Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature

Abstract

Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially CALR-mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.

Keywords

essential thrombocythemia - polycythemia vera - bleeding - risk factors - classification

Authors' Contributions

C.N., J-.C.I., B.P-.P., and K.L. elaborated the study. C.N. did the PubMed analysis. C.N. and J-.C.I. wrote the manuscript. B.P-.P., K.L., and E.L. reviewed the manuscript. All the authors have validated the final version of the manuscript.

Publikationsverlauf

Eingereicht: 26. Mai 2020

Angenommen: 30. September 2020

Artikel online veröffentlicht:
13. November 2020

• References

• 1 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
• 2 Tefferi A, Guglielmelli P, Larson DR. et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124 (16) 2507-2513
• 3 Tefferi A, Rumi E, Finazzi G. et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013; 27 (09) 1874-1881
• 4 Barbui T, Thiele J, Passamonti F. et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 2011; 29 (23) 3179-3184
• 5 Mesa R, Jamieson C, Bhatia R. et al. Myeloproliferative neoplasms, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016; 14 (12) 1572-1611
• 6 Barbui T, Tefferi A, Vannucchi AM. et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 2018; 32 (05) 1057-1069
• 7 Martin K. Risk factors for and management of MPN-associated bleeding and thrombosis. Curr Hematol Malig Rep 2017; 12 (05) 389-396
• 8 Appelmann I, Kreher S, Parmentier S. et al. Diagnosis, prevention, and management of bleeding episodes in Philadelphia-negative myeloproliferative neoplasms: recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society of Thrombosis and Hemostasis Research (GTH). Ann Hematol 2016; 95 (05) 707-718
• 9 Stein BL, Martin K. From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms. Blood 2019; 134 (22) 1902-1911
• 10 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
• 11 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
• 12 Ruggeri M, Rodeghiero F, Tosetto A. et al. Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Chronic Myeloproliferative Diseases Working Party. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 2008; 111 (02) 666-671
• 13 De Stefano V, Za T, Rossi E. et al. GIMEMA CMD-Working Party. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93 (03) 372-380
• 14 Bang S-M, Lee J-S, Ahn JY. et al. Korean MPN Working Party. Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation. Thromb Haemost 2009; 101 (03) 547-551
• 15 Finazzi G, Carobbio A, Thiele J. et al. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia 2012; 26 (04) 716-719
• 16 Chou Y-S, Gau J-P, Yu Y-B. et al. Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage. Eur J Haematol 2013; 90 (03) 228-236
• 17 Kander EM, Raza S, Zhou Z. et al. Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort. Int J Hematol 2015; 102 (05) 587-593
• 18 Borowczyk M, Wojtaszewska M, Lewandowski K. et al. The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms. Thromb Res 2015; 135 (02) 272-280
• 19 Lim Y, Lee J-O, Kim SH. et al. Prediction of thrombotic and hemorrhagic events during polycythemia vera or essential thrombocythemia based on leukocyte burden. Thromb Res 2015; 135 (05) 846-851
• 20 Duangnapasatit B, Rattarittamrong E, Rattanathammethee T. et al. Clinical manifestations and risk factors for complications of philadelphia chromosome-negative myeloproliferative neoplasms. Asian Pac J Cancer Prev 2015; 16 (12) 5013-5018
• 21 Khan I, Shergill A, Saraf SL. et al. Outcome disparities in caucasian and non-Caucasian patients with myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk 2016; 16 (06) 350-357
• 22 Andıç N, Ünübol M, Yağcı E. et al. Clinical features of 294 Turkish patients with chronic myeloproliferative neoplasms. Turk J Haematol 2016; 33 (03) 187-195
• 23 Kaifie A, Kirschner M, Wolf D. et al. Study Alliance Leukemia (SAL). Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry. J Hematol Oncol 2016; 9 (01) 18
• 24 Rottenstreich A, Kleinstern G, Krichevsky S, Varon D, Lavie D, Kalish Y. Factors related to the development of acquired von Willebrand syndrome in patients with essential thrombocythemia and polycythemia vera. Eur J Intern Med 2017; 41: 49-54
• 25 De Stefano V, Ruggeri M, Cervantes F. et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia 2016; 30 (10) 2032-2038
• 26 Rumi E, Boveri E, Bellini M. et al. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria. Oncotarget 2017; 8 (60) 101735-101744
• 27 Bertozzi I, Bogoni G, Biagetti G. et al. Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. Ann Hematol 2017; 96 (08) 1297-1302
• 28 Kamiunten A, Shide K, Kameda T. et al. Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan. Int J Hematol 2018; 107 (06) 681-688
• 29 Krashin E, Cohen O, Pereg D, Lishner M, Leader A. Mean platelet volume and risk of thrombotic and bleeding complications in patients with Philadelphia chromosome negative myeloproliferative neoplasms. Blood Coagul Fibrinolysis 2018; 29 (03) 288-293
• 30 Godfrey AL, Campbell PJ, MacLean C. et al. United Kingdom Medical Research Council Primary Thrombocythemia-1 Study, United Kingdom National Cancer Research Institute Myeloproliferative Neoplasms Subgroup, French Intergroup of Myeloproliferative Neoplasms, the Australasian Leukaemia and Lymphoma Group. Hydroxycarbamide plus aspirin versus aspirin alone in patients with essential thrombocythemia age 40 to 59 years without high-risk features. J Clin Oncol 2018; 36 (34) 3361-3369
• 31 Birgegård G, Besses C, Griesshammer M. et al. Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the Evaluation of Anagrelide Efficacy and Long-term Safety study. Haematologica 2018; 103 (01) 51-60
• 32 Harrison CN, Campbell PJ, Buck G. et al. United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353 (01) 33-45
• 33 Chim C-S, Kwong Y-L, Lie AK-W. et al. Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia. Arch Intern Med 2005; 165 (22) 2651-2658
• 34 Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006; 81 (02) 159-166
• 35 Radaelli F, Colombi M, Calori R. et al. Analysis of risk factors predicting thrombotic and/or haemorrhagic complications in 306 patients with essential thrombocythemia. Hematol Oncol 2007; 25 (03) 115-120
• 36 Alvarez-Larrán A, Cervantes F, Pereira A. et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010; 116 (08) 1205-1210
• 37 Palandri F, Polverelli N, Catani L. et al. Bleeding in essential thrombocythaemia: a retrospective analysis on 565 patients. Br J Haematol 2012; 156 (02) 281-284
• 38 Campbell PJ, MacLean C, Beer PA. et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood 2012; 120 (07) 1409-1411
• 39 Alvarez-Larrán A, Pereira A, Guglielmelli P. et al. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation. Haematologica 2016; 101 (08) 926-931
• 40 Harrison CN, Mead AJ, Panchal A. et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood 2017; 130 (17) 1889-1897
• 41 Gisslinger H, Gotic M, Holowiecki J. et al. ANAHYDRET Study Group. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013; 121 (10) 1720-1728
• 42 Hernández-Boluda JC, Arellano-Rodrigo E, Cervantes F. et al. Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN). Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia. Ann Hematol 2015; 94 (06) 911-918
• 43 Landolfi R, Marchioli R, Kutti J. et al. European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350 (02) 114-124
• 44 Kiladjian J-J, Chevret S, Dosquet C, Chomienne C, Rain J-D. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol 2011; 29 (29) 3907-3913
• 45 Vannucchi AM, Kiladjian JJ, Griesshammer M. et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372 (05) 426-435
• 46 Marchioli R, Finazzi G, Landolfi R. et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005; 23 (10) 2224-2232
• 47 Yesilova AM, Yavuzer S, Yavuzer H. et al. Analysis of thrombosis and bleeding complications in patients with polycythemia vera: a Turkish retrospective study. Int J Hematol 2017; 105 (01) 70-78
• 48 Cerquozzi S, Barraco D, Lasho T. et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J 2017; 7 (12) 662
• 49 Common Terminology Criteria for Adverse Events (CTCAE). 2017;155. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf
• 50 Singer DE, Hughes RA, Gress DR. et al. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323 (22) 1505-1511
• 51 Granger CB, Alexander JH, McMurray JJV. et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
• 52 Agnelli G, Buller HR, Cohen A. et al. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
• 53 McNeil JJ, Wolfe R, Woods RL. et al. ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379 (16) 1509-1518
• 54 Wallentin L, Becker RC, Budaj A. et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 55 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
• 56 Ianotto J-C, Couturier M-A, Galinat H. et al. Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms. Int J Hematol 2017; 106 (04) 517-521
• 57 Rungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms. BMC Cancer 2019; 19 (01) 184
• 58 McMahon B, Stein BL. Thrombotic and bleeding complications in classical myeloproliferative neoplasms. Semin Thromb Hemost 2013; 39 (01) 101-111
• 59 Abdulla A, Davis WM, Ratnaweera N, Szefer E, Ballantyne Scott B, Lee AYY. A meta-analysis of case fatality rates of recurrent venous thromboembolism and major bleeding in patients with cancer. Thromb Haemost 2020; 120 (04) 702-713
• 60 Chu DK, Hillis CM, Leong DP, Anand SS, Siegal DM. Benefits and risks of antithrombotic therapy in essential thrombocythemia: a systematic review. Ann Intern Med 2017; 167 (03) 170-180
• 61 Mital A, Prejzner W, Bieniaszewska M, Hellmann A. Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients. Pol Arch Med Wewn 2015; 125 (12) 914-920
• 62 Mital A, Prejzner W, Świątkowska-Stodulska R, Hellmann A. Factors predisposing to acquired von Willebrand syndrome during the course of polycythemia vera - retrospective analysis of 142 consecutive cases. Thromb Res 2015; 136 (04) 754-757
• 63 Wells Jr RE, Merrill EW. Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Invest 1962; 41: 1591-1598
• 64 Roath S, Davenport P. Leucocyte numbers and quality: their effect on viscosity. Clin Lab Haematol 1991; 13 (03) 255-262
• 65 Tiede A. Diagnosis and treatment of acquired von Willebrand syndrome. Thromb Res 2012; 130 (Suppl. 02) S2-S6
• 66 Franchini M, Mannucci PM. The never ending success story of tranexamic acid in acquired bleeding. Haematologica 2020; 105 (05) 1201-1205
• 67 Rocca B, Tosetto A, Betti S. et al. A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia. Blood 2020; 136 (02) 171-182
• 68 Connolly SJ, Eikelboom JW, Bosch J. et al. COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 205-218
• 69 Carrier M, Abou-Nassar K, Mallick R. et al. AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
• 70 Barbui T, Barosi G, Grossi A. 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 (02) 215-232
• 71 Fang MC, Go AS, Chang Y. et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120 (08) 700-705