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Semin Thromb Hemost 2013; 39(01): 101-111
DOI: 10.1055/s-0032-1331153
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Thrombotic and Bleeding Complications in Classical Myeloproliferative Neoplasms

Brandon McMahon
1   Division of Hematology Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
,
Brady L. Stein
1   Division of Hematology Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
› Author Affiliations
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Publication History

Publication Date:
23 December 2012 (online)

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Abstract

The Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) share an increased risk of thrombotic and hemorrhagic complications. The thromboses are more commonly arterial than venous, but unique to the BCR-ABL–negative MPNs is the involvement of the abdominal veins. Commonly accepted thrombotic risk factors include advanced age and a prior thrombotic episode, although these risk factors are associated with thrombosis regardless of the presence of an MPN. Emerging risk factors may include leukocytosis and presence of the JAK2 V617F mutation or an increase in its allelic burden. Interventions to prevent and/or treat MPN-related thromboses include aspirin, anticoagulation, and cytoreductive therapy. Although phlebotomy is a cornerstone of management in polycythemia vera to lower the risk for thrombosis, the target hematocrit is being reevaluated. Hemorrhagic complications occur with extreme thrombocytosis and may be related to acquired platelet defects such as acquired von Willebrand syndrome. The impact of new mutations and novel therapies, including JAK-inhibitors and interferon, on the thrombotic and hemorrhagic tendency remains to be determined.

Keywords

myeloproliferative neoplasm - polycythemia vera - essential thrombocythemia - myelofibrosis - thrombosis - hemorrhage
 

  • References

  • 1 Noor SJ, Tan W, Wilding GE , et al. Myeloid blastic transformation of myeloproliferative neoplasms—a review of 112 cases. Leuk Res 2011; 35 (5) 608-613
    CrossrefPubMedGoogle Scholar
  • 2 Najean Y, Rain JD. The very long-term evolution of polycythemia vera: an analysis of 318 patients initially treated by phlebotomy or 32P between 1969 and 1981. Semin Hematol 1997; 34 (1) 6-16
    PubMedGoogle Scholar
  • 3 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
    CrossrefPubMedGoogle Scholar
  • 4 Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 2012; 87 (3) 285-293
    PubMedGoogle Scholar
  • 5 Crisà E, Venturino E, Passera R , et al. A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs. Ann Hematol 2010; 89 (7) 691-699
    CrossrefPubMedGoogle Scholar
  • 6 Passamonti F, Rumi E, Caramella M , et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood 2008; 111 (7) 3383-3387
    CrossrefPubMedGoogle Scholar
  • 7 Barbui T, Carobbio A, Cervantes F , et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 2010; 115 (4) 778-782
    CrossrefPubMedGoogle Scholar
  • 8 Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost 2007; 33 (4) 313-320
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Hoekstra J, Bresser EL, Smalberg JH, Spaander MC, Leebeek FW, Janssen HL. Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms. J Thromb Haemost 2011; 9 (11) 2208-2214
    CrossrefPubMedGoogle Scholar
  • 10 Reikvam H, Tiu RV. Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera. Leukemia 2012; 26 (4) 563-571
    CrossrefPubMedGoogle Scholar
  • 11 Darwish Murad S, Plessier A, Hernandez-Guerra M , et al; EN-Vie (European Network for Vascular Disorders of the Liver). Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Intern Med 2009; 151 (3) 167-175
    CrossrefPubMedGoogle Scholar
  • 12 De Stefano V, Fiorini A, Rossi E , et al. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost 2007; 5 (4) 708-714
    CrossrefPubMedGoogle Scholar
  • 13 Colaizzo D, Amitrano L, Tiscia GL , et al. The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost 2007; 5 (1) 55-61
    PubMedGoogle Scholar
  • 14 Kiladjian JJ, Cervantes F, Leebeek FW , 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 (10) 4922-4929
    CrossrefPubMedGoogle Scholar
  • 15 Dentali F, Squizzato A, Brivio L , et al. JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 2009; 113 (22) 5617-5623
    CrossrefPubMedGoogle Scholar
  • 16 Elliott MA, Pardanani A, Lasho TL, Schwager SM, Tefferi A. Thrombosis in myelofibrosis: prior thrombosis is the only predictive factor and most venous events are provoked. Haematologica 2010; 95 (10) 1788-1791
    CrossrefPubMedGoogle Scholar
  • 17 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
    CrossrefPubMedGoogle Scholar
  • 18 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 (1) 33-45
    CrossrefPubMedGoogle Scholar
  • 19 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 (3) 372-380
    CrossrefPubMedGoogle Scholar
  • 20 van Genderen PJ, Lucas IS, van Strik R , et al. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost 1996; 76 (3) 333-338
    PubMedGoogle Scholar
  • 21 Ginsburg AD. Platelet function in patients with high platelet counts. Ann Intern Med 1975; 82 (4) 506-511
    CrossrefPubMedGoogle Scholar
  • 22 Jensen MK, de Nully Brown P, Lund BV, Nielsen OJ, Hasselbalch HC. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol 2000; 110 (1) 116-124
    CrossrefPubMedGoogle Scholar
  • 23 Landolfi R, Ciabattoni G, Patrignani P , et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood 1992; 80 (8) 1965-1971
    CrossrefPubMedGoogle Scholar
  • 24 Rocca B, Ciabattoni G, Tartaglione R , et al. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 1995; 74 (5) 1225-1230
    PubMedGoogle Scholar
  • 25 Santilli F, Romano M, Recchiuti A , et al. Circulating endothelial progenitor cells and residual in vivo thromboxane biosynthesis in low-dose aspirin-treated polycythemia vera patients. Blood 2008; 112 (4) 1085-1090
    CrossrefPubMedGoogle Scholar
  • 26 Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2 (8102) 1219-1222
    PubMedGoogle Scholar
  • 27 Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol 2005; 33 (5) 523-530
    CrossrefPubMedGoogle Scholar
  • 28 Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor?. Blood 2009; 114 (4) 759-763
    PubMedGoogle Scholar
  • 29 Robertson B, Urquhart C, Ford I , et al. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J Thromb Haemost 2007; 5 (8) 1679-1685
    CrossrefPubMedGoogle Scholar
  • 30 Wautier MP, El Nemer W, Gane P , et al. Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and Lu/BCAM. Blood 2007; 110 (3) 894-901
    CrossrefPubMedGoogle Scholar
  • 31 George FD. Microparticles in vascular diseases. Thromb Res 2008; 122 (Suppl. 01) S55-S59
    CrossrefPubMedGoogle Scholar
  • 32 Trappenburg MC, van Schilfgaarde M, Marchetti M , et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 2009; 94 (7) 911-918
    CrossrefPubMedGoogle Scholar
  • 33 Moles-Moreau MP, Ternisien C, Tanguy-Schmidt A , et al. Flow cytometry-evaluated platelet CD36 expression, reticulated platelets and platelet microparticles in essential thrombocythaemia and secondary thrombocytosis. Thromb Res 2010; 126 (5) e394-e396
    CrossrefPubMedGoogle Scholar
  • 34 Duchemin J, Ugo V, Ianotto JC, Lecucq L, Mercier B, Abgrall JF. Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms. Thromb Res 2010; 126 (3) 238-242
    CrossrefPubMedGoogle Scholar
  • 35 Sozer S, Fiel MI, Schiano T, Xu M, Mascarenhas J, Hoffman R. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood 2009; 113 (21) 5246-5249
    CrossrefPubMedGoogle Scholar
  • 36 Teofili L, Martini M, Iachininoto MG , et al. Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood 2011; 117 (9) 2700-2707
    CrossrefPubMedGoogle Scholar
  • 37 Campbell PJ, Scott LM, Buck G , et al; United Kingdom Myeloproliferative Disorders Study Group; Medical Research Council Adult Leukaemia Working Party; Australasian Leukaemia and Lymphoma Group. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366 (9501) 1945-1953
    CrossrefPubMedGoogle Scholar
  • 38 Carobbio A, Finazzi G, Antonioli E , et al. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol 2009; 37 (9) 1016-1021
    CrossrefPubMedGoogle Scholar
  • 39 Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 2009; 124 (4) 409-417
    CrossrefPubMedGoogle Scholar
  • 40 Vannucchi AM, Antonioli E, Guglielmelli P , et al. Clinical profile of homozygous JAK2 617V > F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007; 110 (3) 840-846
    CrossrefPubMedGoogle Scholar
  • 41 Vannucchi AM, Antonioli E, Guglielmelli P , et al; MPD Research Consortium. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 2007; 21 (9) 1952-1959
    CrossrefPubMedGoogle Scholar
  • 42 Antonioli E, Guglielmelli P, Poli G , et al; Myeloproliferative Disorders Research Consortium (MPD-RC). Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 2008; 93 (1) 41-48
    CrossrefPubMedGoogle Scholar
  • 43 Passamonti F, Elena C, Schnittger S , et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011; 117 (10) 2813-2816
    CrossrefPubMedGoogle Scholar
  • 44 Vannucchi AM, Antonioli E, Guglielmelli P , et al. Characteristics and clinical correlates of MPL 515W > L/K mutation in essential thrombocythemia. Blood 2008; 112 (3) 844-847
    CrossrefPubMedGoogle Scholar
  • 45 Beer PA, Campbell PJ, Scott LM , et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008; 112 (1) 141-149
    CrossrefPubMedGoogle Scholar
  • 46 Tefferi A, Pardanani A, Lim KH , et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009; 23 (5) 905-911
    CrossrefPubMedGoogle Scholar
  • 47 Barbui T, Thiele J, Passamonti F , et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood 2012; 119 (10) 2239-2241
    CrossrefPubMedGoogle Scholar
  • 48 Barbui T, Carobbio A, Finazzi G , et al; AGIMM and IIC Investigators. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica 2011; 96 (2) 315-318
    CrossrefPubMedGoogle Scholar
  • 49 Barbui T, Barosi G, Birgegard G , et al; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29 (6) 761-770
    CrossrefPubMedGoogle Scholar
  • 50 Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011; 29 (5) 573-582
    CrossrefPubMedGoogle Scholar
  • 51 Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med 1995; 123 (9) 656-664
    CrossrefPubMedGoogle Scholar
  • 52 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 (3) 115-120
    CrossrefPubMedGoogle Scholar
  • 53 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 (2) 114-124
    CrossrefPubMedGoogle Scholar
  • 54 Tefferi A, Gangat N, Wolanskyj AP. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter?. Blood 2006; 108 (7) 2493-2494
    CrossrefPubMedGoogle Scholar
  • 55 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 (7) 1409-1411
    CrossrefPubMedGoogle Scholar
  • 56 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 (2) 159-166
    CrossrefPubMedGoogle Scholar
  • 57 Landolfi R, Di Gennaro L, Barbui T , et al; European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109 (6) 2446-2452
    CrossrefPubMedGoogle Scholar
  • 58 De Stefano V, Za T, Rossi E , et al; GIMEMA Chronic Myeloproliferative Neoplasms Working Party. Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia. Am J Hematol 2010; 85 (2) 97-100
    PubMedGoogle Scholar
  • 59 Buxhofer-Ausch V, Gisslinger H, Thiele J , et al. Leukocytosis as an important risk factor for arterial thrombosis in WHO-defined early/prefibrotic myelofibrosis: an international study of 264 patients. Am J Hematol 2012; 87 (7) 669-672
    CrossrefPubMedGoogle Scholar
  • 60 Falanga A, Marchetti M, Evangelista V , et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96 (13) 4261-4266
    PubMedGoogle Scholar
  • 61 Gangat N, Wolanskyj AP, Schwager SM, Hanson CA, Tefferi A. Leukocytosis at diagnosis and the risk of subsequent thrombosis in patients with low-risk essential thrombocythemia and polycythemia vera. Cancer 2009; 115 (24) 5740-5745
    CrossrefPubMedGoogle Scholar
  • 62 Papadakis E, Hoffman R, Brenner B. Thrombohemorrhagic complications of myeloproliferative disorders. Blood Rev 2010; 24 (6) 227-232
    CrossrefPubMedGoogle Scholar
  • 63 Ruggeri M, Gisslinger H, Tosetto A , et al. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol 2002; 71 (1) 1-6
    CrossrefPubMedGoogle Scholar
  • 64 Gisslinger H, Müllner M, Pabinger I , et al. Mutation of the prothrombin gene and thrombotic events in patients with polycythemia vera or essential thrombocythemia: a cohort study. Haematologica 2005; 90 (3) 408-410
    PubMedGoogle Scholar
  • 65 Tartaglia AP, Goldberg JD, Berk PD, Wasserman LR. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Semin Hematol 1986; 23 (3) 172-176
    PubMedGoogle Scholar
  • 66 Gruppo Italiano Studio Policitemia (GISP). Low-dose aspirin in polycythaemia vera: a pilot study. Br J Haematol 1997; 97 (2) 453-456
    CrossrefPubMedGoogle Scholar
  • 67 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 (8) 1205-1210 , quiz 1387
    CrossrefPubMedGoogle Scholar
  • 68 Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 2012; 87 (3) 285-293
    PubMedGoogle Scholar
  • 69 Squizzato A, Romualdi E, Middeldorp S. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 2008; (2) CD006503
    PubMedGoogle Scholar
  • 70 Pascale S, Petrucci G, Dragani A , et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119 (15) 3595-3603
    CrossrefPubMedGoogle Scholar
  • 71 Berk PD, Goldberg JD, Silverstein MN , et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304 (8) 441-447
    CrossrefPubMedGoogle Scholar
  • 72 Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986; 23 (2) 132-143
    PubMedGoogle Scholar
  • 73 Di Nisio M, Barbui T, Di Gennaro L , et al; European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators. The haematocrit and platelet target in polycythemia vera. Br J Haematol 2007; 136 (2) 249-259
    CrossrefPubMedGoogle Scholar
  • 74 Marchioli R, Finazzi G, Specchia G, Masciulli A, Mennitto MR, Barbui T. The CYTO-PV: A large-scale trial testing the intensity of cytoreductive therapy to prevent cardiovascular events in patients with polycythemia vera. Thrombosis 2011; 2011: 794240
    PubMedGoogle Scholar
  • 75 Cortelazzo S, Finazzi G, Ruggeri M , et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332 (17) 1132-1136
    CrossrefPubMedGoogle Scholar
  • 76 Björkholm M, Derolf AR, Hultcrantz M , et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 2011; 29 (17) 2410-2415
    CrossrefPubMedGoogle Scholar
  • 77 Passamonti F, Rumi E, Pungolino E , et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004; 117 (10) 755-761
    CrossrefPubMedGoogle Scholar
  • 78 Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia 2008; 22 (11) 1990-1998
    CrossrefPubMedGoogle Scholar
  • 79 Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 2006; 107 (3) 451-458
    CrossrefPubMedGoogle Scholar
  • 80 Quintás-Cardama A, Kantarjian H, Manshouri T , 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 (32) 5418-5424
    CrossrefPubMedGoogle Scholar
  • 81 Kiladjian JJ, Cassinat B, Chevret S , et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008; 112 (8) 3065-3072
    CrossrefPubMedGoogle Scholar
  • 82 Alvarado Y, Cortes J, Verstovsek S , et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol 2003; 51 (1) 81-86
    CrossrefPubMedGoogle Scholar
  • 83 Langer C, Lengfelder E, Thiele J , et al. Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. Haematologica 2005; 90 (10) 1333-1338
    PubMedGoogle Scholar
  • 84 Samuelsson J, Hasselbalch H, Bruserud O , et al; Nordic Study Group for Myeloproliferative Disorders. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer 2006; 106 (11) 2397-2405
    CrossrefPubMedGoogle Scholar
  • 85 Verstovsek S, Mesa RA, Gotlib J , et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366 (9) 799-807
    CrossrefPubMedGoogle Scholar
  • 86 Verstovsek S, Kantarjian H, Mesa RA , et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363 (12) 1117-1127
    CrossrefPubMedGoogle Scholar
  • 87 Verstovsek S, Mesa RA, Gotlib J , et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366 (9) 799-807
    CrossrefPubMedGoogle Scholar
  • 88 Harrison C, Kiladjian JJ, Al-Ali HK , et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366 (9) 787-798
    CrossrefPubMedGoogle Scholar
  • 89 Pardanani A, Gotlib JR, Jamieson C , et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011; 29 (7) 789-796
    CrossrefPubMedGoogle Scholar
  • 90 Moliterno AR, Roboz GJ, Carroll M, Luger S, Hexner E, Bensen-Kennedy DM. An open-label study of CEP-701 in patients with JAK2 V617F-positive polycythemia vera and essential thrombocytosis. ASH Annual Meeting Abstracts. November 16, 2008; 112 (11) 99
    PubMedGoogle Scholar
  • 91 Lee AY, Levine MN, Baker RI , et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (2) 146-153
    CrossrefPubMedGoogle Scholar
  • 92 Spectre G, Kalish Y, Schliamser L, Varon D. Heparin-induced thrombocytopenia in myeloproliferative disorders: a rare or under-diagnosed complication?. Am J Hematol 2008; 83 (5) 420-423
    CrossrefPubMedGoogle Scholar
  • 93 Randi ML, Tezza F, Scapin M , et al. Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis. Acta Haematol 2010; 123 (3) 140-145
    CrossrefPubMedGoogle Scholar
  • 94 Wehmeier A, Fricke S, Scharf RE, Schneider W. A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders. Eur J Haematol 1990; 45 (4) 191-197
    PubMedGoogle Scholar
  • 95 Kaywin P, McDonough M, Insel PA, Shattil SJ. Platelet function in essential thrombocythemia. Decreased epinephrine responsiveness associated with a deficiency of platelet alpha-adrenergic receptors. N Engl J Med 1978; 299 (10) 505-509
    CrossrefPubMedGoogle Scholar
  • 96 Mazzucato M, De Marco L, De Angelis V, De Roia D, Bizzaro N, Casonato A. Platelet membrane abnormalities in myeloproliferative disorders: decrease in glycoproteins Ib and IIb/IIIa complex is associated with deficient receptor function. Br J Haematol 1989; 73 (3) 369-374
    CrossrefPubMedGoogle Scholar
  • 97 Le Blanc K, Lindahl T, Rosendahl K, Samuelsson J. Impaired platelet binding of fibrinogen due to a lower number of GPIIB/IIIA receptors in polycythemia vera. Thromb Res 1998; 91 (6) 287-295
    CrossrefPubMedGoogle Scholar
  • 98 van Genderen PJ, Budde U, Michiels JJ, van Strik R, van Vliet HH. The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count. Br J Haematol 1996; 93 (4) 962-965
    CrossrefPubMedGoogle Scholar
  • 99 van Genderen PJ, Prins FJ, Lucas IS , et al. Decreased half-life time of plasma von Willebrand factor collagen binding activity in essential thrombocythaemia: normalization after cytoreduction of the increased platelet count. Br J Haematol 1997; 99 (4) 832-836
    CrossrefPubMedGoogle Scholar
  • 100 Buss DH, Stuart JJ, Lipscomb GE. The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: an analysis of 129 cases. Am J Hematol 1985; 20 (4) 365-372
    CrossrefPubMedGoogle Scholar
  • 101 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 (4) 716-719
    CrossrefPubMedGoogle Scholar