Thrombosis in Myeloproliferative Disorders: Prevalence, Prognostic Factors, and the Role of Leukocytes and JAK2V617F

ABSTRACT

An underlying myeloproliferative disorder (MPD), especially polycythemia vera (PV) or essential thrombocythemia (ET), is a risk factor for thrombosis. Considering large selected studies, prevalence rates for major thrombosis, at time of diagnosis, range from ~34 to 39% for PV and 10 to 29% for ET; the corresponding figures for thrombosis at follow-up are ~8 to 19% for PV and 8 to 31% for ET. In all instances, arterial events were more frequent than venous events. In both PV and ET, advanced age and history of thrombosis are independent predictors of recurrent thrombosis. In addition, leukocytosis, but not thrombocytosis, has been identified as a potential risk factor for thrombosis in both diseases. The particular observation is consistent with the laboratory demonstration, in these disorders, of increased number of activated granulocytes and granulocyte-platelet aggregates, upregulation of platelet P-selectin and tissue factor expression by granulocytes, and the antithrombotic value of hydroxyurea therapy. Most recently, a JAK2 gain-of-function mutation (JAK2V617F) was described in virtually all patients with PV and ~50% of those with ET. Whether the presence of this specific mutation or its allele burden modifies the risk of thrombosis in patients with MPDs currently is under investigation.

Thrombosis - myeloproliferative - thrombocythemia - polycythemia - JAK2

REFERENCES

• 1 Tefferi A, Gilliland D G. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.  Mayo Clin Proc. 2005;  80 947-958
• 2 Pikman Y, Lee B H, Mercher T et al.. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.  PLoS Med. 2006;  3 1140-1151
• 3 Pardanani A D, Levine R L, Lasho T et al.. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.  Blood. 2006;  108 3472-3476
• 4 James C, Ugo V, Le Couedic J P et al.. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.  Nature. 2005;  434 1144-1148
• 5 Wernig G, Mercher T, Okabe R, Levine R L, Lee B H, Gilliland D G. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model.  Blood. 2006;  107 4274-4281
• 6 Lacout C, Pisani D F, Tulliez M, Moreau Gachelin F, Vainchenker W, Villeval J L. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis.  Blood. 2006;  108 1652-1660
• 7 Mesa R A, Silverstein M N, Jacobsen S J, Wollan P C, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: An Olmsted County study, 1976-1995.  Am J Hematol. 1999;  61 10-15
• 8 Ania B J, Suman V J, Sobell J L, Codd M B, Silverstein M N, Melton III L J. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989.  Am J Hematol. 1994;  47 89-93
• 9 Gruppo Italiano Studio Policitemia . Polycythemia vera: the natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
• 10 Gangat N, Wolanskyj A P, McClure R F et al.. Risk stratification for survival and leukemic transformation in essential thrombocythemia: A single institutional study of 605 patients.  Leukemia. 2006;  21 270-276
• 11 Wolanskyj A P, Schwager S M, McClure R F, Larson D R, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors.  Mayo Clin Proc. 2006;  81 159-166
• 12 Rozman C, Giralt M, Feliu E, Rubio D, Cortes M T. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.  Cancer. 1991;  67 2658-2663
• 13 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;  117 755-761
• 14 Tefferi A. Essential thrombocythemia: scientific advances and current practice.  Curr Opin Hematol. 2006;  13 93-98
• 15 Michiels J J, Abels J, Steketee J, van Vliet H H, Vuzevski V D. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.  Ann Intern Med. 1985;  102 466-471
• 16 Michiels J J, van Genderen P J, Lindemans J, van Vliet H H. Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.  Leuk Lymphoma. 1996;  22(suppl 1) 47-56
• 17 Fenaux P, Simon M, Caulier M T, Lai J L, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases.  Cancer. 1990;  66 549-556
• 18 Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.  J Clin Oncol. 1990;  8 556-562
• 19 Colombi M, Radaelli F, Zocchi L, Maiolo A T. Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients.  Cancer. 1991;  67 2926-2930
• 20 Besses C, Cervantes F, Pereira A et al.. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients.  Leukemia. 1999;  13 150-154
• 21 Jensen M K, de Nully Brown P, Nielsen O J, Hasselbalch H C. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area.  Eur J Haematol. 2000;  65 132-139
• 22 Chim C S, Kwong Y L, Lie A K et al.. Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.  Arch Intern Med. 2005;  165 2651-2658
• 23 Campbell P J, Scott L M, Buck G 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 1945-1953
• 24 Gruppo Italiano Studio Policitemia . Polycythemia vera: the natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
• 25 Passamonti F, Brusamolino E, Lazzarino M et al.. Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.  Haematologica. 2000;  85 1011-1018
• 26 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 2224-2232
• 27 Carobbio A, Finazzi G, Guerini V et al.. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors and Jak2 mutation status.  Blood. 2006(November);  16 , (Epub ahead of print)
• 28 De Stefano V, Za T, Rossi E et al.. Recurrent thrombosis in patients with polycythemia vera or essential thrombocythemia: efficacy of treatment in preventing rethrombosis in different clinical settings.  Blood. 2006;  108 , (abst 119)
• 29 Harrison C N, Campbell P J, Buck G et al.. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.  N Engl J Med. 2005;  353 33-45
• 30 Bounameaux H, Reber-Wasem M A. Superficial thrombophlebitis and deep vein thrombosis. A controversial association.  Arch Intern Med. 1997;  157 1822-1824
• 31 Gangat N, Wolanskyj A P, Tefferi A. Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications.  Eur J Haematol. 2006;  77 327-333
• 32 Anger B R, Seifried E, Scheppach J, Heimpel H. Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases.  Klin Wochenschr. 1989;  67 818-825
• 33 Patel R K, Lea N C, Heneghan M A et al.. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.  Gastroenterology. 2006;  130 2031-2038
• 34 Colaizzo D, Amitrano L, Tiscia G L et al.. The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis.  J Thromb Haemost. 2006;  5 55-61
• 35 Boissinot M, Lippert E, Girodon F et al.. Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis.  Blood. 2006;  108 3223-3224
• 36 Landolfi R, Di Gennaro L, Barbui T et al.. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.  Blood. 2006 November 14;  , (Epub ahead of print)
• 37 Finazzi G. A prospective analysis of thrombotic events in the European collaboration study on low-dose aspirin in polycythemia (ECLAP).  Pathol Biol (Paris). 2004;  52 285-288
• 38 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;  89 215-232
• 39 Elliott M A, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.  Br J Haematol. 2005;  128 275-290
• 40 Harrison C N. Essential thrombocythaemia: challenges and evidence-based management.  Br J Haematol. 2005;  130 153-165
• 41 Harrison C N, Gale R E, Machin S J, Linch D C. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications.  Blood. 1999;  93 417-424
• 42 Vannucchi A M, Grossi A, Pancrazzi A et al.. PRV-1, erythroid colonies and platelet Mpl are unrelated to thrombosis in essential thrombocythaemia.  Br J Haematol. 2004;  127 214-219
• 43 Chiusolo P, La Barbera E O, Laurenti L et al.. Clonal hemopoiesis and risk of thrombosis in young female patients with essential thrombocythemia.  Exp Hematol. 2001;  29 670-676
• 44 Zamora L, Espinet B, Florensa L, Besses C, Bellosillo B, Sole F. Clonality analysis by HUMARA assay in Spanish females with essential thrombocythemia and polycythemia vera.  Haematologica. 2005;  90 259-261
• 45 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 1132-1136
• 46 Tefferi A, Gangat N, Wolanskyj A P. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter?.  Blood. 2006;  108 2493-2494
• 47 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low-dose aspirin in polycythemia vera.  N Engl J Med. 2004;  350 114-124
• 48 Baxter E J, Scott L M, Campbell P J et al.. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
• 49 Levine R L, Wadleigh M, Cools J et al.. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.  Cancer Cell. 2005;  7 387-397
• 50 Kralovics R, Passamonti F, Buser A S et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
• 51 Steensma D P, Dewald G W, Lasho T L et al.. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.  Blood. 2005;  106 1207-1209
• 52 Jones A V, Kreil S, Zoi K et al.. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.  Blood. 2005;  106 2162-2168
• 53 Tefferi A, Gilliland D G. JAK2 in myeloproliferative disorders is not just another kinase.  Cell Cycle. 2005;  4 1053-1056
• 54 Antonioli E, Guglielmelli P, Pancrazzi A et al.. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia.  Leukemia. 2005;  19 1847-1849
• 55 Heller P G, Lev P R, Salim J P et al.. JAK2V617F mutation in platelets from essential thrombocythemia patients: correlation with clinical features and analysis of STAT5 phosphorylation status.  Eur J Haematol. 2006;  77 210-216
• 56 Jamieson C H, Gotlib J, Durocher J A et al.. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation.  Proc Natl Acad Sci USA. 2006;  103 6224-6229
• 57 Bellanne-Chantelot C, Chaumarel I, Labopin M et al.. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders.  Blood. 2006;  108 346-352
• 58 Wolanskyj A P, Lasho T L, Schwager S M et al.. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance.  Br J Haematol. 2005;  131 208-213
• 59 Tefferi A, Lasho T L, Schwager S M et al.. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera.  Cancer. 2006;  106 631-635
• 60 Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia.  Br J Haematol. 2006;  132 244-245
• 61 Pemmaraju N, Moliterno A R, Williams D, Rogers O, Spivak J L. Heterogeneous JAK2V617F allele burden in essential thrombocytosis: gender and clinical correlates.  Blood. 2006;  108 , (abst 670)
• 62 Vannucchi A M, Antonioli E, Guglielmelli P et al.. Influence of the Jak2V617F mutational load at diagnosis on major clinical aspects in patients with polycythemia vera.  Blood. 2006;  108 , (abst 5)
• 63 Vannucchi A M, Barosi G, Rambaldi A, Marchioli R, Barbui T. Clinical significance of JAK2V617F homozygosity in the chronic myeloproliferative disorders. A study on 1306.  Blood. 2006;  108 , (abst 664)
• 64 Falanga A, Marchetti M, Barbui T, Smith C W. Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils.  Semin Hematol. 2005;  42 239-247
• 65 Maugeri N, Giordano G, Petrilli M P et al.. Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?.  J Thromb Haemost. 2006;  4 2593-2598
• 66 Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera.  Exp Hematol. 2005;  33 523-530
• 67 Arellano-Rodrigo E, Alvarez-Larran A, Reverter J C, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status.  Haematologica. 2006;  91 169-175
• 68 Falanga A, Marchetti M, Evangelista V et al.. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.  Blood. 2000;  96 4261-4266
• 69 Alvarez-Larran A, Garcia-Pagan J C, Abraldes J G et al.. Increased CD11b neutrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythaemia vera.  Br J Haematol. 2004;  124 329-335
• 70 Maugeri N, Brambilla M, Camera M et al.. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation.  J Thromb Haemost. 2006;  4 1323-1330
• 71 Grunebach F, Bross-Bach U, Kanz L, Brossart P. Detection of a new JAK2 D620E mutation in addition to V617F in a patient with polycythemia vera.  Leukemia. 2006;  20 2210-2211
• 72 Tefferi A, Pardanani A. Mutation screening for JAK2V617F: when to order the test and how to interpret the results.  Leuk Res. 2006;  30 739-744