJM 2014;371:654
  2. Al-Nouri et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015;125:616
  3. Reese et al. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma registry and the BloodCenter of Wisconsin. Am J Hematol 2015;90:406
  4. Lechner and Obermeier. Cancer-related microangiopathic hemolytic anemia. Clinical and laboratory features in 168 reported cases. Medicine 2012;91 (Epub)
  5. Bennett et al. Thrombotic thrombocytopenic pupura associated with clopidogrel. NEJM 2000;342:1773
  6. Noris and Remuzzi. Thrombotic microangiopathy after kidney transplantation. Am J Transplant 2010; 10:1517
  7. Novitzky et al. Thrombotic thrombocytopenic purpura in patients with retroviral infection is highly responsive to plasma infusion therapy. Br J Haematol 2005;128:373
  8. George et al. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 2004;44:294
  9. Jodele et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood 2016;127:989 (Complement gene variants and upregulation of complement pathways associated with TMA after HSCT)
  10. Eremina et al. VEGF inhibition and renal thrombotic microangiopathy. NEJM 2008;358:1129 (HUS caused by bevacizumab)
  11. Thomas et al. How we manage thrombotic microangiopathies in pregnancy. Br J Haematol 2016
  12. Henderson et al. Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med 2014;160:695 (Modest reduction in risk for adverse outcomes with ASA, no apparent adverse effects)
  13. Peyvandi et al. Thrombotic microangiopathy without renal involvement: two novel mutations in complement-regulator genes. J Thromb Haemost 2016;14:340
  14. Kavanagh et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016;128:2824
  15. Hunt et al. A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER. Blood 2017;129:896
  16. Warkentin T. Ischemic limb gangrene with pulses. NEJM 2015;373:642

Disseminated intravascular coagulation and related coagulopathies
  1. Toh and Alhamdi. Current consideration and management of disseminated intravascular coagulation. Hematology 2013:286
  2. Gando et al. Disseminated Intravascular Coagulation. Nat Rev Dis Primers 2016;2: 16037
  3. Wada et al. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013;11:761
  4. Singh et al. Trends in the Incidence and Outcomes of Disseminated Intravascular Coagulation in Critically Ill Patients (2004-2010): A Population-Based Study. Chest 2013;143:1235
  5. Squizzato et al. Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost 2016;115:871
  6. Thachil et al. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015;13:671
  7. Levi and Meijers. DIC: Which laboratory tests are most useful. Blood Reviews 2010 (Epub)
  8. Kitchens C. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology 2009;240
  9. Gando et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey. Crit Care Med 2008;36:145 (Presence of DIC associated with double the risk of organ dysfunction and death)
  10. Gando et al. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 2013;11:826
  11. Raza et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013;11:307 (Fibrinolytic activation common in trauma and correlates with poor outcome)
  12. Chang et al. Advances in the understanding of trauma-induced coagulopathy. Blood 2016;128:1043
  13. Chalmers et al. Purpura fulminans: recognition, diagnosis, and management. Arch Dis Child 2011; 96:1066
  14. Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723
  15. Dempfle C. Coagulopathy of Sepsis. Thromb Haemost 2004;91:213
  16. Levi M. Disseminated intravascular coagulation in cancer patients. Best Pract Res Clin Haematol 2009;22:129
  17. Martí-Carvajal et al. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev 2015 (Epub)
  18. Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and the peri-partum period. Thromb Res 2009;123:S63-S64
  19. Hall D. Abruptio placentae and disseminated intravascular coagulopathy. Semin Perinatol 2009;33:189
  20. Thachil and Toh. Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. Blood Rev 2009;23:167
  21. Kanayama and Tamura. Amniotic fluid embolism: pathophysiology and new strategies for management. J Obstet Gynaecol Res 2014;40:1507
  22. Aird WC.  The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome.  Blood 2003;101:3765
  23. Ono et al. Severe secondary deficiency of von Willebrand factor–cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006;107:528
  24. Hawiger et al. New paradigms in sepsis: from prevention to protection of failing microcirculation. J Thromb Haemost 2015;13:1743
  25. Umemura et al. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost 2016;14:518 (Some evidence of benefit in sepsis-associated DIC)
  26. Toussaint and Gerlach. Activated protein C for sepsis. NEJM 2009;361:2646
  27. Tolti et al. Protective effects of activated protein C in sepsis. Thromb Haemost 2008;100:582
  28. Bernard et al.  Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis.  NEJM 2001;344:699
  29. Nick et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 2004;104:3878
  30. Brunkhorst et al. Protein C concentrations correlate with organ dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology 2007;107:15
  31. Dhainaut et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004;2:1924 (possible greater benefit from rAPC administartion in patients with DIC vs those without)
  32. Ranieri et al. Drotrecogin Alfa (Activated) in Adults with Septic Shock. NEJM 2012;366: 2055 (No apparent benefit to rAPC; with editorial)
  33. Cornet et al. Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome. J Thromb Haemost 2013;11:894
  34. O'Sullivan et al. Emerging roles for hemostatic dysfunction in malaria pathogenesis. Blood 2016;127:2281
  35. Allingstrup et al. Antithrombin III for critically ill patients. Cochrane Database Syst Rev 2016 (No evidence of benefit in any category studied)
  36. Vincent et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients With Sepsis and Suspected Disseminated Intravascular Coagulation. Crit Care Med 2013; 41:2069 (Treatment safe, possibly beneficial in sickest patients; with editorial)
  37. Tagami et al. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2015;13:31 (No apparent reduction in mortality with rhTM)
  38. Cornet et al. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007;98:579
  39. Kerlin et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003;102:3085
  40. Warkentin and Pai. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis? J Thromb Haemost 2016;14:231
  41. Ferro et al. Hyperfibrinolysis in liver disease. Clin Liver Dis 2009;13: 21
  42. Glas et al. Coagulopathy and its management in patients with severe burns. J Thromb Haemost 2016;14:865
  43. Gold et al. Bites of venomous snakes. NEJM 2002;347:347
  44. Warrell D. Snake Bite. Lancet 2010;375:77
  45. Amdo and Welker.  An approach to the diagnosis and treatment of cryofibrinogenemia.  Am J Med 2004;116:332


Acquired bleeding disorders

Vitamin K deficiency/vitamin K antagonists

  1. Alperin J. Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients. JAMA 1987; 258:1916
  2. Booth and Suttie.  Dietary Intake and Adequacy of Vitamin K. J Nutr 1998;128:785
  3. van der Meer et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557
  4. Weibert et al.  Correction of Excessive Anticoagulation with Low-Dose Oral Vitamin K1. Ann Intern Med 1997;126:959
  5. van Rein et al. Vitamin K1 in oral solution or tablets: a crossover trial and two randomized controlled trials to compare effects. J Thromb Haemost 2014;12:2017 (Tablets as effective as solution)
  6. Sarin et al.  Prolonged coagulopathy related to superwarfarin overdose. Ann Intern Med 2005;142:156
  7. Schulman and Furie. How I treat poisoning with vitamin K antagonists. Blood 2015;125:438 (Superwarfarin and warfarin poisoning)

Liver disease

  1. Tripodi and Mannucci. The coagulopathy of chronic liver disease. NEJM 2011;365:147
  2. Hersch et al. The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor. Blood 1987; 69:1315
  3. Ferro et al. Hyperfibrinolysis in liver disease. Clin Liver Dis 2009;13:21
  4. Kujovich J. Hemostatic defects in end stage liver disease. Crit Care Clin 2005;21:563
  5. Lisman and Porte. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116:878
  6. Tripodi et al. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011;9:1713
  7. Dabbagh et al. Coagulopathy Does Not Protect Against Venous Thromboembolism in Hospitalized Patients With Chronic Liver Disease. Chest 2010;137:1145
  8. Ambrosino et al. The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. Thromb Haemost 2017;117:139 (1.5-2-fold increase in risk of VTE)
  9. De Pietri et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy. A randomized controlled trial. Hepatology 2015 (Epub) (Less than 10% of TEG-guided group got blood products, with no bleeding complications, vs 100% of patients treated based on INR and plt count)

Autoimmune clotting factor deficiency (factor VIII and other antibodies)

  1. Ma and Carrizosa. Acquired Factor VIII Inhibitors: Pathophysiology and Treatment. Hematology 2006;426
  2. Baglin et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007; 109:1870 (1 case/1.5 million people/yr; median age 78; 9% died of bleeding; 20% relapse rate)
  3. Knoebl et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012;10:622
  4. Onitilo et al. Rituximab in the treatment of acquired factor VIII inhibitors. Thromb Haemost 2006;96:84
  5. Baudo et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012;120:39 (Both rVIIa and activated prothrombin complex concentrate over 90% effective)
  6. Collins et al. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012;120:47 (Corticosteroids plus cyclophosphamide more effective than steroids alone or rituximab)
  7. Tiede et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood 2015;125:1091 (FVIII activity and inhibitor titer at presentation have prognostic utility)
  8. Tiede et al. Anti–factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study. Blood 2016;127:2289
  9. Franchini et al. The efficacy of rituximab in the treatment of inhibitor-associated hemostatic disorders. Thromb Haemost 2006;96:119
  10. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008;141:149
  11. Abshire and Kenet. Recombinant factor VIIa: review of efficacy, dosing requirements, and safety in patients with congenital and acquired factor VIII and IX inhibitors.  J Thromb Haemost 2004;2:899
  12. GSchaffer and Phillips. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 1997;127:206
  13. Donohoe and Levine. Acquired factor V inhibitor after exposure to topical human thrombin related to an otorhinolaryngological procedure. J Thromb Haemost 2015;13:1787

Acquired von Willebrand disease

  1. Kumar et al.  Acquired von Willebrand disease.  Mayo Clin Proc 2002;77:181
  2. Blackshear et al. Hypertrophic Obstructive Cardiomyopathy, Bleeding History, and Acquired von Willebrand Syndrome: Response to Septal Myectomy. Mayo Clin Proc 2011;86:181
  3. Blackshear et al. Remission of recurrent gastrointestinal bleeding after septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy-associated acquired von Willebrand syndrome. J Thromb Haemost 2015;13:191
  4. Blackshear et al. Shear stress-associated acquired von Willebrand syndrome in patients with mitral regurgitation. J Thromb Haemost 2014;12:1966
  5. Voisin et al. Acquired von Willebrand syndrome associated with monoclonal gammopathy. A single-center study of 36 patients. Medicine 2011;90:404
  6. Lavin et al. Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy. J Thromb Haemost 2016;14:1200
  7. Nascimbene et al. Acquired von Willebrand syndrome associated with left ventricular assist device. Blood 2016;127:3133
  8. Van Belle et al. Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement. NEJM 2016;375:335 (VWF multimer defects following TAVR associated with aortic regurgitation and higher mortality)
  9. Roberts et al. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104:3858

Trauma and massive transfusion

  1. Hardy et al.  The coagulopathy of massive transfusion.  Vox Sang 2005;89:121
  2. Hardy et al. Massive transfusion and coagulopathy: pathyphysiology and implications for clinical management.  Can J Anesth 2006;53:S40
  3. Hess J. Blood and coagulation support in trauma care. Hematology 2007:187
  4. White et al. Early hemostatic responses to trauma identified with hierarchical clustering analysis. J Thromb Haemost 2015;13:978 (Lower fibrinogen, more fibrinolysis, more bleeding in most severely injured patients)

Complications of pregnancy

  1. Oyelese and Ananth. Postpartum hemorrhage: epidemiology, risk factors and causes. Clin Obstet Gynecol 2010;53:147
  2. Collins et al. Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study. Blood 2014;124:1727 (Viscoelastic measurements predict progression to severe hemorrhage)
  3. Kanayama and Tamura. Amniotic fluid embolism: pathophysiology and new strategies for management. J Obstet Gynaecol Res 2014;40:1507
  4. Wei et al. Clinical diagnosis and treatment of acute fatty liver of pregnancy: A literature review and 11 new cases. J Obst Gyn Res 2010; 36:751

Other/general

  1. Konkle BA. Acquired disorders of platelet function. Hematology 2011:391
  2. Meijer et al. Association of Risk of Abnormal Bleeding With Degree of Serotonin Reuptake Inhibition by Antidepressants. Arch Intern Med 2004;164:2357
  3. Yaguchi et al. Platelet function in sepsis.  J Thromb Haemost 2004;2:2096
  4. Chowdhury et al. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004;125:69
  5. Noris and Remuzzi. Uremic bleeding: closing the circle after 30 years of controversies? Blood 1999;94:2569
  6. Squizzato et al. Thyroid Dysfunction and Effects on Coagulation and Fibrinolysis: A Systematic Review. J Clin Endocrinol Metab 2007;92:2415
  7. Qureshi et al. Intracerebral haemorrhage. Lancet 2009;373:1632
  8. DeLoughery T. Critical care clotting catastrophes. Crit Care Clin 2005; 21:531
  9. Hunt BJ. Bleeding and coagulopathies in critical care. NEJM 2014;370:847
  10. Biancari et al. Prediction of severe bleeding after coronary surgery: the WILL-BLEED Risk Score. Thromb Haemost 2017; 117: 429
  11. Müller et al. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost 2015;13:989 (12 ml/kg FFP raised clotting factor levels by 10-12% but did no enhance thrombin generation in non-bleeding critically ill patients with a long INR)
  12. Goeijenbier et al. Review: viral infections and mechanisms of thrombosis and bleeding. J Med Virol 2012;84:1680


Treatment of bleeding disorders (see also Transfusion Medicine section)
  1. Mannucci and Levi. Prevention and treatment of major blood loss. NEJM 2007;356:2301
  2. Johansson et al. How I treat patients with massive hemorrhage. Blood 2014;124:3052 (Discusses role of TEG and antifibrinolytic Rx)
  3. Pavord and Maybury. How I treat postpartum hemorrhage. Blood 2015;125:2759
  4. Levy J.  Hemostatic agents. Transfusion 2004;44:58S
  5. Pandit and Sarode. Blood component support in acquired coagulopathic conditions: Is there a method to the madness? Am J Hematol 2012 (Epub)
  6. Ragni MV. The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders. Hematology 2013:44
  7. Mannucci P. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90:2515
  8. Desborough et al. Desmopressin for treatment of platelet dysfunction and reversal of antiplatelet agents: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2017;15:263
  9. Kaufman and Vischeri.  Cellular mechanisms of the hemostatic effects of DDAVP.  J Thromb Haemost 2003;1:682
  10. Colucci et al. The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects. Blood 2014;123:1905
  11. CRASH-2 Investigators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23 (Antifibrinolytic therapy reduced mortality and bleeding rate, did not increase risk of thrombotic events. See also the accompanying editorial)
  12. CRASH-2 Collaborators.The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377:1096 (Treatment within 3 hours of injury reduces death from bleeding)
  13. Wardrop et al. Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders. Cochrane Database Syst Rev. 2013 Jul 29;7:CD009733
  14. Myles et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. NEJM 2017;376:136 (Tranexamic acid reduced bleeding risk and transfusion requirements, and did not increase thrombotic risk; it was associated with a higher risk of seizures)
  15. Berntrop et al. No increased risk of venous thrombosis in women taking tranexamic acid. Thromb Haemost 2001;86:714
  16. Hoots WK. Challenges in the Therapeutic Use of a "So-Called" Universal Hemostatic Agent: Recombinant Factor VIIa. Hematology 2006;426
  17. Roberts et al. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104:3858
  18. Franchini et al. Recombinant factor VIIa An update on its clinical use. Thromb Haemost 2005; 93:1027
  19. Goodnough and Shander. Recombinant factor VIIa: safety and efficacy. Curr Opin Hematol 2007;14:504
  20. Abshire and Kenet. Recombinant factor VIIa: review of efficacy, dosing requirements, and safety in patients with congenital and acquired factor VIII and IX inhibitors.  J Thromb Haemost 2004;2:899
  21. Abshire T. Safety update on recombinant factor VIIa in the treatment of congenital and acquired hemophilia. Semin Hematol 2008;45 (suppl 1): S3
  22. Friederich et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet 2003;361:201
  23. Mayer et al. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage.  NEJM 2005;352:777
  24. Mayer et al. Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage. NEJM 2008;358:2127 (Treatment with rFVIIa reduced hematoma growth but did not improve survival or functional outcome; with editorial)
  25. Martinowitz et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost 2005;3:640
  26. O'Connell et al. Thromboembolic Adverse Events After Use of Recombinant Human Coagulation Factor VIIa. JAMA 2006;295:293
  27. Levi et al. Safety of r ecombinant activated factor VII in randomized clinical trials. NEJM 2010;363:1791 (Increased incidence of arterial thromboembolism, particularly in elderly patients. See also the accompanying editorial)
  28. Logan et al. Off-Label Use of Recombinant Factor VIIa in U.S. Hospitals: Analysis of Hospital Records. Ann Intern Med 2011;154:516 (97% of use off-label)
  29. Yank et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications. Ann Intern Med 2011;154:529 (No evidence of reduced mortality, increased risk of thromboembolism)
  30. Karkouti et al. Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery. Circulation 2008;118:331
  31. Lavigne-Lissalde et al. Recombinant human FVIIa for reducing the need for invasive second-line therapies in severe refractory postpartum hemorrhage: a multicenter, randomized, open controlled trial. J Thromb Haemost 2015;13:520 (rVIIa use reduced need for "second-line" therapies; 5% of recipients had thrombotic events)
  32. Ekezue et al. Clotting factor product administration and same-day occurrence of thrombotic events, as recorded in a large healthcare database during 2008–2013. J Thromb Haemost 2015;13:2168 (Off-label use of factor IX concentrate and rVIIa associated with increased risk of thrombosis)
  33. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  British Committee for Standards in Haematology, Blood Transfusion Task Force. Br J Haematol 2004;126:11
  34. Levy and Goodnough. How I use fibrinogen replacement therapy in acquired bleeding. Blood 2015;125:1387
  35. Stansworth et al. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;126:139
  36. Dara et al. Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy.  Crit Care Med 2005; 33:2667 (higher incidence of acute lung injury, no survival benefit with prophylactic FFP transfusion to non-bleeding pts)
  37. Bilicen et al. Effect of Fibrinogen Concentrate on Intraoperative Blood Loss Among Patients With Intraoperative Bleeding During High-Risk Cardiac Surgery. A Randomized Clinical Trial. JAMA 2017;317:738 (Raising fibrinogen to 250 mg/dL did not reduce intraoperative bleeding, associated with more thrombotic complications)
  38. Falanga and Rickles. Management of thrombohemorrhagic syndromes (THS) in hematologic malignancies. Hematology 2007:165


Antithrombotic drugs

 General

  1. Guyatt et al. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7S
  2. Holbrook et al. Evidence-Based Management of Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e152S
  3. De Caterina et al. General mechanisms and targets of anticoagulants (Section 1). Thromb Haemost 2013;109:569
  4. Nutescu et al. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:15
  5. Greineder et al. Advanced drug delivery systems for antithrombotic agents. Blood 2013;122:1565
  6. Yarrington et al. Cardiovascular Management in Pregnancy. Antithrombotic Agents and Antiplatelet Agents. Circulation 2015;132:1354

Heparin, low molecular weight heparin and fondaparinux

  1. Hemker HC. A century of heparin: past, present and future. J Thromb Haemost 2016;14:2329
  2. Smythe et al. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:165
  3. de Swart et al.  Kinetics of intravenously administered heparin in normal humans. Blood 1982;60:1251
  4. Eikelboom and Hirsh. Monitoring unfractionated heparin with the aPTT: Time for a fresh look. Thromb Haemost 2006;96:547
  5. Winkler et al. Laboratory monitoring of heparin: challenges and opportunities. Laboratory Medicine 2007; 38:499
  6. Vardi et al. Activated partial thromboplastin time monitoring in patients receiving unfractionated heparin for venous thromboembolism in relation to clinical outcomes. Thromb Haemost 2009;102:799 (Poor correlation between aPTT results and clinical outcomes)
  7. Guervil et al. Activated Partial Thromboplastin Time Versus Antifactor Xa Heparin Assay in Monitoring Unfractionated Heparin by Continuous Intravenous Infusion. Ann Pharmacother 2011;45:861
  8. Hanslik et al. Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols. Blood 2015;126:2091 (Anti-Xa assay correlated better with dose than ACT or aPTT)
  9. Meesters et al. Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial. Thromb Haemost 2016;116:205 (Higher protamine doses associated with more bleeding)
  10. Garcia et al. Parenteral Anticoagulants. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e24S
  11. Lim et al. Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients with Severe Renal Insufficiency. Ann Intern Med 2006;144:673
  12. Douketis et al. Prophylaxis Against Deep Vein Thrombosis in Critically Ill Patients With Severe Renal Insufficiency With the Low-Molecular-Weight Heparin Dalteparin. An Assessment of Safety and Pharmacodynamics: The DIRECT Study. Arch Intern Med 2008;168:1805 (dalteparin prophylaxis safe in severe renal failure)
  13. Greer and Nelson-Piercy. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401
  14. Greer and Hunt. Low molecular weight heparin in pregnancy: current issues. Br J Haematol 2005;128:593
  15. Patel et al. Population Pharmacokinetics of Enoxaparin During the Antenatal Period. Circulation 2013;128:1462 (Half-life of enoxaparin prolonged in later pregnancy, once-daily administration may be appropriate)
  16. Despotis et al. Anticoagulation Monitoring during Cardiac Surgery. A Review of Current and Emerging Techniques. Anesthesiology 1999;91:1122
  17. Avidan et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;130:107
  18. DeCarolis et al. Enoxaparin outcomes in patients with moderate renal imparment. Arch Intern Med 2012;172:1713 (4.7-fold increased risk of major bleeding with CrCl 30-50)
  19. Arora and Goldhaber. Anticoagulants and transaminase elevation. Circulation 2006:e698
  20. Kishimoto et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. NEJM 2008;358:2457
  21. Blossom et al. Outbreak of adverse reactions associated with contaminated heparin. NEJM 2008;359:2674
  22. Fox et al. Influence of Renal Function on the Efficacy and Safety of Fondaparinux Relative to Enoxaparin in Non–ST-Segment Elevation Acute Coronary Syndromes. Ann Intern Med 2007;147:304 (Fondaparinux safer in patients with impaired renal function)
  23. Eikelboom et al. Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials. Circulation 2009;120:2006
  24. Mazzolai et al. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006;108:1569
  25. Samama et al. Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury. J Thromb Haemost 2013;11:1833 (Fondaparinux 2.5 mg/d more effective than LMWH)
  26. Trujillo-Santos et al. Once versus twice daily enoxaparin for the initial treatment of acute venous thromboembolism. J Thromb Haemost 2017;15:429 (Once-daily dosing associated with more VTE recurrence but less major bleeding and death)
Vitamin K antagonists
  1. Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 29:97 (An entertaining account of the discovery of warfarin and its development as an anticoagulant drug)
  2. Hirsh J. Solving the mystery of excessive warfarin-induced bleeding: a personal historical perspective. Thromb Haemost 2014; 112:853 (An account of the research that led to the widespread use of the INR for monitoring warfarin)
  3. Ageno et al. Oral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e44S
  4. Witt et al. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:187
  5. Björck et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol 2016;1:172 ("Well-managed warfarin therapy is associated with a low risk of complications")
  6. Osterberg and Blaschke.  Adherence to medication.  NEJM 2005;353:487
  7. Kimmel et al. The Influence of Patient Adherence on Anticoagulation Control With Warfarin. Results From the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med 2007;167:229 (36% of patients missed at least 20% of warfarin doses, with associated 2-fold increased risk of under-anticoagulation)
  8. Heneghan et al. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012;379:322
  9. White et al. Comparison of Outcomes Among Patients Randomized to Warfarin Therapy According to Anticoagulant Control. Results From SPORTIF III and V. Arch Intern Med 2007;167:239
  10. Shikata et al.  Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and -glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004;103:2630 (much of the interpatient variation in warfarin sensitivity is genetic)
  11. Rieder et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.  NEJM 2005;352:2285
  12. Schwarz et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. NEJM 2008;358:999 (VKORC genotype is the major determinant of initial variability in response to warfarin)
  13. Anderson et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Circulation 2007;116:2563
  14. International Warfarin Pharmacogenetics Consortium. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. NEJM 2009;360:753 (pharmacogenetic algorithm better able to estimate therapeutic warfarin dose than clinical algorithm or fixed dose; see also the accompanying editorial)
  15. Wadelius et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009;113:784
  16. Eckman et al. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation. Ann Intern Med 2009;150:73
  17. Lenzini et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008; 6:1655
  18. Gong et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 2011;118:3163
  19. Anderson et al. A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II). Circulation 2012;125:1997 (Better INR control and fewer adverse events using pharmacogenetic information to guide dosing)
  20. Kimmel et al. A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing. NEJM 2013;369:2283 (Genotype-guided dosing did not improve anticoagulation control; with editorial)
  21. Pirmohamed et al. A randomized trial of genotype-guided dosing of warfarin. NEJM 2013;369:2294 (Genotype-guided dosing did improve anticoagulation control; with editorial)
  22. Perera et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 2013;382:790 (Novel CYP2C polymorphism found in 25% of study population, associated with increased sensitivity to warfarin)
  23. Perlstein et al. The Creating an Optimal Warfarin Nomogram (CROWN) Study. Thromb Haemos 2012;107:59 Supplementary material
  24. Shahabi et al. An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance. Thromb Haemost 2016;116:2015
  25. Schulman et al. Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios. A Randomized Trial. Ann Intern Med 2011;155:653 (Every 12 weeks monitoring as safe as every 4 weeks for patients with stable INRs)
  26. Lubetsky et al.  Vitamin K intake and sensitivity to warfarin in patients consuming regular diets.  Thromb Haemost 1999;81:396
  27. Schurgers et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood 2004;104:2682
  28. Booth et al.  Dietary vitamin K1 and the stability of oral anticoagulation: proposal of a diet with constant vitamin K1 content. Thromb Haemost 1997;77:504
  29. Kim et al. Relationship between dietary vitamin K intake and the stability of anticoagulation effect in patients taking long-term warfarin. Thromb Haemost 2010; 104 (epub). (Restriction of dietary vitamin K intake leads to less stable anticoagulant control)
  30. de Assis et al. Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy. A Randomized Controlled Trial. Circulation 2009;120:1115 (Modifying vit K intake according to INR improves anticoagulant control)
  31. Witt et al. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood 2009;114:952 (Less frequent monitoring may be appropriate for patients with stable INR control)
  32. Sconce et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005;93:872
  33. Sconce et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007;109:2419
  34. Theuwissen et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: dose–response relationship in healthy volunteers. J Thromb Haemost 2013;11:1085 (Very low doses of vit K2 can affect INR; study does not really address stability)
  35. Boonyawat et al. The effect of low-dose oral vitamin K supplementation on INR stability in patients receiving warfarin. A randomised trial. Thromb Haemost 2016;116:403 (Vit K 150 mcg/d improved INR stability)
  36. Conway et al. Suppression of Hemostatic System Activation by Oral Anticoagulants in the Blood of Patients with Thrombotic Diatheses. J Clin Invest 1987;80:1535
  37. Schulman S.  Care of patients receiving long-term anticoagulant therapy.  NEJM 2003;349:675
  38. Heneghan et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006;367:404
  39. Matchar et al. Effect of Home Testing of International Normalized Ratio on Clinical Events. NEJM 2010;363:1608
  40. Veeger et al. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. a retrospective study of 2300 consecutive patients with venous thromboembolism.  Br J Haematol 2005;128:513
  41. Dlott et al. National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation. Circulation 2014;129:1407 (Mean time in therapeutic range arounc 53%)
  42. Palareti et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348:423   (0.25 fatal bleeding episodes per 100 patient-years)
  43. Linkins et al.  Clinical Impact of Bleeding in Patients Taking Oral Anticoagulant Therapy for Venous Thromboembolism. A meta-analysis. Ann Intern Med 2003;139:893
  44. Wysowski et al Bleeding complications with warfarin use. A prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007;167:1414
  45. Levi et al. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 2008;111:4471 (bleeding risk from VKAs in "real life" likely to be higher than that reported in clinical trials)
  46. Dargaud et al. Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels. J Thromb Haemost 2013;11:1043
  47. Poli et al. The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study. J Thromb Haemost 2013;11:1053 (Major bleeding rate 2.4/100 pt-yrs; risk stratification models not accurate in patients over 80)
  48. Dunn and Turpie. Perioperative Management of Patients Receiving Oral Anticoagulants. A Systematic Review. Arch Intern Med. 2003;163:901
  49. Odén et al. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002;325:1073
  50. Aguilar et al. Treatment of Warfarin-Associated Intracerebral Hemorrhage: Literature Review and Expert Opinion. Mayo Clin Proc 2007;82:82
  51. Holbrook et al. Systematic Overview of Warfarin and Its Drug and Food Interactions. Arch Intern Med 2005;165:1095
  52. Clark et al. Warfarin Interactions With Antibiotics in the Ambulatory Care Setting. JAMA Intern Med 2014;174:409
  53. Wahl M.  Myths of dental surgery in patients receiving anticoagulant therapy.  J Am Dental Assoc 2000;131:77 (More risky to stop warfarin than to do dental procedures without stopping)
  54. Bacci et al. Management of patients undergoing anticoagulant treatment. Thromb Haemost 2010 (epub). ("Dental extractions can be performed easily and safely in anticoagulated outpatients")
  55. Samuels N. Herbal remedies and anticoagulant therapy.  Thromb Haemost 2005;93:3
  56. Schalekamp et al. Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake Inhibitors and Coumarins. Arch Intern Med 2008;168:180
  57. Lopes et al. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011;118:6269
  58. Tagalakis et al. Use of warfarin and risk of urogenital cancer: a population-based, nested case-control study. Lancet Oncol 2007;8:395 (Warfarin use associated with decreased risk of prostate cancer)
  59. Warkentin et al. Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome. Blood 2015;126:486
  60. Arora and Goldhaber. Anticoagulants and transaminase elevation. Circulation 2006:e698
  61. Wheeler et al. Anticoagulation-related nephropathy. J Thromb Haemost 2016;14:461
  62. Veronese et al. Vitamin K antagonists' use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost 2015;13:1665 (No clear evidence of an adverse effect of VKAs on bone health)
  63. Lau et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA 2017;317:1151 (Higher risk of fracture with warfarin treatment)
Antiplatelet drugs
  1. Eikelboom et al. Antiplatelet Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e89S
  2. Weitz et al. New Antithrombotic Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e120S
  3. Kaplan and Jackson. The role of platelets in atherothrombosis. Hematology 2011:51
  4. Michelson AD. Advances in antiplatelet therapy. Hematology 2011:62
  5. Adamski et al. Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors. Thromb Haemost 2014;112:224
  6. Li et al. Reversal of the anti-platelet effects of aspirin and clopidogrel. J Thromb Haemost 2012;10:521 (Normalization of in vitro platelet aggregation occurs 4 days after stopping aspirin, but takes 10 days after stopping clopidogrel)
  7. US Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009;150:396
  8. Antithrombitic Trialists' Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849
  9. Greving et al. Cost-Effectiveness of Aspirin Treatment in the Primary Prevention of Cardiovascular Disease Events in Subgroups Based on Age, Gender, and Varying Cardiovascular Risk. Circulation 2008;117:2875
  10. Undas et al. Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid. J Thromb Haemost 2014;12:1776
  11. Hovens et al. Aspirin in the prevention and treatment of venous thromboembolism. J Thromb Haemost 2006;4:1470
  12. Glynn et al. Effect of low-dose aspirin on the occurrence of venous thromboembolism. Ann Intern Med 2007;147:525 (ASA 100 mg qod had no apparent effect on occurence of VTE in women)
  13. Simes et al Aspirin for the Prevention of Recurrent Venous Thromboembolism. The INSPIRE Collaboration. Circulation 2014;130:1062 (ASA reduces recurrence rate by about one-third, does not increase bleeding risk; with editorial)
  14. Berger et al. Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men. A Sex-Specific Meta-analysis of Randomized Controlled Trials. JAMA 2006;295:306
  15. Campbell et al. Aspirin Dose for the Prevention of Cardiovascular Disease: A Systematic Review. JAMA 2007;297:2018 (81 mg/d is enough)
  16. Xian et al. Association of Discharge Aspirin Dose With Outcomes After Acute Myocardial Infarction. Insights From the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. Circulation 2105;132:174 (Low-dose ASA as effective as high-dose, with less bleeding)
  17. Seshasai et al. Effect of aspirin on vascular and nonvascular outcomes. Meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:209 ("Aspirin prophylaxis in people without prior cardiovascular disease does not lead to reductions in either cardiovascular death or cancer mortality")
  18. Chan et al. Long-term aspirin use and mortality in women. Arch Intern Med 2007;167:562
  19. Devereaux et al. Aspirin in patients undergoing noncardiac surgery. NEJM 2014;370:1494 (No significant decrease in death or MI, increased risk of major bleeding)
  20. Palmer et al. Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease. A Systematic Review and Meta-analysis.Ann Intern Med 2012;156:445 (No clear evidence of benefit)
  21. Polzin et al. Antiplatelet effects of aspirin in chronic kidney disease patients. J Thromb Haemost 2016;14:375 (CKD decreases antiplatelet response to ASA)
  22. Eshaghian et al. Role of clopidogrel in managing atheroembolic cardiovascular disease. Ann Intern Med 2007;146:434
  23. Gurbel et al. Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease. The ONSET/OFFSET Study. Circulation 2009;120:2577
  24. Roe et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. NEJM 2012;367:1297
  25. James et al. Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack. Circulation 2012;125:2914 (Higher rate of intracranial bleeding with ticagrelor)
  26. Hiatt et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. NEJM 2017;376:32 (No significant difference in safety or efficacy)
  27. Bonaca et al. Long-term use of ticagrelor in patients with prior myocardial infarction. NEJM 2015;372:1791 (Ticagrelor reduced risk of MI, stroke or cardiovascular death but increased risk of major bleeding; with editorial)
  28. O'Donoghue et al. Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention. Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial. Circulation 2016;133:248 (Cangrelor reduced rate of death, MI and other vascular complications vs clopidogrel without an increase in rate of major bleeding)
  29. Bhatt et al. Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events. NEJM 2013;368:1303 (Cangrelor + ASA arm had fewer ischemic events than clopidogrel + ASA arm, no increased bleeding; with editorial)
  30. Angiolillo et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. A randomized controlled trial. JAMA 2012;307:265
  31. Bates and Lau.  Controversies in antiplatelet therapy for patients with cardiovascular disease.  Circulation 2005;111:e267
  32. Fries and Grosser. The Cardiovascular Pharmacology of COX-2 Inhibition. Hematology 2005:445-451
  33. Solomon et al. Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas. Circulation 2006;114:1028 (nearly 2-fold increase in cardiovascular risk)
  34. Haag et al. Cyclooxygenase Selectivity of Nonsteroidal Anti-inflammatory Drugs and Risk of Stroke. Arch Intern Med 2008;168:1219 (Increased risk with both nonselective and COX-2 selective NSAIDs)
  35. Tricoci et al. Thrombin-receptor antagonist voraxapar in acute coronary syndromes. NEJM 2012;366:20 (Treatment had no effect on death from cardiovascular events, but increased bleeding risk)
  36. Morrow et al. Vorapaxar in the Secondary Prevention of Atherothrombotic Events. NEJM 2012;366:1404 (Some reduction of cardiovascular events in treatment group, but increased risk of severe bleeding and intracranial hemorrhage)
  37. Scrica et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial (Lower risk of death or ischemic events, more major bleeding with voraxapar)
  38. Cavender et al. Vorapaxar in Patients With Diabetes Mellitus and Previous Myocardial Infarction. Findings From the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 Trial. Circulation 2015;131:1047 (Significant overall benefit of vorapaxar in high risk patients)
  39. Bohula et al. Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack. Results from TRA 2°P-TIMI 50 (Vorapaxar reduced rates of cardiac death, MI and stroke, with an increased risk of moderate or severe bleeding)

Antiplatelet drug resistance/monitoring

  1. Sanderson et al.  Narrative Review: Aspirin Resistance and Its Clinical Implications.  Ann Intern Med 2005;142:370
  2. Hankey and Eikelboom.  Aspirin resistance.  Lancet 2006;367:606
  3. Undas et al. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109:2285
  4. Snoep et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events. Arch Intern Med 2007;167:1593
  5. Grosser et al Drug Resistance and Pseudoresistance. An Unintended Consequence of Enteric Coating Aspirin. Circulation 2013;127:377 (True aspirin resistance is rare; "pseudoresistance" found with enteric-coated ASA)
  6. Cattneo M. The clinical relevance of response variabilitiy to antiplatelet therapy. Hematology 2011:70
  7. Nührenberg et al. Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation. Thromb Haemost 2015;114:1020
  8. Wisman et al. Platelet-reactivity tests identify patients at risk of secondary cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 2014;12:736
  9. Breet et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754 (Comparison of various methods for assessing antiplatelet drug resistance)
  10. Siller-Matula et al. How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors – is an algorithm the answer? Thromb Haemost 2015;113:37
  11. Shuldiner et al. Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy. JAMA 2009;302:849
  12. Mega et al. Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI. A Meta-analysis JAMA 2010;304:1821 (with editorial)
  13. Liang et al. Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial. J Thromb Haemost 2015;13:347 (Blood levels affected by genotype, BMI, diabetes, PPI, and renal function, not by ASA use)
  14. Price et al. Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention: The GRAVITAS Randomized Trial. JAMA 2011;305:1061 (No apparent benefit from high dose clopidogrel in patients with high on-treatment platelet reactivity)
  15. Mega et al. Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease. JAMA 2011;306:2221 (Tripling drug dose effective for CYP2C19*2 heterozygotes but not homozygotes)
  16. Parodi et al. High Residual Platelet Reactivity After Clopidogrel Loading and Long-term Cardiovascular Events Among Patients With Acute Coronary Syndromes Undergoing PCI. JAMA 2011;306:1215 (Clopidogrel resistance in vitro associated with higher incidence of subsequent vascular events)
  17. Stone et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614
  18. Collet et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. NEJM 2012;367:2100 (No apparent benefit to increasing clopidogrel dose in patients with in vitro clopidogrel resistance)
  19. Gurbel et al. Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization. The TRILOGY ACS Platelet Function Substudy. JAMA 2012;308:1785 (More effective in vitro platelet inhibition by prasugrel vs clopidogrel not associated with better outcomes)
  20. Mayer et al. A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost 2014; 112:342 (Switching to prasugrel in patients with clopidogrel resistance resulted in better outcomes)
  21. Montalescot et al. High On-Treatment Platelet Reactivity as a Risk Factor for Secondary Prevention After Coronary Stent Revascularization. A Landmark Analysis of the ARCTIC Study. Circulation 2014;129;2136 (Adjusting antiplatelet therapy based on platelet function tests did not reduce recurrent ischemic events after stenting; with editorial)
  22. Bonello et al. Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost 2012;10:1999
  23. Wang et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016;316:70 (Benefit of clopidogrel limited to patients who do not carry loss-of-function allele)
  24. Kazi et al. Cost-Effectiveness of Genotype-Guided and Dual Antiplatelet Therapies in Acute Coronary Syndrome. Ann Intern Med 2014;160:221
  25. Zimmerman and Hohlfeld. Clinical implications of aspirin resistance. Thrombos Haemos 2008;100:379
  26. Sibbing et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714 (omeprazole attenuated antiplatelet effect of clopidogrel; other PPIs did not)
  27. Ho et al. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA 2009;301:937
  28. Rossini et al. Perioperative management of oral antiplatelet therapy and clinical outcomes in coronary stent patients undergoing surgery. Thromb Haemost 2015;113:221 (Stopping antiplatelet drugs increases risk of adverser cardiac events, does not reduce bleeding risk)
Direct thrombin and Xa inhibitors - general
  1. Burnett et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016;41:206
  2. Yeh et al. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014;124:1020
  3. Ageno et al. Oral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e44S
  4. Weitz et al. New Antithrombotic Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e120S
  5. Ageno et al. Selection and assessment of patients treated with the novel oral anticoagulant drugs: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013;11:177
  6. Martin et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016;1308
  7. Schulman and Crowther. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012;119:3016
  8. Gosselin and Adcock. The laboratory's 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost 2016;14:886
  9. Gladstone et al. How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society. Ann Intern Med 2015;163:382
  10. Noseworthy et al. Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. Chest 2016; 150:1302 (The three drugs have similar efficacy; bleeding risk lowest with apixaban, highest with rivaroxaban)
  11. Graham et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Int Med 2016;176:1662 (Relatively high risk of intra- and extracranial bleeding with rivaroxaban)
  12. van der Hulle et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014;12:320 (Comparable efficacy to warfarin, somewhat lower risk of bleeding)
  13. van Es et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968 (Similar effficacy, less bleeding with new agents)
  14. Sardar et al. Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Thromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials. Drugs 2013; 73:1171
  15. Liew et al. Extended-duration new oral anticoagulants for venous thromboprophylaxis in patients undergoing total hip arthroplasty: a meta-analysis of the randomized controlled trials. J Thromb Haemost 2014;12:107 (60% reduction in VTE risk, no increase in major bleeding with NOACs vs LMWH)
  16. Vene et al. Risk of Thromboembolic Events in Patients with Non-Valvular Atrial Fibrillation After Dabigatran or Rivaroxaban Discontinuation – Data from the Ljubljana Registry. PLOS One2016;11:e0156943 (Stopping DOAC associated with 20-fold increase in the short-term risk of thromboembolism; peak incidence about 14 days after stopping)
  17. Chai-Adisaksopha et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:2012 (Less fatal bleeding, lower case-fatality rate for major bleeding, less cardiovascular mortality and lower all-cause mortality with DOACs vs warfarin)
  18. Maung et al. Trauma patients on new oral anticoagulation agents have lower mortality than those on warfarin. J Trauma Acute Care Surg 2016 (epub)
  19. Sharma et al. Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism. Systematic Review and Meta-Analysis. Circulation 2015;132:194 (Efficacy of NOACs at least as good as warfarin in patients > 75, with different bleeding patterns; higher GI bleed risk with dabigatran)
  20. Maura et al. Comparison of the Short-Term Risk of Bleeding and Arterial Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Newly Treated With Dabigatran or Rivaroxaban Versus Vitamin K Antagonists. A French Nationwide Propensity-Matched Cohort Study. Circulation 2015;132:1252 (No significant differences in thromboembolic or bleeding rates between VKA and DOAC users)
  21. Cohen et al. Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PLoS One 2015;10:e0144856 (NOACs have comparable efficacy for VTE, apixaban has best safety profile)
  22. Ferrandis et al. The perioperative management of new direct oral anticoagulants: a question without answers. Thromb Haemost 2013;110:515
  23. Paikin et al. Timing the first post-operative dose of anticoagulants: Lessons learned from clinical trials. Chest 2015 (ePub) (Wait at least 6 hours after surgery to begin prophylaxis with NOAC)
  24. Tripodi A. The laboratory and the direct oral anticoagulants. Blood 2013;121:4032
  25. Garcia et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013; 11:245
  26. Lega et al. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost 2014;12:337 (Relative risk of bleeding vs warfarin not increased with GFR < 50)
  27. Beyer-Westendorf et al. Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting. Thromb Haemost 2016;116:651 (Limited data shows a 2% risk of embryopathy from DOACs)
  28. Pengo et al. Questions and answers on the use of dabigatran and perpectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). Thromb Haemost 2011;106:868
  29. Ruff et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet 2013;383:955
  30. Lega et al . Consistency of safety and efficacy of new oral anticoagulants across subgroups of patients with atrial fibrillation. PLoS One 2014; 9:e91398 ("NOAC appeared to be more effective and safer than VKA ... irrespective of patient comorbidities")
  31. Adam et al. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med 2012;157:796
  32. Chan et al. New oral anticoagulants for stroke prevention in atrial fibrillation: impact of study design, double counting and unexpected findings on interpretation of study results and conclusions. Thromb Haemost 2014;111:781
  33. Graham et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Int Med 2016 (Epub). (Bleeding risk and mortality with rivaroxaban higher than with dabigatran)
  34. Lip et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. Thromb Haemost 2016;116:975 (Apixaban and dabigatran users had lowest bleed risk)
  35. Huo M. New oral anticoagulants in venous thromboembolism prophylaxis in orthopaedic patients: Are they really better? Thromb Haemost 2011;106:45
  36. Hylek E. Therapeutic potential of oral factor Xa inhibitors (editorial). NEJM 2010; 363:2559
  37. Neumann et al. Oral Direct Factor Xa Inhibitors Versus Low-Molecular-Weight Heparin to Prevent Venous Thromboembolism in Patients Undergoing Total Hip or Knee Replacement. A Systematic Review and Meta-analysis. Ann Intern Med 2012;156:710
  38. Adam et al. Comparative Effectiveness of New Oral Anticoagulants and Standard Thromboprophylaxis in Patients Having Total Hip or Knee Replacement: A Systematic Review. Ann Intern Med 2013;159:275
  39. Miclotte et al. Pragmatic approach to manage new oral anticoagulants in patients undergoing dental extractions: a prospective case-control study. Clin Oral Investig 2016 (Epub) (Omitting a single AM dose prior to dental extraction avoids excess bleeding)
  40. Eerenberg et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation 2011;124 1573 (PCC reversed the in vitro anticoagulant effect of rivaroxaban, but not dabigatran)
  41. Barco et al. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haem 2016;172:255 (Partial restoration of thrombin generation at dose of 37.5 iu/kg, not at lower dose)
  42. Miesbach et al. New direct oral anticoagulants - current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012;108:625
  43. Siegal et al. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014;123:1152
  44. Harel et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol 2014 (ePub) (No difference in efficacy or safety between NOACs and VKAs in patients with CrCl 30-50)
  45. Raccah et al. Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest 2016 (Epub) (Apixaban less likely to cause bleeding in patients with decreased kidney function)
  46. Steinberg et al. Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes : The ORBIT-AF II Registry. J Am Coll Cardiol 2016;24:2597 (Off label dosing markedly increases complication rates)
  47. Perzborn et al. Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo. J Thrombo Haemost 2014;12:1054
  48. Liakoni et al. Hepatotoxicity of new oral anticoagulants (NOACs). Drug Saf 2015 (Epub)

Rivaroxaban

  1. Eriksson et al. A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After Total Hip Replacement. Circulation 2006;114:2382
  2. Eriksson et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. NEJM 2008; 358:2765 ("major" VTE rate 0.2% with rivaroxaban, 2% with enoxaparin; no significant difference in bleeding rate)
  3. Lassen et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. NEJM 2008;358:2776 ("major" VTE rate 1% with rivaroxaban, 2.6% with enoxaparin; bleeding rates similar)
  4. Kakkar et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31
  5. Turpie et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:1673 (7% vs 10% VTE rate with rivaroxaban vs enoxaparin, 0.7% vs 0.3% major bleeding)
  6. Beyer-Westendorf et al. Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery. Findings from the ORTHO-TEP registry. Thromb Haemost 2013;154 (Retrospective study suggesting rivaroxaban more effective)
  7. Lazo-Langer et al. Rivaroxaban vs. low molecular weight heparin for the prevention of venous thromboembolism after hip or knee arthroplasty: a cohort study. J Thromb Haemost 2014;12:1626 (RR of VTE 40% lower with rivaroxaban, no difference in bleeding rates)
  8. Camporese et al. Efficacy of Rivaroxaban for thromboprophylaxis after Knee Arthroscopy (ERIKA). A phase II, multicentre, double-blind, placebo-controlled randomised study. Thromb Haemost 2016;116:205 (10 mg/d of rivaroxaban x 7 days superior to placebo in this small study)
  9. Cohen et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. NEJM 2013;368:513
  10. Buller et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein–DVT Dose-Ranging Study. Blood 2008;112:2242
  11. Nisio et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 2016;116:739 (Standard dose of rivaroxaban safe & effective in patients with weights between 50-140 kg)
  12. EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. NEJM 2010;363:2499 (Rivaroxaban as effective and safe as warfarin after acute DVT. Extended treatment with rivaroxaban safe & effective)
  13. EINSTEIN-PE investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. NEJM 2012;366:1287 (Rivaroxaban noninferior to standard therapy)
  14. Prins et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21
  15. Wells et al. Long-term anticoagulation with rivaroxaban for preventing recurrent VTE: A benefit–risk analysis of EINSTEIN EXTENSION. Chest 2016 (Epub) (Rivaroxaban reduced VTE incidence from 9.6% to 3% in one year; 0.7% incidence of major bleeding)
  16. Weitz et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. NEJM 2017;376:1211 (Recurrent VTE incidence reduced by 75% with 10 mg/day rivaroxaban, major bleeding rate 0.4%/yr vs 0.3% with ASA)
  17. Patel et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM 2011;365:883 (Rivaroxaban non-inferior to warfarin)
  18. Mahaffey et al. End of Study Transition From Study Drug to Open-Label Vitamin K Antagonist Therapy: The ROCKET AF Experience. Circ Cardiovasc Qual Outomes 2013;6:470 (Excess strokes following withdrawal of rivaroxaban likely due to poor INR control during transition to warfarin)
  19. Mega et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012;366:9 (Rivaroxaban reduced risk of death from cardiovascular events, with some increased risk of major bleeding)
  20. Mani et al. Ex vivo effects of low-dose rivaroxaban on specific coagulation assays and coagulation factor activities in patients under real life conditions. Thromb Haemost 2013;109:127
  21. Mahaffey et al. Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy: A Subgroup Analysis of a Randomized Trial. Ann Intern Med 2013;158:861
  22. Wasserlauf et al. Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol 2013;112:454 (Less fatal bleeding, no significant difference in overall mortality)
  23. Ageno et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016;3:e12 (Rivaroxaban-treated patients generally younger, healthier; they had less recurrent VTE and lower mortality)
  24. Piccini et al Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation. Circulation 2016;133:352 (Polypharmacy associated with higher bleed risk)
  25. Gibson et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. NEJM 2016;375:2423 (Low dose rivaroxaban plus antiplatelet therapy caused less bleeding than warfarin plus antiplatelet therapy)
  26. Brunner-Ziegler et al. Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. J Thromb Haemost 2016;14:316 (Evening dosing may be preferable)
  27. Wiesen et al. The direct factor Xa inhibitor rivaroxaban passes into human breast milk. Chest 2016;150:e1

Apixaban

  1. Lassen et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. NEJM 2009;361:594
  2. Lassen et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375:807 (40% lower risk of VTE or death with apixaban)
  3. Lassen et al. Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement. NEJM 2010;363:2487 (Apixiban group had less VTE, no increase in bleeding)
  4. Huang et al. Apixaban versus enoxaparin in patients with total knee arthroplasty. A meta-analysis of randomised trials. Thromb Haemost 2011;105: 245 (Apixaban as effective and safer than enoxaparin)
  5. Connolly et al. Apixaban in patients with atrial fibrillation. NEJM 2011;364:806 (The "AVERROES" trial; `Apixaban better than aspirin in patients for whom warfarin treatment deemed "unsuitable")
  6. Granger et al. Apixaban versus warfarin in patients with atrial fibrillation. NEJM 2011;365:981 (Apixaban more effective and safer than warfarin, associated with slightly lower mortality; with editorial)
  7. Lopes et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 2012;380:1749 (Outcomes with apixaban superior to those with warfarin regardless of CHADS score or bleeding risk)
  8. Avezum et al. Apixaban compared with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. Circulation 2015;132:624 (> 25% of patients in this trial had significant valvular disease; relative benefit of apixaban in this group no different from that in overall trial)
  9. Wallentin et al. Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation. Circulation 2013;127:2166 (Patients predicted to have worse INR control on warfarin had greater benefit from apixaban)
  10. Alexander et al. Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. NEJM 2011;365:699 (Apixaban increased bleeding, did not reduce ischemic events significantly)
  11. Garcia et al. Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures. Blood 2014;124:3692 (Short term interruption of treatment safe; some patients may not need to stop Rx)
  12. Komócsi et al. Use of New-Generation Oral Anticoagulant Agents in Patients Receiving Antiplatelet Therapy After an Acute Coronary Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med 2012;172:1537 (Combined use of new anticoagulants + antiplatelet therapy associated with dramatic increase in major bleeding)
  13. Goldhaber et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. NEJM 2011;365:2167 (Extended thromboprophylaxis with apixaban not superior to a shorter course of enoxaparin, caused more bleeding)
  14. Agnelli et al. Oral apixaban for the treatment of acute venous thromboembolism. NEJM 2013;369:799 (The AMPLIFY trial; Apixaban as effective as standard treatment, caused less bleeding)
  15. Agnelli et al. Apixaban for extended treatment of venous thromboembolism. NEJM 2013;368:699 (Apixaban lowered VTE recurrence rate from 8.8% to 1.7% over 12 mo without increasing bleeding risk; with editorial)
  16. Pathak et al. Meta-Analysis on Risk of Bleeding With Apixaban in Patients With Renal Impairment. Am J Cardiol 2015;115:323 (Apixaban is as safe or safer than "conventional agents" in patients with mild or moderate renal impairment)
  17. Chang et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 2015 (Epub) ("These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone")
  18. Raccah et al. Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest 2016 (Epub) (Apixaban less likely to cause bleeding in patients with decreased kidney function)

Edoxaban

  1. Edoxaban (Savasaya) - the fourth new oral anticoagulant. JAMA 2015;314:76
  2. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. NEJM 2013;369:1406 (Similar efficacy, less bleeding with edoxaban)
  3. Giugliano et al. Edoxaban versus warfarin in patients with atrial fibrillation. NEJM 2013;369:2093 (Similar efficacy, less bleeding and lower cardiovascular mortality with edoxaban)
  4. Brekelmans et al. Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016;3:e437 (Edoxaban more effective than warfarin for treating and preventing recurrence of PE with RV dysfunction)
  5. Raskob et al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016;3:e228 (Edoxaban as effective as warfarin, caused less bleeding)

Betrixaban

  1. Cohen et al. Extended thrombophrophylaxis with Betrixaban in acutely ill medical patients. NEJM 2016;375:534 (Comparable efficacy and safety to LMWH)

Dabigatran

  1. van Ryn et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116
  2. Hawes et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013;11:1493 (PT/INR and PTT often normal at therapeutic dabigatran levels)
  3. Chan et a. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015;13:353 (Considerable variation in blood levels between patients associated with age, weight, renal function)
  4. Eriksson et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178 (Dabigatran as effective and safe as enoxaparin)
  5. Eriksson et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370:949 (Dabigatran as effective and safe as enoxaparin)
  6. Connolly et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM 2009;361:1139 (Dabigatran as efficacious as warfarin, caused less bleeding. See also the accompanying editorial)
  7. Eikelboom et al. Dabigatran versus warfarin in patients with mechanical heart valves. NEJM 2013;369:1206 (Dabigatran treatment associated with more thrombosis and more bleeding; see also letters to the editor)
  8. Eikelboom et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation. An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011;123:2363 (Overall bleeding risk with dabigatran relative to warfarin rises above age 75)
  9. Connolly et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013;126:237 (More bleeding with 150 mg bid than 110 mg bid, no reduction in stroke risk)
  10. Hernandez et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2015;175:18 (Higher risk of non-CNS bleeding vs warfarin in this "real-world" study, especially in African-Americans and patients with CKD)
  11. Hijazi et al. Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation. A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis. Circulation 2014;129:961 (GFR <80 associated with higher bleeding rates)
  12. Healey et al. Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation 2012;126:343 (Bleeding rates similar for warfarin & dabigatran)
  13. Schulman et al. Perioperative Management of Dabigatran. A Prospective Cohort Study. Circulation 2015;132:167
  14. Dans et al. Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial. Circulation 2013;127:634 (More bleeding with concomitant antiplatelet Rx, which did not affect the advantages of dabigatran vs warfarin)
  15. Schulman et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 2009;361:2342 (Efficacy and safety of fixed-dose dabigatran comparable to warfarin)
  16. Schulman et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. NEJM 2013;368:709 (Dabigatran effective for extended Rx of VTE, less bleeding than with warfarin but more than with placebo; with editorial)
  17. Schulman et al. Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis. Circulation 2014;129:764 (Similar rates of recurrence and lower bleeding rate - 1.2% vs 1.7% - with dabigatran)
  18. Goldhaber et al. Treatment of acute pulmonary embolism with dabigatran versus warfarin A pooled analysis of data from RE-COVER and RE-COVER II. Thromb Haemost 2016;116:714 (Dabigatran as effective as warfarin, associated with 40% less bleeding)
  19. Wallentin et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975
  20. Uchino and Hernandez. Dabigatran association with higher risk of acute coronary events. Meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012;172:397 (1.3-fold increase in risk of MI or ACI with dabigatran)
  21. Shah and Gage. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011;123:2562 (Dabigatran more cost-effective in patients at high risk of stroke or hemorrhage unless INR control with warfarin excellent)
  22. Glund et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:911
  23. Pollack et al. Idarucizumab for Dabigatran Reversal. NEJM 2015;373:511 (With editorial)

Other/investigational agents

  1. Travers et al. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014;124:3183 (In mice)
  2. Büller et al. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. NEJM 2015;372:232 (Less thrombosis and less bleeding with this drug than with enoxaparin in patients undergoing knee replacement; see editorial)
  3. Andreozzi et al. Sulodexide for the Prevention of Recurrent Venous Thromboembolism. The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Circulation 2015;132:1891 (Drug reduced VTE recurrence rate by 50% with no apparent increase in bleed risk)
  4. Fredenburgh et al. Emerging anticoagulant strategies. Blood 2017;129:147

Thrombolytic treatment

  1. Goldhaber S. Thrombolytic Therapy for Patients With Pulmonary Embolism Who Are Hemodynamically Stable But Have Right Ventricular Dysfunction: Pro. Arch Intern Med 2005;165:2197
  2. Thabut and Logeart. Thrombolysis for Pulmonary Embolism in Patients With Right Ventricular Dysfunction: Con. Arch Intern Med 2005;165:2200 (This and the previous reference debate the use of thrombolysis in patients with non-massive pulmonary embolism.  See also each author's rebuttal)
  3. Perlroth et al. Effectiveness and Cost-effectiveness of Thrombolysis in Submassive Pulmonary Embolism. Arch Intern Med 2007;167:74
  4. Ibrahaim et al. Thrombolytic Therapy and Mortality in Patients With Acute Pulmonary Embolism. Arch Intern Med 2008;168:2183 (inappropriate use of thrombolytics in low risk patients may increase mortality; see commentary)
  5. Wang et al. Efficacy and Safety of Low Dose Recombinant Tissue-Type Plasminogen Activator for the Treatment of Acute Pulmonary Thromboembolism. A Randomized, Multicenter, Controlled Trial. Chest 2010;137:254 (50 mg dose as effective as 100 mg dose, associated with less bleeding)
  6. Enden et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012;379:31 (15% reduction in risk of post-thrombotic syndrome; some increase in bleeding risk)
  7. Wahlgren et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275 (Altepase safe and effective if used within 3 hours of stroke onset)
  8. Impact of Female Sex on Death and Bleeding After Fibrinolytic Treatment of Myocardial Infarction in GUSTO V. Arch Intern Med 2007;167:2054
  9. Hemmelgarn et al. Prevention of dialysis catheter malfunction with recombinant tissue plasminogen activator. NEJM 2011;364:303

Anticoagulant drugs: causes and treatment of bleeding complications

  1. Schulman et al. Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:257S
  2. Frontera et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2015 (Epub)
  3. Scherz et al. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost 2013;11:435 (Existing bleeding scores not able to predict bleeding accurately in elderly patients; with useful editorial that describes a common-sense approach to this problem)
  4. Carrier et al. Systematic Review: Case-Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Venous Thromboembolism. Ann Intern Med 2010;152:578 (Benefits of anticoagulation outweigh risks only if recurrence rate more than 3-fold higher than bleeding risk)
  5. Ruíz-Giménez et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100:26
  6. Riva et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study. Thromb Haemost 2014;112:511
  7. Frey et al. Physical activity and risk of bleeding in elderly patients taking anticoagulants. J Thromb Haemost 2015;13:197 (Higher level of activity associated with lower bleeding risk)
  8. Davidson et al. Bleeding Risk of Patients With Acute Venous Thromboembolism Taking Nonsteroidal Anti-Inflammatory Drugs or Aspirin. JAMA Intern Med 2014;174:947 (1.7-fold increase in bleeding risk when NSAIDs or ASA added to anticoagulant therapy)
  9. Vanassche et al. Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials. Thromb Haemost 2014;112:918
  10. Pottegård et al. Antithrombotic drugs and subarachnoid haemorrhage risk. A nationwide case-control study in Denmark. Thromb Haemost 2015;114:1064 (ASA, clopidogrel and VKA only associated with increased risk of SAH in first three months of treatment)
  11. Gaist et al. Association of Antithrombotic Drug Use With Subdural Hematoma Risk. JAMA 2017;317:836 (Risk doubles with antithrombotic Rx, highest with VKA + antiplatelet drug and VKA in older pts)
  12. Schalekamp et al. Effect of oral antiplatelet agents on major bleeding in users of coumarins.Thromb Haemost 2008;100:1076
  13. Hawryluk et al. Management of anticoagulation following central nervous system hemorrhage in patients with high thromboembolic risk. J Thromb Haemost 2010;8:1500 (Restarting before 72 h associated with more bleeding; restarting after 72 h associated with more thrombosis)
  14. Kuramatsu et al. Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage. JAMA 2015;313:824 (Reversal within 4h, good BP control associated with smaller hematomas; restarting anticoagulants after 3-4 weeks generally safe, associated with fewer ischemic events)
  15. Nielsen et al. Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding. A Nationwide Cohort Study. Circulation 2015;132:517 (Better outcomes if anticoagulants are restarted)
  16. Paciaroni et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011;9:893 (Significant reduction in PE, non-significant decrease in mortality, increased risk of enlarging hematoma)
  17. Albrecht et al. Benefits and Risks of Anticoagulation Resumption Following Traumatic Brain Injury. JAMA Intern Med 2014;174:1244 (Net benefit from re-starting warfarin following discharge, despite increased bleeding risk)
  18. Donato et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood 2015;126:494 (Therapeutic anticoagulation does not increase risk of ICH in patients with brain mets)
  19. Zwicker et al. A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation. J Thromb Haemost 2016;14:1736 (Anticoagulation did not increase risk of IC bleeding with brain mets but increased risk 4x with gliomas)
  20. Chai-Adisaksopha et al. Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding. A meta-analysis. Thromb Haemost 2015;114:657 (Restarting warfarin after GI bleed reduces thromboembolism and mortality, no significant increase in recurrent GI bleed rate)
  21. Sørensen et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009; 374:1967 (Bleeding risk increased according to number of antithrombotics prescribed; 5-fold higher for triple therapy vs aspirin)
  22. Lamberts et al. Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention. A Nationwide Cohort Study. Circulation 2012;126:1185 (Persistently high bleeding risk, "no safe therapeutic window")
  23. Shehab et al. National Estimates of Emergency Department Visits for Hemorrhage-Related Adverse Events From Clopidogrel Plus Aspirin and From Warfarin. Arch Intern Med 2010;170:1926 (1.2% of patients on dual antiplatelet therapy required emergency attention for acute bleeding, vs 2.5% of those on warfarin)
  24. Abraham et al. Risk of Lower and Upper Gastrointestinal Bleeding, Transfusions, and Hospitalizations With Complex Antithrombotic Therapy in Elderly Patients. Circulation 2013;128:1869 (Combining antithrombotic drugs increases UGI bleed risk by 40-60%, LGI bleed risk by30%)

Warfarin/Vitamin K antagonists

  1. Kooistra et al; Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists. JAMA Int Med 2016;176:1176 (Bleeding risk only mildly increased past age 80, but thrombotic risk rose sharply)
  2. Witt et al. Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding. Arch Intern Med 2012;172:1484 (Warfarin resumption within 90 days associated with lower risk of thrombosis and death)
  3. Van Den Ham et al. The patterns of anticoagulation control and the risk of stroke, bleeding and mortality in patients with non-valvular atrial fibrillation. J Thromb Haemost 2013;11:107 (Unstable INR → 11-fold increased mortality)
  4. Warkentin et al. Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis. J Thromb Haemost 2012;10:512 (Overall bleeding risk similar with each drug, risk of intracranial bleeding higher with warfarin)
  5. Fischer et al. Hemorrhage During Warfarin Therapy Associated With Cotrimoxazole and Other Urinary Tract Anti-infective Agents. Arch Intern Med 2010;170:617 (TMP Sulfa associated with higher bleeding risk than other commonly used antibiotics in warfarin-treated pts)
  6. Hylek et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000;160:1612 (INR > 6 associated with 4.4% of major bleeding)
  7. Lind et al. Thrombomodulin as a Marker for Bleeding Complications During Warfarin Treatment. Arch Intern Med 2009;169:1210
  8. Greinacher et al. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015;113:911
  9. DeLoughery T. Venous Thromboembolism in the ICU and Reversal of Bleeding on Anticoagulants. Crit Care Clin 2005; 21:497
  10. Dentali et al. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006;4:1853
  11. Lubetsky et al. Comparison of Oral vs Intravenous Phytonadione (Vitamin K1) in Patients With Excessive Anticoagulation. A Prospective Randomized Controlled Study. Arch Intern Med. 2003;163:2469
  12. DeZee et al. Treatment of Excessive Anticoagulation With Phytonadione (Vitamin K). A Meta-analysis. Arch Intern Med 2006;166:391
  13. Crowther et al. Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin. A Randomized Trial. Ann Intern Med 2009;150:293 (vit K did not reduce bleeding rates in non-bleeding patients with INRs between 4.5 and 10)
  14. Rashidi and Tahhan. Fresh frozen plasma dosing for warfarin reversal: a practical formula. Mayo Clin Proc 2013;88:244
  15. Dentali et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011;106:429
  16. Hickey et al. Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department. Circulation 2013;128:360 (PCC caused faster reversal, less need for RBC transfusion)
  17. Chai-Adisaksopha et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 2016;116:879 (PCC reduces overall mortality, corrects INR more quickly, and causes less volume overload without increasing risk of thrombosis)
  18. Majeed et al. Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost 2014;11:189 (No difference in mortality with PCC vs FFP after adjustment for severity of bleed; non randomized study)
  19. Marshall et al. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost 2016;14:324 (20% incidence of TACO; risk higher if > 3 U FFP transfused)
  20. Sarode et al. Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding. A Randomized, Plasma-Controlled, Phase IIIb Study. Circulation 2013;128:1234 (PCC much more effective, equally safe)
  21. Skolnick et al. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010;116:693 (rVIIa did not reduce warfarin-related blood loss)

DOACs

  1. Siegal et al. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014;123:1152
  2. Ruff et al. Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation 2016;134: 248
  3. Eerenberg et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation 2011;124 (Epub) (PCC reversed the in vitro anticoagulant effect of rivaroxaban, but not dabigatran)
  4. Arellano-Rodrigo et al. Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers. Transfus Med Rev 2015 (Epub)
  5. Zahir et al. Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate. Circulation 2015;131:82 (50 IU/kg of PCC reversed edoxaban effect on bleeding duration)
  6. Ruff et al. Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation 2016; 134:248
  7. Glund et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:911
  8. Pollack et al. Idarucizumab for Dabigatran Reversal. NEJM 2015;373:511 (With editorial)
  9. Siegal et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. NEJM 2015;373:2413 (With editorial)
  10. Connolly et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. NEJM 2016;375:1131 (with editorial)
  11. Thalji et al. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 2016 (Epub) (An experimental reversal agent with activity against all DOACs)
  12. Ansell et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017;117:238
  13. Levy et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:623
  14. Desai et al. Gastrointestinal bleeding with the new oral anticoagulants - defining the issues and the management strategies. Thromb Haemost 2013;110:205
  15. Holster et al. New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis. Gastroenterology 2013;146:106
  16. Hernandez et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Int Med 2014 (ePub) (Higher overall bleeding risk with dabigatran than warfarin, particularly GI bleeding, in this postapproval data analysis)
  17. Majeed et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013;128:2325 (Bleeding from dabigatran required more RBC, less plasma, and had trend toward lower mortality than bleeding from warfarin)
  18. Beyer-Westendorf et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955 (Major bleeding rates somewhat lower than for VKAs and outcomes not worse; benefits of PCC administration appear modest)
  19. Chai-Adisaksopha et al. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450 (TSOACs cause less bleeding than VKAs; no increase in risk of GI bleeding)
  20. Crowther and Warkentin.Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008;111:4871
  21. Ansell et al. Use of PER977 to reverse the anticoagulant effect of edoxaban (letter). NEJM 2014 (ePub)
  22. Beyer-Westendorf et al. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol 2016;3:e480 (About a third of women at risk have excessive vaginal bleeding on Xa inhibitors. Look for anatomic abnormalities when bleeding is severe or recurrent)

Antiplatelet drugs

  1. Berger et al. Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease. Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial. Circulation 2010;121:2575
  2. Cohen M. Expanding the recognition and assessment of bleeding events associated with antiplatelet therapy in primary care. Mayo Clin Proc 2009;84:149
  3. Feely et al. Safety of clopidogrel in hip fracture surgery. Mayo Clin Proc 2013;88:149
  4. Steinhubl et al. Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding. Ann Intern Med 2009;150:379
  5. García Rodríguez et al. Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications. Circulation 2011;123:1108
  6. Vilahur et al. Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007;5:82 (Using platelet transfusion to reverse clopidogrel effect)
  7. Baharoglu et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016;387:2605 (Worse outcomes with platelet transfusion in this setting; with editorial)
  8. Teng et al. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost 2016;14:2342 (No evidence of benefit)

Bridging anticoagulation for surgery, etc.

  1. Douketis et al. Perioperative Management of Antithrombotic Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e362S
  2. Ortel T. Perioperative management of patients on chronic antithrombotic therapy. Blood 2012;120:4699
  3. Spyropoulos et al. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost 2016;14:875
  4. Keeling et al. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haem 2016;175:602
  5. Baron et al. Management of Antithrombotic Therapy in Patients Undergoing Invasive Procedures. NEJM 2013;368:2113
  6. Spyropoulos and Douketis. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954
  7. Douketis et al. Perioperative bridging in patients with atrial fibrillation. NEJM 2015;373:823 (No increase in thromboembolism without bridging, less major bleeding)
  8. Clark et al. Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. JAMA Intern Med 2015; 175:1163 (More bleeding, no significant reduction in recurrent VTE with bridging; retrospective study, with editorial)
  9. Douketis et al. Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin. Assessment of a Standardized Periprocedural Anticoagulation Regimen. Arch Intern Med 2004;164:1319
  10. Douketis et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. J Thromb Haemost 2015;113:437 (Bridging increased bleed risk, did not affect thrombosis rate)
  11. Kim et al. Heparin bridging in warfarin anticoagulation therapy initiation could increase bleeding in non-valvular atrial fibrillation patients: a multicenter propensity-matched analysis. J Thromb Haemost 2015;13:182 (Stroke rates similar, bleeding rate higher with bridging)
  12. Dunn et al. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost 2007;5:2211 (Non-randomized trial of enoxaparin 1.5 mg/kg prior to surgery - 20% major bleeds with major surgery)
  13. Garcia et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168:63 (Risk of thrombosis low, comparable to risk of major bleeding if bridging anticoagulation given)
  14. Skeith et al. Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study. J Thromb Haemost 2012;2298 (Interruption of warfarin, no pre-op LMWH, post-op LMWH only for hospitalized pts appeared safe in this non-randomized study)
  15. Wysokinski et al. Periprocedural Anticoagulation Management of Patients With Nonvalvular Atrial Fibrillation. Mayo Clin Proc 2008;83:639 (Incidence of thromboembolism after interruption of anticoagulation low, not influenced by bridging)
  16. Jamula et al. Perioperative anticoagulation in patients having implantation of a cardiac pacemaker or defibrillator: a systematic review and practical management guide. J Thromb Haemost 2008;6:1615 (Continuing warfarin less risky than bridging with heparin)
  17. Feng et al. Oral anticoagulation continuation compared with heparin bridging therapy among high risk patients undergoing implantation of cardiac rhythm devices. Thromb Haemost 2012;108:1124 (Safer to continue warfarin than bridge)
  18. Birnie et al. Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation. NEJM 2013;368:2084 (Safer to continue warfarin than to bridge with heparin or LMWH)
  19. Passaglia et al. Early postoperative bridging anticoagulation after mechanical heart valve replacement: a systematic review and meta-analysis. J Thromb Haemost 2015;13:1557 (Modest decrease in thromboembolism and increase in bleeding with bridging)
  20. Tafur et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost 2012;10:261 (Bridging and restarting heparin within 24 hours of procedure increase bleeding risk)
  21. Siegal et al. Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists. Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates. Circulation 2012;126:1630 (Bridging associated with higher bleeding risk, similar risk of thromboembolism vs no bridging)
  22. Steinberg et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Circulation 2015;131:488 (Higher rates of bleeding and adverse events when bridging used. "These data do not support the use of routine bridging". With editorial)
  23. Beyer-Westendorf et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; (ePub) (Higher risk of bleeding with heparin bridging, unclear benefit; continuation or brief interruption of NOAC safe for most procedures)
  24. Mathew et al. Efficacy and safety of early parenteral anticoagulation as a bridge to warfarin after mechanical valve replacement. Thromb Haemost 2014;112:1077 (Bridging with therapeutic heparin caused more bleeding, did not lower rate of thromboembolism)
  25. O'Donnell et al. Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin. Ann Intern Med 2007;146:184 (Heparin levels high during surgery if LMWH continued until night prior to surgery)
  26. Leijtens et al. High complication rate after total knee and hip replacement due to perioperative bridging of anticoagulant therapy based on the 2012 ACCP guideline. Arch Orthop Trauma Surg 2014;134:1335
  27. Sherwood et al. Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation. Circulation 2014;129:1850 (Risk of stroke or embolism < 0.5% per 30 days with discontinuation of either drug)

Thrombosis

VTE

Venous thromboembolism - general, risk factors

  1. Heit et al. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016;41:3
  2. Goldhaber and Bounameaux. Pulmonary embolism and deep vein thrombosis. Lancet 2012;379:1835
  3. Galanaud et al. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013;11:402
  4. Zakai et al. Racial and Regional Differences in Venous Thromboembolism in the United States in 3 Cohorts. Circulation 2014;129:1502 (With editorial)
  5. van Langevelde et al. Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. Blood 2012;120:933 (Differences in risk factors for DVT and PE)
  6. Rosendaal F. Venous Thrombosis: The Role of Genes, Environment, and Behavior. Hematology 2005:1-12.
  7. Kearon et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016;14:1480
  8. Khorana et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902
  9. Kearon C. Natural history of venous thromboembolism.  Circulation 2003;107:1-22
  10. Mearns et al. Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:1043 (Most recurrent VTE events of the same type - DVT vs PE - as index event; in PE patients, case-fatality rate for recurrent events 41%)
  11. Alving et al. Consultations on Patients with Venous or Arterial Diseases. Hematology 2003:540-558
  12. Dobromirski and Cohen. How I manage venous thromboembolism risk in hospitalized medical patients. Blood 2012;120:1562
  13. Kyrle and Eichinger. Deep vein thrombosis.  Lancet 2005;365:1163
  14. Roach et al. Differential risks in men and women for first and recurrent venous thrombosis: the role of genes and environment. J Thromb Haemost 2014;12:1593
  15. Pomp et al. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007;139:289 (2.4 fold increased risk of VTE in obesity, 24-fold increase in obese women using OC)
  16. Parkin et al. Body Mass Index, Surgery, and Risk of Venous Thromboembolism in Middle-Aged Women. A Cohort Study. Circulation 2012;125:1897 (VTE risk increases with increasing BMI, particularly after surgery)
  17. Holst et al. Risk factors for venous thromboembolism. Results from the Copenhagen City Heart Study. Circulation 2010;121:1896 (Obesity and smoking, but not dyslipidemia or diabetes, increased risk of VTE)
  18. Sweetland et al. Smoking, Surgery, and Venous Thromboembolism Risk in Women. United Kingdom Cohort Study. Circulation 2013;127:1276
  19. Enga et al. Cigarette smoking and the risk of venous thromboembolism: The Tromsø Study. J Thromb Haemost 2012;10:2068 (Heavy smoking a modest risk factor for VTE)
  20. Rogers et al. Triggers of hospitalization for venous thromboembolism. Circulation 2012;125:2092 (Infection, treatment with erythropoiesis-stimulating agents, and transfusion identified as possible triggers for VTE)
  21. Cohen et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:387 (VTE prophylaxis is under-utilized, particularly in medical patients)
  22. Ocak et al. Risk of venous thrombosis in patients with major illnesses: results from the MEGA study. J Thromb Haemost 2013;11:116 (Major illness + immobilization or thrombophilia → high risk)
  23. Kaplan et al. VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Chest 2015;149:1107 (Over a third of patients had VTE, despite thromboprophylaxis)
  24. Mahan et al. External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR). Thromb Haemost 2014;112:692
  25. Sorensen et al. Venous thromboembolism and subsequent hospitalization due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370:1773 (increased risk of MI and stroke following VTE)
  26. Klok et al. Risk of arterial cardiovascular events in patients after pulmonary embolism. Blood 2009;114:1484 (2-fold increased risk of arterial events following unprovoked PE)
  27. Green D. Risk of future arterial cardiovascular events in patients with idiopathic venous thromboembolism. Hematology 2009;259
  28. Huerta et al. Risk Factors and Short-term Mortality of Venous Thromboembolism Diagnosed in the Primary Care Setting in the United Kingdom. Arch Intern Med 2007;167:935
  29. Spencer et al. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007;167:1471 (More VTEs diagnosed in the 3 months after hospitalization than during hospitalization, suggesting need for extended prophylaxis)
  30. Lecumberri et al. Dynamics of case-fatality rates of recurrent venous thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013;110:834 (Mortality from recurrent VTE high in first 3 mo, then declines; mortality rate from bleeding stable over time)
  31. Spencer et al. Patient Outcomes After Deep Vein Thrombosis and Pulmonary Embolism. The Worcester Venous Thromboembolism Study. Arch Intern Med 2008;168:425 (Patients with PE had higher mortality, but similar rate of subsequent PE as patients with DVT; 5 year recurrence rate about 5% in both groups)
  32. Palareti and Schellong. Isolated distal deep vein thrombisis: what we know and what we are doing. J Thromb Haemost 2012;10:11
  33. Palareti G. How I treat isolated distal deep vein thrombosis (IDDVT). Blood 2014;123:1802
  34. Silverstein et al. Venous thrombosis in the elderly: more questions than answers. Blood 2007;110:3097
  35. Sweetland et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 2009;339:b4583 (70-fold increased risk of VTE in 12 weeks after surgery; highest risk after hip, knee or cancer surgery)
  36. Barbar et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010;8:2450
  37. Rogers et al. Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007;204:1211 (The "Rogers score" to assess risk of postop VTE)
  38. Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon 2005;51:70 (The "Caprini score")
  39. Januel et al. Symptomatic In-Hospital Deep Vein Thrombosis and Pulmonary Embolism Following Hip and Knee Arthroplasty Among Patients Receiving Recommended Prophylaxis: A Systematic Review. JAMA 2012;307:294 (VTE rate about 1% for knee replacement, about 0.5% for hip replacement if LMWH or direct IIa or Xa inhibitor given)
  40. van Adrichem et al. Risk of venous thrombosis after arthroscopy of the knee: results from a large population-based case–control study. J Thromb Haemost 2015;13:1441 (18-fold increased VTE risk in first 3 mo after arthroscopy)
  41. Pierfrancheschi et al. The short- and long-term risk of venous thromboembolism in patients with acute spinal cord injury. A prospective cohort study. Thromb Haemost 2013:109:34 (High risk of VTE despite prophylaxis in 1st 3 mo after injury; age, prior VTE and paraplegia increased risk)
  42. Engbers et al. The contribution of immobility risk factors to the incidence of venous thrombosis in an older population. J Thromb Haemost 2014;12:290
  43. Dunn et al. The magnitude of an iatrogenic disorder: A systematic review of the incidence of venous thromboembolism for general medical inpatients. Thromb Haemost 2006;95:758
  44. Tang et al. Heart failure and risk of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol 2016;3:e30 (Hospitalized patients with heart failure have a 1.5-fold increased risk of VTE)
  45. White et al. Incidence of Venous Thromboembolism in the Year Before the Diagnosis of Cancer in 528 693 Adults. Arch Intern Med 2005;165:1782
  46. Dennis et al. The timing, extent, progression and regression of deep vein thrombosis in immobile stroke patients: observational data from the CLOTS multicenter randomized trials. J Thromb Haemost 2011;9:2193 (15% had a DVT within a month of stroke; most asymptomatic)
  47. Mauck et al. Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study. J Thromb Haemost 2013;11:1279 (0.4% incidence of VTE after 35 days; higher incidence in older or hospitalized pts)
  48. Geerts et al.  A prospective study of venous thromboembolism after major trauma.  NEJM 1994;331:1601
  49. Tichelaar et al. Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review. Thromb Haemost 2012;107:827
  50. Schreijer et al. Activation of coagulation system during air travel: a crossover study. Lancet 2006;367:832 (17% of subjects had biochemical evidence of hypercoagulability after 8 hour flight)
  51. Chandra et al. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med 2009;151:180 (VTE risk increases by 26% for each 2-hour increment in air travel duration; overall 3-fold increased VTE risk with travel by any mode)
  52. Yablon et al. Deep vein thrombosis. Prevalence and risk factors in rehabilitation admissions with brain injury. Neurology 2004;63:485  (11% of patients with recent brain injury had DVT at the time of admission to a rehab unit)
  53. Leibson et al. Risk factors for venous thromboembolism in nursing home residents. Mayo Clin Proc 2008;83:151
  54. van Stralen et al. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med 2008;168:21 (Minor leg injuries increased risk of DVT within subsequent 10 weeks; FVL + leg injury 50x increased risk)
  55. Mahmoodi et al. Microalbuminuria and Risk of Venous Thromboembolism. JAMA 2009;301:1790
  56. Mahmoodi et al. Association of Mild to Moderate Chronic Kidney Disease With Venous Thromboembolism. Pooled Analysis of Five Prospective General Population Cohorts. Circulation 2012;126:1964
  57. van Zaane et al. Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case-control study. Blood 2010:115:4344
  58. Debeij et al. High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study. J Thromb Haemost 2014;12:839
  59. Johannesdottir et al. Use of Glucocorticoids and Risk of Venous Thromboembolism. A Nationwide Population-Based Case-Control Study. JAMA Intern Med 2013;173:743 (Increased VTE risk with oral or inhaled steroids)
  60. Baillargeon et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc 2015;90:1038 (No apparent increase in VTE risk with testosterone)
  61. Manco-Johnson M. How I treat venous thrombosis in children. Blood 2006;107:21

Pulmonary embolism

  1. Piazza and Goldhaber. Acute pulmonary embolism: Part I: Epidemiology and diagnosis. Circulation 2006;114::e28
  2. Piazza and Goldhaber. Acute pulmonary embolism: Part II: Treatment and prophylaxis. Circulation 2006;114:e42
  3. Agnelli and Becattini. Acute pulmonary embolism. NEJM 2010;363:266
  4. Aujesky et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011;378:41
  5. Fang et al. Outcomes in Adults With Acute Pulmonary Embolism Who Are Discharged From Emergency Departments. The Cardiovascular Research Network Venous Thromboembolism Study. JAMA Intern Med 2015;175:1060
  6. Wood K. Major Pulmonary Embolism. Review of a Pathophysiologic Approach to the Golden Hour of Hemodynamically Significant Pulmonary Embolism. Chest 2002;121:877
  7. Becattini et al. Acute Pulmonary Embolism: External Validation of an Integrated Risk Stratification Model. Chest 2013;144:1539 (Absence of RV dysfunction + normal troponin had high negative predictive value for death or deterioration)
  8. Smith et al. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 2010;137:1382 (Starting heparin in ED, achieving therapeutic aPTT within 24h both associated with better outcomes)
  9. Kucher et al. Massive pulmonary embolism. Circulation 2006;113:577  (Thrombolysis did not reduce mortality or recurrent PE at 90 days; IVC filter placement associated with improved 90-day survival in this retrospective study)
  10. Laporte et al. Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism. Findings From the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008;117:1711
  11. Vedovati et al. Multidetector CT Scan for Acute Pulmonary Embolism: Embolic Burden and Clinical Outcome. Chest 2012;146:1417 (Central PE associated with high risk of deterioration and death)
  12. Wiener et al. Time Trends in Pulmonary Embolism in the United States. Evidence of Overdiagnosis. Arch Intern Med 2011;171:831 (CT angio finds more PE, but with minimal decrease in PE mortality and increased complications from anticoagulation)
  13. Weiner et al. When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. BMJ 2013;347: f3368 (80% rise in incidence of PE since 1998 with minimal decrease in mortality suggests that many clinically unimportant emboli are being found with newer imaging techniques)
  14. den Exter et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood 2013;122:1144 (SSPE similar to more proximal clots with respect to risk profile and clinical outcome)
  15. Raja et al. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2015;163:701 '
  16. Hakemi et al. The Prognostic Value of Undetectable Highly Sensitive Cardiac Troponin I in Patients With Acute Pulmonary Embolism. Chest 2015;147:685. (Negative test had excellent negative predictive value for death or need for thrombolysis)
  17. Becattini et al. Risk Stratification of Patients With Acute Symptomatic Pulmonary Embolism Based on Presence or Absence of Lower Extremity DVT: Systematic Review and Meta-analysis. Chest 2016;149: 192 (Concomitant DVT associated with nearly 2x risk of death within 30 days)
  18. O'Connell C. How I treat incidental pulmonary embolism. Blood 2015;125:1877
  19. Rizkallah et al. Prevalence of Pulmonary Embolism in Acute Exacerbations of COPD. A Systematic Review and Metaanalysis. Chest 2009;135:786 (one in four COPD patients hospitalized for acute exacerbation may have PE)
  20. Prandoni et al. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. NEJM 2016;375:1524 (17%)
  21. Le Gal et al. Diagnosis and management of subsegmental pulmonary embolism.  J Thromb Haemost 2006;4:724
  22. Ro et al. Autopsy-proven untreated previous pulmonary thromboembolism: frequency and distribution in the pulmonary artery and correlation with patients’ clinical characteristics. J Thromb Haemost 2011;9:922 (Over 90% of patients dying of PE had evidence of previous emboli)
  23. Kline et al. Prospective Evaluation of Right Ventricular Function and Functional Status 6 Months After Acute Submassive Pulmonary Embolism. Frequency of Persistent or Subsequent Elevation in Estimated Pulmonary Artery Pressure. Chest 2009;136:1202 (About 7% of patients getting heparin had elevated RV pressure after 6 mo, vs 11% who got thrombolytic therapy)
  24. Alonso-Fernández et al. Association Between Obstructive Sleep Apnea and Pulmonary Embolism. Mayo Clin Proc 2013;88:579 (OSA prevalence increased in patients with PE)
  25. Enga et al. Atrial fibrillation and future risk of venous thromboembolism:the Tromsø study. J Thromb Haemost 2015;13:10 (Increased PE risk, possibly from RA thrombi)
  26. Doyen et al. Patent Foramen Ovale and Stroke in Intermediate-Risk Pulmonary Embolism. Chest 2014;146:967 (All strokes complicating PE associated with PFO and large shunt; TEE almost 3 x more sensitive than TTE for PFO dx)
  27. Kuo et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest 2015;148:667 (Catheter directed therapy improves outcomes and minimizes bleeding risk)
  28. Poterucha et al. Surgical pulmonary embolectomy. Circulation 2015;132:1146

Diagnosis of venous thromboembolism

  1. Bates et al. Diagnosis of DVT. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e351S
  2. Huisman and Klok. Current challenges in diagnostic imaging of venous thromboembolism. Blood 2015;126:2376
  3. Dronkers et al. Current and future perspectives in imaging of venous thromboembolism. J Thromb Haemost 2016;14:1696
  4. Huisman and Klok. Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost 2013;11:412
  5. Wells et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995;345:1326 (The "Wells score" for determining pre-test probability of DVT)
  6. Silveira et al. Performance of Wells Score for Deep Vein Thrombosis in the Inpatient Setting. JAMA Intern Med 2015;175:1112 (Wells score less useful in predicting DVT for inpatients)
  7. Büller et al. Safely Ruling Out Deep Venous Thrombosis in Primary Care. Ann Intern Med 2009;150:229
  8. Tomkowski et al. Accuracy of compression ultrasound in screening for deep venous thrombosis in acutely ill medical patients. Thromb Haemost 2007;97:191 (Ultrasound less sensitive for both proximal and distal DVT than venography)
  9. Johnson et al. Risk of Deep Vein Thrombosis Following a Single Negative Whole-Leg Compression Ultrasound. A Systematic Review and Meta-analysis. JAMA 2010; 303:438 (0.6% of patients with negative US have VTE in next 3 months)
  10. Tan et al. Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood 2014;124:623
  11. Stein et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism.  A systematic review.  Ann Intern Med 2004;140:589
  12. Kearon et al. A Randomized Trial of Diagnostic Strategies after Normal Proximal Vein Ultrasonography for Suspected Deep Venous Thrombosis: D-Dimer Testing Compared with Repeated Ultrasonography. Ann Intern Med 2005;142:490
  13. Bernardi et al. Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis. A Randomized Controlled Trial. JAMA 2008;300:1653 (proximal US + D-dimer equivalent to whole leg US)
  14. Linkins et al. Selective D-Dimer Testing for Diagnosis of a First Suspected Episode of Deep Venous Thrombosis: A Randomized Trial. Ann Intern Med 2013;158:93 (Suggests that US without D-Dimer testing more cost-effective for inpatients or outpts with high pretest probability of DVT)
  15. Woller et al. Assessment of the Safety and Efficiency of Using an Age-Adjusted D-dimer Threshold to Exclude Suspected Pulmonary Embolism. Chest 2014;146:1444 (1.5% false-negative rate)
  16. Chan et al. Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials. Thromb Haemost 2015;114:1049 (Venography-diagnosed DVT 10-20x more prevalent than symptomatic DVT)
  17. Huisman and Klock. How I diagnose acute pulmonary embolism. Blood 2013;121:4443
  18. Perrier et al.  Cost-effectiveness analysis of diagnostic strategies for suspected pulmonary embolism including helical computed tomography. Am J Respir Crit Care Med 2003;167:39
  19. PIOPED Investigators. Value of the Ventilation/Perfusion Scan in Acute Pulmonary Embolism Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990;263:2753 (High probability scans had good specificity but low sensitivity; overall specificity very low)
  20. Stein et al. Multidetector Computed Tomography for Acute Pulmonary Embolism. NEJM 2006;354:2317 (PIOPED II study)
  21. Ghanima et al.  Management of suspected pulmonary embolism (PE) by D-dimer and multi-slice computed tomography in outpatients: an outcome study. J Thromb Haemost 2005;3:1926 (risk of recurrent VTE within 3 mo 0.6% or less with negative high-res CT scan)
  22. Righini et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008;371:1343
  23. Carrier et al. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010;8:1716 ("Subsegmental PE may not be clinically relevant")
  24. Kearon et al. An Evaluation of D-Dimer in the Diagnosis of Pulmonary Embolism. Ann Intern Med 2006;144:812
  25. Fedullo and Tapson. The evaluation of suspected pulmonary embolism.  NEJM 2003;349:1247
  26. Anderson et al. Computed Tomographic Pulmonary Angiography vs Ventilation-Perfusion Lung Scanning in Patients With Suspected Pulmonary Embolism. JAMA 2007;2743 (CT more sensitive than VQ scan, but may give more false positive results)
  27. Wiener et al. Time Trends in Pulmonary Embolism in the United States. Evidence of Overdiagnosis. Arch Intern Med 2011;171:831 (CT angio finds more PE, but with minimal decrease in PE mortality and increased complications from anticoagulation)
  28. Weiner et al. When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. BMJ 2013;347: f3368 (80% rise in incidence of PE since 1998 with minimal decrease in mortality suggests that many clinically unimportant emboli are being found with newer imaging techniques)
  29. Moody A.  Magnetic resonance direct thrombus imaging. J Thromb Haemos 2003;1:1403

Treatment of acute venous thromboembolism

  1. Barritt and Jordan. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;1:1309. (A landmark paper)
  2. Hull et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. NEJM 1979;301:855
  3. Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost 2012;10:507 (Evidence supporting a standard treatment duration of 3 months)
  4. Streiff et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis 2016;41:32
  5. Kearon and Akl. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014;123:1794
  6. Boutitie et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ 2011;342:d3036
  7. Kearon et al. Antithrombotic Therapy for VTE Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S
  8. Kearon et al. Antithrombotic Therapy for VTE Disease : CHEST Guideline and Expert Panel Report. Chest 2016;149:315 (Update of above 2012 guidelines)
  9. Baglin et al. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012;10:698
  10. Castellucci et al. Clinical and Safety Outcomes Associated With Treatment of Acute Venous Thromboembolism. A Systematic Review and Meta-analysis. JAMA 2014;312:1122 (UFH/VKA inferior to LMWH/VKA; rivaroxaban and apixaban appear safer than other treatments)
  11. Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. NEJM 2003;349:1695
  12. Hull et al.  Heparin for 5 days compared with 10 days in the initial treatment of proximal venous thrombosis.  NEJM 1990;322:1260
  13. Brandjes et al.  Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis.  NEJM 1992;327:1485
  14. Hull et al.  Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.  NEJM 1986;315:1109
  15. Heit et al. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood 2011;118:4992 (Lower-intensity heparin + standard warfarin therapy effective in preventing recurrence)
  16. Levine et al.  A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.  NEJM 1996;334:677
  17. Quinlan et al. Low-Molecular-Weight Heparin Compared with Intravenous Unfractionated Heparin for Treatment of Pulmonary Embolism. A Meta-Analysis of Randomized, Controlled Trials.  Ann Intern Med 2004;140:175
  18. Kearon et al.  Comparison of Fixed-Dose Weight-Adjusted Unfractionated Heparin and Low-Molecular-Weight Heparin for Acute Treatment of Venous Thromboembolism. JAMA 2006;296:935 (unfractionated heparin as effective as LMWH)
  19. Wells et al. A Randomized Trial Comparing 2 Low-Molecular-Weight Heparins for the Outpatient Treatment of Deep Vein Thrombosis and Pulmonary Embolism. Arch Intern Med 2005;165:733 (No significant difference between tinzaparin and dalteparin)
  20. Horner et al. The Anticoagulation of Calf Thrombosis (ACT) Project: Results From the Randomized Controlled External Pilot Trial. Chest 2014;146:1468 (11% of patients managed without anticoagulation had proximal extension or PE, vs none of the patients given anticoagulants in this small study)
  21. Righini et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol 2016;3:e556 (Nadroparin-treated patients had modest, non-significant decrease in clot progression vs placebo, with more bleeding)
  22. Bates and Ginsberg.  How we manage venous thromboembolism during pregnancy.  Blood 2002;100:3470
  23. Prandoni P. How I treat venous thromboembolism in patients with cancer. Blood 2005;106:4027
  24. Kyrle PA. How I treat recurrent deep-vein thrombosis. Blood 2016;127:696
  25. Le Gal et al. Diagnosis and management of subsegmental pulmonary embolism.  J Thromb Haemost 2006;4:724
  26. Goy et al. Sub-segmental pulmonary embolism in three academic teaching hospitals: a review of management and outcomes. J Thromb Haemost 2015;13:214 (No recurrent clots in patients with SSPE whether or not they were anticoagulated)
  27. Nieto et al. Acute venous thromboembolism in patients with recent major bleeding. The influence of the site of bleeding and the time elapsed on outcome. J Thromb Haemost 2006;4:2367 (Anticoagulant therapy relatively safe if begun at least two weeks after bleeding episode)
  28. Lobo et al. Venous thromboembolism in patients with intracranial bleeding. Thromb Haemost 2011;106:750
  29. Sareyyupoglu et al. A More Aggressive Approach to Emergency Embolectomy for Acute Pulmonary Embolism. Mayo Clin Proc 2010;85:785
  30. Kakkos et al. Review on the value of graduated elastic compression stockings after deep vein thrombosis. Thromb Haemost 2006;96:441

Thrombolytic treatment of venous thromboembolism

  1. Vedantham et al. Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:68
  2. Wang et al. The role of thrombolytic therapy in pulmonary embolism. Blood 2015;125:2191
  3. Chatterjee et al. Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage. A Meta-analysis. JAMA 2014;311:2414 (Lower mortality, more bleeding and intracranial hemorrhage with thrombolysis in patients with hemodynamic instability or RV dysfunction; with editorial)
  4. Goldhaber S. Thrombolytic Therapy for Patients With Pulmonary Embolism Who Are Hemodynamically Stable But Have Right Ventricular Dysfunction: Pro. Arch Intern Med 2005;165:2197
  5. Thabut and Logeart. Thrombolysis for Pulmonary Embolism in Patients With Right Ventricular Dysfunction: Con. Arch Intern Med 2005;165:2200 (This and the previous reference debate the use of thrombolysis in patients with non-massive pulmonary embolism.  See also each author's rebuttal)
  6. Perlroth et al. Effectiveness and Cost-effectiveness of Thrombolysis in Submassive Pulmonary Embolism. Arch Intern Med 2007;167:74
  7. Meyer et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. NEJM 2014;370:1402 (Thrombolytic Rx decreased risk of hemodynamic decompensation, increased risk of major bleeding & stroke; with editorial)
  8. Nakamura et al. Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis. J Thromb Haemost 2014;12:1086 (Thrombolytic Rx did not lower mortality but did lower risk of clinical deterioration)
  9. Kline et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014;12:459 (Better outomes with thrombolysis)
  10. Kucher et al. Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism. Circulation 2014;129:479 (More rapid hemodynamic improvement with thrombolysis, no increased bleeding)
  11. Sharifi et al. Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013;111:273 (A lower dose of TPA reduced pulmonary pressures quickly, did not cause bleeding; trend towards better survival vs placebo)
  12. Vedantham S. Endovascular procedures in the management of DVT. Hematology 2011:156
  13. Enden et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012;379:31 (15% reduction in risk of post-thrombotic syndrome; some increase in bleeding risk)
  14. Haig et al. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol 2016;3:e64 (28% lower risk of PTS in patients treated with thrombolysis; no difference in QOL scores, however. With editorial)
  15. Bashir et al. Comparative Outcomes of Catheter-Directed Thrombolysis Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-Extremity Proximal Deep Vein Thrombosis. JAMA Intern Med 2014;174:1494
Prophylaxis of venous thromboembolism
  1. Kahn et al. Prevention of VTE in Nonsurgical Patients. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e195S
  2. Gould et al. Prevention of VTE in Nonorthopedic Surgical Patients. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S
  3. Falck-Ytter et al. Prevention of VTE in Orthopedic Surgery Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e278S
  4. Hull et al. Benefit-to-harm ratio of thromboprophylaxis for patients undergoing major orthopedic surgery. Thromb Haemost 2014;111:199
  5. Sobieraj et al. Prolonged Versus Standard-Duration Venous Thromboprophylaxis in Major Orthopedic Surgery. A Systematic Review. Ann Intern Med 2012;156:720
  6. Kapoor et al. Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta-analysis. J Thromb Haemost 2017;15:284 (Direct Xa inhibitors prevent 4 times as many symptomatic DVTs as LMWH, without an increased bleeding risk)
  7. Qaseem et al. Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med 2011;155:625
  8. Dobromirski and Cohen. How I manage venous thromboembolism risk in hospitalized medical patients. Blood 2012;120:1562
  9. Selby and Geerts. Prevention of venous thromboembolism: consensus, controversies, and challenges. Hematology 2009;286
  10. Leonardi et al. The Rate of Bleeding Complications After Pharmacologic Deep Venous Thrombosis Prophylaxis. Arch Surg 2006;141:790 ("most patients undergoing general surgery can receive pharmacologic prophylaxis safely")
  11. Francis C. Prophylaxis for Thromboembolism in Hospitalized Medical Patients. NEJM 2007;356:1438
  12. Dentali et al.  Meta-analysis: Anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients.  Ann Intern Med 2007;146:278
  13. Violi et al. Should all acutely ill medical patients be treated with antithrombotic drugs? Thromb Haemost 2013;109:589
  14. Flanders et al. Hospital Performance for Pharmacologic Venous Thromboembolism Prophylaxis and Rate of Venous Thromboembolism. A Cohort Study. JAMA Intern Med 2014;174:1577 (No difference in VTE rates between high-performing and low-performing hospitals; with editorial)
  15. Cohen et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:387
  16. Hostler et al. Validation of the International Medical Prevention Registry on Venous Thromboembolism Bleeding Risk Score. Chest 2016;149:372 (IMPROVE score)
  17. Phung et al. Dosing frequency of unfractionated heparin thrombophrophylaxis. A meta-analysis. Chest 2011;140:374 (Twice daily dosing as effective as three times daily)
  18. Wang et al. Efficacy and safety of high-dose thrombpprophylaxis in morbidly obese inpatients. Thromb Haemost 2014;11:88 (UFH 7500 bid or tid, or enoxaparin 40 mg bid, more effective and no less safe than lower doses for morbidly obese patients)
  19. Kakkar et al. Low-molecular-weight heparin and mortality in acutely ill medical patients. NEJM 2011;365:2463 (LMWH prophylaxis did not alter mortality from any cause)
  20. Samama et al.  A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.  NEJM 1999;341:793
  21. Kakkar et al. Low-molecular-weight heparin and mortality in acutely ill medical patients. NEJM 2011;365:2463 (LMWH prophylaxis did not decrease mortality)
  22. Sherman et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism
    after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007;369:1347
    (VTE risk 43% lower with enoxaparin than UFH)
  23. Fowler et al. Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients. JAMA 2014;312:2135 (LMWH more effective, lower overall cost due to lower PE and HIT rates)
  24. Paciaroni et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011;9:893 (Significant reduction in PE, non-significant decrease in mortality, increased risk of enlarging hematoma)
  25. Camporese et al. Low-Molecular-Weight Heparin versus Compression Stockings for Thromboprophylaxis after Knee Arthroscopy. A Randomized Trial. Ann Intern Med 2008;149:73 (LMWH superior)
  26. van Adrichem et al. Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting. NEJM 2017;376:515 (No significant benefit from LMWH prophylaxis - incidence of VTE low in both treatment and control groups; with editorial)
  27. Ettema et al. Prevention of venous thromboembolism in patients with immobilization of the lower extremities: a meta-analysis of randomized controlled trials. J Thromb Haemost 2008;6:1093 (40% reduction in VTE risk, no excess bleeding risk with LMWH)
  28. Wein et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients. A meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1476 (Both UFH and LMWH reduce VTE risk; LMWH more effective in preventing DVT)
  29. Hull et al. Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility. A Randomized Trial. Ann Intern Med 2010;153:8 (Prophylaxis for 28 days vs 10 days reduces VTE more than it increases bleeding in older patients and women)
  30. Cohen et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325
  31. Ageno et al. Safety and efficacy of low-dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study. J Thromb Haemost 2012;10:2291 (Low dose fondaparinux safe and "relatively effective" in patients with CCr between 20 and 50)
  32. Shatzel et al. Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis: a single-center retrospective cohort study. J Thromb Haemost 2015;13:1245 (Low rate of VTE in hospitalized cirrhotics, not affected by thromboprophylaxis; UFH caused more bleeding than LMWH)
  33. Collen et al. Prevention of venous thromboembolism in neurosurgery: A metaanalysis. Chest 2008;134:237
  34. Brenner B. Interventions to prevent venous thrombosis after air travel, are they necessary? Yes. J Thromb Haemost 2006;4:2302; Rosendaal F. Interventions to prevent venous thrombosis after air travel: are they necessary? No. J Thromb Haemost 2006;4:2306
  35. Glynn et al. Effect of low-dose aspirin on the occurrence of venous thromboembolism. Ann Intern Med 2007;147:525 (ASA 100 mg qod had no apparent effect on occurence of VTE in women)
  36. Anderson et al. Aspirin Versus Low-Molecular-Weight Heparin for Extended Venous Thromboembolism Prophylaxis After Total Hip Arthroplasty: A Randomized Trial. Ann Intern Med 2013;158:800 (ASA as effective as LMWH for extended prophylaxis following 10 days of LMWH)
  37. Lyman et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer. J Clin Oncol 2007;25:5490
  38. CLOTS Trials Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet 2009;373:1958 (No apparent benefit from GCS)
  39. CLOTS Trials Collaboration: Thigh-length versus below-knee stockings for deep venous prophylaxis after stroke. A randomized trial. Ann Intern Med 2010;153:553. (More VTE events in patients using below-knee stockings. See editorial discussing this and the previous article)
  40. CLOTS Trials Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013;382:616 (Significant decrease in DVT risk when IPC added to standard thromboprophylaxis)
  41. Arabi et al. Use of Intermittent Pneumatic Compression and Not Graduated Compression Stockings Is Associated With Lower Incident VTE in Critically Ill Patients: A Multiple Propensity Scores Adjusted Analysis. Chest 2013;144:152
  42. Evans and Green. ASH evidence-based guidelines: statins in the prevention of venous thromboembolism. Hematology 2009;273
  43. Kunutsor et al. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol 2017;4:e83 (25% risk reduction with statins; rosuvastatin appears most effective)
VTE recurrence risk
  1. Kyrle et al. Risk assessment for recurrent venous thrombosis. Lancet 2010;376:2032
  2. Kyrle et al. The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. J Thromb Haemost 2016;14: 2402 (Male sex, proximal DVT or PE associated with highest recurrence risk)
  3. Bjøri et al. Hospital-related first venous thromboembolism and risk of recurrence. J Thromb Haemost 2016;14:2368
  4. Hron et al. Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation. JAMA 2006;296:397
  5. Alikhan et al. Risk Factors for Venous Thromboembolism in Hospitalized Patients With Acute Medical Illness. Analysis of the MEDENOX Study. Arch Intern Med 2004;164:963
  6. Fox et al. The relationship between inflammation and venous thrombosis A systematic review of clinical studies. Thromb Haemost 2005;94:362
  7. Baglin et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.  Lancet 2003;362:523
  8. Christiansen et al. Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events.  JAMA. 2005;293:2352 (Clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy)
  9. Prandoni et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007;92:199 (Unprovoked VTE had 2.3 fold higher recurrence risk)
  10. Iorio et al. Risk of Recurrence After a First Episode of Symptomatic Venous Thromboembolism Provoked by a Transient Risk Factor. A Systematic Review. Arch Intern Med 2010;170:1710 ("The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked")
  11. Lindmarker et al. The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. J Int Med 2000;247:601 (High risk of recurrence in contralateral leg)
  12. Coppens et al. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 6:1474
  13. Kearon et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008; 112:4432 (single or multiple thrombophilic defects not associated with higher risk of recurrence during warfarin Rx; possible increased risk with APL antibody)
  14. Lijfering et al. Risk of Recurrent Venous Thrombosis in Homozygous Carriers and Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A. Circulation 2010;121:1706 (Homozygotes had only a 1.2-fold increased risk of recurrent VTE)
  15. McRae et al. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006;368:371 (Men have 50% higher risk of recurrence than women)
  16. Roach et al. Sex Difference in Risk of Second but Not of First Venous Thrombosis. Paradox Explained. Circulation 2014;129:51 (Hormone Rx, pregnancy major contributors to risk of first VTE episode in women; men have 2x higher recurrence risk)
  17. Eichinger et al. Risk Assessment of Recurrence in Patients With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism. The Vienna Prediction Model. Circulation 2010;121:1630 (Male sex, proximal DVT or PE, and high D-dimer independent predictors of recurrence)
  18. Roach et al. Sex difference in the risk of recurrent venous thrombosis: a detailed analysis in four European cohorts. J Thromb Haemost 2015;13:1815 (Men have 2x higher recurrence risk then women without "reproductive risk factors")
  19. Tritschler et al. Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model. Blood 2015;126:1949 (Model does not work well in older patients)
  20. Cushman et al. Hormonal factors and risk of recurrent venous thrombosis: the Prevention of Recurrent Venous Thromboembolism trial. J Thromb Haemost 2006;4:2199 (OCP or estrogen-related VTE has lower recurrence risk)
  21. Le Gal et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Thromb Haemost 2010; 104:498 (Recurrence risk low, but not lower than risk in women with VTE not related to estrogen use)
  22. Eischer et al. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemost 2014;12:635 (Low risk of recurrence - 6% in 5 yrs - after stopping anticoagulation)
  23. Novacek et al. Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism. Gastroenterology 2010;139:779
  24. Palla et al. The clinical course of pulmonary embolism patients anticoagulated for 1 year: results of a prospective, observational, cohort study. J Thromb Haemos 2010;8:68. (9.6% recurrence rate. 80% of recurrences happened within 10 days of dx and 75% of recurrences were fatal)
  25. Douketis et al. The Risk for Fatal Pulmonary Embolism after Discontinuing Anticoagulant Therapy for Venous Thromboembolism. Ann Intern Med 2007;147:766 (0.19-0.49 events per 100 person-years)
  26. Palareti et al.  D-dimer testing to determine the duration of anticoagulation therapy. NEJM 2006;355:1780
  27. Verhovsek et al. Systematic Review: D-Dimer to Predict Recurrent Disease after Stopping Anticoagulant Therapy for Unprovoked Venous Thromboembolism. Ann Intern Med 2008;149:481 (positive D-dimer associated with 9% annual recurrence risk after stopping treatment, vs 3.5% for negative D-dimer)
  28. Palareti et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014;124:196 (Negative D-dimer, using age- and gender-specific cutoffs, during and after anticoagulant therapy predicts a lower risk of recurrent VTE after stopping treatment)
  29. Kearon et al. D-Dimer Testing to Select Patients With a First Unprovoked Venous Thromboembolism Who Can Stop Anticoagulant Therapy: A Cohort Study. Ann Intern Med 2015;162:27 (Negative D-dimer not sufficient evidence to stop treatment in men with unprovoked VTE; test was helpful in women with estrogen-associated VTE)
  30. Prandoni et al.  The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med 1996;125:1
  31. Seinturier et al. Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study. J Thromb Haemost 2006;3:1362 (Proximal DVT has higher recurrence risk than distal DVT)
  32. Galanaud et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost 2014;12:436 (2.7% annualized recurrence rate, vs 5.2% for proximal DVT)
  33. Prandoni et al.  Residual Venous Thrombosis as a Predictive Factor of Recurrent Venous Thromboembolism. Ann Intern Med. 2002;137:955
  34. Siragusa et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood 2008;112:511 (absence of residual clot by US associated with low rate of VTE recurrence)
  35. Eichinger et al. Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism. Arch Intern Med 2008;168:1678 (1.6-fold higher recurrence rate in obese individuals)
  36. Grifoni et al.Association of Persistent Right Ventricular Dysfunction at Hospital Discharge After Acute Pulmonary Embolism With Recurrent Thromboembolic Events. Arch Intern Med 2006;166:2151
  37. White et al. Death due to recurrent thromboembolism among younger healthier individuals hospitalized for idiopathic pulmonary embolism. Thromb Haemost 2008;99:683
Secondary prevention of venous thromboembolism
  1. Hull et al.  Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. NEJM 1982;307:1676
  2. Kearon et al.  Comparison of Low-Intensity Warfarin Therapy with Conventional-Intensity Warfarin Therapy for Long-Term Prevention of Recurrent Venous Thromboembolism.  NEJM 2003;349:631
  3. Ridker et al.  Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism.  NEJM 2003;348:1425
  4. Ost et al. Duration of Anticoagulation Following Venous Thromboembolism. A Meta-analysis.  JAMA 2005;294:706
  5. Palareti et al.  D-dimer testing to determine the duration of anticoagulation therapy. NEJM 2006;355:1780
  6. Schulman et al. A Comparison of Six Weeks with Six Months of Oral Anticoagulant Therapy after a First Episode of Venous Thromboembolism. NEJM 1995;332:1661
  7. Schulman et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006;4:734 (10 year followup of above trial)
  8. Prandoni et al. Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis. A Randomized Trial. Ann Intern Med 2009;150:577 (Prolonging duration of anticoagulation benefits patients with residual clot) (see also the accompanying editorial)
  9. Schulman et al. The Duration of Oral Anticoagulant Therapy after a Second Episode of Venous Thromboembolism. NEJM 1997;336:393
  10. Kearon et al.  A Comparison of Three Months of Anticoagulation with Extended Anticoagulation for a First Episode of Idiopathic Venous Thromboembolism. NEJM 1999;340:901
  11. Agnelli et al. Three Months versus One Year of Oral Anticoagulant Therapy for Idiopathic Deep Venous Thrombosis. NEJM 2001;345:165
  12. Agnelli et al.  Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism.  Ann Intern Med 2003;139:19
  13. Couturaud et al. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. JAMA 2015;314:31 (24 mo vs 6 mo of anticoagulation after unprovoked PE decreased recurrence risk, increased bleeding risk, did not affect mortality. Benefit not maintained after therapy stopped)
  14. Hull and Townshend. Long-term treatment of deep-vein thrombosis with low-molecular-weight heparin: An update of the evidence. Thromb Haemost 2013;110:14
  15. Lee et al.  Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. NEJM 2003;349:146
  16. Becattini et al. Aspirin for preventing the recurrence of venous thromboembolism. NEJM 2012;366:1959 (100 mg/day aspirin reduced recurrence rate from 11.2% to 6.6% with no increase in major bleeding; with editorial)
  17. Simes et al Aspirin for the Prevention of Recurrent Venous Thromboembolism. The INSPIRE Collaboration. Circulation 2014;130:1062 (ASA reduces recurrence rate by about one-third, does not increase bleeding risk; with editorial)
  18. Sardar et al. Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Thromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials. Drugs 2013; 73:1171
  19. Lyman et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer. J Clin Oncol 2007;25:5490
  20. Schmidt et al. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case–control study. J Thromb Haemost 2014;12:1207 (Statin use reduced VTE recurrence risk by about 30%; with commentary)
Postphlebitic syndrome and chronic venous insufficiency
  1. Kahn et al. Guidance for the prevention and treatment of the post-thrombotic syndrome. J Thromb Thrombolysis 2016;41:144
  2. Jain and Cifu. Prevention, diagnosis and treatment of postthrombotic syndrome. JAMA 2016;315:1048
  3. Baldwin et al. Post-thrombotic syndrome: a clinical review. J Thromb Haemost 2013;11:795
  4. Schulman et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006;4:734
  5. Kahn et al. Determinants and Time Course of the Postthrombotic Syndrome after Acute Deep Venous Thrombosis. Ann Intern Med 2008;149:698
  6. Kahn S. How I treat postthrombotic syndrome. Blood 2009;114:4624
  7. Bergan et al. Chronic venous disease. NEJM 2006;355:488
  8. Kahn S. The post-thrombotic syndrome: progress and pitfalls. Br J Haematol 2006;134:357
  9. de Araujo et al.  Managing the patient with venous ulcers.  Ann Intern Med 2003;138:326
  10. Raju and Neglén. Chronic venous insufficiency and varicose veins. NEJM 2009;360:2319
  11. Prandoni et al. Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial. Blood 2012;119:1561 (No advantage to thigh-high stockings)
  12. Kahn et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014;383:880 (Stockings did not prevent PTS)
  13. Cushman et al. Risk factors for peripheral venous disease resemble those for venous thrombosis: the San Diego Population Study. J Thromb Haemost 2010;8:1730
  14. Galanaud et al. Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency. J Thromb Haemost 2013;11:474 (Obesity and contralateral venous insufficiency increase risk of PTS)
  15. Bharath et al. Genetic polymorphisms of vein wall remodeling in chronic venous disease: a narrative and systematic review. Blood 2014;124:1242

VTE and oral contraceptives or hormone replacement therapy

  1. Canonico et al. Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study. Circulation 2007;115:840 (Oral but not transdermal estrogens increased VTE risk)
  2. Roach et al. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013;11:124 (OC users had 6.3 fold greater VTE risk, HRT uses had 4-fold greater risk; non-oral HRT safe)
  3. Kujovich J.  Hormones and pregnancy: thromboembolic risks for women.  Br J Haematol 2004;126:443
  4. van Vlijmen et al. The impact of a male or female thrombotic family history on contraceptive counseling: a cohort study. J Thromb Haemost 2016;14:1741 (FH of hormone-related VTE increases risk)
  5. Gomes and Dietcher.  Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy.  A Clinical Review.  Arch Intern Med 2004;164:1965
  6. van Vlijmen et al. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016;14:1393 (FVL or prothrombin mutation alone not sufficient reason to withhold OC)
  7. van Hylckama Vlieg and Middeldorp. Hormone therapies and venous thrombembolism: where are we now? J Thromb Haemost 2011;9:257
  8. Sweetland et al. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 2012;10:2277 (Highest risk with estrogen-progestin combination, no increased risk with transdermal estrogen)
  9. Bird et al. Drospirenone and non-fatal venous thromboembolism: is there a risk difference by dosage of ethinyl-estradiol? J Thromb Haemost 2013;11:1059
  10. Holmegard et al. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost 2014;12:297 (High endogenous estradiol or testosterone levels did not increase VTE risk)
  11. Eischer et al. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemost 2014;12:635 (Low risk of recurrence - 6% in 5 yrs - after stopping anticoagulation)
  12. Martinelli et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016;127:1417 (Estrogen-containing hormonal therapy is safe in an anticoagulated patient)

Pregnancy

  1. Bates et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S
  2. Bates et al. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis 2016;41:92
  3. Greer I. Pregnancy complicated by venous thrombosis. NEJM 2015;373:540
  4. Middeldorp S. How I treat pregnancy-related venous thromboembolism. Blood 2011;118:5394
  5. Sultan et al. Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood 2014;124:2872 (Preeclampsia and postpartum infection, BMI>30 or C-section associated with increased risk for 6 weeks pospartum; postpartum hemorrhage and preterm birth increased risk during 1st 3 weeks only)
  6. Romualdi et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2013;11:270
  7. Heit et al. Trends in the Incidence of Venous Thromboembolism during Pregnancy or Postpartum: A 30-Year Population-Based Study. Ann Intern Med 2005;143:697
  8. James A. Pregnancy-associated thrombosis. Hematology 2009;277
  9. Marki and Plante. Venous thromboembolic disease and pregnancy. NEJM 2008;359;2025
  10. Bourjeily et al. Pulmonary embolism in pregnancy. Lancet 2010; 375:500
  11. American College of Obstetricians and Gynecologists Practice Bulletin: Thromboembolism in pregnancy. Obst Gynecol 2011;118:718
  12. Heit et al. Trends in the Incidence of Venous Thromboembolism during Pregnancy or Postpartum: A 30-Year Population-Based Study. Ann Intern Med 2005;143:697
  13. Blanco-Molina et al. Venous thromboembolism during pregnancy or postpartum: Findings from the RIETE Registry. Thromb Haemost 2007;97:186 (40% of VTE episodes occurred in 1st trimester)
  14. Blanco-Molina et al. Venous thromboembolism during pregnancy, postpartum or during contraceptive use. Findings from the RIETE Registry. Thromb Haemost 2010; 103:306
  15. Kamel et al. Risk of a thrombotic event after the 6-week postpartum period. NEJM 2014;370:1307 (11-fold increased risk of thrombosis in first 6 weeks after delivery, 2-fold increased risk in next 6 weeks)
  16. Sultan et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 2013;121:3953 (Stillbirth, C-section, obstetric hemorrhage, medical comorbidities and BMI > 30 strong risk factors for postpartum VTE)
  17. Revel et al. Contribution of indirect computed tomographic venography to the diagnosis of postpartum venous thromboembolism. J Thromb Haemost 2008;6:1478 (21% of CTV studies positive, showing ovarian or iliac thrombosis)
  18. Schaefer et al. Vitamin K antagonists and pregnancy outcome - A multi-centre prospective study. Thromb Haemost 2006;95:949 (relatively small risk of embryopathy)
  19. De Stefano et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006;135:386 (Highest recurrence risk if prior VTE during pregnancy, estrogen use, or unprovoked)
  20. Greer and Nelson-Piercy. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401
  21. Patel et al. Population Pharmacokinetics of Enoxaparin During the Antenatal Period. Circulation 2013;128:1462 (Half-life of enoxaparin prolonged in later pregnancy, once-daily administration may be appropriate)
  22. Salim et al. Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women. A randomised controlled trial. Thromb Haemost 2016; 116:687 (Adjusting dose according to anti-Xa levels did not improve outcomes)
  23. Mazzolai et al. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006;108:1569
  24. Patel and Hunt. Where do we go now with low molecular weight heparin use in obstetric care? J Thromb Haemost 2008;6:1461
  25. Bates and Ginsberg.  How we manage venous thromboembolism during pregnancy.  Blood 2002;100:3470
  26. Kujovich J.  Hormones and pregnancy: thromboembolic risks for women.  Br J Haematol 2004;126:443
  27. James et al. Acute Myocardial Infarction in Pregnancy: A United States Population-Based Study. Circulation 2006 (3-4 fold increased risk of MI during pregnancy)
  28. Mantha et al. Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review. J Thromb Haemost 2010;8:263 (Not enough evidence to justify routine use of LMWH in this setting)
  29. Rodger et al. Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood 2014;123:822 (LMWH treatment reasonable in women with hx of late pregnancy loss, pre-eclampsia, placental abruption, or SGA newborn)
  30. Kaandorp et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. NEJM 2010;362:1586 (Neither treatment improved live-birth rate)
  31. Clark et al. SPIN: the Scottish Pregnancy Intervention Study: a multicentre randomised controlled trial of low molecular weight heparin and low dose aspirin in women with recurrent miscarriage. Blood 2010;115:4162 (Antithrombotic treatment did not improve live-birth rate)
  32. Visser et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. Thromb Haemost 2011;105:295 (no significant difference in live birth rates comparing enoxaparin, aspirin, or enoxaparin plus aspirin)
  33. Schleussner et al. Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss: A Multicenter Trial With a Minimization Randomization Scheme. Ann Intern Med 2015;162:601 (No improvement in live-birth rates with LMWH injections)
  34. Martinelli et al. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood 2012;119:3269 (LMWH did not prevent late pregnancy complications)
  35. Pasquier et al. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood 2015;125:2200 (No apparent benefit from enoxaparin treatment)
  36. Gris et al. Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. Thromb Haemost 2011;106:1053 (Enoxaparin 40 mg/day decreased inicidence of pregnancy complication from 25% to 9%)
  37. Kingdom and Drewlo. Is heparin a placental anticoagulant in high-risk pregnancies? Blood 2011;118:4780
  38. Özkan et al. Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve Thrombosis in Pregnancy With Low-Dose, Slow Infusion of Tissue-Type Plasminogen Activator. Circulation 2013;128:532
  39. van Hagen et al. Pregnancy in Women With a Mechanical Heart Valve. Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation 2015;132:132 (Only 58% of pregnancies were uncomplicated and resulted in a live birth; with editorial)

Other aspects of venous thromboembolic disease

  1. Ageno et al. Guidance for the management of venous thrombosis in unusual sites. J Thromb Thrombolysis 2016;41:129
  2. Kucher N. Deep-vein thrombosis of the upper extremities. NEJM 2011; 364:861
  3. Bleker et al. Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis. J Thromb Haemost 2016;14:973
  4. Kleinjan et al. Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management Study. Ann Intern Med 2014;160:451
  5. Sartori et al. Whole-Arm Ultrasound to Rule Out Suspected Upper-Extremity Deep Venous Thrombosis in Outpatients. JAMA Intern Med 2015;175:1226 (>98% sensitivity; editorial)
  6. Lechner et al. Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence. J Thromb Haemost 2008; 6:1269 (lower incidence of thrombophilia, PE risk, and recurrence risk with arm DVT)
  7. Linneman et al. Hereditary and acquired thrombophilia in patients with upper extremity deep-vein thrombosis - Results from the MAISTHRO registry. Thromb Haemost 2008;100:440
  8. Muñoz et al. Clinical outcome of patients with upper-extremity deep vein thrombosis. Results from the RIETE registry. Chest 2008;133:143
  9. Flinterman et al. Recurrent Thrombosis and Survival After a First Venous Thrombosis of the Upper Extremity. Circulation 2008;118:1366
  10. Van Rooden et al. Deep vein thrombosis associated with central venous catheters – a review. J Thromb Haemost 2005;3:2409
  11. Baskin et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159
  12. Barco et al. Home parenteral nutrition-associated thromboembolic and bleeding events: results of a cohort study of 236 individuals. J Thromb Haemost 2016;14:1364
  13. Evans et al. Risk of symptomatic DVT associated with peripherally inserted central catheters. Chest 2010;138:803 (Prior DVT, larger catheter, longer surgery duration predicted DVT)
  14. Winters et al. Central venous catheters and upper extremity deep vein thrombosis in medical inpatients: the Medical Inpatients and Thrombosis (MITH) Study. J Thromb Haemost 2015;13:2155 (Catheter-associated upper extremity clots account for half of hospital-acquired DVTs in medical patients; risk higher with peripherally-inserted catheters)
  15. Young et al. Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet 2009;373:567 (warfarin 1 mg/day did not reduce incidence of catheter-related thrombosis; adjusting to INR 1.5-2 reduced incidence slightly, but with more bleeding)
  16. Martinelli et al. How I treat rare venous thromboses. Blood 2008;112:4818
  17. Menon et al.  Budd-Chiari syndrome.  NEJM 2004;350:578
  18. Ageno et al. Incidence rates and case fatality rates of portal vein thrombosis and Budd-Chiari Syndrome. Thromb Haemost 2017;117:794
  19. Clair et al. Mesenteric ischemia. NEJM 2016;374:959
  20. Murad et al. Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Interm Med 2009;151:167 (50% of patients in this series had a myeloproliferative disorder)
  21. Ageno et al. How I treat splanchnic vein thrombosis. Blood 2014;124:3685
  22. Ageno et al. Long-term Clinical Outcomes of Splanchnic Vein Thrombosis. Results of an International Registry. JAMA Intern Med 2015;175:1474 ("Most patients with SVT have a substantial long-term risk of thrombotic events...anticoagulant treatment appears to be safe and effective in most patients")
  23. De Gottardi et al. Antithrombotic treatment with direct-acting oral anticoagulants (DOACs) in patients with splanchnic vein thrombosis and cirrhosis. Liver Int 2016 (Epub) (Retrospective analysis of 94 cases; DOACs appear effective and safe)
  24. Boissinot et al. Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis. Blood 2006;108:3223
  25. Smalberg et al. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012;120:4921 (30-40% of patients with splanchnic vein thrombosis have a myeloproliferative disorder or bear the JAK2 mutation)
  26. Dentali et al. Inherited thrombophilic abnormalities and risk of portal vein thrombosis - A meta-analysis. Thromb Haemost 2008;99:675
  27. Amitrano et al. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007;102:2464 (Anticoagulation allows recanalization in 45%; most recurrences in non-anticoagulated patients with myeloproliferative disorders)
  28. Plessier et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 2010;51:210 (Recanalization occurs in 1/3 who get early anticoagulation; thrombus extension, intestinal infarction, severe bleeding and death are "rare")
  29. Spaander et al. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J Thromb Haemost 2013;11:452 (Recurrent thrombosis more common in patients with inherited or acquired prothrombotic conditions)
  30. Villa et al. Enoxaparin Prevents Portal Vein Thrombosis and Liver Decompensation in Patients With Advanced Cirrhosis. Gastroenterology 2012;143:1263 (Lower incidences of PVT, liver decompensation & death in enoxaparin-treated pts; no bleeding events)
  31. Hoekstra et al. Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms. J Thromb Haemost 2011;9:2208 (Recurrent or progressive thrombosis in up to 50%; mortality mainly due to underlying disease rather than thrombosis)
  32. Riva et al. Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study. J Thromb Haemost 2015;13:1019 (Major bleeding rate 1.24/100 pt-yrs in this cohort of selected patients, similar to rates reported for other VTE patients; presence of varices an independent predictor of bleeding)
  33. Riva et al. Clinical history and antithrombotic treatment of incidentally detected splanchnic vein thrombosis: a multicentre, international prospective registry. Lancet Haematol 2016;3:e267 (Prognosis similar to that of clinically suspected SVT, antithrombotic therapy appeared beneficial; most patients had cirrhosis or cancer)
  34. Coutinho and Stam. How to treat cerebral venous and sinus thrombosis. J Thromb Haemost 2010;8:877
  35. Stam J. Thrombosis of the cerebral veins and sinuses.  NEJM 2005;352:1791
  36. Dentali et al. Natural history of cerebral vein thrombosis: a systematic review.  Blood 2006;108:1129
  37. Canhão et al. Causes and predictors of death in cerebral venous thrombosis. Stroke 2005;36:1720
  38. Ferro et al. Prognosis of Cerebral Vein and Dural Sinus Thrombosis. Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;35:664
  39. Stam J. Thrombosis if the cerebral veins and sinuses.  NEJM 2005;352:1791
  40. Martinelli et al. Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis. Circulation 2010;121:2740 (3% had recurrent CST and 7% had DVT or PE; most recurrences in first year after stopping treatment)
  41. Rehak and Wiedemann. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost 2010;8:1886
  42. Janssen et al. Retinal vein occlusion: A form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 2005; 93: 1021
  43. Kuhli-Hattenbach et al. Coagulation disorders and the risk of retinal vein thrombosis. Thromb Haemost 2010;103:299 (Young age, family history, absence of cardiovascular risk factors increased likelihood of thrombophilia in RVT)
  44. Squizzato et al. Antithrombotic and fibrinolytic drugs for retinal vein occlusion: A systematic review and a call for action. Thromb Haemost 2010;103:271
  45. Wong and Scott. Retinal-vein occlusion. NEJM 2010;363:2135
  46. Wysokinska et al. Ovarian vein thrombosis: Incidence of recurrent venous thromboembolism and survival. Thromb Haemost 2006;96:126
  47. Barham and Shah. Phlegmasia cerulea dolens.  NEJM 2007;356:e3
  48. Ocak et al. Venous and arterial thrombosis in dialysis patients. Thromb Haemost 2011;106:1046
  49. Lamontagne et al. Nonleg Venous Thrombosis in Critically Ill Adults. A Nested Prospective Cohort Study. JAMA Int Med 2014;174:689

Superficial venous thrombosis

  1. Cosmi B. Management of superficial venous thrombosis. J Thromb Haemost 2015;13:1175
  2. Kitchens CS. How I treat superficial venous thrombosis. Blood 2011;117:39
  3. Decousus et al. Superficial Venous Thrombosis and Venous Thromboembolism. A Large, Prospective Epidemiologic Study. Ann Intern Med 2010;152:218 (25% of patients had DVT or PE at diagnosis; another 10% had VTE within 3 months)
  4. Decousus et al. Fondaparinux for the Treatment of Superficial-Vein Thrombosis in the Legs. NEJM 2010;363:1222 (Plus editorial)
  5. Beyer-Westendorf et al. Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial. Lancet Haematol 2017; 4:e105 (Rivaroxaban 10 mg/d as effective and safe as fondaparinux 2.5 mg/d)
  6. Leizorovicz et al. Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study. Blood 2013;122:1724 (Symptomatic extension of SVT occured in 7.3% of placebo-treated patients in above study; about 9% of patients with extension developed DVT or PE)
  7. van Langevelde et al. Increased risk of venous thrombosis in persons with clinically diagnosed superficial vein thrombosis: results from the MEGA study. Blood 2011;118:4239 (6-fold increased risk of DVT, 4-fold increased risk of PE)
  8. Roach et al. The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood 2013;122:4264 (Surgery, cast immobilization, pregnancy, or cancer + hx SVT = 30x higher DVT risk)
  9. Cannegieter et al. Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study. Blood 2015;125:229 (3.4% incidence of DVT or PE within 3 mo of isolated SVT; risk remains high for over 5 y)
  10. Di Minno et al. Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2016;14:964 (DVT and PE prevalence in patients with SVT about 18% and 7% respectively)
  11. Frappé et al. Annual diagnosis rate of superficial vein thrombosis of the lower limbs: the STEPH community-based study. J Thromb Haemost 2014;12:831 (Incidence 0.64%/yr; 25% had concomitant DVT, 5% had PE)

Chronic thromboembolic pulmonary hypertension

  1. Piazza and Goldhaber. Chronic thromboembolic pulmonary hypertension. NEJM 2011;364:351
  2. Hoepner et al. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011
  3. Lang and Kerr. Risk factors for chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006;3:568
  4. Pengo et al. Incidence of Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism.  NEJM 2004;350:2257
  5. Condliffe et al. Improved Outcomes in Medically and Surgically Treated Chronic Thromboembolic Pulmonary Hypertension. Am J Respir Crit Care Med 2008; 177:1122
  6. Pepke-Zaba et al. Chronic thromboembolic pulmonary hypertension (CTEPH). Results from an international prospective registry. Circulation 2011;124:1973
  7. Delcroix et al. Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension. Results From an International Prospective Registry. Circulation 2016;133:859 (3-year survival nearly 90% in both operated and non-operated patients)
  8. Guérin et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014;112:598 (Higher incidence than previously thought; presentation can mimic acute PE)
  9. Suntharalingam et al. Long-term Use of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension. Chest 2008;134:229
  10. Lang et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. Thromb Haemst 2013;110:83 (Younger age, proximal clot, lower pulmonary vascular resistance associated with better surgical outcomes)

Vena cava filters

  1. Duffett and Carrier. Inferior vena cava filters. J Thromb Haemost 2017;15:3
  2. White et al. High Variation Between Hospitals in Vena Cava Filter Use for Venous Thromboembolism. JAMA Intern Med 2013;173:506
  3. Decousus et al. A Clinical Trial of Vena Caval Filters in the Prevention of Pulmonary Embolism in Patients with Proximal Deep-Vein Thrombosis. NEJM 1998;338:409
  4. The PREPIC Study Group. Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism. The PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) Randomized Study. Circulation 2005;112:416 (8 year followup of above trial; filters decreased PE risk, increased DVT risk, and did not affect survival)
  5. Mismetti et al. Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism: A Randomized Clinical Trial. JAMA 2015;313:1627 (More recurrent PE in filter group than in control group)
  6. White et al. Outcomes After Vena Cava Filter Use in Noncancer Patients With Acute Venous Thromboembolism. A Population-Based Study. Circulation 2016;133:2018 (Filters reduced mortality in patients with acute VTE and contraindication to anticoagulation, not in other patients; they markedly increased risk of subsequent DVT. With editorial)
  7. Spencer et al. A Population-Based Study of Inferior Vena Cava Filters in Patients With Acute Venous Thromboembolism. Arch Intern Med 2010;170:1456 (13% of patients had IVC filters placed after acute VTE. Filters used inappropriately in at least 26% of cases)
  8. Sarosiek et al. Indications, Complications, and Management of Inferior Vena Cava FiltersThe Experience in 952 Patients at an Academic Hospital With a Level I Trauma Center. JAMA Intern Med 2013;173:513 (Only 8.5% of "removable" filters removed; 7.8% incidence of VTE with filter in place. With editorial)
  9. Hajduk et al. Vena Cava Filter Occlusion and Venous Thromboembolism Risk in Persistently Anticoagulated Patients. A Prospective, Observational Cohort Study.Chest 2010;137:877
  10. Streiff M.  Vena caval filters: a comprehensive review.  Blood 2000;95:3669
  11. Ku and Billett. Long lives, short indications.  The case for removable vena cava filters. Thromb Haemost 2005;93:17
  12. Nicholson et al. Prevalence of Fracture and Fragment Embolization of Bard Retrievable Vena Cava Filters and Clinical Implications Including Cardiac Perforation and Tamponade. Arch Intern Med 2010;170:1827 (16% incidence of strut fracture, some with life-threatening consequences)
  13. Desai et al. Retrieval of Inferior Vena Cava Filters With Prolonged Dwell Time. A Single-Center Experience in 648 Retrieval Procedures. JAMA Intern Med 2015;175:1572 (Removing retrievable filters safe regardless of dwell time)
  14. Rajasekhar and Crowther. ASH evidence-based guidelines: what is the role of inferior vena cava filters in the perioperative prevention of venous thromboembolism in bariatric surgery patients? Hematology 2009;302
  15. Imberti et al. Evidence and clinical judgement: vena cava filters. Thromb Haemost 2014;11: 618
  16. Jia et al. Caval Penetration by Inferior Vena Cava Filters. A Systematic Literature Review of Clinical Significance and Management. Circulation 2015;132:944 (19% incidence; most patients asymptomatic but about 1/5 had organ or structural damage)

Arterial disease

Arterial thrombosis: general

  1. Vandvik et al. Primary and Secondary Prevention of Cardiovascular Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e637S
  2. Jackson S. Arterial thrombosis - insidious, unpredictable and deadly. Nat Med 2011;17:1423
  3. Davi et al. Platelet activation and atherothrombosis. NEJM 2007;357:2482
  4. Rothwell et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 2005;366;1773
  5. Lidegaard et al. Thrombotic stroke and myocardial infarction with hormonal contraception. NEJM 2012;366:2257 (Relative risk of arterial events increased with increasing dose of ethinyl estradiol)
  6. Vidula et al. Biomarkers of Inflammation and Thrombosis as Predictors of Near-Term Mortality in Patients with Peripheral Arterial Disease: A Cohort Study. Ann Intern Med 2008;148:85
  7. Levine et al. Venous and arterial thromboembolism in severe sepsis. Thromb Haemost 2008;99:892 (3.2% of patients with sepsis had thromboembolic event within 28 days of hospitalization; most events were arterial)
  8. Green D. Risk of future arterial cardiovascular events in patients with idiopathic venous thromboembolism. Hematology 2009;259
  9. Phillips et al. Therapeutic approaches in arterial thrombosis. J Thromb Haemost 2005;3:1577
  10. Bates and Lau.  Controversies in antiplatelet therapy for patients with cardiovascular disease.  Circulation 2005;111:e267
  11. Fries and Grosser. The Cardiovascular Pharmacology of COX-2 Inhibition. Hematology 2005:445-451
  12. Ridker et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. NEJM 2005;352:1293  (aspirin lowered risk of stroke, but not risk of MI or cardiovascular death, in healthy women over 45 years)
  13. Dentali et al. Combined Aspirin and Oral Anticoagulant Therapy Compared With Oral Anticoagulant Therapy Alone Among Patients at Risk for Cardiovascular Disease. A Meta-analysis of Randomized Trials. Arch Intern Med 2007;167:117
  14. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral Anticoagulant and Antiplatelet Therapy and Peripheral Arterial Disease. NEJM 2007;357:217 (Adding warfarin to antiplatelet therapy did not increase efficacy but did increase bleeding risk. See also the accompanying editorial)
  15. Ruggeri Z.  Platelets in atherothrombosis.  Nat Med 2002;8:1227
  16. Patrono et al. Low-dose aspirin for the prevention of atherothrombosis. NEJM 2005;353:2373
  17. Antithrombotic Trialists' Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71
  18. Bhatt et al. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. NEJM 2006;354:1706  (Addition of clopidogrel to aspirin not significantly more effective than aspirin alone in reducing rate of MI, stroke, or death from cardiovascular disease)

Acute coronary syndromes/myocardial infarction

  1. Goodman et al. Acute ST-Segment Elevation Myocardial Infarction. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:708S
  2. Harrington et al. Antithrombotic Therapy for Non–ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:670S
  3. Anand et al. Relationship of Activated Partial Thromboplastin Time to Coronary Events and Bleeding in Patients With Acute Coronary Syndromes Who Receive Heparin. Circulation. 2003;107:2884
  4. FUTURA/OASIS-8 Trial Group. Low-Dose vs Standard-Dose Unfractionated Heparin for Percutaneous Coronary Intervention in Acute Coronary Syndromes Treated With Fondaparinux. JAMA 2010;304:1339 (Higher rates of death, MI and vessel occlusion, no less major bleeding with low-dose heparin)
  5. LaPointe et al. Enoxaparin Dosing and Associated Risk of In-Hospital Bleeding and Death in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes. Arch Intern Med 2007;167:1539
  6. Fox et al. Influence of Renal Function on the Efficacy and Safety of Fondaparinux Relative to Enoxaparin in Non–ST-Segment Elevation Acute Coronary Syndromes. Ann Intern Med 2007;147:304 (Fondaparinux safer in patients with impaired renal function)
  7. COMMIT collaborative group. Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607
  8. Blasco-Colmenares et al. Aspirin Plus Clopidogrel and Risk of Infection After Coronary Artery Bypass Surgery. Arch Intern Med 2009;169: 788 (50% increased incidence of infection associated with dual antiplatelet therapy, vs aspirin alone)
  9. Andersson et al. Association of Clopidogrel Treatment With Risk of Mortality and Cardiovascular Events Following Myocardial Infarction in Patients With and Without Diabetes. JAMA 2012;308:882 (Less benefit from clopidogrel in diabetics)
  10. Wiviott et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. NEJM 2007;357:2001 (Prasugrel treatment associated with fewer ischemic events but more bleeding)
  11. Montalescot et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:9665 (fewer ischemic events, no increased bleeding with prasugrel)
  12. Wiviott et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 371:1353 (Fewer ischemic events with prasugrel than with clopidogrel, no difference in severe bleeding)
  13. Morrow et al. Effect of the Novel Thienopyridine Prasugrel Compared With Clopidogrel on Spontaneous and Procedural Myocardial Infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38. Circulation 2009;119:2758 (24% reduction in MI risk with prasugrel)
  14. Wallentin et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. NEJM 2009;361:1045 (see also the accompanying editorial)
  15. Cannon et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375:283
  16. Bhatt et al. Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events. NEJM 2013;368:1303 (Cangrelor + ASA arm had fewer ischemic events than clopidogrel + ASA arm, no increased bleeding; with editorial)
  17. Stone et al. Antithrombotic Strategies in Patients With Acute Coronary Syndromes Undergoing Early Invasive Management. JAMA 2007;298:2497 (no benefit from adding IIb-IIIa inhibitors to bilvalirudin in angioplasty patients)
  18. Dumaine et al. Intravenous Low-Molecular-Weight Heparins Compared With Unfractionated Heparin in Percutaneous Coronary Intervention. Quantitative Review of Randomized Trials. Arch Intern Med 2007;167:2423 (LMWH heparin as effective as UH, causes less bleeding)
  19. Fox et al. Influence of Renal Function on the Efficacy and Safety of Fondaparinux Relative to Enoxaparin in Non–ST-Segment Elevation Acute Coronary Syndromes. Ann Intern Med 2007;147:304 (Fondaparinux safer in patients with impaired renal function)
  20. Szummer et al. Association Between the Use of Fondaparinux vs Low-Molecular-Weight Heparin and Clinical Outcomes in Patients With Non–ST-Segment Elevation Myocardial Infarction. JAMA 2015;313:707 (Fondaparinux treatment associated with less bleeding and lower mortality)
  21. Alexander et al. Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. NEJM 2011;365:699 (Apixaban increased bleeding, did not reduce ischemic events significantly)
  22. Oldgren et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013 (Epub)
  23. Dewilde et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107 (Double therapy associated with less bleeding, no increase in thrombotic events vs triple therapy)
  24. Yeh et al. Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. JAMA 2016;315:1735
  25. Steg et al. Anticoagulation With Otamixaban and Ischemic Events in Non–ST-Segment Elevation Acute Coronary Syndromes. The TAO Randomized Clinical Trial. JAMA 2013;310:1145 (No reduction in ischemic events vs heparin, more bleeding with this intravenous Xa inhibitor)
  26. James et al. Acute Myocardial Infarction in Pregnancy: A United States Population-Based Study. Circulation 2006  (3-4 fold increased risk of MI during pregnancy)

Stroke/embolism in heart disease (AF, CHF)

  1. You et al. Antithrombotic Therapy for Atrial Fibrillation. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e531S
  2. Whitlock et al. Antithrombotic and Thrombolytic Therapy for Valvular Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e576S
  3. Lip and Lane. Stroke prevention in atrial fibrillation: a systematic review. JAMA 2015;313:1950
  4. Steinberg BA..How I use anticoagulation in atrial fibrillation. Blood 2016;128:2891
  5. Lip et al. Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach. The Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263 (CHADS2-VASc score)
  6. Lip G. Can we preidict stroke risk in atrial fibrillation? Clin Cardiol 2012;35 (S1): 21
  7. Lane and Lip. Use of the CHA2DS2-VASc and HAS-BLED Scores to Aid Decision Making for Thromboprophylaxis in Nonvalvular Atrial Fibrillation. Circulation 2012;126:860
  8. Focks et al. Low performance of bleeding risk models in the very elderly with atrial fibrillation using vitamin K antagonists. J Thromb Haemost 2016;14:1715
  9. Melgaard et al. Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation. JAMA 2015;314:1030 (Higher score → higher risk, but predictive accuracy "modest")
  10. Bekwelem et al. Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation. Incidence, Risk Factors, and Outcomes. Circulation 2015;132:796 (0.24 events/100 patient-years or 11% of thromboembolic events in AF; 25% mortality; with editorial)
  11. McAlister elt al. The prediction of postoperative stroke or death in patients with preoperative atrial fibrillation undergoing non-cardiac surgery: a VISION sub-study. J Thromb Haemost 2015;13:1768
  12. Westenbrink et al. Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial. J Thromb Haemost 2015;13:699
  13. Marijon et al. Causes of Death and Influencing Factors in Patients with Atrial Fibrillation: A Competing Risk Analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy Study. Circulation 2013 (Epub) (Most deaths in anticoagulated patients not due to stroke)
  14. Gómez-Outes et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2016;23:2508 (Most deaths due to cardiac problems, with a small fraction of deaths due to stroke and bleeding; with editorial)
  15. Xian et al. Association of Preceding Antithrombotic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation. JAMA 2017;317: 1057 (84% of stroke patients with AF were inadequately anticoagulated; inadequately treated patients had more severe strokes and higher mortality)
  16. Torn et al. Optimal Level of Oral Anticoagulant Therapy for the Prevention of Arterial Thrombosis in Patients With Mechanical Heart Valve Prostheses, Atrial Fibrillation, or Myocardial Infarction. A Prospective Study of 4202 Patients. Arch Intern Med 2009;169:1203 (Optimal range 2.5-2.9 for prosthetic valves, 3.0-3.4 for AF, 3.5-3.9 for MI)
  17. Crandall et al. Contemporary management of atrial fibrillation: update on anticoagulation and invasive management strategies. Mayo Clin Proc 2009;84:643
  18. Adam et al. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med 2012;157:796
  19. Hughes et al. Stroke and thromboembolism in atrial fibrillation: A systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost 2008;99:295
  20. McBane et al. Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation. Thromb Haemost 2008;99:951 (Smaller emboli end up in brain; older patients and those with marked atrial enlargement tend to have larger emboli that end up in the periphery)
  21. Reynolds et al. Warfarin Anticoagulation and Outcomes in Patients With Atrial Fibrillation. Chest 2004126:1938 (Supports target INR range of 2-3)
  22. Singer et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297 (Patients over 85 and patients with a history of ischemic stroke benefit most; see also the accompanying editorial)
  23. Friberg et al. Net clinical benefit of warfarin in patients with atrial fibrillation. Circulation 2012;125:2298 (Risk of ischemic stroke without treatment exceeds risk of intracranial bleeding with treatment in almost all patients)
  24. Agarwal et al. Current Trial-Associated Outcomes With Warfarin in Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation: A Meta-analysis. Arch Intern Med 2012;172:623 (Annual incidence of stroke or embolism in warfarin-treated patients about 1.7%)
  25. Chao et al. Use of Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation Who Have a History of Intracranial Hemorrhage. Circulation 2016;133:1540 (Warfarin may benefit those with CHA2DS2-VASc score ≧6)
  26. Carrero et al. Warfarin, Kidney Dysfunction, and Outcomes Following Acute Myocardial Infarction in Patients With Atrial Fibrillation. JAMA 2014;311:991 (Benefits of warfarin not reduced in the presence of CKD)
  27. Shah et al. Warfarin Use and the Risk for Stroke and Bleeding in Patients With Atrial Fibrillation Undergoing Dialysis. Circulation 2014;129:1196 (Warfarin did not reduce stroke risk but did increase bleeding risk in dialysis pts with Afib)
  28. ACTIVE Investigators.  Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903 (Warfarin superior to antiplatelet therapy)
  29. ACTIVE Investigators. Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation. NEJM 2009;360:2066 (fewer strokes, more bleeding)
  30. Connolly et al. Net Clinical Benefit of Adding Clopidogrel to Aspirin Therapy in Patients With Atrial Fibrillation for Whom Vitamin K Antagonists Are Unsuitable. Ann Intern Med 2011;155:579 (Post-hoc analysis of the ACTIVE trial. "Modest" net clinical benefit from adding clopidogrel)
  31. Hart et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation. Ann Intern Med 2007;146:857 (Warfarin reduces stroke risk by 60%, ASA by 20%)
  32. Mant et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493 (Warfarin more effective in over-75 patients, bleeding risk no higher)
  33. Olesen et al Stroke and bleeding in atrial fibrillation with chronic kidney disease. NEJM 2012;367:625 (Increased risk of stroke or embolism in CKD; warfarin decreased risk, ASA did not; both drugs increased bleeding risk)
  34. Connolly et al. Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range. Circulation 2008;118:2029
  35. Steinberg et al. Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation. Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation 2013;128:721 (Adding ASA to warfarin increases major bleeding risk by 50%)
  36. Hansen et al. Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With Atrial Fibrillation. Arch Intern Med 2010;170:1433
  37. Lamberts et al. Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Risk in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy: A Nationwide Cohort Study. Ann Intern Med 2014;161:690 (Higher risk of bleeding and thromboembolism with NSAID use)
  38. Paciaroni and Agnelli. Should oral anticoagulants be restarted after warfarin-associated cerebral haemorrhage in patients with atrial fibrillation? Thromb Haemost 2014;11:14
  39. Connolly et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM 2009;361:1139 (Dabigatran as efficacious as warfarin, caused less bleeding. See also the accompanying editorial)
  40. Connolly et al. Apaxaban in patients with atrial fibrillation. NEJM 2011;364:806 (Apixaban better than aspirin in patients for whom warfarin treatment deemed "unsuitable")
  41. Gibson et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. NEJM 2016;375:2423 (Low dose rivaroxaban plus antiplatelet therapy caused less bleeding than warfarin plus antiplatelet therapy)
  42. Oldgren et al. Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS2 Score: A Subgroup Analysis of the RE-LY Trial. Ann Intern Med 2011;115:660 (Higher CHADS2 score→ more complications)
  43. Graham et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Int Med 2016;176:1662 (Relatively high risk of intra- and extracranial bleeding with rivaroxaban)
  44. Oral et al. Risk of Thromboembolic Events After Percutaneous Left Atrial Radiofrequency Ablation of Atrial Fibrillation. Circulation 2006;114:759 (1% risk of thromboembolism, usually within 2 weeks of procedure)
  45. Dotsenko and Kakkar. Antithrombotic therapy in patients with chronic heart failure: rationale, clinical evidence and practical implications. J Thromb Haemost 2007;5:224
  46. Homma et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. NEJM 2012; 366:1859 (Warfarin reduced risk of ischemic stroke vs aspirin but increased bleeding risk)
  47. Massie et al. Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial. Circulation 2009;119:1616 (No advantage to either warfarin or clopidogrel vs ASA)
  48. Delewi et al. Left ventricular thrombus formation after acute myocardial infarction. Heart 2012;98:1743
  49. Lee et al. Anticoagulation in ischemic left ventricular aneurysm. Mayo Clin Proc 2015;90:441 (Anticoagulation may not protect against embolism in this setting)
  50. Sherwood et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from ROCKET AF. Circulation 2014 (ePub). (Risk of stroke less than 0.5% per 30 days with either drug)

Prosthetic valves/LVADs

  1. Eikelboom et al. Dabigatran versus warfarin in patients with mechanical heart valves. NEJM 2013;369:1206 (Dabigatran treatment associated with more thrombosis and more bleeding; see also letters to the editor)
  2. Sun et al. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 2009;374:565
  3. Mérie et al. Association of Warfarin Therapy Duration After Bioprosthetic Aortic Valve Replacement With Risk of Mortality, Thromboembolic Complications, and Bleeding. JAMA 2012;308:2118 (Stopping warfarin within 6 mo of valve replacement associated with increased cardiovascular death)
  4. Makkar et al. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. NEJM 2015;373:2015 (22/55 patients had reduced leaflet motion after bioprosthetic valve placement; this resolved in all those patients treated with anticoagulation. With editorial)
  5. Meurin et al. Low-Molecular-Weight Heparin as a Bridging Anticoagulant Early After Mechanical Heart Valve Replacement. Circulation 2006;113:564
  6. Caldeira et al. Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: systematic review and meta-analysis. J Thromb Haemost 2014;12:650
  7. Gherli et al.  Comparing Warfarin With Aspirin After Biological Aortic Valve Replacement. A Prospective Study.  Circulation. 2004;110:496
  8. Castilho et al. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis. J Thromb Haemost 2014;12:1218 (Significantly less mortality with thrombolysis, more bleeding and embolic events with thrombolysis; no randomized trials. With editorial commentary)
  9. Özkan et al. Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve Thrombosis in Pregnancy With Low-Dose, Slow Infusion of Tissue-Type Plasminogen Activator. Circulation 2013;128:532
  10. Kreuziger et al. Antithrombotic therapy for left ventricular assist devices in adults: a systematic review. J Thromb Haemost 2015;13:946
  11. Eckman and John. Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation 2012;125:3038
  12. Susen et al. Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis. J Thromb Haemost 2015;13:1757
  13. Nascimbene et al. Acquired von Willebrand syndrome associated with left ventricular assist device. Blood 2016;127:3133

Stroke/TIA

  1. Lansberg et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e601S
  2. Paciaroni et al. Timing of anticoagulation therapy in patients with acute ischaemic stroke and atrial fibrillation. Thromb Haemost 2016;116:403
  3. Saver J. Cryptogenic stroke. NEJM 2016;374:2065
  4. Rothwell et al. Medical treatment in acute and long-term secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet 2011;377:1681
  5. O'Donnell et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376:112
  6. Pezzini et al. Predictors of Long-Term Recurrent Vascular Events After Ischemic Stroke at Young Age. The Italian Project on Stroke in Young Adults. Circulation 2014;129:1668
  7. Fagniez et al. Hematological disorders related cerebral infarction are mostly multifocal. J Neurol Sci 2011 (Epub)
  8. Blustin et al. The Association Between Thromboembolic Complications and Blood Group in Patients With Atrial Fibrillation. Mayo Clin Proc 2015;90:216 (Blood group O protective)
  9. Stoll et al. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008;112:3555
  10. Scott and Smith. Moyamoya Disease and Moyamoya Syndrome. NEJM 2009;360:1226
  11. Kizer and Devereux.  Patent foramen ovale in young adults with unexplained stroke.  NEJM 2005;353:2361
  12. Wöhrle J. Closure of patient foramen ovale after cryptogenic stroke (comment). Lancet 2006;368:350
  13. Handke et al. Patent Foramen Ovale and Cryptogenic Stroke in Older Patients. NEJM 2007;:357:2262
  14. Anzola et al. Patent foramen ovale (PFO) and cryptogenic stroke. J Thromb Haemost 2010;8:1675
  15. Furlan et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. NEJM 2012;366:991 (No advantage to closure vs medical therapy)
  16. Meier et al. Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism. NEJM 2013;368:1083 (No advantage to closure vs medical therapy)
  17. Carroll et al. Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke. NEJM 2013;368:1092 (Possible advantage to closure; with editorial)
  18. Naess et al. Do all young ischemic stroke patients need long-term secondary preventive medication? Neurology 2005;65:609
  19. Gladstone et al. Atrial fibrillation in patients with cryptogenic stroke. NEJM 2014;370:2467 (16% of patients with cryptogenic stroke aged 55 or older had episodes of AF when monitored for 30 days; editorial)
  20. Sanna et al. Cryptogenic stroke and underlying atrial fibrillation. NEJM 2014;370:2478 (9% of patients 40 and older with cryptogenic stroke found to have AF when monitored for 6 months with an insertable cardiac monitor; incidence rose to 12% at 12 mo; editorial)
  21. Shen et al. Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation. Blood 2016;127:1336
  22. Chalela et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369:293 (MRI more accurate than CT in diagnosis of acute stroke)
  23. Khaja and Grotta. Established treatments for acute ischaemic stroke.  Lancet 2007;369:319
  24. Wahlgren et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275 (Altepase safe and effective if used within 3 hours of stroke onset)
  25. Hacke et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. NEJM 2008;359:1317 (more favorable neurologic outcome with thrombolysis, despite higher rate of intracranial hemorrhage)
  26. Parsons et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. NEJM 2012;366:1099 (Tenecteplase gave superior outcomes)
  27. IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352
  28. Wardlaw et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012;379:2364
  29. Anderson et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. NEJM 2016;374:2313 (Outcomes similar with 0.6 mg/kg vs 0.9 mg/kg altepase in Asian patients; with editorial)
  30. Zhu et al. Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke. A Pilot Trial. Circulation 2015;132:1104 (25 pts; treatment appeared beneficial)
  31. Berkhemer et al. A randomized trial of intraarterial treatment for acute ischemic stroke. NEJM 2015;372:11 (Mechanical or thrombolytic intra-arterial treatment appears superior to standard care)
  32. Xian et al. Risks of Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Receiving Warfarin and Treated With Intravenous Tissue Plasminogen Activator. JAMA 2012;307:2600 (No increase in ICH rate for patients with INR 1.7 or less)
  33. Su et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 2008;14:731 (Imatinib reduces hemorrhagic complications following tPA treatment of stroke in mice)
  34. Saver et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. NEJM 2015;372:2285 (with editorial)
  35. Jovin et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. NEJM 2015;372:2296 (with editorial)
  36. Badhiwala et al. Endovascular Thrombectomy for Acute Ischemic Stroke. A Meta-analysis. JAMA 2015;314:1832 (Thrombectomy associated with improved functional outcome vs standard care with tPA)
  37. Zinkstock et al. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet 2013;380:26 (Higher risk of ICH, no improvement in neuro outcomes if ASA given prior to 24h after tPA)
  38. Chimowitz et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. NEJM 2005;352:1305 (Warfarin caused more bleeding and was no more effective in preventing stroke, brain hemorrhage, or death from vascular causes than aspirin)
  39. Halkes et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665 (Adding extended-release dipyridamole to aspirin reduces risk of death, stroke or MI by 18%)
  40. Sacco et al. Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke. NEJM 2008;359:1238 (Combined risk of stroke and major bleeding similar in both groups)
  41. SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. NEJM 2012;367:817 (Adding clopidogrel did not reduce stroke risk, increased risk of bleedig & death)
  42. Wang et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. NEJM 2013;369:11 (Adding clopidogrel to aspirin reduced stroke risk by about 30%, without increasing bleeding risk; with editorial)
  43. Johnston et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. NEJM 2016;375:35 (Ticagrelor not superior to ASA)
  44. Rothwell and Warlow. Timing of TIAs preceding stroke. Time window for prevention is very short. Neurology 2005;64: 772 (TIAs that precede a stroke usually do so by hours to a few days)
  45. Wu et al. Early risk of stroke after transient ischemic attack. A systematic review and meta-analysis. Arch Intern Med 2007;167:2417 (9% risk of stroke within 30 days)
  46. Johnston et al. National Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol 2006; 60:301
  47. Bos et al. Incidence and prognosis of transient neurological attacks. JAMA 2007;298:2877
  48. Sherman et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism
    after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007;369:1347
    (VTE risk 43% lower with enoxaparin than UFH)
  49. Paciaroni et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011;9:893 (Significant reduction in PE, non-significant decrease in mortality, increased risk of enlarging hematoma)

Peripheral vascular disease

  1. Alonso-Coello et al. Antithrombotic Therapy in Peripheral Artery Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e669S
  2. Creager et al. Acute limb ischemia. NEJM 2012;366:2198
  3. Piazza and Creager. Thromboangiitis obliterans. Circulation 2010;121:1858
  4. Andersen et al. Upper limb arterial thromboembolism: a systematic review on incidence, risk factors, and prognosis, including a meta-analysis of risk-modifying drugs. J Thromb Haemost 2013;11:836


Hypercoagulable disorders

General

  1. Nagalla and Bray. Personalized medicine in thrombosis: back to the future. Blood 2016;127:2665 (Discusses the challenges of using genetic testing in the diagnosis and management of thrombotic disorders)
  2. Stevens et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis 2016;41:154
  3. Ortel et al. How I treat catastrophic thrombotic syndromes. Blood 2015;126:1285
  4. Kitchens et al. Thrombotic storm revisited: preliminary diagnostic criteria suggested by the Thrombotic Storm Study Group. Am J Med 2011;124:290
  5. Middeldorp S. Is thrombophilia testing useful? Hematology 2011:150 ("Because testing for thrombophilia serves a limited purpose, this test should not be performed on a routine basis")
  6. De Stefano and Rossi. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost 2013;2013;110:697
  7. Rosendaal F. Venous Thrombosis: The Role of Genes, Environment, and Behavior. Hematology 2005:1-12.
  8. Margaglione and Grandone. Population genetics of venous thromboembolism. Thromb Haemost 2011;105:221
  9. Cushman M. Inherited Risk Factors for Venous Thrombosis. Hematology 2005:452-457
  10. Prandoni P. Acquired Risk Factors for Venous Thromboembolism in Medical Patients. Hematology 2005:458-461
  11. Bauer K.  Management of thrombophilia.  J Thromb Haemost 2003;1:1429
  12. Ho et al. Risk of Recurrent Venous Thromboembolism in Patients With Common Thrombophilia. A Systematic Review. Arch Intern Med 2006;166:729
  13. Bauer and Rosenberg. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70:343
  14. Bauer et al. Aging-associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest 1987; 80:1527
  15. Schreijer et al. Activation of coagulation system during air travel: a crossover study. Lancet 2006;367:832 (Interaction of inherited and acquired risk factors influenced hypercoagulability after 8 hour flight)
  16. Conway et al. Suppression of Hemostatic System Activation by Oral Anticoagulants in the Blood of Patients with Thrombotic Diatheses. J Clin Invest 1987;80:1535
  17. Favaloro E. Diagnostic Issues in Thrombophilia: A Laboratory Scientist's View. Semin Hematol 2005;31:11
  18. Tripodi A. A Review of the Clinical and Diagnostic Utility of Laboratory Tests for the Detection of Congenital Thrombophilia. Semin Hematol 2005;31:25
  19. Coppens et al. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 6:1474
  20. Rabinovich et al. Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. J Thromb Haemost 2014;12:14 (No association found)
  21. Wu et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94:17
  22. van Vlijmen et al. Oral Contraceptives and the Absolute Risk of Venous Thromboembolism in Women With Single or Multiple Thrombophilic Defects. Results From a Retrospective Family Cohort Study. Arch Intern Med 2007;167:282
  23. Hron et al. Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation. JAMA 2006;296:397
  24. Brooks et al. Valves of the deep venous system: an overlooked risk factor. Blood 2009;114:1276 (Variation in endothelial protein C receptor and thrombomodulin expression may be a factor in VTE pathogenesis)
  25. Undas et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009;114:4272
Inherited Thrombophilia
  1. Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008;112:19
  2. Mannucci and Franchini. Classic thrombophilic gene variants. Thromb Haemost 2015;114:885
  3. Morange et al. Genetics of venous thrombosis: update in 2015. Thromb Haemost 2015;114:910 ("Common polymorphisms are estimated to account for only about 5% of VT heritability")
  4. Tang and Hu. Ethnic diversity in the genetics of venous thromboembolism. Thromb Haemost 2015;114:901
  5. Caspers et al. Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort. Thromb Haemost 2012;108:247
  6. Heit J. Thrombophilia: common questions on laboratory assessment and management. Hematology 2007:127
  7. Pabinger et al. Mortality and inherited thrombophilia: results from the European Prospective Cohort on Thrombophilia. J Thromb Haemost 2012;10:217 (No increased mortality associated with inherited thrombophilia, regardless of whether there is a history of thrombosis)
  8. Bezemer et al. The Value of Family History as a Risk Indicator for Venous Thrombosis. Arch Intern Med 2009; 169:610 ("Family history may be more useful for risk assessment than thrombophilia testing")
  9. Sørensen et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost 2011;9:320 (Siblings of patients with VTE are at 2-fold higher risk for VTE)
  10. Zöller et al. Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden. J Thromb Haemost 2014;12:306 (Positive family hx a modest risk factor for recurrence)
  11. Zöller et al. Family history of venous thromboembolism as a risk factor and genetic research tool. Thromb Haemost 2015;114:890
  12. Sundquist et al. Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study. J Thromb Haemost 2015;13:2180 (In patients with unprovoked VTE, FH of VTE associated with higher risk of recurrence, particularly in women)
  13. Couturaud et al. Factors that predict thrombosis in relatives of patients with venous thromboembolism. Blood 2014;123:2124 (Unprovoked VTE or VTE at young age in proband predict VTE in relatives; FVL and PT gene variants do not)
  14. Bucciarelli et al. Influence of proband’s characteristics on the risk for venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms. Blood 2013;122:2555 (Relatives of heterozygous probands and those with VTE had higher risk than relatives of homozygotes or those without VTE)
  15. Holzhauer et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood 2012;120:1510 (Affected relatives of children with AT, PC or PS deficiency at highest risk)
  16. Zöller et al. Age- and Gender-Specific Familial Risks for Venous Thromboembolism. A Nationwide Epidemiological Study Based on Hospitalizations in Sweden. Circulation 2011;124:1012
  17. Vossen et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005;3:459
  18. Lijfering et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009;113:5314 (Antithrombin, protein C and protein S deficiencies strongest risk factors for first VTE)
  19. Brouwer et al. The Pathogenesis of Venous Thromboembolism: Evidence for Multiple Interrelated Causes. Ann Intern Med 2006;145:807   (additive effect of thrombophilic defects)
  20. de Haan et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012;120:656
  21. Young et al. Impact of Inherited Thrombophilia on Venous Thromboembolism in Children. A Systematic Review and Meta-Analysis of Observational Studies. Circulation 2008;118:1373
  22. Lijfering et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114:2031
  23. Segal et al. Predictive Value of Factor V Leiden and Prothrombin G20210A in Adults With Venous Thromboembolism and in Family Members of Those With a Mutation. JAMA 2009;301:2472 (FVL mutation, but not PT mutation, associated with higher VTE recurrence risk)
  24. Lijfering et al. Risk of Recurrent Venous Thrombosis in Homozygous Carriers and Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A. Circulation 2010;121:1706 (Homozygotes had only a 1.2-fold increased risk of recurrent VTE)
  25. Goldenberg and Manco-Johnson. Protein C deficiency. Haemophilia 2008;14:1214
  26. Price et al. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonat Med 2011 (epub) (Homozygous protein C or S deficiency)
  27. Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995;85:607
  28. Bertina et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64
  29. Rees D. The Population Genetics of Factor V Leiden (Arg506Gln). Br J Haematol 1996;95:579
  30. Koster et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503
  31. Juul et al.  Factor V Leiden and the Risk for Venous Thromboembolism in the Adult Danish Population.  Ann Intern Med 2004;140:330
  32. Couturaud et al. Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006;96:744 (2-3 fold increased VTE risk, 70% of episodes provoked)
  33. Parker et al. Discrepancy between phenotype and genotype on screening for factor V Leiden after transplantation. Blood 2001;97:2525
  34. Prüller et al. Activated Protein C Resistance Assay and Factor V Leiden (letter). NEJM 2014;371:685 (Suggests functional testing for APC resistance more reliable and economical than DNA testing)
  35. Procare-GEHT Group. ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the Factor V Leiden mutation. Br J Haematol 2006;135:697
  36. Vasan et al. ABO Blood Group and Risk of Thromboembolic and Arterial Disease. A Study of 1.5 Million Blood Donors. Circulation 2016;133:1449 (Non-O blood type increased incidence of both arterial and venous events, may account for over 30% of VTE events)
  37. Coppens et al. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood 2006;108:2604 (Modest increased risk of VTE, no increased risk of arterial events)
  38. Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. No Evidence of Association Between Prothrombotic Gene Polymorphisms and the Development of Acute Myocardial Infarction at a Young Age. Circulation 2003;107:1117
  39. Ridker et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. NEJM 1995;332:912
  40. Ye et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66155 cases and 91307 controls. Lancet 2006;367:651 (Modest increase in coronary risk with FV Leiden and prothrombin gene mutation)
  41. Pruissen et al. Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin. J Thromb Haemost 2008; 6:1639 (inherited thrombophilia does not increase risk of stroke recurrence)
  42. Madonna et al. Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke. Stroke 2002;33:51 (moderate hyperhomocysteinemia, but not FV Leiden or prothrombin G20210A, associated with stroke risk in young adults)
  43. Lijfering et al. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009;113:1225 (free protein S levels below 5th percentile associated with increased risk of new & recurrent VTE)
  44. Pintao et al.Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood 2013;122:3210 (No significant association between total or free protein S levels < 2.5th percentile and VTE in unselected individuals)
  45. Alhenc-Gelas et al. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost 2016;115:465 (Poor correlation between protein S levels and genotype. Protein S levels <30% associated with modest increase in VTE risk)
  46. Rodgers G. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency - An update. Thromb Haemost 2009;101:806
  47. Bezemer et al. No Association Between the Common MTHFR 677CT Polymorphism and Venous Thrombosis. Results From the MEGA Study. Arch Intern Med 2007;167:497
  48. Wu et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94:17
  49. Straczek et al. Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women. Impact of the Route of Estrogen Administration. Circulation 2005;112:3495 (Use of oral, but not transdermal, estrogen magnified thrombotic risk in women with thrombophilia)
  50. Jilma et al. Homozygosity in the Single Nucleotide Polymorphism Ser128Arg in the E-Selectin Gene Associated With Recurrent Venous Thromboembolism. Arch Intern Med 2006;166:1655
  51. Austin et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007; 110:908 (2-fold increased risk of VTE in sickle trait)
  52. Hernandez et al. Novel genetic predictors of venous thromboembolism risk in African Americans. Blood 2016;127:1923 (Polymorphisms in thrombomodulin gene associated with decr protein expression, 2.3-fold higher VTE risk)
  53. Bezemer et al. Gene variants associated with deep vein thrombosis. JAMA 2008;299:1306 (3 newly discovered polymorphisms that increase VTE risk)
  54. Rabinovich et al. Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. J Thromb Haemost 2014;12:14 (No association found)
Inherited Thrombophilia and Pregnancy/Contraception
  1. American College of Obstetricians and Gynecologists Practice Bulletin: Inherited thrombophilias in pregnancy. Obst Gynecol 2011;118:730
  2. Skeith et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016;127:1650 (No evidence of benefit)
  3. Isermann et al.  The thrombomodulin–protein C system is essential for the maintenance of pregnancy.  Nat Med 2003;9:331
  4. Kovalevsky et al.  Evaluation of the Association Between Hereditary Thrombophilias and Recurrent Pregnancy Loss.  A meta-analysis. Arch Intern Med. 2004;164:558
  5. Gerhardt et al. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016;128:2343
  6. Folkeringa et al. High risk of pregnancy-related venous thromboembolism in woman with multiple thrombophilic defects. Br J Haematol 2007; 138:110
  7. Gris et al.  Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study.  Blood 2003;102:3504
  8. van Vlijmen et al. Oral Contraceptives and the Absolute Risk of Venous Thromboembolism in Women With Single or Multiple Thrombophilic Defects. Results From a Retrospective Family Cohort Study. Arch Intern Med 2007;167:282
  9. van Vlijmen et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 2011;118:2055
  10. Di Nisio et al. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. Blood 2011;118:2670 (Evidence linking failure of ART and thrombophilia is inconclusive)
  11. Rodger et al. The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies. PLOS Medicine 2010;7:e1000292 (Small increase in risk for late pregnancy loss with FVL; no association with pre-eclampsia or SGA newborn)
  12. Bouvier et al. Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study. Blood 2014;123:414 (Women with FVL or PT polymorphism had higher risk for early pregnancy loss; LMWH may improve pregnancy outcomes in thrombophilic women with hx of late pregnancy complications)
  13. Rodger et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost 2014;12:469 (PT polymorphism not associated with significantly higher risk of adverse pregnancy outcomes; slight increased risk of pregnancy loss with FVL)
Inherited Thrombophilia and Risk of VTE Recurrence
  1. Van den Belt A et al. Recurrence of venous thromboembolism in patients with familial thrombophila. Arch Intern Med 1997;157:2227
  2. Baglin et al.  Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.  Lancet 2003;362:523 (Presence of thrombophilia was at most a weak predictor of recurrence)
  3. Christiansen et al. Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events.  JAMA. 2005;293:2352 (Clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy)
  4. Coppens et al. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008;6:1474
  5. Reitter-Pfoertner et al. The influence of thrombophilia in the long-term survival of patients with a history of venous thromboembolism. Thromb Haemost 2013;109:74 (No effect on survival)
Antiphospholipid Antibodies
  1. Giannakopoulos et al. How we diagnose the antiphospholipid syndrome. Blood 2009;113:985
  2. Giannakopoulos and Krilis. How I treat the antiphospholipid syndrome. Blood 2009;114:2020
  3. Lim W. Antiphospholipid antibody syndrome. Hematology 2009;233
  4. Ruiz-Irastorza et al. Antiphospholipid syndrome. Lancet 2010;376:1498
  5. Miyakis et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295
  6. Cervera et al. Antiphospholipid syndrome.  Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.  Arth Rheum 2002;46:1019
  7. Ortel T. Thrombosis and the Antiphospholipid Syndrome. Hematology 2005:462-468
  8. Gebhart et al. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood 2015;125:3477
  9. Giannakopoulos and Krills. Pathogenesis of the antiphospholipid syndrome. NEJM 2013;368:1033
  10. Erkan et al. 14th international congress on antiphospholipid antibodies task force report on antiphospholipid syndrome treatment trends. Autoimmune Rev 2014 (ePub)
  11. Lim et al. Management of Antiphospholipid Antibody Syndrome: A Systematic Review. JAMA 2006;295:1050
  12. Garcia et al. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood 2013;122:817 ("Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality")
  13. Metjian and Lim. ASH evidence-based guidelines: should asymptomatic patients with antiphospholipid antibodies receive primary prophylaxis to prevent thrombosis? Hematology 2009;247 (No)
  14. Garcia et al. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review. Blood 2007;110:3122
  15. Galli et al.  Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827
  16. Proven et al.  Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies.  Mayo Clin Proc 2004;79:467
  17. Arvanitakis et al. Relation of Antiphospholipid Antibodies to Postmortem Brain Infarcts in Older People. Circulation 2015;131:182 (No apparent relationship between positive premortem APL test results and brain infarcts)
  18. de Groot et and Urbanus. The significance of autoantibodies against β2-glycoprotein I. Blood 2012;120:266.
  19. De Groot et al. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost 2005;3:1993 (Lupus anticoagulant in combination with antiprothrombin or anti-b2-glycoprotein I antibodies associated with 10-fold increased relative risk of DVT)
  20. Pengo et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118:4714 ("Triple-positive" individuals with LAC, ACL and B2GPI antibodies had 37% incidence of thrombosis at 10 years)
  21. Pengo et al. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost 2013;11:1527 (98% of "triple-positive" individuals remained positive after 12 weeks, vs 84% of double-positive and 40% of single-positive individuals)
  22. Galli et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood 2007;110:1178 (IgG antibodies to ß2-glycoprotein I more strongly associated with thrombosis than was IgG or IgM anticardiolipin antibody)
  23. APASS Investigators.  Antiphospholipid Antibodies and Subsequent Thrombo-occlusive Events in Patients With Ischemic Stroke.  JAMA 2004;291:576  (presence of ACL or lupus anticoagulant in stroke patients did not predict recurrent thrombosis)
  24. Schulman et al. Anticardiolipin Antibodies Predict Early Recurrence of Thromboembolism and Death among Patients with Venous Thromboembolism following Anticoagulant Therapy. Am J Med 1998;104:332 (VTE recurrence risk 29% vs 14% in those with and without ACA respectively; 4-year mortality 15% vs 6%).
  25. Devreese et al. Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. Blood 2010;115:870
  26. Pengo et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8:237 ("Triple positive" patients with LAC, ACL, and B2GPI antibodies at high risk for recurrent thrombosis)
  27. Gris et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012;119:2624 (Annual incidence of DVT about 1.5%)
  28. Tektonidou et al. Cognitive Deficits in Patients With Antiphospholipid Syndrome. Arch Intern Med 2006;166:2278
  29. Galli and Barbui. Antiphospholipid Syndrome: Clinical and Diagnostic Utility of Laboratory Tests. Semin Hematol 2005;31:17
  30. Galli et al.  Anti–ß2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003;102:2717
  31. de Laat et al.  ß2-glycoprotein I–dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 2004;104:3598
  32. ß2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator. Blood 2011;118:2774
  33. Arachchillage et al. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome. J Thromb Haemost 2014;12:1801
  34. Rand et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers. Blood 2008;112:1687
  35. Rand et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 2010;115:2292
  36. Canaud et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. NEJM 2014;371:303 (Suggests that sirolimus treatment may prevent vascular lesions in APS; with editorial)
  37. Crowther et al.  A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. NEJM 2003;349:1133
  38. Finazzi et al. A randomized clinical trial of high-intensity warfarin vs.conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005;3:848
  39. Cohen et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426 (No difference in clinical outcomes between warfarin and rivaroxaban treatment)
  40. Sciascia et al. The efficacy of hydroxychloroquine in altering pregnancy
  41. outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost 2016;115:285
  42. Erkan et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals. Arth Rheum 2007;56:2382 (No benefit from low dose ASA. Rate of thrombosis <3%/yr, most events in setting of other risk factors for thrombosis)
  43. Derksen et al.  Management of the obstetric antiphospholipid syndrome.  Arth Rheum 2004;50:1028
  44. Clark et al. The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. Blood 2013;122:341 (LAC associated with late pregnancy loss)
  45. Bouvier et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 2014;123:404 (LMWH + ASA had limited efficacy in preventing pregnancy complications; high IgM cardiolipin Ab associated with placenta-mediated complications)
  46. Marchetti et al. Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study. J Thromb Haemost 2016;14:675 (anti beta2-GPI Ab associated with severe pre-eclampsia)
  47. Asherson RA. Multiorgan failure and antiphospholipid antibodies: the catastrophic antiphospholipid (Asherson’s) syndrome. Immunobiology 2005;210:727
  48. Comellas-Kirkerup et al. Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study. Blood 2010;116:3058 (<30% had either thrombosis or pregnancy morbidity during followup)

Homocysteine

  1. Humphrey et al. Homocysteine Level and Coronary Heart Disease Incidence: A Systematic Review and Meta-analysis. Mayo Clin Proc 2008;83:1203 (risk of CHD events rises by 20% for every 5 micromolar increase in HC level)
  2. Bazzano et al. Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases. A Meta-analysis of Randomized Controlled Trials. JAMA 2006;296:2720
  3. Clarke et al. Effects of Lowering Homocysteine Levels With B Vitamins on Cardiovascular Disease, Cancer, and Cause-Specific Mortality. Meta-analysis of 8 Randomized Trials Involving 37 485 Individuals. Arch Intern Med 2010;170:1622 (No significant effect on cardiovascular events or mortality)
  4. Kluijtmans et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.  Blood 2003;101:2483
  5. Quinlivan et al.  Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease.  Lancet 2002;359:227 (treatment of hyperhomocysteinemia)
  6. Toole et al.  Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death.  The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial.  JAMA 2004;291:565 (moderate reduction of homocysteine after stroke had no effect on vascular outcomes during 2 years of follow-up)
  7. HOPE 2 Investigators. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. NEJM 2006;354:1567 (Vitamin supplements lowered homocysteine levels but did not decrease risk of cardiovascular events)
  8. Bønaa et al. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. NEJM 2006;354:1578 (Vitamins did not lower risk of cardiovascular events, may have even increased risk)
  9. Frederiksen et al.Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study.  Blood 2004;104:3046. (Questions cause and effect relationship between hyperhomocysteinemia and vascular disease)
  10. Menon et al. Relationship Between Homocysteine and Mortality in Chronic Kidney Disease. Circulation 2006;113:1572 (Homocysteine not an independent risk factor for all-cause or cardiovascular mortality)
  11. den Heijer et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood 2007;109:139 (Lowering homocysteine did not seem to prevent recurrent venous thrombosis)
  12. Jamison et al. Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease. JAMA 2007;298:1163 (No apparent benefit to lowering HC level)
  13. Bailey and Ayling. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. PNAS 2009; 106: 15424 (Utility of high dose folate supplementation limited by slow metabolism in some people)
  14. Ebbing et al. Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. JAMA 2009;302:2119 (Increased cancer incidence after treatment with folate + B12)
  15. SEARCH Collaborative Group. Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors. A Randomized Trial. JAMA 2010;303:2486 (No benefit on vascular outcomes with folate/B-12 Rx)
  16. Xu et al. Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease. The Renal Substudy of the China Stroke Primary Prevention Trial. JAMA Int Med 2016;176:1443 (Folic acid + enalapril more effective than enalapril alone in delaying progression of CKD)
Other
  1. Kitchens et al. Thrombotic storm revisited: preliminary diagnostic criteria suggested by the Thrombotic Storm Study Group. Am J Med 2011;124:290
  2. Tripodi et al. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood 2004;104:3631
  3. Kyrle et al. High Plasma Levels of Factor VIII and the Risk of Recurrent Venous Thromboembolism. NEJM 2000;343:457
  4. Wells et al. Elevated factorVIII is a risk factor for idiopathic venous thromboembolism in Canada – is it necessary to define a new upper reference range for factorVIII? Thromb Haemost 2005;93:842
  5. Timp et al. Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study. J Thromb Haemost 2015;13:1823 (High fVIII predicts recurrence risk in a dose-dependent manner)
  6. Kuipers et al. Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers. Blood 2009;113:2064
  7. Cushman et al. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 2009;114:2878 (only elevated factor XI level associated with higher VTE risk)
  8. Fox et al. The relationship between inflammation and venous thrombosis A systematic review of clinical studies. Thromb Haemost 2005;94:362
  9. Levine et al. Venous and arterial thromboembolism in severe sepsis. Thromb Haemost 2008;99:892 (3.2% of patients with sepsis had thromboembolic event within 28 days of hospitalization; most events were arterial)
  10. Grainge et al. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:657 (8-fold increase in risk for VTE during flares of IBD)
  11. Chung et al. Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study. J Thromb Haemost 2014;12:452 (>10-fold increased risk of VTE, risk highest in younger pts)
  12. Weishaupt et al. Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial. Lancet Haematol 2016;3:e72 (Treatment effective in reducing pain in most patients)
  13. Hall et al. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).  Blood 2003;102:3587
  14. Prins and Hirsh. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151:1721
  15. Tefs et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood 2006;108:3021 (No increased incidence of VTE in severe plasminogen deficiency)
  16. Meltzer et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010;116:113 (Modest increase in VTE risk associated with hypofibrinolysis)
  17. Meltzer et al. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood 2010;116:529 (Elevated alpha-2 antiplasmin levels independently associated with risk of MI)
  18. Alessi and Juhan-Vague. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008;99:995
  19. Samad and Ruf. Inflammation, obesity, and thrombosis. Blood 2013;122:3415
  20. Fagniez et al. Hematological disorders related cerebral infarction are mostly multifocal. J Neurol Sci 2011 (Epub)
  21. Etminan et al. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ  2005;330:63
  22. Rolfs et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005;366:1794
  23. Ocak et al. Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients. J Thromb Haemost 2012;10:2484 (Risk of PE, MI and stroke significantly higher in dialysis patients than in general population)
  24. Kazory and Ducloux. Acquired hypercoagulable state in renal transplant recipients. Thromb Haemost 2004;91:646
  25. Tripodi et al. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011;9:1713
  26. White et al. Incidence of Venous Thromboembolism in the Year Before the Diagnosis of Cancer in 528 693 Adults. Arch Intern Med 2005;165:1782
  27. Chew et al. Incidence of Venous Thromboembolism and Its Effect on Survival Among Patients With Common Cancers. Arch Intern Med 2006;166:458
  28. Blom et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.  JAMA 2005;293:715
  29. Carrier et al. Systematic Review: The Trousseau Syndrome Revisited: Should We Screen Extensively for Cancer in Patients with Venous Thromboembolism? Ann Intern Med 2008;149:323 (10% of pts with unprovoked VTE diagnosed w/ cancer within 12 mo; abd/pelvic CT increased diagnostic yield significantly)
  30. Agnelli et al. A Clinical Outcome-Based Prospective Study on Venous Thromboembolism After Cancer Surgery: The @RISTOS Project. Ann Surg 2006;243:89 (Late VTE common after cancer surgery; VTE most common cause of death at 30 days after surgery)
  31. Novacek et al. Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism. Gastroenterology 2010;139:779
  32. Smith et al. Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke? The Caerphilly Study. Circulation 2005;112:3080 (High fibrinogen, D-dimer, PAI-1 activity, and factor VIIc levels all associated with higher risk of coronary disease and stroke)
  33. Doggen et al. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII. Blood 2006; 108:4045   (Elevated VIII, IX and XI, but lower XII, found in MI patients vs controls) 
  34. Ataga and Key. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology 2007;91
  35. Ataga et al. β-Thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol 2007;139:3
  36. Kourtzelis et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 2010;116:631
  37. Stuijver et al. The effect of hyperthyroidism in procoagulant, anticoagulant and fibrinolytic factors. Thromb Haemost 2012;108:1077

White blood cells: function/pathology
  1. Phillipson and Kubes. The neutrophil in vascular inflammation. Nat Med 2011;17:1381
  2. Silvestre-Roig et al. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 2016;127:2173
  3. Wirths et al. Neutrophil homeostasis and its regulation by danger signaling. Blood 2014;123: 3563
  4. Yipp and Kubes. NETosis: how vital is it? Blood 2013;122:2784 (Neutrophil extracellular traps)
  5. Martinod and Wagner. Thrombosis: tangled up in NETs. Blood 2014;123:2768 (Role of neutrophils in thrombosis)
  6. Jorch and Kubes. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 2017;23:279
  7. Tefferi et al. How to Interpret and Pursue an Abnormal Complete Blood Cell Count in Adults. Mayo Clin Proc 2005;80:923
  8. Pillay et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 2010;116:625
  9. Craig et al. An upper bound for the half-removal time of neutrophils from circulation (letter). Blood 2016;128:1989 (Less than 15 hours)
  10. (Author unknown) Leukoagglutination. Blood 2010;115:924 (Pseudoleukopenia due to EDTA-dependent white cell clumping)
  11. Abel et al. Effects of Biochemically Confirmed Smoking Cessation on White Blood Cell Count. Mayo Clin Proc 2005;80:1022 (significant decrease in WBC and ANC after quitting)
  12. Swirski and Nahrendorf. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 2013;339:161
  13. Spite et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 2009;461:1287
  14. Geng et al. Emergence, origin, and function of neutrophil–dendritic cell hybrids in experimentally induced inflammatory lesions in mice. Blood 2013;121:1690 (PMNs recruited into tissues can differentiate into PMN-DC hybrid cells)
  15. Stock and Hoffman. White blood cells 1: non-malignant disorders. Lancet 2000;355:1351
  16. Gibson and Berliner. How we evaluate and treat neutropenia in adults. Blood 2014;124:1251
  17. Bartels et al. Understanding chronic neutropenia: life is short. Br J Haematol 2016;172:157
  18. Hsieh et al. Prevalence of Neutropenia in the U.S. Population: Age, Sex, Smoking Status, and Ethnic Differences. Ann Intern Med 2007;146:486
  19. Papadaki et al. Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells. Blood 2003;101:2591
  20. Klein. C. Congenital neutropenia. Hematology 2009;344
  21. Newburger PE. Disorders of Neutrophil Number and Function. Hematology 2006;104-110
  22. Dale et al. Cyclic neutropenia. Semin Hematol 2002;39:89-94
  23. Horwitz et al. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007;109:1817
  24. Starkebaum G. Chronic Neutropenia Associated With Autoimmune Disease. Semin Hematol 2002; 39:121-127
  25. Palmblad and von dem Borne. Idiopathic, Immune, Infectious, and Idiosyncratic Neutropenias. Semin Hematol 2002;39:113-120
  26. de Fontbrune et al. Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood 2015;126:1643 (Generally a benign entity. GCSF increases ANC but usually not needed. ANC <200 at diagnosis associated with higher rate of bacterial infxn)
  27. Zeidler et al. Outcome and management of pregnancies in severe chronic neutropenia patients by the European Branch of the Severe Chronic Neutropenia International Registry. Haematologica 2014;99:1395
  28. Ibáñez et al. Population-Based Drug-Induced Agranulocytosis. Arch Intern Med 2005;165:869
  29. Andersohn et al. Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs. Ann Intern Med 2007;146:657
  30. Levine et al. Neutropenia in Human Immunodeficiency Virus Infection. Data From the Women's Interagency HIV Study. Arch Intern Med 2006;166:405
  31. Cottle et al. Risk and Benefit of Treatment of Severe Chronic Neutropenia With Granulocyte Colony-Stimulating Factor. Semin Hematol 2002;39:134-140
  32. Rosenberg et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 2006;107:4628
  33. Collin et al. Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol 2015;169:173
  34. Vinh et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 2010;115:1519
  35. Dickinson et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 2011;118:2656 (myclobacterial infection, pulmonary alveolar proteinosis, MDS and AML)
  36. Hsu et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 2011;118:2653
  37. Pasquet et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 2013;121:822
  38. Jacobsen et al. The expanding role(s) of eosinophils in health and disease. Blood 2012;120:3882
  39. Farahi et al. Use of 111-Indium–labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects. Blood 2012;120:4068
  40. Rothenbert M. Eosinophilia. NEJM 1998;338:1592
  41. Lombardi and Passalacqua. Eosinophilia and Diseases: Clinical Revision of 1862 Cases. Arch Intern Med 2003;163:1371
  42. Phipps et al. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood 2007;110:1578
  43. Leslie M. Mast cells show their might. Science 2007;317:614
  44. Metcalfe D. Mast cells and mastocytosis. Blood 2008;112:946
  45. Pejler et al. Mast cell proteases: multifaceted regulators of inflammatory disease. Blood 2010;115:4981
  46. Kunder et al. Mast cell modulation of the vascular and lymphatic endothelium. Blood 2011;118:5383
  47. Steinman and Banchereau. Taking dendritic cells into medicine. Nature 2007;449:419
  48. Lämmermann et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 2008;453:51
  49. Dale et al. The phagocytes: neutrophils and monocytes. Blood 2008;112:935
  50. Geissmann et al. Development of Monocytes, Macrophages, and Dendritic Cells. Science 2010;327:5966
  51. Zhu and Paul CD4 T cells: fates, functions, and faults. Blood 2008;112:1557
  52. LeBien and Tedder. B lymphocytes: how the develop and function. Blood 2008;112:1570
  53. Caligiuri M. Human natural killer cells. Blood 2008;112:461
  54. Natkunam Y. The biology of the germinal center. Hematology 2007:210
  55. Carter R. B cells in health and disease.  Mayo Clin Proc 2006;81:377

Biology of cancer
  1. Siegel et al. Cancer statistics, 2015. CA 2015;65: 5
  2. Hanahan and Weinberg. The hallmarks of cancer. Cell 2000;100:57
  3. Hanahan and Weinberg. Hallmarks of cancer: the next generation. Cell 2011;144:646
  4. Golub et al. Molecular classification of cancer: class discovery and class prediction by gene expression profiling. Science 1999;286:531
  5. Fröhling and Döhner. Chromosomal abnormalities in cancer. NEJM 2008;359:722
  6. Croce C. Oncogenes and cancer. NEJM 2008;358:502
  7. Huff et al. The paradox of response and survival in cancer therapeutics. Blood 2006;107:431 (Cancer stem cells)
  8. Jordan et al. Cancer stem cells.  NEJM 2006;355:1253
  9. Vogelstein et al. Cancer genome landscapes. Science 2013;339:1546
  10. Hoejimakers J. Genome maintenance mechanisms for preventing cancer. Nature 2001;411:366
  11. Hahn and Weinberg. Rules for making human tumor cells. NEJM 2002;347:1593
  12. Evan and Vousden. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342
  13. Hotchkiss et al. Mechanisms of disease: cell death. NEJM 2009;1570
  14. Vogelstein and Kinzler.  Cancer genes and the pathways they control. Nat Med 2004;10:789
  15. Greaves M. Leukaemia 'firsts' in cancer research and treatment. Nat Rev Cancer 2016;16:163
  16. Palucka and Coussens. The basis of oncoimmunology. Cell 2016;164:1233
  17. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. NEJM 2016;375:1767
  18. Tomasetti and Vogelstein. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78 (Oncogenic mutations happen in proportion to the number of dividing stem cells in a tissue; with editorial)
  19. Popovic et al. Ubiquitination in disease pathogenesis and treatment. Nat Med 2014;20:1242
  20. Esteller M. Epigenetics in cancer. NEJM 2008;358:1148
  21. Sjöblom et al. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science 2006;314:5797 (tumor cells have on average 90 mutated genes)
  22. Greenman et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446: 153
  23. Brivantou and Darnell. Signal transduction and the control of gene expression. Science 2002;295:813
  24. Aparicio and Caldas. The implications of clonal genome evolution for cancer medicine. NEJM 2013;368:842
  25. Key et al. The effect of diet on risk of cancer. Lancet 2002;360:861
  26. Roodman GD.  Mechanisms of bone metastasis.  NEJM 2004;350:1655
  27. Chiang and Massagué. Molecular basis of metastasis. NEJM 2008;359:2814
  28. Leong and Karsan. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006;107:2223
  29. Higgins C. Multiple molecular mechanisms for multidrug resistance transporters. Nature 2007; 446:749
  30. Ventura et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007;445:661
  31. Xue et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.  Nature 2007;445:656
  32. Platanias L.  MAP kinase signalling pathways and hematologic malignancies.  Blood 2003;101:4667
  33. Chen et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 2016;535:148
  34. Di Croce et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002;295:1079
  35. Kaplan et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820
  36. Murtaza et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013;497:108
  37. Jaiswal et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. NEJM 2014:371:2488 (>10 fold increased risk of heme malignancy in pts with somatic mutations in peripheral blood cells)
  38. Xie et al.Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014;20:1472 ("The blood cells of more than 2% of individuals [5–6% of people older than 70 years] contain mutations that may represent premalignant events)
  39. Genovese et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. NEJM 2014;371:2477 (Results similar to above article)
  40. Steensma et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126:9
  41. Andor et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med 2016;22:105

Cytogenetic, immunopathologic and molecular analysis in hematologic malignancy
  1. O'Keefe et al. Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. Blood 2010; 115:2731
  2. Morice et al. Predictive Value of Blood and Bone Marrow Flow Cytometry in B-Cell Lymphoma Classification: Comparative Analysis of Flow Cytometry and Tissue Biopsy in 252 Patients. Mayo Clin Proc 2008;83:776
  3. Quackenbush J. Microarray Analysis and Tumor Classification. NEJM 2006;354:2463
  4. Ko et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutatant TET2. Nature 2010;468:839
  5. Podar and Anderson. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications.  Blood 2005;105:1383
  6. Saez et al. Splicing factor gene mutations in hematologic malignancies. Blood 2017;129:1260
  7. Gough et al. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 2011;118:6247
  8. Cottini et al Rescue of Hippo coactivator YAP1 triggers DNA damage–induced apoptosis in hematological cancers. Nat Med 2014;20:599 (with editorial)
  9. Bernatsky et al. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med 2008;168:378
  10. Martin-Perez et al. Polycomb proteins in hematologic malignancies. Blood 2010;116:5465
  11. Tegg et al. Anticipation in familial hematologic malignancies. Blood 2011;117:1308

Acute Leukemia

Biology of acute leukemia

  1. Dores et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 2012;119:34
  2. The Cancer Genome Atlas Research Network. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. NEJM 2013;368:2059 (At least one "driver" mutation found in almost every case; average number of mutations per case around 13)
  3. Lindsley and Ebert. The biology and clinical impact of genetic lesions in myeloid malignancies. Blood 2013;122:3741
  4. Welch et al. The origin and evolution of mutations in acute myelogenous leukemia. Cell 2012;150:264
  5. Bodini et al. The hidden genomic landscape of acute myeloid leukemia: subclonal structure revealed by undetected mutations. Blood 2015;125:600
  6. Hong et al. Initiating and Cancer-Propagating Cells in TEL-AML1–Associated Childhood Leukemia. Science 2008;319:336 (demonstration of presence of leukemia stem cells)
  7. Lane et al. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood 2009;114:1150
  8. Ho et al. Evolution of acute myelogenous leukemia stem cell properties after treatment and progression. Blood 2016;128:1671
  9. Mullighan et al. Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia. Science 2008;322:1377 (cells responsible for relapse are different than those giving rise to original disease, often present as minor subpopulations at diagnosis)
  10. Parkin et al. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood 2013;121:369 (Relapse is due to incomplete eradication of AML "founder clones")
  11. Viale et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 2009:457:51
  12. Krause et al. Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells. Nat Med 2006;12:1175
  13. Jin et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12:1167
  14. Liu et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding a-catenin (CTNNA1) in myeloid cell transformation. Nat Med 2007;13:78
  15. Lessard and Sauvageau.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423:255
  16. Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis? Br J Haematol 2005;128:18
  17. Pedersen-Bjergaard and Rowley. The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 1994;83:2780
  18. Peterson et al. Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts. Blood 2007;110:799
  19. Wang et al. The Leukemogenicity of AML1-ETO Is Dependent on Site-Specific Lysine Acetylation. Science 2011;333:765 ("Lysine acetyltransferases represent a potential therapeutic target in AML")
  20. Mardis et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. NEJM 2009; 361:1058
  21. Patel et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. NEJM 2012; 366:1079
  22. Sachs and Lotem. Control of programmed cell death in normal and leukemic cells: new implications for therapy. Blood 1993;82:15
  23. Pedersen-Bjergaard et al. Genetic pathways in therapy-related myelodysplasia and acute myelogenous leukemia. Blood 2002;99:1909
  24. Link et al. Identification of a Novel TP53 Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML. JAMA 2011;305:1568 (Inherited mutation predisposing to therapy-related AML)
  25. Wong et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukemia. Nature 2014;518:552 (TP53 mutations present in a subset of hematopoietic stem cells prior to therapy predispose to t-AML)
  26. Wolfraim et al.  Loss of Smad3 in Acute T-Cell Lymphoblastic Leukemia.  NEJM 2004;351:552
  27. Mullighan et al. CREBBP mutations in relapsed acute lymphoblastic leukemia. Nature 2011;471:235
  28. Mullighan et al. BCR-ABL-1 lymphoblastic leukemia is characterized by the deletion of Ikaros. Nature 2008;453:110 (Ikaros gene deleted in 84% of Ph+ ALL or CML lymphoid blast crisis, but not in chronic phase CML)
  29. Roberts et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. NEJM 2014;371:1005
  30. Ito et al. PML targeting eradicates quiescent leukaemia-inititating cells. Nature 2008;453:1072 (PML expression critical to maintenance of leukemia stem cells in CML; arsenic trioxide targets PML gene)
  31. Wang et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 2009;459: 847
  32. Godley and Le Beau. The histone code and treatments for acute myeloid leukemia. NEJM 2012;366:960
  33. Colmone et al. Leukemic Cells Create Bone Marrow Niches That Disrupt the Behavior of Normal Hematopoietic Progenitor Cells. Science 2008;322:1861
  34. Yilmaz et al. PTEN dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006;441:475
  35. Zhang et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006;441:518
  36. Guo et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 2008;453:529
  37. Eppert et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011;17:1086 (Expression of "stem cell" genes by blasts associated with worse prognosis in AML)
  38. Abdel-Wahab and Levine. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013;121:3563
  39. Li et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 2016;22:792 (With editorial)
  40. Delhommeau et al. Mutation in TET2 in myeloid cancers. NEJM 2009;360:2289 (Mutation an early event in AML, MDS, MPD. See also the accompanying editorial)
  41. Dey et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 2012;337:1541 (With editorial)
  42. Wang et al. Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation. Science 2013;340:622 (with editorial)
  43. Chan et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 2015;21:178 (potential "synthetic lethal" treatment approach; with editorial)
  44. Swaminathan et al. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nat Med 2013;19:1014 (Identification of an important safeguard against leukemogenesis in B cells)
  45. Chantepie et al. Hematogones: a new prognostic factor for acute myeloblastic leukemia. Blood 2011;117:1315
  46. Gurbuxani et al.  Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome.  Blood 2004;103:399
  47. Raaijmakers et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010; 464:852
  48. Hole et al. Do reactive oxygen species play a role in myeloid leukemias? Blood 2011;117:5816
  49. Dawson et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011;478:529
  50. Placke et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 2014;124:13
  51. Chen et al. DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat Med 2015;21:335
  52. Walter et al. Clonal architecture of secondary acute myeloid leukemia. NEJM 2012;366:1090 (85% of marrow cells clonal; founding clone with hundreds of mutations and subclones with many more)
  53. Makishima et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012;119:3203
  54. Damm et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 2012;119:3211
  55. Mansour et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 2014;346:1373 (Mutation enhances binding of MYB transcription factor, enhancing TAL1 expression in T-ALL; with editorial)
  56. Esposito et al. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med 2015;21:1481 (With editorial)
  57. Fucikova et al. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients. Blood 2016;128:3113
  58. Schneider et al. SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med 2017;23;250
  59. Herold et al. Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies. Nat Med 2017;23:256
  60. Göllner et al. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nat Med 2017;234: 23:69
  61. Guryanova et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 2016;22:1488

Inherited myeloid malignancy

  1. Kohlmann and Schiffman. Discussing and managing hematologic germ line variants. Blood 2016;128:2497
  2. Drazer et al. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood 2016;128:1800
  3. Churpek et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 2015;126:2484
  4. Shinawi et al. Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q. Blood 2008;112:1042
  5. Owen et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 2008;112:4639
  6. Spinner et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014;123:809
  7. Vinh et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 2010;115:1519 (GATA-2 deficiency)
  8. Dickinson et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 2011;118:2656 (myclobacterial infection, pulmonary alveolar proteinosis, MDS and AML)
  9. Hsu et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 2011;118:2653
  10. Ganapathi et al. GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood 2015;125:56

AML: General

  1. Arber et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391
  2. Döhner et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424
  3. Döhner et al. Acute myeloid leukemia. NEJM 2015;373:1136
  4. Ferrara and Schiffer. Acute myeloid leukaemia in adults. Lancet 2013;381:484
  5. Vardiman et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114:937
  6. Walter et al. Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients. Blood 2013;121:2424 (Morphology does not provide independent prognostic information in AML if molecular features are known)
  7. Cheson et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642
  8. Kern et al.  Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial.  Blood 2003;101:64
  9. Elliott et al. Early peripheral blood blast clearance during induction chemotherapy for acute myeloid leukemia predicts superior relapse-free survival. Blood 2007;110:4172
  10. Estey and Pierce. Routine bone marrow exam during first remission of acute myelogenous leukemia. Blood 1996;87:3899
  11. Buccisano et al. Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia. Blood 2012;119:332
  12. Jourdan et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood 2013;121:2213 (MRD best predictor of relapse)
  13. Ivey et al. Assessment of Minimal Residual Disease in Standard-Risk AML. NEJM 2016;374:422 (With editorial)
  14. Wang et al. In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood 2014;124:1880
  15. Derolf et al. Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 2009;113: 3666 (5 yr "relative survival" rates 65% for age <18, 58% for ages 19-41, 36% for ages 41-60, 15% for ages 61-70, 5% for ages 71-80, 1% for age >80)
  16. Kayser et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011;117:2137
  17. Morton et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008. Blood 2013;121:2996
  18. Nardi et al. Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms. J Clin Oncol 2012;30:2340
  19. Matutes et al. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 2011;117:3163 (MPAL is a poor risk disease; authors recommend transplantation in 1st remission)

AML: clinical implications of molecular and cytogenetic changes

Prognosis/General

  1. Grimwade et al. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 2016;127:29
  2. Döhner and Gaidzik. Impact of genetic features on treatment decisions in AML. Hematology 2011;36
  3. Röllig et al. Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System. J Clin Oncol 2011;29:2758
  4. Rockova et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood 2011;118:1069
  5. Damm et al. Integrative prognostic risk score in acute myeloid leukemia with normal karyotype. Blood 2011;117:4561
  6. Barabé et al. Modeling the Initiation and Progression of Human Acute Leukemia in Mice. Science 2007;316:600
  7. Klco et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314:811 (Persistence of AML-assosiated mutations in remission marrow → worse prognosis)
  8. Mrózek and Bloomfield. Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia. Hematology 2006;169-77
  9. Mrózek et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007;109:431
  10. Welch and Link. Genomics of AML: clinical applications of next-generation sequencing. Hematology 2011;30

Cytogenetics

  1. Koeffler H. Syndromes of acute nonlymphocytic leukemia. Ann Intern Med 1987;107:748
  2. Moorman et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007;109:3189
  3. Byrd et al.  Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461).  Blood 2002;100:4325
  4. Marcucci et al.  Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461.  J Clin Oncol 2004;22:2410
  5. Farag et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood 2006;108:63
  6. Perrot et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood 2011;118:679
  7. Haferlach et al. Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. Blood 2012;119:2122 (Monosomy or 4 or more cytogenetic abnormalities associated with very poor outcome)
  8. Kayser et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood 2012;119:551 (Poor response to induction therapy, 9% 4-year survival)
  9. Medeiros et al. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood 2010;116:2224 (3% 4 yr survival!)
  10. Appelbaum et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol 2006;135:165 (t(8;21) and inv(16))
  11. Bacher et al. Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity. Blood 2012;119:4719
  12. Grimwade et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354
  13. Middeke et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood 2014;123:2960 (High relapse rate, low 3 year OS)
  14. Herold et al. Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis. Blood 2014;124:1304

Molecular analysis

  1. The Cancer Genome Atlas Research Network. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. NEJM 2013;368:2059 (At least one "driver" mutation found in almost every case; average number of mutations per case around 13)
  2. Papaemmanuil et al. Genomic classification and prognosis in acute myeloid leukemia. NEJM 2016;374:2209 (>5000 driver mutations identified; with editorial)
  3. Metzeler et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood 2016;128:686 (NPM1, FLT3, CEBPA, TP53, DNMT3A and RUNX1 most important risk factors)
  4. Klco et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA 2015;314:811 (Persistence of AML-assosiated mutations in remission marrow → worse prognosis)
  5. Grossman et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012;120:2963
  6. Ommen et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood 2010;115:198
  7. Lindsley et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125:1367 (Mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 associated with secondary AML, worse prognosis)
  8. Cairoli et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 2006;107:3463
  9. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology 2013:220
  10. Gale et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008;111:2776 (high FLT3 mutant level a strong negative prognostic factor)
  11. Bacher et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood 2008;111:2527
  12. Bullinger et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 2008;111:4490 (gene expression signature associated with FLT3 gene mutation a better predictor of outcome than FLT3 mutation status itself)
  13. Kayser et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009;114:2386
  14. Levis M. FLT3/ITD AML and the law of unintended consequences. Blood 2011;117:6987
  15. Falini et al.  Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype.  NEJM 2005;352:254
  16. Schnittger et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005;106:3733
  17. Schlenk et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. NEJM 2008;358:1909 (mutations of nucleophosmin or CEBPA genes in the absence of FLT3-ITD mutations conferred better prognosis; with editorial)
  18. Falini et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood 2011;117:1109
  19. Gaidzik et al. RUNX1 Mutations in Acute Myeloid Leukemia: Results From a Comprehensive Genetic and Clinical Analysis From the AML Study Group. J Clin Oncol 2011;29:1364
  20. Shen et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011;118:5593
  21. Wouters and Delwel. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016;127:42
  22. Marcucci et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. NEJM 2008;358:1919 (microRNA signature identified that gave improved prognosis in AML patients with high-risk molecular features; with editorial)
  23. Marcucci et al. The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 2011;117:1121
  24. Allan et al. Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy. Blood 2004;104:3872
  25. Zuber et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011;478:524
  26. Kharas et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 2010;16:903
  27. Ley et al. DNMT3A mutations in acute myeloid leukemia. NEJM 2010;363:2424 (DNA methyltransferase gene mutations found in one-third of those with intermediate-risk cytogenetic profile and were an independent predictor of poor outcome)
  28. Schnittger et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 2010;116:5486
  29. Chou et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011;118:3803
  30. Metzeler et al. TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol 2011;29:1373

Gene expression profiling

  1. Gentles et al. Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia. JAMA 2010;304:2706
  2. Eisfeld et al. miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia. Blood 2012;120:249.
  3. Gönen et al. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood 2012;120:2297
  4. Bullinger et al.  Use of Gene-Expression Profiling to Identify Prognostic Subclasses in Adult Acute Myeloid Leukemia.  NEJM 2004;350:1605
  5. Haferlach et al. Global approach to the diagnosis of leukemia using gene expression profiling. Blood 2005;106:1189
  6. Valk et al.  Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia.  NEJM 2004;350:1617
  7. Wouters et al. A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects. Blood 2009;113:291

AML in the elderly

  1. Appelbaum et al. Age and acute myeloid leukemia. Blood 2006:107:3481 (Poor performance status + advanced age = 80% mortality within 30 days of starting Rx)
  2. Walter et al. Prediction of Early Death After Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia With Pretreatment Risk Scores: A Novel Paradigm for Treatment Assignment. J Clin Oncol 2011;29:4417 (PS and age most important predictors of early death; in a multicomponent model age appears to be a surrogate for other risk factors)
  3. Menzin et al. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 2002;162:1597 (median survival 2 months, 2-yr OS 6% in pts 65 and up)
  4. Klepin et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood 2013;121:4287
  5. Fröhling et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B.  Blood 2006;108:3280 (Patients >70 and those with unfavorable karyotype had median survival of 7 mo, 3 year overal survival 6%)
  6. Löwenberg et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood 2010;115:2586 (No apparent benefit)
  7. Fehniger et al. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 2011;117:1828 (30% response rate)
  8. Cashen et al. Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Older Patients With Acute Myeloid Leukemia. J Clin Oncol 2010;28:556 (24% CR rate; medial OS 7.7 mo)
  9. Fenaux et al. Azacitidine Prolongs Overall Survival Compared With Conventional Care Regimens in Elderly Patients With Low Bone Marrow Blast Count Acute Myeloid Leukemia. J Clin Oncol 2020;28:562 (Azacitidine prolonged survival and reduced time spent in hospital)
  10. Dombret et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291 (Azacitidine increased median OS by about 4 mo compared to standard AML Rx)
  11. Burnett et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood 2013;122:1384
  12. Attar et al. Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502. J Clin Oncol 2013;31:923 (65% CR rate)
  13. Erba H. Prognostic factors in elderly patients with AML and the implications for treatment. Hematology 2007:429
  14. Krug et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010;376:2000 (Web site - requires password)
  15. Prébet et al. Acute Myeloid Leukemia With Translocation (8;21) or Inversion (16) in Elderly Patients Treated With Conventional Chemotherapy: A Collaborative Study of the French CBF-AML Intergroup. J Clin Oncol 2009;27:4747 (88% CR rate, 31% 5 year OS)
  16. Juliusson et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009; 113:4179 ("Most AML patients up to 80 should be considered for intensive therapy")
  17. Kantarjian et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 2010;116:4422 (Median survival 4.6 mo, 8-week mortality 36%, 1-year survival 28%)
  18. Rowe et al.  A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004;103:479 (No difference among three different anthracyclines; no benefit from GM-CSF priming)
  19. Sekeres et al. Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood 2009;113;28 (Delaying treatment not harmful in elderly patients)
  20. Gardin et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy:results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood 2007;109:5129 (6 cycles of outpatient treatment more successful than single course of high dose consolidation treatment)
  21. Clavio et al. Adding low-dose gemtuzumab ozogamicin to fludarabine, Ara-C and idarubicin (MY-FLAI) may improve disease-free and overall survival in elderly patients with non-M3 acute myeloid leukaemia: results of a prospective, pilot, multi-centre trial and comparison with a historical cohort of patients. Br J Haematol 2007; 138:186
  22. Burnett et al. Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy Improves Survival in Older Patients With Acute Myeloid Leukemia. J Clin Oncol 2012;30:3924
  23. Amadori et al. Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17). J Clin Oncol 2013;31:4424 (Adding GO produced no apparent benefit)
  24. Quintás-Cardama et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012;120:4840
  25. Tassara et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood 2014;123:4027 (No difference in EFS or OS, but better PFS with addition of valproate)

AML variants/subtypes

  1. Koeffler H. Syndromes of acute nonlymphocytic leukemia. Ann Intern Med 1987;107:748
  2. Olopade et al. Clinical, morphologic and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 1992;80:2873
  3. Roumer et al.  M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 50 cases bye the Groupe Francais d'Hematologie Cellulaire (GFHC) and the Groupe Francais de Cytogenetiquie Hematologique (GFCH).  Blood 2003;101:1277
  4. Hasserjian et al. Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification. Blood 2010;115:1985
  5. Oki et al. Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center. Blood 2006;107:880
  6. Weinberg et al. Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood 2009;113:1906
  7. Wolach and Stone. How I treat mixed-phenotype acute leukemia. Blood 2015;125:2477

AML treatment

  1. Döhner et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424
  2. Ofran et al. How I treat acute myeloid leukemia presenting with preexisting comorbidities. Blood 2016;128:488
  3. Dombret and Gardin. An update of current treatments for adult acute myeloid leukemia. Blood 2016;127:53
  4. Rashidi et al. Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood 2016;128:763
  5. Roboz G. Novel approaches to the treatment of acute myeloid leukemia. Hematology 2011: 43
  6. Stein and Tallman. Emerging therapeutic drugs for AML. Blood 2016;127:71
  7. Schiller GJ. High-risk acute myelogenous leukemia: treatment today … and tomorrow. Hematology 2013:201
  8. Pratz and Levis. How I treat FLT3-mutated AML. Blood 2017;129:565
  9. Forman and Rowe. The myth of the second remission of acute leukemia in the adult. Blood 2013;121:1077
  10. Fernandez et al. Anthracycline Dose Intensification in Acute Myeloid Leukemia. NEJM 2009;361:1249 (90mg/m2 daunorubicin produced superior CR and survival rates than 45 mg/m2, no more toxicity)
  11. Lee et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 2011;118:3832 (90 mg/m2 improved CR rate and survival vs 45 mg/m2)
  12. Burnett et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 2015;125:3878 (No evidence of benefit from higher dose)
  13. Luskin et al. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood 2016;127:1551
  14. Mandelli et al. Daunorubicin Versus Mitoxantrone Versus Idarubicin As Induction and Consolidation Chemotherapy for Adults With Acute Myeloid Leukemia: The EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 2009;27:5397 (Idarubicin 10 mg/m2 and mitoxantrone 12 mg/m2 both superior to daunomycin 50 mg/m2)
  15. Löwenberg et al. Cytarabine dose for acute myeloid leukemia. NEJM 2011;364:1027 (2000 mg/m2 no more effective, and more toxic, than 1000 mg/m2)
  16. Löwenberg B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 2013;121:26
  17. Willemze et al. High-Dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years With Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial. J Clin Oncol 2014;32:218 (Modest improvement in survival for pts given HDAC vs standard dose cytarabine; benefit more pronounced in younger and high-risk pts)
  18. Löwenberg et al. Effect of Priming with Granulocyte Colony-Stimulating Factor on the Outcome of Chemotherapy for Acute Myeloid Leukemia. NEJM 2003;349:743
  19. Braess et al. Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG. Blood 2009;113:3903 (61% OS @ 2 years; neutrophil recovery 2 weeks sooner than with standard induction)
  20. Ohtake et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood 2011;117:2358 (50 mg/m2 daunorubicin x 5 days = 12 mg/m2 idarubicin x 3 days)
  21. Holowiecki et al. Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study. J Clin Oncol 2012;30:2441
  22. Miyawaki et al. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 2011;117:2366 (2 regimens equally effective overall, HiDAC better with favorable cytogenetics)
  23. Farag et al. Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study. J Clin Oncol 2005;23:482
  24. Atallah et al. Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia. Blood 2007;110:3547 (20% mortality rate during induction for unselected group of 1534 adults with non-M3 AML)
  25. Schiller et al. Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. Blood 1992;80:2977
  26. Hokland and Ommen. Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood 2011;117:2577 (Role of MRD monitoring during remission)
  27. Bradstock et al. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood 2005;105:481
  28. Moore et al. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222.  Blood 2005;105:3420
  29. Neubauer et al. Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study. J Clin Oncol 2008;26:4603
  30. Tsimberidou et al. The role of gemtuzumab ozogamicin in acute leukaemia therapy. Br J Haematol 2006;132:398
  31. Castaigne et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012;379:1508 (3 yr EFS 40.8% with low-dose fractionated Mylotarg, 17.1% without)
  32. Petersdorf et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 2013;121:4854 (Adding gemtuzumab did not improve CR rate or OS)
  33. Stone et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:54
  34. Ravandi et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013;121:4655
  35. Welch et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. NEJM 2016;375:2023 (Presence of TP53 mutation predicted favorable response to treatment; with editorial)
  36. Cassileth et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. NEJM 1998;339:1649
  37. Thepot et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010;116:3735
  38. Sekeres et al. A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. Blood 2011;118:523 (14% overall response rate, medial overall survival 2 months in this group of older pts)
  39. Illendula et al. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science 2015;347:779 (Promising experimental agent - with editorial)
  40. Bakst et al. How I treat extramedullary acute myeloid leukemia. Blood 2011;118:3785

AML treatment - older patients

  1. Ossenkoppele and Löwenberg. How I treat the older patient with acute myeloid leukemia. Blood 2015;125:767
  2. Löwenberg et al. High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia. NEJM 2009;361:1235 (Higher CR rate, no more toxicity with 90 mg/m2 daunorubicin vs 45 mg/m2)
  3. Gardin et al. Superior Long-Term Outcome With Idarubicin Compared With High-Dose Daunorubicin in Patients With Acute Myeloid Leukemia Age 50 Years and Older. J Clin Oncol 2013;31:321
  4. Nand et al. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood 2013;122:3432 (44% of good-risk, 35% of poor-risk patients had CR)

Treatment of relapsed or refractory AML

  1. Thol et al. How I treat refractory and early relapsed acute myeloid leukemia. Blood 2015;126:319
  2. Craddock et al. Biology and management of relapsed acute myeloid leukaemia. Br J Haematol 2005;129:18
  3. Chevallier et al. Long-Term Disease-Free Survival After Gemtuzumab, Intermediate-Dose Cytarabine, and Mitoxantrone in Patients With CD33+ Primary Resistant or Relapsed Acute Myeloid Leukemia. J Clin Oncol 2008;26:5192 (50% CR, 53% DFS at 2 years)
  4. Ravandi et al. Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood 2010;116:5818 (Of pts with < 50% reduction in marrow blasts, 22% responded to salvage Rx; median survival less than 4 mo)
  5. Hospital et al. Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup. Blood 2014;124:1342 (Gemtuzumab ozogamicin given before transplant improves outcome)

AML: Stem cell transplantation

APML

  1. Lallamand-Breietenbach and de Thé. Retinoic acid plus arsenic trioxide, the ultimate panacea for acute promyelocytic leukemia? Blood 2013;122:2008
  2. Tallman and Altman. How I treat promyelocytic leukemia. Blood 2009;114:5126
  3. Sanz and Lo-Coco. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol 2011;29:495
  4. Lo-Coco and Ammatuna. The Biology of Acute Promyelocytic Leukemia and Its Impact on Diagnosis and Treatment. Hematology 2006;156-61
  5. Wei et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 2015;21:457
  6. Tallman et al. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood 2010;116:5650 (No)
  7. Montesinos et al. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood 2011;117:1799 (Adverse prognostic feature)
  8. Licht J. Acute Promyelocytic Leukemia — Weapons of Mass Differentiation. NEJM 2009;360:928
  9. Ablain and de The. Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood 2011;117:5795
  10. Ablain et al. Activation of a promyelocytic leukemia–tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat Med 2014;20:167 (With editorial; suggests inducing differentiation is not the sole basis of APL cure with arsenic or ATRA)
  11. Sanz et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875
  12. Adès et al. Is Cytarabine Useful in the Treatment of Acute Promyelocytic Leukemia? Results of a Randomized Trial From the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006;24:5703
  13. Adès et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 2008;111:1078 (Adding cytarabine to ATRA + ida may be beneficial in APL patients with WBC > 10K)
  14. Lo-Coco et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010;116:3171
  15. Patatanian and Thompson. Retinoic acid syndrome: a review. J Clin Pharm Ther 2008;33:331
  16. Chen et al. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood 2011;117:6425
  17. Tallman et al.  All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol.  Blood 2002;100:4298
  18. Tallman et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000;95:90
  19. Montesinos et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 2009;113:775
  20. Sanz and Montesinos. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood 2014;123:2777
  21. Soignet et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. NEJM 1998;339:1341
  22. Sanz et al.  Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103:1237
  23. Sanz et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 2008;112:3130 (5 year DFS 84%)
  24. Sanz et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137
  25. Avvisati et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 2011;117:4716 (12 year EFS 69%; no apparent benefit from maintenance therapy after molecular remission confirmed)
  26. Estey et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107:3469
  27. Burnett et al. Arsenic trioxide and all- trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:1295
  28. Lo-Coco et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. NEJM 2013;369:111 (100% CR, 97% 2-yr EFS; less hematologic toxicity than ATRA+chemo, more liver problems)
  29. Ravandi et al. Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin. J Clin Oncol 2009;27:504 (ATRA + ATO with or without GO can replace chemotherapy-containing regimens)
  30. Iland et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120:1570 (95% CR, 2 year OS 93%)
  31. Abaza et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 2017;129:1283 (5-year OS 88%; relapse is rare)
  32. Zhu et al. Oral Tetra-Arsenic Tetra-Sulfide Formula Versus Intravenous Arsenic Trioxide As First-Line Treatment of Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trial. J Clin Oncol 2013;31:4216 (Oral arsenic compound as effective and safe as IV ATO)
  33. Asou et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RAR transcript after consolidation therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 study (PCR negative patients had better outcome without maintenance)
  34. Adès et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2010; 115:1690 (10 year survival 77%)
  35. Grimwade et al. Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy. J Clin Oncol 2009;27:3650 (MRD monitoring was most powerful predictor of relapse. Early treatment with arsenic trioxide prevented frank relapse in most MRD positive pts)
  36. Chendamarai et al. Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy. Blood 2012;119:3413
  37. Au et al. Oral arsenic trioxide–based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study. Blood 2011;118:6535
  38. Mathews et al. Single-Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Long-Term Follow-Up Data. J Clin Oncol 2010;28:3866 (80% 5 year DFS)
  39. Powell et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116:3751
  40. Echaniz-Laguna et al. Mitochondrial myopathy caused by arsenic trioxide therapy. Blood 2012;119:4272
  41. Yanada et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 2013;121:3095
  42. Zhu et al. Resistance to arsenic in acute promyelocytic leukemia (letter). NEJM 2014;370:1864 (PML gene mutations in arsenic-binding domain cause resistance)
  43. Schwartz et al. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2 plasmin inhibitor deficiency. Ann Intern Med 1986; 105:873
  44. Falanga and Rickles. Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 2003; 16: 463.
  45. Tallman et al. The Double Hazard of Thrombophilia and Bleeding in Acute Promyelocytic Leukemia. Semin Thrombos Hemost 2007; 33:330
  46. Stein et al. The coagulopathy of acute promyelocytic leukemia revisited. Best Pract Res Clin Haematol 2009;22:153
  47. Sanz and Montesinos. Open issues on bleeding and thrombosis in acute promyelocytic leukemia. Thromb Res 2010;125:S51
  48. de la Serna et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008;111:3395. (Death during induction due to hemorrhage in 5%, infection in 2.3%, ATRA syndrome in 1.4%)
  49. Park et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011;118:1248 (Overall early death rate 17.3%)
  50. Yang and Hladnik. Treatment of acute promyelocytic leukemia during pregnancy. Pharmacotherapy 2009;29:709


ALL: biology/general

  1. Pui et al. Acute lymphoblastic leukemia. Lancet 2008;371:1030
  2. Bassan and Hoelzer. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol 2011;29:532
  3. Hunger and Mullighan. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood 2015;125:3977
  4. Forman and Rowe. The myth of the second remission of acute leukemia in the adult. Blood 2013;121:1077
  5. Armstrong and Look.  Molecular Genetics of Acute Lymphoblastic Leukemia. J Clin Oncol 2005;23:6306
  6. Pullarkat et al. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood 2008;111:2563. (t(9;22), -7, +8, and 11q23 rearrangement had worse prognosis; cytogenetics most important prognostic factor in adult ALL)
  7. Moorman et al. A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood 2010;115:206
  8. Castor et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005;11:630  (Different molecular subtypes of ALL target cells at different stages of development)
  9. Mullighan et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446:758
  10. Roberts et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. NEJM 2014;371:1005
  11. Bercovich et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372:1484
  12. Asnafi et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 2009;113:3918
  13. Buonamici et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 2009;459: 1000
  14. Thomas et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood 2009;113:6330 (CD20 expression an independent predictor of poor outcome)
  15. Mancini et al. A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood 2005;105:3434
  16. Nachman J. Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 2005;130:166 (improved survival in patients treated with pediatric vs adult protocols)
  17. Stock et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008;112:1646 (more intensive chemo, more aggressive CNS prophylaxis in childrens' protocols associated with better results)
  18. Bassan et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009;113:4153 (Presence of MRD best predictor of relapse)
  19. Conter et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115:3206 (Presence of MRD at day 33 and 78 highly predictive of outcome in childhood ALL)
  20. Brüggemann et al. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood 2012;120:4470
  21. Beldjord et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood 2014;123: 3739
  22. Gökbuget et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood 2012;120:1868
  23. Girardi et al. The genetics and molecular biology of T-ALL. Blood 2017;129:1113
  24. Asnafi et al. Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study. Blood 2005;105:3072
  25. Marks et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood 2009;114:5136
  26. Jain et al. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood 2016;127:1863
  27. Gökbuget et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 2012;120:2032
  28. Jain et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood 2017;129:572
  29. Safavi and Paulsson. Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis. Blood 2017;129:420 ("Near-haploid" = about 27 chromosomes, "low-hypodiploid" = about 36 chromosomes)

ALL: Treatment

  1. Litzow and Ferrando. How I treat T-cell acute lymphoblastic leukemia in adults. Blood 2015;126:833
  2. Marks and Rowntree. Management of adults with T-cell lymphoblastic leukemia. Blood 2017;129:1134
  3. Wolach and Stone. How I treat mixed-phenotype acute leukemia. Blood 2015;125:2477
  4. Gökbuget N. How I treat older patients with ALL. Blood 2013;122:1366
  5. Curran and Stock. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood 2015;125:3702
  6. Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology 2013:118
  7. Advani A.New immune strategies for the treatment of acute lymphoblastic leukemia: antibodies and chimeric antigen receptors. Hematology 2013:131
  8. Nakano and Hunger. Blood consult: Therapeutic strategy and complications in the adolescent and young adult with acute lymphoblastic leukemia. Blood 2012;119:4372
  9. Hoelzer D. Novel antibody-based therapies for acute lymphoblastic leukemia. Hematology 2011:243
  10. DeAngelo D. The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia. Hematology 2005:123-130
  11. Hunault et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood 2004;104:3028
  12. Rowe et al.  Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005;106:3760 (Overall survival 45% for patients who achieved CR with induction chemotherapy)
  13. Larson et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995;85:2025
  14. Thomas et al. Chemoimmunotherapy With a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome in De Novo Philadelphia Chromosome–Negative Precursor B-Lineage Acute Lymphoblastic Leukemia. J Clin Oncol 2010;28:3880 (95% CR, 3 year OS 50%)
  15. Thomas et al. Outcome of Treatment in Adults With Acute Lymphoblastic Leukemia: Analysis of the LALA-94 Trial. J Clin Oncol 2004;22:4075 (Allo-BMT superior in high-risk patients; auto-BMT no better than standard chemotherapy)
  16. O'Brien et al. High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia. J Clin Oncol 2013;31:676 (20% CR, potential bridge to transplant, 5/65 pts long-term survivors)
  17. Fielding et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007;109:944
  18. Möricke et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008;111:4477
  19. Frey and Luger. How I treat adults with relapsed or refractory Philadelphia chromosome–negative acute lymphoblastic leukemia. Blood 2014;126:589
  20. Gökbuget et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood 2011;118:3504
  21. Maury et al. Rutuximab in B-lineage adult acute lymphoblastic leukemia. NEJM 2016;375:1044 (Rituximab significantly improved event-free survival)
  22. Chevallier et al. Trastuzumab for treatment of refractory/relapsed HER2-positive adult B-ALL: results of a phase 2 GRAALL study. Blood 2012;119:2474
  23. Kantarjian et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. NEJM 2016;375:740 (Higher CR rate, modest improvement in OS with inotuzumab in RR ALL; drug caused VOD in 11%)
  24. Topp et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 2012;120:5185
  25. Topp et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015;16:57 (43% CR; 22% grade 3 or 4 neurotoxicity)
  26. Zugmaier et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood 2015;126:2578
  27. Topp et al. Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia. J Clin Oncol 2014;32:4134
  28. Kantarjian et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. NEJM 2017;376:836 (Median OS 7.7 mo with blinatumomab vs 4 mo with chemo)
  29. Maude et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. NEJM 2014;371:1507 (27/30 patients had CR; 6-mo EFS 67%)
  30. Maude et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 2015;125:4017
  31. Gardner et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016;127:2406
  32. Jabbour et al. Monoclonal antibodies in acute lymphoblastic leukemia. Blood 2015;125:4010

BCR-ABL positive ALL

  1. Fielding AK. Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology 2011:231
  2. Towatari et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 2004;104:3507
  3. Ottmann and Wassmann. Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia. Hematology 2005:118-122
  4. Yanada et al. High Complete Remission Rate and Promising Outcome by Combination of Imatinib and Chemotherapy for Newly Diagnosed BCR-ABL–Positive Acute Lymphoblastic Leukemia: A Phase II Study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006;24:460
  5. Short et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. Blood 2016;128:504 (Patients who have CMR @ 3 mo have excellent long term outcomes without transplant)
  6. Wassmann et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Blood 2006;108:1469
  7. de Labarthe et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 2007;109:1408
  8. Vignetti et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome–positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007;109:3676
  9. Ottman et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007;110:2309
  10. Ravandi et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia. Blood 2010;116:2070 (2 yr OS 64%)
  11. Porkka et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia. Blood 2008;112:1005 (imatinib does not cross BBB well, less effective)
  12. Foà et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. Blood 2011;118:6521 (Dasatinib plus steroids causes complete hematologic remission in over 90% of patients)
  13. Rousselot et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL. Blood 2016;128:774 (36% 5 year OS)
  14. Fielding et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood 2014;123:843 (4 year OS improved from 22% to 38% with addition of imatinib)
  15. Chalandon et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood 2015;125:3711 (Less intense induction plus TKI as effective, less toxic than hyperCVAD plus TKI)
  16. Kim et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood 2015;126:746 (2 year OS 72%; MRD status early in remission predicted outcome)
  17. Comoli et al. BCR-ABL–specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors. Blood 2017;129:582 (Report of 3 patients, all obtained CR)
ALL: Stem Cell Transplantation

AML and ALL: complications

  1. Zuckerman et al. How I treat hematologic emergencies in adults with acute leukemia. Blood 2012;120:1993
  2. Pui C. Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment. Hematology 2006;142-6
  3. Potenza et al.  Leukaemic pulmonary infiltrates in adult acute myeloid leukaemia: a high-resolution computerized tomography study.  Br J Haematol 2003;120:1058
  4. Hogan et al.  Neutropenic Colitis After Treatment of Acute Myelogenous Leukemia With Idarubicin and Cytosine Arabinoside.  Mayo Clin Proc 2002;77:760
  5. Rollig and Ehninger. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015;125:3246
  6. Lichtman and Rowe. Hyperleukocytic leukemias: rheological, clinical, and therapeutic considerations. Blood 1982; 60:279
  7. Blum and Porcu. Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome. Semin Thrombos Hemost 2007;33: 350
  8. Byrd et al. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13:1800
  9. De Stefano et al. The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment. J Thromb Haemost 2005;3:1985  (Highest risk of thrombosis in M3, M4 and M5 AML at presentation, and in ALL during treatment)
  10. Payne and Vora. Thrombosis and acute lymphoblastic leukaemia. Br J Haematol 2007;138:405
  11. Ku et al. Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival. Blood 2009;113:3911
  12. Mitchell et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. Blood 2010;115: 4999 (Asparaginase use, central catheters, steroid use, and thrombophilia risk factors for VTE)
  13. Libourel et al. Disseminated intravascular coagulation at diagnosis is a strong predictor for thrombosis in acute myeloid leukemia. Blood 2016;128:1854
  14. Kwaan H. Double hazard of thrombophilia and bleeding in leukemia. Hematology 2007:151
  15. Hijiya et al. Cumulative Incidence of Secondary Neoplasms as a First Event After Childhood Acute Lymphoblastic Leukemia. JAMA 2007;297:1207 (6% incidence of 2nd neoplasm after 30 yrs)
  16. Nielsen et al. Risk of thyroid cancer, brain cancer, and non-Hodgkin lymphoma after adult leukemia: a nationwide study. Blood 2011;118:4062

Myelodysplastic syndromes

General; biology & pathophysiology

  1. Bejar and Steensma. Recent developments in myelodysplastic syndromes. Blood 2014;124:2793
  2. Tefferi and Vardiman. Myelodysplastic syndromes. NEJM 2009;361:1872
  3. Steensma D. The changing classification of myelodysplastic syndromes: what’s in a name? Hematology 2009;645
  4. Goldberg et al. Incidence and Clinical Complications of Myelodysplastic Syndromes Among United States Medicare BeneficiariesJ Clin Oncol 2010;28:2847
  5. Kwok et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 2015;126:2355 (Over 30% of patients with unexplained cytopenias but not overt MDS have an MDS-associated somatic mutation)
  6. Cargo et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 2015;126:2362 (MDS-associated mutations common in patients with idiopathic cytopenias)
  7. Steensma et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126:9
  8. Graubert and Walter. Genetics of myelodysplastic syndromes: New insights. Hematology 2011:543
  9. Cazzola et al. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013;122:4021
  10. Cazzola et al. Myelodysplastic/myeloproliferative neoplasms. Hematology 2011:264
  11. Malcovati et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013;122:3943
  12. Owen et al. Familial myelodysplasia and acute myeloid leukaemia - a review. Br J Haematol 2008;140:123
  13. Vardiman et al. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292
  14. Howe et al.  The WHO classification of MDS does make a difference.  Blood 2004;103:3265
  15. Vardiman J. Hematopathological Concepts and Controversies in the Diagnosis and Classification of Myelodysplastic Syndromes. Hematology 2006;199-204
  16. Rollison et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 2008;112:45
  17. Malcovati et al. Prognostic Factors and Life Expectancy in Myelodysplastic Syndromes Classified According to WHO Criteria: A Basis for Clinical Decision Making. J Clin Oncol 2005;23:7594
  18. Greenbert et al. Revised international prognositic scoring system for myelodysplastic syndromes. Blood 2012;120:2454
  19. Schanz et al. New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge. J Clin Oncol 2012;30:820
  20. Valcárcel et al. Complex, Not Monosomal, Karyotype Is the Cytogenetic Marker of Poorest Prognosis in Patients With Primary Myelodysplastic Syndrome. J Clin Oncol 2013;31:916
  21. Kuendgen et al. Myelodysplastic Syndromes in Patients Younger Than Age 50. J Clin Oncol 2006;24:5358
  22. Pfeilstöcker et al. Time-dependent changes in mortality and transformation risk in MDS. Blood 2016;128:902 (Risk of death and leukemic transformation decreases over time in high-risk MDS, not in low-risk disease)
  23. Szpurka et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 2006;108:2173  (6/9 pts with RARS + thrombocytosis had JAK-2 mutation; this mutation was rare in other forms of MDS)
  24. Huls et al. Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis. Blood 2010;116:180
  25. Malcovati et al. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood 2009;114:3538
  26. Guidetti et al. Primitive hematopoietic stem cells show a polyclonal pattern in myelodysplastic syndromes. Haematologica 2004; 89:21
  27. Steensma and List. Genetic Testing in the Myelodysplastic Syndromes: Molecular Insights Into Hematologic Diversity.  Mayo Clin Proc 2005;80:681
  28. Steensma et al.  Acquired a-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies.  Blood 2005;105:443
  29. Cazzola et al. Natural history of idiopathic refractory sideroblastic anemia. Blood 1988;71:305
  30. Abitar et al. Myelodysplastic syndrome is not merely "preleukemia". Blood 2002;100:791
  31. West et al. Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure. Blood 2000;95:2093
  32. Aivado et al. Serum proteome profiling detects myelodysplastic syndromes and identifies CXC chemokine ligands 4 and 7 as markers for advanced disease. PNAS 2007;104:1307
  33. Haase et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007;110:4385
  34. Bejar et al. Clinical effect of point mutations in myelodysplastic syndromes. NEJM 2011;364:2496
  35. Papaemmanuil et al. Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts. NEJM 2011;365:1384
  36. Malcovati et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011;118:6239 (Mutation associated with better prognosis, presence of ringed sideroblasts)
  37. Visconte et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 2012;120:3173
  38. Cazzola et al. Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood 2013;121:260
  39. Malcovati et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood 2015;126:233
  40. Wu et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood 2012;120:3106
  41. Issa J. The myelodysplastic syndrome as a prototypical epigenetic disease. Blood 2013;121:3811
  42. Gupta et al. Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation. Br J Haematol 2007; 139:265 (can mimic ITP)
  43. Della Porta et al. Clinical Relevance of Bone Marrow Fibrosis and CD34-Positive Cell Clusters in Primary Myelodysplastic Syndromes. J Clin Oncol 2009;27:754
  44. Such et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121:3005
  45. Itzykson et al. Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia. J Clin Oncol 2013;31:2428
  46. Takahashi et al. Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood 2013;122:2807 (Worse outcomes than de novo CMML)
  47. Wang et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood 2014;123:2645

Treatment

  1. Fenaux and Adès. How we treat lower-risk myelodysplastic syndromes. Blood 2013;121:4280
  2. Stone R. How I treat patients with myelodysplastic syndrome. Blood 2009;113:6296
  3. Sekeres and Cutler. How we treat higher-risk myelodysplastic syndromes. Blood 2014;123:829
  4. Gotlib et al. How I treat atypical chronic myeloid leukemia. Blood 2017;129:838
  5. Gore SD. New Ways to Use DNA Methyltransferase Inhibitors for the Treatment of Myelodysplastic Syndrome. Hematology 2011:550
  6. Adès and Fenaux. Immunomodulating drugs in myelodysplastic syndromes. Hematology 2011:556
  7. Molldrem J et al. Antithymocyte globulin for treatment of bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002;137:156
  8. Steensma et al. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood 2003;101:2156
  9. Sloand et al. Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy. J Clin Oncol 2008;26:2505
  10. Passweg et al. Immunosuppressive Therapy for Patients With Myelodysplastic Syndrome: A Prospective Randomized Multicenter Phase III Trial Comparing Antithymocyte Globulin Plus Cyclosporine With Best Supportive Care—SAKK 33/99. J Clin Oncol 2011;29:303 (29% had hematologic improvement with immunosuppression; no improvement in survival)
  11. Mantovani et al. Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granuolocyte colony-stimulating factor and erythropoietin. Br J Haematol 2000;109:367
  12. Casadevall et al. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial.  Blood 2004;104:321 (Treatment was expensive, and did not improve quality of life)
  13. Jädersten et al. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 2005;106:803
  14. Musto et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol 2005;128:204
  15. Mannone et al. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol 2006;133:513
  16. Park et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 2008;111:574
  17. Greenberg et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood 2009;114:2393
  18. Jädersten et al. Erythropoietin and Granulocyte-Colony Stimulating Factor Treatment Associated With Improved Survival in Myelodysplastic Syndrome. J Clin Oncol 2008;26:3607
  19. Park et al. Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta-analysis. Br J Haem 2016;174:730
  20. Oliva et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol 2017;4:e127 (47% of treated patients had platelet response vs 3% of controls, with fewer bleeding events; more non-heme adverse events in treated group)
  21. Kuendgen et al.  Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid.  Blood 2004;104:1266
  22. Garcia-Manero et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 2006;108:3271
  23. Silverman et al. Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006;24:3895
  24. Fenaux et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223 (Median survival 24.5 mo with azacytidine Rx vs 15 mo in control group)
  25. Lyons et al. Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients With Myelodysplastic Syndromes. J Clin Oncol 2009;27:1850 (Approximately 50% response rate regardless of dosing regimen used)
  26. Itzykson et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011;117:403
  27. Kantarjian et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007;109:52
  28. Lübbert et al. Low-Dose Decitabine Versus Best Supportive Care in Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011;29:1987 (No significant improvement in OS, some improvement in quality of life in decitabine-treated pts)
  29. Steensma et al. Multicenter Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults With Myelodysplastic Syndromes: The Alternative Dosing for Outpatient Treatment (ADOPT) Trial. J Clin Oncol 2009;27:3842
  30. Garcia-Manero et al. Randomized Open-Label Phase II Study of Decitabine in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes. J Clin Oncol 2013;31:2548
  31. Braun et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011;118:3824 (38% overall response rate)
  32. Welch et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. NEJM 2016;375:2023 (Presence of TP53 mutation predicted favorable response to treatment)
  33. Fenaux et al. A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Blood 2007;109:4158 (32% overall response rate)
  34. Adès et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood 2009;113:3947 (67% CR rate in patients with isolated 5q- defect)
  35. Raza et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1–risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008;111:86
  36. Sekeres et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 2012;120:4945 (44% CR, 28% PR)
  37. Komrokji et al. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood 2012;120:3419
  38. Leitch and Vickars. Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron? Hematology 2009;664
  39. Shenoy et al. Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome. Blood 2014;124:873
  40. Olnes and Sloand. Targeting immune dysregulation in myelodysplastic syndromes. JAMA 2011;305:814 (Treatment of MDS with immunosuppressive drugs)
MDS:  Stem Cell Transplantation

5q- syndrome

  1. Boultwood et al. The 5q- syndrome. Blood 1994;84:3253
  2. Mukherjee et al. Blood consult: treating del(5q) myelodysplastic syndromes. Blood 2012;119:342
  3. List et al.  Efficacy of Lenalidomide in Myelodysplastic Syndromes.  NEJM 2005;352:549
  4. List et al. Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion.  NEJM 2006;355:1456
  5. Fenaux et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011;118:3765 (Lenalidomide reduced transfusion requirements and may have lowered risk of leukemic transformation)
  6. Tehranchi et al. Persistent Malignant Stem Cells in del(5q) Myelodysplasia in Remission. NEJM 2010;363:1025
  7. Fang et al. A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. Nat Med 2016;22:727

Myeloproliferative disorders

Biology

  1. Vainchecker and Kralovics. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 2017;129:667
  2. Rumi and Cazzola. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017;129:680
  3. Vannucchi and Harrison. Emerging treatments for classical myeloproliferative neoplasms. Blood 2017;129:693
  4. Zhao et al. Inhibtion of the Bcl-xL deamidation pathway in myeloproliferative disorders. NEJM 2008;359:2778 (BCR-ABL and JAK-2 mutation both block apoptosis in response to DNA damage in myeloid stem cells)
  5. Papadantonakis et al. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012;120:1774
  6. Landgren et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden. Blood 2008;112:2199 (5-7 fold increased risk of MPD in first-degree relatives of patients)
  7. Rollison et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 2008;112:45
  8. Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 2012;119:3219
  9. Beer et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008;112:141
  10. Sanada et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009;460:904
  11. Ishii et al. Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders. Blood 2009;113:5942
  12. Panova-Noeva et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood 2011;118:2599 (Possible prothrombotic effect of JAK2 mutation, and antithrombotic effect of myelosuppressive treatment)
  13. Klampfl et al. Somatic mutations in calreticulin in myeloproliferative neoplasms. NEJM 2013;369:2379 (Most patients with JAK2-negative ET or MF have mutations in CALR; with editorial)
  14. Nangalia et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. NEJM 2013;369:2391 (With editorial)
  15. Cazzola and Kralovics. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 2014;123: 3714
  16. Tefferi et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv 2016;1:21 (98% of PV patients have JAK2 mutations; for ET, 52% have JAK2 mutations, 26% CALR, and 4% CALR. Several other mutations predicted poor prognosis)
  17. Ortmann et al. Effect of Mutation Order on Myeloproliferative Neoplasms. NEJM 2015;372;601 (Order of acquisition of JAK2 and TET2 mutations affects MPN phenotype and response to therapy; with editorial)
  18. Osorio et al. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat Med 2016;22:91 (with editorial)
  19. Wen et al. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med 2015;21:1473
  20. Feenstra et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 2016;127:325
  21. Cabagnols et al. Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood 2016;127:333

General Clinical

  1. Tefferi et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092
  2. Barbui et al. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet. J Clin Oncol 2011;29:761
  3. Tefferi and Barbui. Essential Thrombocythemia and Polycythemia Vera: Focus on Clinical Practice. Mayo Clin Proc 2015;90:1283
  4. Geyer and Mesa Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 2014;124:3529
  5. Tefferi et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014;124:2507 (Life expectancy in ET reduced, but less so than in PV. Mutational status markedly affects prognosis in MF, not in ET)
  6. Geyer et al. Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients. Blood 2014;123: 3803
  7. Campbell and Green. Management of Polycythemia Vera and Essential Thrombocythemia. Hematology 2005:201-208
  8. Björkholm et al. Treatment-Related Risk Factors for Transformation to Acute Myeloid Leukemia and Myelodysplastic Syndromes in Myeloproliferative Neoplasms. J Clin Oncol 2011;29:2410 (Alkylating agents and P32, but not hydroxyurea, increased risk of transformation to AML/MDS)
  9. Thepot et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010;116:3735
  10. Vardiman et al. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292
  11. Vardiman and Hyjek. World Health Organization classification, evaluation, and genetics of the myeloproliferative neoplasm variants. Hematology 2011:250
  12. Barosi et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood 2009;113:4829
  13. Tefferi et al. Atypical myeloproliferative disorders: diagnosis and management.  Mayo Clin Proc 2006;81:553
  14. Ruggeri et al.  The Rate of Progression to Polycythemia Vera or Essential Thrombocythemia in Patients with Erythrocytosis or Thrombocytosis. Ann Intern Med 2003;139:470
  15. Passamonti et al.  Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.  Am J Med 2004;117:755
  16. Giona et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome. Blood 2012;119:2219 (Low complication rate during median 10 year followup)
  17. Barbui et al. Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 2012;120:569
  18. Adir and Humbert. Pulmonary hypertension in patients with chronic myeloproliferative disorders. Eur Respir J 2010;35:1396
  19. Mischenko and Tefferi. Treatment options for hydroxyurea-refractory disease complications in myeloproliferative neoplasms: JAK2 inhibitors, radiotherapy, splenectomy and transjugular intrahepatic portosystemic shunt. Eur J Haematol 2010; 85:192
  20. Quintás-Cardama et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 2013;122:893. (Complete molecular response in about 18% of patients)
  21. Davis M.  Erythromelalgia.  Mayo Clin Proc 2004;79:298
  22. Koch et al.  Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.  Mayo Clin Proc 2003;78:1223
  23. Barbui and Finazzi. Myeloproliferative Disease in Pregnancy and Other Management Issues. Hematology 2006;246-52
  24. Ruggeri et al. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 2008;111:666 (Thrombosis and major bleeding common after surgery)
  25. Rumi et al. Familial Chronic Myeloproliferative Disorders: Clinical Phenotype and Evidence of Disease Anticipation. J Clin Oncol 2007;25:5630
  26. Tam et al. The natural history and treatment outcome of blast phase BCR-ABL–negative myeloproliferative neoplasms. Blood 2008;112:1628 (46% remission rate with induction chemotherapy, but responses not durable. Stem cell transplant gave best outcome)
  27. Kennedy et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood 2013;121:2725 (2 yr OS 15%)
  28. Frederiksen et al. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood 2011;118:6515 (Modest increased risk for non-hematologic cancers in CML, ET, PV)

Hemostasis in myeloproliferative disorders

  1. Barbui et al. Myeloproliferative neoplasms and thrombosis. Blood 2013;122:2176
  2. Casini et al. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost 2013;11:1215
  3. Tefferi and Elliott. Thrombosis in Myeloproliferative Disorders: Prevalence, Prognostic Factors, and the Role of Leukocytes and JAK2V617F. Semin Thrombos Hemost 2007; 33:313
  4. Barbui et al. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood 2009;114:759
  5. Marchetti et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008;112:4061 (acquired deficiency of free protein S in patients with ET and PV)
  6. Lamrani et al. Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. Blood 2014;124:1136 (Accelerated formation of unstable clots; acquired defect in large VWF multimers; deficiency of platelet GP VI)
  7. Lancellotti et al. Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost 2015;13:1226
  8. Carobbio et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011;117:5857 (Overall risk of thrombosis about 2%/pt/yr; extreme thrombocytosis associated with lower risk of arterial events)
  9. Barbui et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood 2012;120:5128 (Age > 60, CV risk factors, prior thrombosis, and JAK2 mutation increase thrombotic risk in ET)
  10. Patrono et al. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood 2013;121:1701
  11. Etheridge et al. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. PNAS 2014;111:2295
  12. Hoekstra et al. Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms. J Thromb Haemost 2011;9:2208 (Recurrent or progressive thrombosis in up to 50%; mortality mainly due to underlying disease rather than thrombosis)
  13. De Stefano et al. Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment. Thromb Haemost 2016;115:240
JAK2 V617F Mutation
  1. Spivak J.Narrative Review: Thrombocytosis, Polycythemia Vera, and JAK2 Mutations: The Phenotypic Mimicry of Chronic Myeloproliferation. Ann Intern Med 2010;152:300
  2. Levine and Wernig. Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders. Hematology 2006;233-9
  3. Dawson et al. JAK2 phosphorylates histone H3Y41 and excludes HP1 from chromatin. Nature 2009; 461:814
  4. Brooks et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 2014;344:710 (structure-function relationship in JAK2: with editorial)
  5. Silvennionen and Hubbard. Molecular insights into regulation of JAK2 in myeloproliferative neoplasms. Blood 2015;125:3388
  6. Baxter et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054
  7. Kralovics R.  A gain-of-function mutation of JAK2 in myeloproliferative disorders.  NEJM 2005;352:1779
  8. James et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144
  9. Delhommeau et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood 2007;109:71
  10. Teofili et al. Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood 2011;117:2700
  11. Xu et al. JAK2V617F: prevalence in a large Chinese hospital population. Blood 2007;109:339 (Mutation found in about 1% of randomly selected blood samples; most positive samples from individuals without overt MPD)
  12. Passamonti et al. 
  13. Tefferi A. Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era. Hematology 2006;240-5
  14. Lippert et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006;108:1865 (Mutation common in both diseases, but mutant gene expression higher in PV than ET)
  15. Steensma et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. Blood 2005;106:1207
  16. Lambert et al. In essential thrombocythemia, multiple JAK2-V617F clones are present in most mutant-positive patients: a new disease paradigm. Blood 2009;114:3018
  17. Campbell et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005;366:1945
  18. Passamonti et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011;117:2813 (Associated with higher Hgb levels, lower WBC and platelet counts, but similar outcomes)
  19. Tiedt et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 2008;111:3931 (Higher levels of mutant JAK-2 expression lead to P vera phenotype as opposed to ET phenotype)
  20. Boissinot et al. Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis. Blood 2006;108:3223
  21. Colaizzo et al. The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost 2007;5:55
  22. Kiladjian et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008;111:4922
  23. Dentali et al. JAK2V617F mutation for the early diagnosis of Ph– myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009;113: 5617
  24. Smalberg et al. The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis. Blood 2011;117:3968 (This haplotype constitutes an inherited risk factor for myeloproliferative disorders, including JAK2 V617F negative cases)
  25. Vannucchi et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007;110:840 (Homozygosity associated with more symptoms and higher risk of cardiovascular events)
  26. Barosi et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 2007;110:4030
  27. Beer et al. Two routes to leukemic transformation after a JAK2 mutation–positive myeloproliferative neoplasm. Blood 2010;115:2891 (JAK2 + AML preceded by myelofibrotic stage; JAK2-negative AML may arise from a separate clone)
  28. Passamonti et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 2007; 110:485
  29. Pardanani et al. JAK2V617F Mutation Screening as Part of the Hypercoagulable Work-up in the Absence of Splanchnic Venous Thrombosis or Overt Myeloproliferative Neoplasm: Assessment of Value in a Series of 664 Consecutive Patients. Mayo Clin Proc 2008;83:457
  30. Dentali et al. JAK2V617F mutation for the early diagnosis of Ph– myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009;113:5617 (JAK-2 often associated with splanchnic vein thrombosis but not other forms of VTE)
  31. Passamonti et al. The JAK2 V617F mutation in patients with cerebral venous thrombosis. J Thromb Haemost 2012;10:998 (6.6% of patients had the mutation, most of whom had clinical evidence of MPD)
  32. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology 2009;636

JAK-2 inhibitor treatment of myeloproliferative disorders

  1. Mascarenhas and Hoffman. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood 2013;121:4832
  2. Vannucchi et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. NEJM 2015;372:426 (Ruxolitinib superior to "standard therapy" in PV patients who fail hydroxyurea)
  3. Vertovsek et al. Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. NEJM 2010;363:1117 (This is the same drug as ruxolitinib. Treatment reduces splenomegaly and constitutional symptoms, independent of JAK2 mutation status; with editorial)
  4. Harrison et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. NEJM 2012;366:787 (Treatment associated with significant improvement in splenomegaly and symptoms, better QOL, modest toxicity)
  5. Verstovsek et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. NEJM 2012;366:799 (Treatment associated with less splenomegaly, improved symptoms, improved survival)
  6. Verstovsek et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012;120:1202
  7. Passamonti et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood 2014;123:1833 (Ruxolitnib appears to improve survival)
  8. Cervantes et al. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood 2017;129:832 (Maybe but evidence weak)
  9. Cervantes et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122:4047
  10. Deininger et al. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood 2015;126:1551 (Treatment decreases allele burden, about 10% of patients achieve partial or complete mol remission)
  11. Guglielmelli et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood 2014;123:2157 (Efficacy of ruxolitnib not dependent on JAK2 mutation status)
  12. Tefferi A. Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms. NEJM 2012;366:844
  13. Heine et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013;122:1192 (May account for the anti-inflammatory and immunomodulatory effects of the drug)
  14. Komrokji et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood 2015;125:2649
  15. Meyer et al. Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood 2014;124:2280 (Possible explanation for thrombocytopenia caused by JAK2 inhibitors)

Marrow & stem cell transplant in myeloproliferative disorders

Myelofibrosis/myeloid metaplasia

  1. Papadantonakis et al. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012;120:1774
  2. Rumi et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 2014;124:1062 (65% of 617 patients had JAK2 mutation, 23% CALR, 4% MPL, 9% triple negative. CALR mutations associated with better prognosis)
  3. Tefferi et al. Targeted deep sequencing in primary myelofibrosis. Blood Adv 2016;1:105 (>80% have mutations in JAK2, CALR or MPL)
  4. Tefferi A. How I treat myelofibrosis. Blood 2011;117:3494
  5. Cervantes F. How I treat myelofibrosis. Blood 2014;124:2635
  6. Mesa R. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood 2009;113:5394
  7. Cervantes et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol 2012;30:2981
  8. Tefferi et al. One thousand patients with primary myelofibrosis: The Mayo Clinic experience. Mayo Clin Proc 2012;87:25
  9. Dupriez et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996;88:1013
  10. Cervantes et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113:2895
  11. Passamonti et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703
  12. Morel et al. Identification during the follow-up of time-dependent prognostic factors for the competing risks of death and blast phase in primary myelofibrosis: a study of 172 patients. Blood 2010;115:4350
  13. Guglielmelli et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood 2009;114:1477
  14. Tefferi et al. Predictors of greater than 80% 2-year mortality in primary myelofibrosis: a Mayo Clinic study of 884 karyotypically annotated patients. Blood 2011;118:4595 (Circulating blasts > 9%, WBC > 40K and specific cytogenetic abnormalities associated with poor prognosis)
  15. Lasho et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012;120:4168
  16. Xu et al .Unique features of primary myelofibrosis in Chinese. Blood 2012;119:2469 (Patients younger, less splenomegaly and constintutional symptoms, more anemia/thrombocytopenia)
  17. Mesa et al.  A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003;101:2534
  18. Mesa et al.  Durable Responses to Thalidomide-Based Drug Therapy for Myelofibrosis With Myeloid Metaplasia.  Mayo Clin Proc 2004;79:883
  19. Tefferi et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006;108:1158 (Dramatic improvement in a subset of patients)
  20. Jabbour et al. Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood 2011;118:899 (Lenalidomide plus prednisone more effective than either lenalidomide or thalidomide alone)
  21. Quintás-Cardama et al. Lenalidomide Plus Prednisone Results in Durable Clinical, Histopathologic, and Molecular Responses in Patients With Myelofibrosis. J Clin Oncol 2009; 27:4760
  22. Mesa et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 2010;116:4436 ("Only modestly active", myelosuppressive)
  23. Tefferi et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol 2009;27:4563
  24. Silver et al. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. Blood 2011;117:6669
  25. Guglielmelli et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood 2011;118:2069 (69% of patients experienced complete symptom relief; 15-25% had improved blood counts)
  26. Tefferi et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. NEJM 2015;373:908 (Responses only seen in patients with JAK2 mutations; myelosuppression main side effect. With editorial)
  27. Mesa et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005;105:973 (very poor outcome regardless of treatment used)
  28. Vaidya et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood 2011;117:5612
  29. Barbui et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 2010;115:778 (Age >60, JAK-2 mutation and leukocytosis increased risk)
Polycythemia vera/erythrocytosis
  1. McMullin et al. Management of polycythaemia vera: a critical review of current data. Br J Haem 2016;172:337
  2. Vannucchi AM. How I treat polycythemia vera. Blood 2014;124:3212
  3. Silver et al. Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis. Blood 2013;122:1881 (Direct measurement of red cell mass more sensitive than Hb or Hct measurements; some patients had normal EPO levels)
  4. Spivak et al. Two clinical phenotypes in polycythemia vera. NEJM 2014;371:808 (Gene expression profiling predicts risk of marrow fibrosis & leukemic transformation)
  5. Kwaan and Wang. Hyperviscosity in Polycythemia Vera and Other Red Cell Abnormalities. Semin Hematol 2003;29:451
  6. Di Nisio et al. The hematocrit and platelet target in polycythemia vera.  Br J Haematol 2007;136:249 (No apparent effect on adverse event rate as long as hematocrit is less than 55 and platelets less than 600K)
  7. Marchiolli et al. Cardiovascular events and intensity of treatment in polycythemia vera. NEJM 2013;368:22 (Fewer cardiovascular deaths or major thrombotic events with target Hct < 45 versus a target Hct of 45-50; with editorial and letters )
  8. Johansson et al. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 2005; 129:701
  9. Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med 1995;123:656
  10. Kiladjian et al. Treatment of Polycythemia Vera With Hydroxyurea and Pipobroman: Final Results of a Randomized Trial Initiated in 1980. J Clin Oncol 2011;29:3907 (24% of HU-treated patients developed MDS or AML after 20 years; 32% developed myelofibrosis)
  11. Barbui et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood 2012;119:2239 (less thrombosis, no impact on overall or leukemia-free survival)
  12. Landolfi et al. Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera. NEJM 2004;350:114
  13. Elliott and Tefferi. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005;128:275
  14. Marchioli et al. Vascular and Neoplastic Risk in a Large Cohort of Patients With Polycythemia Vera. J Clin Oncol 2005;23:2224
  15. Landolfi et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007;109:2446
  16. Finazzi et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664(hydroxyurea treatment did not increase leukemia risk)
  17. Alvarez-Larrán et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012;119:1363 (Decreased WBC and platelets with HU treatment predicted better survival and fewer thrombohemorrhagic complications, respectively)
  18. Kiladjian et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha–2a. Blood 2006;108:2037
  19. Kiladjian et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065
  20. Gisslinger et al. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood 2015;126:1782
  21. Masarova et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol 2017;4:e165 (80% hematologic response rate, 63% molecular response rate, 22% stopped treatment due to toxicity; with editorial)
  22. Scott et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. NEJM 2007;356:459 (Variant JAK2 mutations present in most cases of JAK2 V617F negative polycythemia vera and idiopathic erythrocytosis)
  23. Gangat et al. Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation. Br J Haematol 2007;138:354
  24. Passamonti et al. A dynamic prognostic model to predict survival in post–polycythemia vera myelofibrosis. Blood 2008;111:3383 (Hgb < 10, plts < 100K, WBC > 30K all predicted worse survival)

Erythrocytosis- general

  1. Birgegård and Wide. Serum erythropoietin in the diagnosis of polycythaemia and after phlebotomy treatment. Br J Haematol 1992;81:603
  2. Klippel et al. Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis.  Blood 2003;102:3569
  3. Lasho et al. LNK mutations in JAK2 mutation-negative erythrocytosis (letter). NEJM 2010;363:1189
  4. Wu et al. Preoperative Hematocrit Levels and Postoperative Outcomes in Older Patients Undergoing Noncardiac Surgery. JAMA 2007;297:2481
  5. Percy et al. A Gain-of-Function Mutation in the HIF2A Gene in Familial Erythrocytosis. NEJM 2008;358:162
  6. Franke et al. Erythrocytosis: the HIF pathway in control. Blood 2013;122:1122
  7. McMullin M. Idiopathic erythrocytosis: a disappearing entity. Hematology 2009;629
  8. Johansson et al. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 2005; 129:701
  9. Zhou et al. Clinical Improvement with JAK2 Inhibition in Chuvash Polycythemia (letter). NEJM 2016;375:404
Thrombocytosis/thrombocythaemia
  1. Skoda R. Thrombocytosis. Hematology 2009;159
  2. Cervantes F. Management of essential thrombocythemia. Hematology 2011:215
  3. Buss et al. Occurrence, etiology and clinical significance of extreme thrombocytosis: a study of 280 cases. Am J Med 1994;96:247
  4. Schafer A.  Thrombocytosis. NEJM 2004;350:1211
  5. Beer et al. how I treat essential thrombocythemia. Blood 2011;117:1472
  6. Marty et al. Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors. Blood 2014;123:1372
  7. Etheridge et al. A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis. Blood 2014;123:1059
  8. Rumi et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123:1544 (Lower thrombotic risk, similar risk of marrow fibrosis, no transformation to PV in CALR mutated ET)
  9. Rotunno et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552 (Thrombotic risk no higher than patients lacking CALR mutation)
  10. Giona et al. CALR mutations in patients with essential thrombocythemia diagnosed in childhood and adolescence. Blood 2014;123:3677
  11. Chachoua et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood 2016;127:1325
  12. Passamonti et al. A prognostic model to predict survival in 867 World Health Organization–defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 2012;120:1197 (Age > 60, WBC > 11K, history of thrombosis are adverse prognostic features)
  13. Barbui et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood 2012;120:5128 (Age > 60, CV risk factors, prior thrombosis, and JAK2 mutation increase thrombotic risk in ET)
  14. Gnatenko et al. Class prediction models of thrombocytosis using genetic biomarkers. Blood 2010;115:7 (Gene expression profiling better than 90% accurate in distinguishing ET from reactive thrombocytosis)
  15. Harrison C. Essential thrombocythaemia: challenges and evidence-based management. Br J Haematol 2005;130:153
  16. Wilkins et al. Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 2008;111:60
  17. Harrison et al. A large proportion of patients with a diagnosis of essential thrombocytosis do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 1999;93:417
  18. Axelrod et al. Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia. Blood 2000;96:3310
  19. Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood 1984;64:1
  20. Carobbio et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011;117:5857 (Overall risk of thrombosis about 2%/pt/yr; extreme thrombocytosis associated with lower risk of arterial events)
  21. Alvarez-Larrán et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010;116:1205. (Among pts < 60 with no prior vascular events, only those who are JAK-2 positive or who have cardiovascular risk factors appear to benefit from aspirin prophylaxis)
  22. Pascale et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012;119:3595 (Twice-daily ASA more effective in blocking platelet thromboxane synthesis in ET)
  23. Carobbio et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and JAK2 mutation status. Blood 2007;109:2310
  24. Carobbio et al. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. Blood 2008;112:3135 (thrombotic events associated with lower platelet counts and higher white counts, plus JAK2 mutation)
  25. Carobbio et al. Leukocytosis and Risk Stratification Assessment in Essential Thrombocythemia. J Clin Oncol 2008;26:2732
  26. Carobbio et al. Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria. Blood 2010; 116:1051 (Probability of thrombosis associated with degree of leukocytosis but not of thrombocytosis)
  27. Campbell et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood 2012;120:1409 (Abnormal platelet count correlated with bleeding risk; high WBC correlated with both bleeding and thrombosis)
  28. Vannucchi et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 2008;112:844 (lower hemoglobin levels, higher platelet counts, more microvessel disease)
  29. Wolanskyj et al. Essential Thrombocythemia Beyond the First Decade: Life Expectancy, Long-term Complication Rates, and Prognostic Factors. Mayo Clin Proc 2006;81.159
  30. Barbui et al. Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 2012;120:569
  31. Cortelazzo et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. NEJM 1995;332:1132
  32. Tefferi et al. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? (letter)  Blood 2006;108:2493
  33. Tefferi A. The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development.  Mayo Clin Proc 2005;80:97
  34. Birgegård et al. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004;89:520
  35. Harrison et al. Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia. NEJM 2005;353:33 (hydroxyurea plus aspirin superior to anagrelide plus aspirin; with editorial)
  36. Gisslinger et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720 (Anagrelide non-inferior to HU in preventing thrombotic complications; aspirin use not controlled for)
  37. Quintás-Cardama et al. Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera. J Clin Oncol 2009;27:5418 (OR rate 81% in ET)
  38. Masarova et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol 2017;4:e165 (80% hematologic response rate, 63% molecular response rate, 22% stopped treatment due to toxicity; with editorial)
  39. Baerlocher et al. Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia. NEJM 2015;373:920 (89% attained normal platelet count; neutropenia common. With editorial)
  40. Campbell et al. Reticulin Accumulation in Essential Thrombocythemia: Prognostic Significance and Relationship to Therapy. J Clin Oncol 2009;27:2991 (Reticulin grade at diagnosis is an independent prognostic factor in ET. Anagrelide treatment associated with greater increase in reticulin over time than hydroxyurea treatment)
  41. Barbui et al.  Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.  Haematologica 2004;89:215
  42. Passamonti et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 2007; 110:485
  43. Skeith et al. Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. Blood 2017;129:934 (2.5% incidence antepartum, 4.4% postpartum)
Eosinophilia/hypereosinophilic syndrome
  1. Reiter and Gotlib. Myeloid neoplasms with eosinophilia. Blood 2017;129:704
  2. Klion A. How I treat hypereosinophilic syndromes. Blood 2015;126:1069
  3. Tefferi  et al. Eosinophilia: secondary, clonal and idiopathic. Br J Haematol 2006;133:468
  4. Tefferi et al. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc 2010;85:158
  5. Roufosse et al. The hypereosinophilic syndrome revisited.  Ann Rev Med 2003;54:169
  6. Bain B. The idiopathic hypereosinophilic syndrome and eosinophilic leukemias. Haematologica 2004;89:133
  7. Bain B. Eosinophilic leukemia and idiopathic hypereosinophilic syndrome are mutually exclusive diagnoses. Blood 2004;104:3836
  8. Cools et al. A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome.  NEJM 2003;348:1201
  9. Pardanani et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038
  10. David et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood 2007;109:61
  11. Cheah et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood 2014;123:3574
  12. Jovanovic et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA–positive chronic eosinophilic leukemia. Blood 2007;109:4635
  13. Klion et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood 2007;110:3552
  14. Rothenberg et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. NEJM 2008;358:1215
  15. Seybolt et al. Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia.  Clin Infect Dis 2006;42:363
Mastocytosis
  1. Valent et al. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood 2017;129:1420
  2. Theoharides et al. Mast cells, mastocytosis, and related disorders. NEJM 2015;373:163
  3. Valent et al. How I treat patients with advanced systemic mastocytosis. Blood 2010;116:5812
  4. Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood 2013;121:3085
  5. Lim et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009;113:5727
  6. Gotlib et al. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood 2013;121:2393
  7. Pardanani et al. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood 2009;114:3769 (Mast cell disease is a clinically heterogeneous set of conditions)
  8. Georgin-Lavialle et al. Mast cell leukemia. Blood 2013;121:1285
  9. Kluin-Nelemans et al.  Cladribine therapy for systemic mastocytosis,  Blood 2003;102:4270
  10. Barete et al. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood 2015;126:1009
  11. Ustun et al. Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis. J Clin Oncol 2014;32:3264 (3-yr OS 57% in this retrospective study)
  12. Shah et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood 2006;108:286
  13. Gotlib et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. NEJM 2016;374:2530
  14. Blatt et al. Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis. Blood 2015;126:2832
  15. Orfao et al. Recent advances in the understanding of mastocytosis: the role of KIT mutations. Br J Haematol 2007; 138:12
  16. Schwaab et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013;122:2460
  17. Akin et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis. Blood 2007;110:2331
  18. Hamilton et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J All Clin Immunol 2011;128:147 (Mimics systemic mastocytosis; no clonal mast cell proliferation)

Chronic neutrophilic leukemia

  1. Maxson and Tyner. Genomics of chronic neutrophilic leukemia. Blood 2017;129:715
  2. Maxson et al. Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML. NEJM 2013;368:1781
  3. Gotlib et al. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood 2013;122:1707

Chronic myelogenous leukemia

General

  1. Thompson et al. Diagnosis and treatment of chronic myeloid leukemia in 2015. Mayo Clin Proc 2015;90:1440
  2. Baccarani et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872
  3. Quintás-Cardama and Cortes. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood 2009;113:1619
  4. Schemionek et al. BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. Blood 2010; 115:3185
  5. Kim et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy. Blood 2017;129:38 (With editorial)
  6. Verma et al. Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood 2009;114:2232
  7. Radivoyevitch et al. Quantitative modeling of chronic myeloid leukemia: insights from radiobiology. Blood 2012;119:4363
  8. Hochhaus A. Managing chronic myeloid leukemia as a chronic disease. Hematology 2011:128
  9. Melo and Ross. Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure? Hematology 2011:136
  10. Jamieson et al.  Granulocyte–Macrophage Progenitors as Candidate Leukemic Stem Cells in Blast-Crisis CML.  NEJM 2004;351:657
  11. Michor et al. Dynamics of chronic myeloid leukemia.  Nature 2005;435:1267
  12. Oehler V. Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice. Hematology 2013:176
  13. Radich J. How I monitor residual disease in chronic myeloid leukemia. Blood 2009;114:3376
  14. Kantarjian et al. Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response. J Clin Oncol 2009;27:3659
  15. Kreutzman et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 2010;116:772
  16. Fabarius et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011;118:6760 (Add'nl Ph chromosome, trisomy 8, isochromosome 17q and trisomy 19 associated with worse prognosis and progression to blast crisis)
  17. Wang et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood 2016;127:2742
  18. Saußele et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV. Blood 2015;126:42
  19. Prost et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature 2015;525:380 (Pioglitazone treatment resulted in sustained molecular remission in 3 patients with residual disease despite nilotinib treatment. See also NEJM summary of this research)

Tyrosine kinase inhibitors in CML - general

  1. Cortes and Kantarjian. How I treat newly diagnosed chronic phase CML. Blood 2012;120:1390
  2. Hughes and Ross. Moving treatment-free remission into mainstream clinical practice in CML. Blood 2016;128:17 (About half of patients with stable deep molecular response can maintain remission off TKI therapy)
  3. Larson RA. Is there a best TKI for chronic phase CML? Blood 2015;126:2370
  4. Smith and Shah. Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease. Hematology 2011:121
  5. Jabbour et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 2011;118:4541
  6. Branford et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood 2013;121:3818
  7. Jain et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 2013;121:4867
  8. Branford et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014;124:511
  9. Sobrinho-Simões et al. In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib. Blood 2010;116:1329 (Absence of detectable BCR-ABL transcripts does not imply the absence of the leukemic clone)
  10. Iacobucci et al. Comparison Between Patients With Philadelphia-Positive Chronic Phase Chronic Myeloid Leukemia Who Obtained a Complete Cytogenetic Response Within 1 Year of Imatinib Therapy and Those Who Achieved Such a Response After 12 Months of Treatment. J Clin Oncol 2006;24:454 (DFS at 4 years similar in early and late responders)
  11. Ibrahim et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:3733
  12. Hehlmann et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 2007;109:4686
  13. Russo et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013;121:5138 (Some patients had molecular or cytogenetic progress, none had blast crisis or new cytogenetic abnormality; all responded to imatinib when re-treated)
  14. Branford et al. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 2009;114:5426
  15. Kantarjian et al. New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. Ann Intern Med 2006;145:913
  16. O'Hare et al.Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110:2242
  17. Soverini et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011;118:1208
  18. Parker et al. Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. Blood 2012;199:2234
  19. Jain et al. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood 2016;127:1269
  20. Jabbour et al. Predictive factors for outcome and response in patients treated with second-generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase after imatinib failure. Blood 2011;117:1822 (Poor performance status, no cytogenetic response to imatinib associated with low response rate)
  21. Milojkovic et al. Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients. Blood 2012;119:1838
  22. Tam et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood 2008;112:516
  23. Garg et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 2009;114:4361 (Third-line TKI therapy typically does not give durable response)
  24. Dahlén et al. Cardiovascular Events Associated With Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Population-Based Cohort Study. Ann Intern Med 2016;165:161 (1.5-fold higher risk of arterial events, 2-fold higher VTE risk in TKI-treated patients)
  25. Quintás-Cardama et al. Tyrosine kinase inhibitor–induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009; 114:261 (Dasatinib treatment causes impaired platelet aggregation)
  26. Haouala et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117:e75
  27. Verma et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood 2011;118:4353 (No evidence that TKIs increase risk of 2nd malignancies)
  28. Efficace et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 2011;118:4554 (Fatigue most common problem, especially in younger patients)
  29. Sweet and Oehler. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider? Hematology 2013:184
  30. Rousselot et al. Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease. J Clin Oncol 2014;32:424
  31. Rea et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood 2017;129:846 (43% had molecular relapse at median of 4 mo, all patients responded to retreatment)

Imatinib

  1. Druker et al. Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. NEJM 2001;344:1031
  2. Druker et al. Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. NEJM 2001;344:1038
  3. Picard et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3469
  4. Larson et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022 (Adequate plasma concentration predicts better clinical response)
  5. Kantarjian et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. NEJM 2002;346:645
  6. Gugliotta et al. Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood 2011;117:5591
  7. Hehlmann et al. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol 2014;32:416 (>4.5 log reduction of BCR-ABL)
  8. Jabbour et al. Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clin Proc 2009;84:161
  9. Kantarjian et al.  High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia.  Blood 2004;103:2873
  10. Hughes et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008;112:3965 (escalation to 800 mg in patients with suboptimal response at 6 mo appeared beneficial)
  11. Baccarani et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood 2009;113:4497 (No significant difference in response rate)
  12. Preudhomme et al. Imatinib plus Peginterferon Alfa-2a in Chronic Myeloid Leukemia. NEJM 2010;363:2511 (Addition of peginterferon doubled rate of molecular response at 12 months, but caused more toxicity)
  13. Simonsson et al. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 2011;118:3228
  14. Druker et al. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. NEJM 2006;355:2408 (89% 5-year overall survival, 83% event-free survival)
  15. Hochhaus et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon- treatment. Blood 2008;111:1039
  16. Hochhaus et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. NEJM 2017;376:917 (Efficacy maintained over 11 year followup without major toxicity; with editorial)
  17. Rousselot et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007;109:58 (6 of 12 patients remained in molecular remission during median followup of 18 mo)
  18. Ross et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515 (About half remained in molecular remission after 2 yr; the rest were all successfully re-treated)
  19. Hughes et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010;116:3758 (Patients with major molecular response had durable responses/remissions)
  20. Kerkelä et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.  Nature Med 2006;12:908
  21. Atallah et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007; 110:1233 (1.7% incidence, only 0.6% considered due to drug)
  22. Fitter et al. Long-term imatinib therapy promotes bone formation in CML patients. Blood 2008;111:2538
  23. Vandyke et al. Dysregulation of bone remodeling by imatinib mesylate. Blood 2010;115:766
  24. Pye et al. The effects of imatinib on pregnancy outcome. Blood 2008;111:5505
  25. Mauro MJ. Defining and Managing Imatinib Resistance. Hematology 2006;226-39
  26. Jabbour et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009;113:2154
  27. Yeung et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015;125:915 (This strategy considered to produce excellent results, more cost-effective than routine use of newer agents)

Dasatinib

  1. Kantarjian et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. NEJM 2010;362:2260 (Dasatinib superior)
  2. Kantarjian et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION) (Dasatinib shows "faster and deeper" responses; transformation to accelerated or blast phase occurred in 2.3% vs 5% with imatinib)
  3. Jabbour et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494
  4. Radich et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012;120:3898 (Dasatanib produced more complete cytogenetic responses, better molecular responses, more toxicity; similar survival in both arms at medial 3 year followup)
  5. Talpaz et al. Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias. NEJM 2006;354:2531
  6. Hochhaus et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109:2303
  7. Guilhot et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007;109:4143
  8. Cortes et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007;109:3207 (about a third of patients had good response to dasatinib)
  9. Kantarjian et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007;109:5143 (Dasatinib superior)
  10. Müller et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009; 114:4944
  11. Shah et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 2014;123:2317 (Long term outcomes good if <10% BCR-ABL transcripts within 3 mo)
  12. Bergeron et al. Lung Abnormalities after Dasatinib Treatment for Chronic Myeloid Leukemia: A Case Series. Am J Respir Crit Care Med 2007;176:814
  13. Montani et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128

Nilotinib

  1. Saglio et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. NEJM 2010;362:2251 (Nilotinib superior)
  2. Cortes et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010;28:392
  3. Kantarjian et al. Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL. NEJM 2006;354:2542
  4. Katarjian et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 2011;117:1141
  5. Kantarjian et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007;110:3540
  6. le Coutre et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 2008;111:1834
  7. Cortes et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 2011;117:5600
  8. Rosti et al. Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia. Blood 2009;114:4933
  9. Wang et al. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood 2015;125:2771 (MMR in 28% getting imatinib, 52% getting nilotinib after 1 yr)
  10. Kim et al. Clinical cardiac safety profile of nilotinib. Haematologica 2012; 97:883 (20% of patients developed ECG abnormalities, including prolonged QT; clinical cardiac adverse events uncommon)

Other TKIs

  1. Cortes et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011;118:4567
  2. Khoury et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403
  3. Cortes et al. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial. J Clin Oncol 2012;30:3486
  4. Kantarjian et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014;123:1309
  5. Cortes et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. NEJM 2012;367:2075
  6. Parker et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood 2016;127:1870 (Ponatinib effective in TKI-resistant disease with multiple mutations in BCR-ABL)
  7. Cortes et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. NEJM 2013;369:1783 (Ponatinib effective; 9% incidence of serious thrombotic events)
CML: Stem Cell Transplantation

Accelerated phase & blast crisis

  1. Radich J. The biology of CML blast crisis. Hematology 2007:384
  2. Hehlman R. How I treat CML in blast crisis. Blood 2012;120:737
  3. Ito et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010;466:765
  4. Wadhwa et al. Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood 2002;99:2304
  5. Apperley et al. Dasatinib in the Treatment of Chronic Myeloid Leukemia in Accelerated Phase After Imatinib Failure: The START A Trial. J Clin Oncol 2009; 27:3472
  6. Jiang et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011;117:3032 (SCT superior in patients with CML > 1yr, Hgb < 10, or periph blasts > 5%)

Lymphoproliferative disorders: biology, classification and staging  

Classification, epidemiology & diagnosis

  1. Swerdlow et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375
  2. Campo et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019
  3. Morton et al. Proposed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph). Blood 2007;110:695
  4. Jaffe et al. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood 2008;112:4384
  5. Jaffe E. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology 2009;523
  6. Craig and Foon. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008;111:3941
  7. Morton et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006;107:265
  8. Harris et al. A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 1994;84:1361
  9. Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the international lymphoma study group classification of non-Hodgkin's lymphoma. Blood 1997;89:3909
  10. Berger et al. Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood 1994;83:2829
  11. Herling et al.  A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories.  Blood 2004;104:328
  12. Hehn et al.  Utility of Fine-Needle Aspiration As a Diagnostic Technique in Lymphoma.  J Clin Oncol 2004;22:3046 (Showing that FNA is NOT helpful!)
  13. Brudno et al. Discordant bone marrow involvement in non-Hodgkin lymphoma. Blood 2016;127:965
  14. Goldin et al.  Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 2004;104:1850
  15. Wang et al. Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood 2007;109:3479 (Having a first-degree relative with heme malignancy increases risk for NHL by about 50%)
  16. Morton et al. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes. Blood 2008;112:5150 (examines a broad range of potential risk factors for NHL)
  17. Rothman et al. A nested case-control study of non-Hodgkin's lymphoma and serum organochlorine residues. Lancet 1997;350:240
  18. Colt et al. Organochlorine exposure, immune gene variation, and risk of non-Hodgkin lymphoma. Blood 2009;113:1899
  19. Beaugerie et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374:1617 (5-fold increased risk of LPD in patients who took thiopurines)
  20. Khan et al. Risk of Lymphoma in Patients With Ulcerative Colitis Treated With Thiopurines: A Nationwide Retrospective Cohort Study. Gastroenterology 2013;146:1007 (4-fold increased risk)
  21. Scott et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 2014;123:1214

Biology

  1. Mullighan C. Genome sequencing of lymphoid malignancies. Blood 2013;122:3899
  2. Cerhan et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood 2007;110:4455 (Genetic variation in genes for immune response, kinase signaling, lymphocyte trafficking and coagulation associated with risk for NHL)
  3. Natkunam Y. The biology of the germinal center. Hematology 2007:210
  4. Carter R. B cells in health and disease.  Mayo Clin Proc 2006;81:377
  5. Rothman et al. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 2006;7:27 (Modest increase in lymphoma risk associated with common polymorphisms in cytokine genes)
  6. Lan et al. Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population-based case-control studies. Blood 2009;114:264
  7. Young et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008;112:3088
  8. O'Shea et al. The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood 2008;112:3126
  9. Xu-Monette et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood 2012;119:3668
  10. Martin-Subero et al. New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood 2009;113:2488
  11. Roulland et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J Exp Med 2006;203:2425 (see also the NEJM commentary on this paper)
  12. Smedby et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood 2008;111:4029
  13. Chiron et al. Toll-like receptors: lessons to learn from normal and malignant human B cells. Blood 2008;112:2205 (a link between inflammation and lymphomagenesis?)
  14. Thorley-Lawson and Gross.  Persistence of the Epstein-Barr virus and the origins of associated lymphomas.  NEJM 2004;350:1328
  15. Timms et al.  Target cells of Epstein-Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma.  Lancet 2003;361:217
  16. Sarid et al.  Virology, Pathogenetic Mechanisms, and Associated Diseases of Kaposi Sarcoma–Associated Herpesvirus (Human Herpesvirus 8).  Mayo Clin Proc 2002;77:941
  17. Alizadeh et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403;503
  18. Shipp et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002;8:68
  19. Lossos et al.  Prediction of Survival in Diffuse Large-B-Cell Lymphoma Based on the Expression of Six Genes.  NEJM 2004;350:1828
  20. Korsmeyer S. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 1992;80:879
  21. Reed J. Bcl-2–family proteins and hematologic malignancies: history and future prospects. Blood 2008;111:3322
  22. Lenz et al. Stromal gene signatures in large B-cell lymphomas. NEJM 2008;359:2313 (see also accompanying editorial)
  23. Lossos et al. Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large cell lymphoma. Blood 2001;98:945
  24. Cerchetti et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas. Nature Medicine 2009;15:1369
  25. Dierks et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Med 2007;13:944
  26. Pon and Marra. Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma. Blood 2016;127:181
  27. Shipp et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nature Medicine 2001;8:68
  28. Rosenwald et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. NEJM 2002;346:1937
  29. Alizadeh et al. Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. Blood 2011;118:1350
  30. Hu et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 2013;121:4021
  31. Lenz et al. Oncogenic CARD11 mutations in human diffuse large cell lymphoma. Science 2008;319:1676 (A potential new therapeutic target for DLBCL)
  32. Compagno et al. Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma. Nature 2009; 459:717
  33. Ngo et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011;470:115
  34. Savage et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 2009;114:3533
  35. Kato et al. Frequent inactivation of A20 in B-cell lymphoma. Nature 2009;459:712
  36. Davis et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88
  37. Xu-Monette et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood 2012;120:3986 (TP53 mutation, but not deletion or LOH, associated with worse prognosis).
  38. Steidl et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011;471:377
  39. Morin et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011;476:298
  40. Werner et al. Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target. Blood 2017;129:823
  41. Hummel et al. A Biologic Definition of Burkitt's Lymphoma from Transcriptional and Genomic Profiling. NEJM 2006;354:2419
  42. Dave et al. Molecular Diagnosis of Burkitt's Lymphoma  NEJM 2006;354:2431
  43. Pasqualucci et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011;471:189 (CREBBP mutations cause defective inactivation of BCL6 and defective activation of P53)
  44. Aukema et al. Double-hit B-cell lymphomas. Blood 2011; 117:2319 (Lymphomas other than Burkitt's with c-myc breakpoint mutation)
  45. Abramson and Shipp.Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 2005;106:1164
  46. Arnold et al. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. NEJM 1983; 309:1593
  47. Willis and Dyer. The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies. Blood 2000;96:808
  48. Pals et al.Lymphoma dissemination: the other face of lymphocyte homing. Blood 2007;110:3102
  49. Hagner et al. Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction. Blood 2009;113:5526
  50. Purdue et al. A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma. Blood 2009;114:2730 (Higher sCD30, a marker for chronic B-cell stimulation, associated with higher risk for NHL)
  51. Laurent et al. Distribution, function, and prognostic value of cytotoxic T lymphocytes in follicular lymphoma: a 3-D tissue-imaging study. Blood 2011;118:5371
  52. Steidl and Gascoyne. The molecular pathogeneis of primary mediastinal large B-cell lymphoma. Blood 2011;118:2659
  53. Bertrand et al. A prospective study of Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma. Blood 2010;116:3547 (No evidence that EBV antibody profile predicts risk of NHL in immunocompetent patients)
  54. Jiang et al. Mechanisms of epigenetic deregulation in lymphoid neoplasms. Blood 2013;121:4271
  55. Wang et al. Polycomb genes, miRNA, and their deregulation in B-cell malignancies. Blood 2015;125:1217
  56. Coso et al. Pressing the right buttons: signaling in lymphomagenesis. Blood 2014;123:2614
  57. Melenotte et al. B-cell non-Hodgkin lymphoma linked to Coxiella burnetii. Blood 2016;127:113
  58. Neven et al. A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency. Blood 2013;122:3713 (Childhood lymphomas)

Staging/Imaging

  1. Kwee et al. Imaging in staging of malignant lymphoma: a systematic review. Blood 2008;111:504
  2. Seam et al. The role of FDG-PET scans in patients with lymphoma. Blood 2007;110:3507
  3. Ansell and Armitage. Positron emission tomographic scans in lymphoma: convention and controversy. Mayo Clin Proc 2012;87:571
  4. Haioun et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005;106:1376
  5. Juweid. ME. Utility of Positron Emission Tomography (PET) Scanning in Managing Patients with Hodgkin Lymphoma. Hematology 2006;259-65
  6. Hernandez-Maraver et al. Positron emission tomography/computed tomography: diagnostic accuracy in lymphoma. Br J Haematol 2006;135:293
  7. Zinzani et al. Role of [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in the Follow-Up of Lymphoma. J Clin Oncol 2009;27:1781
  8. Terasawa et al. Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography for Interim Response Assessment of Advanced-Stage Hodgkin's Lymphoma and Diffuse Large B-Cell Lymphoma: A Systematic Review. J Clin Oncol 2009;27:1906
  9. Dupuis et al. Impact of [18F]Fluorodeoxyglucose Positron Emission Tomography Response Evaluation in Patients With High–Tumor Burden Follicular Lymphoma Treated With Immunochemotherapy: A Prospective Study From the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. J Clin Oncol 2012;30:4317 (PET results "strongly predictive" of treatment outcome)
  10. Khan et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood 2013;122: 61 (Suggests PET-CT superior to marrow biopsy for identifying marrow involvement)
  11. Thompson et al. Utility of Routine Post-Therapy Surveillance Imaging in Diffuse Large B-Cell Lymphoma. J Clin Oncol 2014;32:3506 (Routine surveillance imaging does not improve outcomes)
  12. Cohen et al. Evaluating surveillance imaging for diffuse large B-cell lymphoma and Hodgkin lymphoma. Blood 2017;129:561 ("Current imaging approaches do not detect most relapses prior to clinical signs and symptoms or improve survival")
  13. Kurtz et al. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood 2015;125:3679
  14. Roschewski et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015;16:541
  15. Brudno et al. Discordant bone marrow involvement in non-Hodgkin lymphoma. Blood 2016;127:965

Chronic lymphocytic leukemia

Review articles

  1. Digherio and Hamblin. Chronic lymphocytic leukemia. Lancet 2008;371:1017
  2. Hallek et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 2008;111:5446
  3. Binet et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 2006;107:859
  4. Shanafelt et al. Narrative Review: Initial Management of Newly Diagnosed, Early-Stage Chronic Lymphocytic Leukemia. Ann Intern Med 2006;145:435
  5. Chiorazzi et al. Chronic lymphocytic leukemia. NEJM 2005;352:804
  6. Stevenson and Calgaris-Cappio.  Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004;103:4389
  7. Burger and Montserrat. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood 2013;121:1501
  8. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012;120:4684

Monoclonal B-cell lymphocytosis

  1. Strati and Shanafelt. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 2015;126:454
  2. Ghia and Caligaris-Cappio. Monoclonal B-cell lymphocytosis: right track or red herring? Blood 2012;119:4358
  3. Shim et al. Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. Blood 2014;123:1319 (7% of apparently healthy blood donors over 45 yo had MBL)
  4. Rawstron et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. NEJM 2008;359:575 (5% of adults have circulating monoclonal B-cells with a CLL phenotype; they develop frank CLL at a rate of about 1% per year. See also the accompanying editorial)
  5. Shanafelt et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009;113:4188 (B-cell count > 11K independent predictor of need for eventual treatment)
  6. Shanafelt et al. Brief Report: Natural History of Individuals With Clinically Recognized Monoclonal B-Cell Lymphocytosis Compared With Patients With Rai 0 Chronic Lymphocytic Leukemia. J Clin Oncol 2009;27:3959 (MBL pts had lower likelihood of requiring treatment than stage 0 CLL pts. Circulating B-cell count predicts time to treatment)
  7. Fazi et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood 2011;118:6618
  8. Landgren et al. B-Cell Clones as Early Markers for Chronic Lymphocytic Leukemia. NEJM 2009;360:659 (almost all patients diagnosed with CLL have clonal B-cell population in blood prior to diagnosis; with editorial)
Biology, prognosis
  1. Chiorazzi and Ferrarini. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 2011;117:1781
  2. Shanafelt T. Predicting clinical outcome in CLL: how and why. Hematology 2009;421
  3. Pflug et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood 2014;124:49
  4. Grever et al. Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997. J Clin Oncol 2007;25:799 (del 17p and del 11q22 were the most significant negative prognostic indicators)
  5. Guièze and Wu. Genomic and eipgenomic heterogeneity in chronic lymphocytic leukemia. Blood 2015;126:445
  6. Parikh et al. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood 2016;127:1753 (Yes, although the results do not determine the decision to treat outside of a clinical trial)
  7. Lia et al. Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines. Blood 2012;119:2981 (Size of deletion determines phenotype; larger deletions worse)
  8. Tsai et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study. Blood 2009;114:4928
  9. Maurer et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood 2011;118:2821 (FLC abnormalities associated with worse prognosis)
  10. Dagklis et al. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)–like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood 2009;114: 26
  11. Forconi and Moss. Perturbation of the normal immune system in patients with CLL. Blood 2015;126:573 (New treatments targeting B-cell receptor signaling may allow immune reconstitution in CLL)
  12. Nieto et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia–like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood 2009;114:33
  13. Shanafelt et al. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004;103:1202
  14. Deaglio et al. In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood 2006;108:1135
  15. Malavasi et al. CD38 and chronic lymphocytic leukemia: a decade later. Blood 2011;118:3470
  16. Lin et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009;113:3168 (unmutated IgVH best predictor of short remission)
  17. Orchard et al.  ZAP-70 expression and prognosis in chronic lymphocytic leukemia.  Lancet 2004;363:105
  18. Rassenti et al.  ZAP-70 compared with immunoglobulin heavy-chain mutation status as a predictor of disease progression in chronic lymphocytic leukemia.  NEJM 2004;351:893
  19. Del Principe et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2006; 108:853
  20. Rassenti et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood 2008;112:1923 (ZAP-70 expression strongest risk factor)
  21. Claus et al. Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood 2014;124:42
  22. Bulian et al. CD49d Is the Strongest Flow Cytometry–Based Predictor of Overall Survival in Chronic Lymphocytic Leukemia. J Clin Oncol 2014;32:897
  23. Kwok et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood 2016;128:2770
  24. Letestu et al. Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters. Blood 2010;116:4588
  25. Brenner et al. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood 2008;111:4916
  26. Tsimberidou et al. Assessment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by Absolute Lymphocyte Counts in 2,126 Patients: 20 Years of Experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2007;25:4648 (No difference in treatment outcome between CLL and SLL without lymphocytosis)
  27. Calin et al. A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 2005;353:1793
  28. Baliakas et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 2015;29:329 (SF3B1 and TTP53 mutations carried worst prognosis)
  29. Puente et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011;475:101
  30. Klein et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001;194:1625
  31. Hamblin et al. Unmutated Ig Vh genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848
  32. Rosenwald et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001;194:1639
  33. Fabbri et al. Association of a MicroRNA/TP53 Feedback Circuitry With Pathogenesis and Outcome of B-Cell Chronic Lymphocytic Leukemia. JAMA 2011;305:59 (Establishes a molecular link between 13q deletion, p53 function and ZAP70 expression)
  34. Gonzalez et al. Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial. J Clin Oncol 2011;29:2223 (TP53 mutations associated with lower treatment response rates and shorter OS)
  35. Rossi et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012;119:521 (About 11% of CLL patients have NOTCH1 mutations; prognosis similar to that with p53 mutations)
  36. Villamor et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 2013;27:1100
  37. Wang et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. NEJM 2011;365:2497
  38. Jeromin et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 2014;28:18
  39. Wan and Wu. SF3B1 mutations in chronic lymphocytic leukemia. Blood 2013;121:4627
  40. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology 2011:96
  41. Nowakowski et al. Using Smudge Cells on Routine Blood Smears to Predict Clinical Outcome in Chronic Lymphocytic Leukemia: A Universally Available Prognostic Test. Mayo Clin Proc 2007; 82:449 (More smudge cells = better prognosis)
  42. Nowakowski et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J Clin Oncol 2009;27:1844 (10 year survival 50% with 30% or fewer smudge cells, 80% for more than 30% smudge cells)
  43. Shanafelt et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood 2011;117:1492
  44. Mauro et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999;94:448
  45. Abrisqueta et al. Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clínic of Barcelona experience. Blood 2009;114:2044
  46. Foon et al. Genetic relatedness of lymphoid malignancies. Transformation of chronic lymphocytic leukemia as a model. Ann Intern Med 1993;119:63
  47. Goldin and Slager. Familial CLL: Genes and environment. Hematology 2007:339
  48. Del Giudice et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 2009;114:638
Complications
  1. Schwartz and Shamsuddin. The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia. Hum Pathol 1981; 12:432
  2. Mauro et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000;95:2786
  3. Borthakur et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab - incidence and predictors. Br J Haematol 2007;136:800 (6.5% incidence of AIHA or PRCA)
  4. Dearden et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008;111:1820
  5. Visco et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood 2008;111:1110 (5% incidence of ITP, correlated with worse survival; chemotherapy superior to IVIG as Rx)
  6. Moreno et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010;116:4771 (Autoimmune cytopenia not an independent adverse prognostic factor in CLL)
  7. Morrison V. Management of infectious complications in patients with chronic lymphocytic leukemia. Hematology 2007:338
  8. Ahn et al. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood 2016;128:1940
  9. Tsimberidou et al. Other Malignancies in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol 2009;27:904 (Risk of 2nd cancer about twice the expected value in CLL patients)
Treatment
  1. Jain and O'Brien. Initial treatment of CLL: integrating biology and functional status. Blood 2015;126:463
  2. Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Hematology 2013:138
  3. Thompson and Wierda. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood 2016;127:279
  4. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012;120:4684
  5. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013:158
  6. Dighiero et al. Chlorambucil in chronic lymphocytic leukemia. NEJM 1998;338:1506
  7. Hillmen et al. Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study. J Clin Oncol 2014;32:1236 (Median PFS 24 mo)
  8. Woyach et al. Impact of Age on Outcomes After Initial Therapy With Chemotherapy and Different Chemoimmunotherapy Regimens in Patients With Chronic Lymphocytic Leukemia: Results of Sequential Cancer and Leukemia Group B Studies. J Clin Oncol 2013;31:440 (Older adults did as well with chlorambucil as with fludarabine; rituximab beneficial at all ages)
  9. Rai et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. NEJM 2000;343:1750
  10. Eichhorst et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006;107:885
  11. Eichorst et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382
  12. Catovsky et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230 (FC superior to F alone or to chlorambucil, but no difference in survival; see editorial)
  13. Flinn et al. Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793 (FC gave better CR rate and longer PFS, with more heme toxicity but no increase in infection)
  14. Smith et al. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 2011;118:3525 (4.7% incidence of myeloid neoplasia, higher incidence with FC vs F alone)
  15. Byrd et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712).  Blood 2003;101:6
  16. Byrd et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011.  Blood 2005;105:54
  17. Woyach et al. Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712. J Clin Oncol 2011;29:1349
  18. Keating et al. Early Results of a Chemoimmunotherapy Regimen of Fludarabine, Cyclophosphamide, and Rituximab As Initial Therapy for Chronic Lymphocytic Leukemia. J Clin Oncol 2005;23:4079
  19. Tam et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008;112:975 (OR rate 95%, median TTP 80 mo, 6 year OS 77%)
  20. Thompson et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303 (PFS at 12.8 yrs 53% for pts with mutated IGHV, 9% for those with unmutated IGHV)
  21. Lamanna et al. Sequential Therapy With Fludarabine, High-Dose Cyclophosphamide, and Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia Produces High-Quality Responses: Molecular Remissions Predict for Durable Complete Responses. J Clin Oncol 2009; 27:491
  22. Hallek et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164 (Addition of rituximab improved progression-free and overall survival)
  23. Fischer et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208
  24. Abrisqueta et al. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood 2013;122:3951
  25. Fischer et al. Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209
  26. Chanan-Khan et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood 2005;106:3348  (55% CR rate)
  27. Badoux et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011;118:3489 (65% overall response rate; treatment increased immunoglobulin levels)
  28. Strati et al Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734 (58% had response lasting > 36 mo)
  29. Kay et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2006;109:405    (91% OR, 41% CR)
  30. Parikh et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 2011;118:2062
  31. Lepretre et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood 2012;119:5104 (Similar efficacy to FCR with more toxicity)
  32. Woyach and Johnson. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 2015;126:471
  33. Farooqui et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169
  34. Burger et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. NEJM 2015;373:2425 (Risk of progression or death 84% lower with ibrutinib than with chlorambucil)
  35. Thompson et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haem 2016;175:462
  36. Wierda et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011;118:5119
  37. Danese et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood 2011;117:3505 (Initial therapy containing rituximab as effective in patients older than 66 as in younger patients)
  38. Wierda et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 2011;117:6450 (Ofatumumab, fludarabine + cyclophosphamide; 50% CR in one arm)
  39. Goede et al. Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions. NEJM 2014;370:1101 (Better PFS and OS with obinutuzumab aka GA101 + Chl vs rituximab + Chl)
  40. Brown et al. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood 2015;125:2779 (Both combinations effective, reasonably safe)
  41. Byrd et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 2015;127:79 (67% OR, 20% CR with 2000 mg dose, well-tolerated)
  42. Byrd et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497 (High response rates, modest toxicity)
  43. Friedberg et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578 (55% overall response rate in CLL)
  44. Pettitt et al. Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial. J Clin Oncol 2012;30:1647
  45. Cheah and Fowler. Idelalisib in the management of lymphoma. Blood 2016;128:331
  46. O'Brien et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood 2015;126:2686 (97% response rate, 19% CR; well-tolerated)
  47. Lampson et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 2016;128:195
  48. Strati et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood 2014;123: 3727
  49. Weeks et al. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. NEJM 1991;325:81
  50. Eichhorst et al. Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis. Blood 2011;117:1817
  51. Maddocks-Christianson et al. Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br. J Haematol 2007; 139:398 (2.5-fold increased risk of 2nd lymphoid malignancy after treatment with purine nucleoside analog)
  52. Jain et al. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol 2017;4:e67 (Ruxolitinib significantly lessened constitutional symptoms)

Relapsed & Refractory CLL

  1. Brown JR. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology 2011:110
  2. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012;120:4684
  3. Montserrat et al. How I treat refractory CLL. Blood 2006;107:1276
  4. Arnason and Brown. Alemtuzumab Use In Relapsed and Refractory Chronic Lymphocytic Lymphoma. Hematology 2011:119
  5. Wierda et al. Chemoimmunotherapy With Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2005;23:4070
  6. Ferrajoli et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291 (Overall response rate 32%, 7% CR)
  7. Andritsos et al. Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia. J Clin Oncol 2008;26:2519
  8. Badoux et al. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2013;31:584 (12% CR, 12% PR; 70% alive @ 36 mo)
  9. Lamanna et al. Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia. J Clin Oncol 2006;24:1575
  10. Badoux et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016
  11. Tam et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059 (Poor survival with salvage regimens if relapse within 3 yrs)
  12. Montillo et al. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia. Blood 2011;118:4079
  13. Badoux et al. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 2011;118:2085 (65% overall response rate, but many infections and no survival benefit)
  14. O'Brien et al. Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2007;25:1114 (Bcl-2 antisense Rx improved response rates)
  15. Kalos et al. T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia. Sci Transl Med 2011;95:95ra73 (Dramatic responses in 3 patients with refractory CLL)
  16. Porter et al. Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. NEJM 2011;365:725 (More detailed description of one of 3 patients described in previous paper)
  17. Mato and Porter. A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood 2015;126:478
  18. Tsimberidou et al. Phase I-II Study of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy in Patients With Richter's Syndrome or Fludarabine-Refractory Chronic Lymphocytic Leukemia, J Clin Oncol 2007;26:196
  19. Fischer et al. Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559
  20. Woyach and Johnson. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 2015;126:471
  21. Byrd et al. Targeting BTK with ibruitnib in relapsed chronic lymphocytic leukemia. NEJM 2013;369:32 (PFS 75% at 26 mo; with editorial)
  22. Farooqui et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169
  23. Ryan et al. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood 2016;128:2899
  24. Woyach J. How I manage ibrutinib-refractory chronic lymphocytic leukemia. Blood 2017;129:1270
  25. Furman et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. NEJM 2014;370:997 (Adding PI3K inhibitor idelalisib increased OR rate from 13% to 81% - with editorial)
  26. Brown et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390
  27. Woyach et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014;123:1810
  28. Woyach et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibruitinib. NEJM 2014;370:2286
  29. Brown et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood 2015;125:2915 (Ibruntinib + benda/rituximab or FCR; PFS 86% at 1 year, 70% at 3 years)
  30. Byrd et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497 (High response rates, modest toxicity)
  31. Jaglowski et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood 2015;126:842 (Faster and more durable responses than with single-agent ibrutinib)
  32. Mato et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood 2016;128:2199 (Many patients who fail one KI due to toxicity or disease progression respond to an alternative one)
  33. Byrd et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. NEJM 2016;374:323 (ORR 95%, 100% in those with 17p deletion; with editorial)
  34. Roberts et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. NEJM 2016;374:311 (79% ORR, 20% CR; with editorial)
  35. Cartron et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 2014;124:2196
  36. Sharman et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood 2015;125:2336
  37. Barr et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood 2016;127:2411

B-Prolymphocytic leukemia

  1. Dearden C. How I treat prolymphocytic leukemia. Blood 2012;120:538
  2. van der Velden et al. B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma. Blood 2014;124:412 (Many B-PLL cases whether or not they have t(11;14) have characteristics in common with MCL)

Stem Cell Transplantation in CLL

Richter syndrome



Non-Hodgkin's lymphomas

General

  1. Winter et al.  Low-grade lymphoma.  Hematology 2004:203
  2. Lenz and Staudt. Aggressive lymphomas. NEJM 2010;362:1417
  3. Ansell SM. Non-Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc 2015;90:1152
  4. Armitage et al.  New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. J Clin Oncol 1998;16:2780
  5. Pulte et al. Ongoing Improvement in Outcomes for Patients Diagnosed as Having Non-Hodgkin Lymphoma From the 1990s to the Early 21st Century. Arch Intern Med 2008;168:469
  6. Bradford et al. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood 2009;113:5064
  7. McMillan A. Central nervous system-directed preventative therapy in adults with lymphoma. Br J Haematol 2005;131:13
  8. Caruso et al. Thrombotic complications in adult patients with lymphoma: a meta-analysis of 29 independent cohorts including 18 018 patients and 1149 events. Blood 2010;115:5322 (Advanced stage NHL associated with highest risk)
  9. Reeder and Ansell. Novel therapeutic agents for B-cell lymphoma: developing rational combinations. Blood 2011;117:1453
  10. Maloney D. Anti-CD20 antibody therapy for B-cell lymphomas. NEJM 2012;366:2008
  11. Zurawska et al. Hepatitis B virus screening before chemotherapy for lymphoma: a cost-effectivness analysis. J Clin Oncol 2012;30:3167 (Most cost-effective to screen everyone; 10-fold decrease in HBV reactivation rate)
  12. Huang et al. Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation in Patients With Lymphoma and Resolved Hepatitis B. J Clin Oncol 2013;31:2765 (Prophylaxis lowers reactivation rate)
Low-grade lymphoma: reviews, pathology, prognosis, treatment strategies
  1. Winter et al.  Low-grade lymphoma.  Hematology 2004:203
  2. Salles G. Clinical features, prognosis and treatment of follicular lymphoma. Hematology 2007:216
  3. Stevenson and Stevenson. Follicular lymphoma and the immune system: from pathogenesis to antibody therapy. Blood 2012;119:3659
  4. Gascoyne R. Hematopathology Approaches to Diagnosis and Prognosis of Indolent B-Cell Lymphomas. Hematology 2005:299-306
  5. de Jong D. Molecular Pathogenesis of Follicular Lymphoma: A Cross Talk of Genetic and Immunologic Factors. J Clin Oncol 2005;23:6358
  6. Roulland et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J Exp Med 2006;203:2425 (see also the NEJM commentary on this paper)
  7. Solal-Céligny et al.  Follicular Lymphoma International Prognostic Index.  Blood 2004;104:1258    see also: Ghielmini and Mora. Does the FLIPI apply to grade 3 follicular lymphoma? Blood 2005;105:4892
  8. Federico et al. Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 2009;27:4555
  9. Pastore et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 2015;16:1111 (The "M7-FLIPI" score. Incorporating mutation status of 7 genes improves prognostic significance of FLIPI score; online calculator available here)
  10. Tan et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 2013;122:981
  11. Horning and Rosenberg. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. NEJM 1984; 311:1471
  12. Ardeshna et al.  Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.  Lancet 2003;262:516
  13. Solal-Céligny et al. Watchful Waiting in Low–Tumor Burden Follicular Lymphoma in the Rituximab Era: Results of an F2-Study Database. J Clin Oncol 2012;30:3848 (W&W still a reasonable approach)
  14. Armitage and Longo. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood 2016;127:2804
  15. Advani et al. Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy.  J Clin Oncol 2004;22:1454
  16. Hiddemann et al. Treatment Strategies in Follicular Lymphomas: Current Status and Future Perspectives. J Clin Oncol 2005;23:6394
  17. Gribben J. How I treat indolent lymphoma. Blood 2007;109:4617
  18. Jegalian et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011;118:2976
  19. Cheson B.  Radioimmunotherapy of non-Hodgkin lymphomas.  Blood 2003;101:391
  20. Jahnke et al. Low-grade primary central nervous system lymphoma in immunocompetent patients. Br J Haematol 2005;128:616