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Journal of Thrombosis and Thrombolysis

, Volume 45, Issue 4, pp 516–528 | Cite as

Thrombosis in Philadelphia negative classical myeloproliferative neoplasms: a narrative review on epidemiology, risk assessment, and pathophysiologic mechanisms

  • Somedeb Ball
  • Kyaw Zin Thein
  • Abhishek Maiti
  • Kenneth Nugent
Article
First Online:

Abstract

Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte–platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis.

Keywords

Myeloproliferative neoplasm Venous thromboembolism Essential thrombocythemia JAK2V617F mutation Leukocyte activation Microparticles 
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Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood 127:2391–2405PubMedCrossRefGoogle Scholar
  2. 2.
    Titmarsh GJ, Duncombe AS, McMullin MF et al (2014) How common are myeloproliferative neoplasms? A systematic review and metaanalysis. Am J Hematol 89:581–587PubMedCrossRefGoogle Scholar
  3. 3.
    Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U, Mesa RA (2014) Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 92:289–297PubMedCrossRefGoogle Scholar
  4. 4.
    Maynadié M, De Angelis R, Marcos-Gragera R et al (2013) Survival of European patients diagnosed with myeloid malignancies: a HAEMACARE study. Haematologica 98:230–238PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hultcrantz M, Kristinsson SY, Andersson TM-L et al (2012) Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study. J Clin Oncol 30:2995–3001PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Okamura T, Kinukawa N, Niho Y et al (2001) Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients. Int J Hematol 73:194–198PubMedCrossRefGoogle Scholar
  7. 7.
    Antonioli E, Guglielmelli P, Pancrazzi A et al (2005) Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 19:1847–1849PubMedCrossRefGoogle Scholar
  8. 8.
    Tefferi A (2010) Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24:1128–1138PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Barosi G, Bergamaschi G, Marchetti M et al (2007) Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Italian Registry of Myelofibrosis. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 110:4030–4036PubMedCrossRefGoogle Scholar
  10. 10.
    Nangalia J, Massie CE, Baxter EJ et al (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369:2391–2405PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Tefferi A, Thiele J, Vannucchi AM, Barbui T (2014) An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 28:1407–1413PubMedCrossRefGoogle Scholar
  12. 12.
    Pikman Y, Lee BH, Mercher T et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Verstovsek S, Mesa RA, Gotlib J (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Harrison C, Kiladjian JJ, Al-Ali HK (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366:787–798PubMedCrossRefGoogle Scholar
  15. 15.
    Tefferi A, Elliott M (2007) Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost 33:313–320PubMedCrossRefGoogle Scholar
  16. 16.
    Barbui T, Carobbio A, Cervantes F et al (2010) Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 115:778–782PubMedCrossRefGoogle Scholar
  17. 17.
    Gisslinger H, Gotic M, Holowiecki J et al; ANAHYDRET Study Group (2013) Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 121:1720–1728PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Marchioli R, Finazzi G, Landolfi R et al (2005) Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23:2224–2232PubMedCrossRefGoogle Scholar
  19. 19.
    Buxhofer-Ausch V, Gisslinger H, Thiele J et al (2012) Leukocytosis as an important risk factor for arterial thrombosis in WHO-defined early/prefibrotic myelofibrosis: an international study of 264 patients. Am J Hematol 87:669–672PubMedCrossRefGoogle Scholar
  20. 20.
    Campbell PJ, Scott LM, Buck G et al (2005) Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 366:1945–1953PubMedCrossRefGoogle Scholar
  21. 21.
    Montanaro M, Latagliata R, Cedrone M et al (2014) Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients. Am J Hematol 89:542–546PubMedCrossRefGoogle Scholar
  22. 22.
    De Stefano V, Martinelli I (2010) Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med 5:487–494PubMedCrossRefGoogle Scholar
  23. 23.
    Barbui T, Thiele J, Carobbio A et al (2012) Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 120:569–571PubMedCrossRefGoogle Scholar
  24. 24.
    Skeith L, Carrier M, Robinson SE, Alimam S, Rodger MA (2017) Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. Blood 129:934–939PubMedCrossRefGoogle Scholar
  25. 25.
    Khan I, Shergill A, Saraf SL et al (2016) Outcome disparities in Caucasian and non-Caucasian patients with myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk 16:350–357PubMedCrossRefGoogle Scholar
  26. 26.
    Carobbio A, Thiele J, Passamonti F et al (2011) Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 117:5857–5859PubMedCrossRefGoogle Scholar
  27. 27.
    De Stefano V, Za T, Rossi E et al (2008) Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 93:372–380PubMedCrossRefGoogle Scholar
  28. 28.
    De Stefano V, Rossi E, Za T et al (2011) JAK2 V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. Am J Hematol 86:526–528PubMedCrossRefGoogle Scholar
  29. 29.
    Ziakas PD (2008) Effect of JAK2 V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain. Haematologica 93:1412–1414PubMedCrossRefGoogle Scholar
  30. 30.
    Dahabreh IJ, Zoi K, Giannouli S, Zoi C, Loukopoulos D, Voulgarelis M (2008) Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res 33:67–73PubMedCrossRefGoogle Scholar
  31. 31.
    Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Buller HR, Cattaneo M (2009) Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 124:409–417PubMedCrossRefGoogle Scholar
  32. 32.
    Carobbio A, Finazzi G, Antonioli E et al (2009) JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol 37:1016–1021PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    De Stefano V, Za T, Rossi E et al (2010) Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia. Am J Hematol 85:97–100PubMedGoogle Scholar
  34. 34.
    Landolfi R, Di Gennaro L, Barbui T et al (2007) European collaboration on low-dose aspirin in polycythemia vera (ECLAP). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 109:2446–2452PubMedCrossRefGoogle Scholar
  35. 35.
    Carobbio A, Antonioli E, Guglielmelli P et al (2008) Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol 26:2732–2736PubMedCrossRefGoogle Scholar
  36. 36.
    Barbui T, Finazzi G, Carobbio A et al (2012) Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET thrombosis). Blood 120:5128–5133PubMedCrossRefGoogle Scholar
  37. 37.
    Alvarez-Larrán A, Pereira A, Arellano-Rodrigo E, Hernández-Boluda JC, Cervantes F, Besses C (2013) Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study. Br J Haematol 161:865–871PubMedCrossRefGoogle Scholar
  38. 38.
    Hernández-Boluda JC, Arellano-Rodrigo E, Cervantes F et al (2015) Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia. Ann Hematol 94:911–918PubMedCrossRefGoogle Scholar
  39. 39.
    Dombi P, Illés Á, Demeter J et al (2017) Anagrelide reduces thrombotic risk in essential thrombocythaemia vs. hydroxyurea plus aspirin. Eur J Haematol 98:106–111PubMedCrossRefGoogle Scholar
  40. 40.
    Samuelson BT, Vesely SK, Chai-Adisaksopha C, Scott BL, Crowther M, Garcia D (2016) The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis. Blood Coagul Fibrinolysis 27:648–652PubMedCrossRefGoogle Scholar
  41. 41.
    Afshar-Kharghan V, Thiagarajan P (2006) Leukocyte adhesion and thrombosis. Curr Opin Hematol 13:34–39PubMedCrossRefGoogle Scholar
  42. 42.
    Yakubenko VP, Lishko VK, Lam SC-T, Ugarova TP (2002) A molecular basis for integrin aMb2 ligand binding promiscuity. J Biol Chem 50:48635–48642CrossRefGoogle Scholar
  43. 43.
    Vannucchi AM, Antonioli E, Guglielmelli P et al (2007) Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 21:1952–1959PubMedCrossRefGoogle Scholar
  44. 44.
    Passamonti F, Rumi E, Pietra D et al (2006) Relation between JAK2(V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 107:3676–3682PubMedCrossRefGoogle Scholar
  45. 45.
    Cerletti C, Tamburrelli C, Izzi B, Gianfagna F, de Gaetano G (2012) Platelet–leukocyte interactions in thrombosis. Thromb Res 129:263–266PubMedCrossRefGoogle Scholar
  46. 46.
    Falanga A, Marchetti M, Evangelista V et al (2000) Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 96:4261–4266PubMedGoogle Scholar
  47. 47.
    Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedCrossRefGoogle Scholar
  48. 48.
    Fuchs TA, Brill A, Duerschmied D et al (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 107:15880–15885PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Brill A, Fuchs TA, Savchenko AS et al (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136–144PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Demers M, Krause DS, Schatzberg D et al (2012) Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 109:13076–13081PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Di Nisio M, Barbui T, Di Gennaro L et al (2007) European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators. The haematocrit and platelet target in polycythemia vera. Br J Haematol 136:249–259PubMedCrossRefGoogle Scholar
  52. 52.
    Marchioli R, Finazzi G, Specchia G et al; CYTO-PV Collaborative Group (2013) Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368:22–33PubMedCrossRefGoogle Scholar
  53. 53.
    Spivak JL (2002) Polycythemia vera: myths, mechanisms, and management. Blood 100:4272–4290PubMedCrossRefGoogle Scholar
  54. 54.
    Chen H, Angerer JI, Napoleone M et al (2013) Hematocrit and flow rate regulate the adhesion of platelets to von Willebrand factor. Biomicrofluidics 7:64113PubMedCrossRefGoogle Scholar
  55. 55.
    Nuyttens BP, Thijs T, Deckmyn H, Broos K (2011) Platelet adhesion to collagen. Thromb Res 127(Suppl. 2):S26–S29PubMedCrossRefGoogle Scholar
  56. 56.
    Holme PA, Orvim U, Hamers MJ et al (1997) Shear induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler Thromb Vasc Biol 17:646–653PubMedCrossRefGoogle Scholar
  57. 57.
    De Grandis M, Cambot M, Wautier MP et al (2013) JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway. Blood 121:658–665PubMedCrossRefGoogle Scholar
  58. 58.
    Tefferi A, Gangat N, Wolanskyj AP (2006) Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? Blood 108:2493–2494PubMedCrossRefGoogle Scholar
  59. 59.
    Castaman G, Lattuada A, Ruggeri M, Tosetto A, Mannucci PM, Rodeghiero F (1995) Platelet von Willebrand factor abnormalities in myeloproliferative syndromes. Am J Hematol 49:289–293PubMedCrossRefGoogle Scholar
  60. 60.
    Kissova J, Bulikova A, Ovesna P, Bourkova L, Penka M (2014) Increased mean platelet volume and immature platelet fraction as potential predictors of thrombotic complications in BCR/ABL-negative myeloproliferative neoplasms. Int J Hematol 100:429–436PubMedCrossRefGoogle Scholar
  61. 61.
    Gugliotta L, Iurlo A, Gugliotta G, Tieghi A et al (2016) Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms. Leuk Res 46:18–25PubMedCrossRefGoogle Scholar
  62. 62.
    Michiels JJ, Berneman Z, Schroyens W et al (2006) The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera. Semin Thromb Hemost 32:589–604PubMedCrossRefGoogle Scholar
  63. 63.
    Regev A, Stark P, Blickstein D et al (1997) Thrombotic complications in essential thrombocythemia with relatively low platelet counts. Am J Hematol 56:168–172PubMedCrossRefGoogle Scholar
  64. 64.
    Buxhofer-Ausch V, Steurer M, Sormann S et al (2016) Influence of platelet and white blood cell counts on major thrombosis—analysis from a patient registry in essential thrombocythemia. Eur J Haematol 97:511–516PubMedCrossRefGoogle Scholar
  65. 65.
    Augello C, Cattaneo D, Bucelli C et al (2016) CD18 promoter methylation is associated with a higher risk of thrombotic complications in primary myelofibrosis. Ann Hematol 95:1965–1969PubMedCrossRefGoogle Scholar
  66. 66.
    Aird WC (2012) Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2:1–13CrossRefGoogle Scholar
  67. 67.
    Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  68. 68.
    Bevilacqua MP (1993) Endothelial-leukocyte adhesion molecules. Ann Rev Immunol 11:767–804CrossRefGoogle Scholar
  69. 69.
    Mutunga M, Fulton B, Bullock R et al (2001) Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 163:195–200PubMedCrossRefGoogle Scholar
  70. 70.
    Woywodt A, Scheer J, Hambach L et al (2004) Circulating endothelial cells as a marker of endothelial damage in allogeneic hematopoietic stem cell transplantation. Blood 103:3603–3605PubMedCrossRefGoogle Scholar
  71. 71.
    Mancuso P, Burlini A, Pruneri G et al (2001) Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97:3658–3661PubMedCrossRefGoogle Scholar
  72. 72.
    Wassmann S, Werner N, Czech T, Nickenig G (2006) Improvement of endothelial function by systemic transfusion of vascular progenitor cells. Circ Res 99:e74–e83PubMedCrossRefGoogle Scholar
  73. 73.
    Torres C, Fonseca AM, Leander M et al (2013) Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. PLoS ONE 8:e81574PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Rosti V, Bonetti E, Bergamaschi G et al; AGIMM Investigators (2010) High frequency of endothelial colony forming cells marks a nonactive myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. PLoS ONE 5:e15277PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Yoder MC, Mead LE, Prater D et al (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109:1801–1809PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Teofili L, Martini M, Iachininoto MG et al (2011) Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood 117:2700–2707PubMedCrossRefGoogle Scholar
  77. 77.
    Fleischman AG, Aichberger KJ, Luty SB et al (2011) TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood 118:6392–6398PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kleppe M, Kwak M, Koppikar P et al (2015) JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov 5:316–331PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ait-Oufella H, Taleb S, Mallat Z, Tedgui A (2011) Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol 31:969–979PubMedCrossRefGoogle Scholar
  80. 80.
    Kleemann R, Zadelaar S, Kooistra T (2008) Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 79:360–376PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Barbui T, Carobbio A, Finazzi G et al; AGIMM and IIC Investigators (2011) Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica 96:315–318PubMedCrossRefGoogle Scholar
  82. 82.
    Eisenreich A, Bogdanov VY, Zakrzewicz A et al (2009) Cdc2-like kinases and DNA topoisomerase regulate alternative splicing of tissue factor in human endothelial cells. Circ Res 104:589–599PubMedCrossRefGoogle Scholar
  83. 83.
    Chen Y, Wang J, Yao Y et al (2009) Crp regulates the expression and activity of tissue factor as well as tissue factor pathway inhibitor via nf-kappab and erk ½ mapk pathway. FEBS Lett 583:2811–2818PubMedCrossRefGoogle Scholar
  84. 84.
    Steffel J, Akhmedov A, Greutert H, Luscher TF, Tanner FC (2005) Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 112:341–349PubMedCrossRefGoogle Scholar
  85. 85.
    Kawano H, Tsuji H, Nishimura H, Kimura S, Yano S, Ukimura N et al (2001) Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells. Blood 97:1697–1702PubMedCrossRefGoogle Scholar
  86. 86.
    Rajnics P, Kellner Á, Karádi É et al (2016) Increased Lipocalin 2 level may have important role in thrombotic events in patients with polycythemia vera and essential thrombocythemia. Leuk Res 48:101–106PubMedCrossRefGoogle Scholar
  87. 87.
    Dignat George F (2008) Microparticles in vascular diseases. Thromb Res 122:555–559Google Scholar
  88. 88.
    Nomura S, Ozaki Y, Ikeda Y (2008) Function and role of microparticles in various clinical settings. Thromb Res 123:8–23PubMedCrossRefGoogle Scholar
  89. 89.
    Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A (2009) Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 101:439–451PubMedGoogle Scholar
  90. 90.
    Trappenburg MC, van Schilfgaarde M, Marchetti M et al (2009) Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocytopenia. Haematologica 94:911–918PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Taniguchi Y, Tanaka H, Luis EJ et al (2017) Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms. Int J Hematol 106:691–703PubMedCrossRefGoogle Scholar
  92. 92.
    Stein BL, McMahon B, Weiss I et al (2012) Tissue-factor bearing microparticles and thrombotic risk in the myeloproliferative neoplasms. ASH annual meeting abstracts 2012 [abstract 1145]Google Scholar
  93. 93.
    Marchetti M, Tartari CJ, Russo L et al (2014) Phospholipid-dependent procoagulant activity is highly expressed by circulating microparticles in patients with essential thrombocythemia. Am J Hematol 89:68–73PubMedCrossRefGoogle Scholar
  94. 94.
    Duchemin J, Ugo V, Ianotto JC, Lecucq L, Mercier B, Abgrall JF (2010) Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms. Thromb Res 126:238–242PubMedCrossRefGoogle Scholar
  95. 95.
    Han Y, Zhao S, ZhangW, Cen J, Zhang W, Qiu H et al (2013) Clinical significance of circulating microparticles in Ph-myeloproliferative neoplasms (MPN). Blood (ASH Annual Meeting Abstracts), 122; 2013 [abstract 2368]Google Scholar
  96. 96.
    Owens AP III, Mackman N (2011) Microparticles in hemostasis and thrombosis. Circ Res 108:1284–1297PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Key NS, Mackman N (2010) Tissue factor and its measurement in whole blood, plasma, and microparticles. Semin Thromb Hemost 36:865–875PubMedCrossRefGoogle Scholar
  98. 98.
    Mackman N, Tilley RE, Key NS (2007) Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 27:1687–1693PubMedCrossRefGoogle Scholar
  99. 99.
    Van Der Meijden PEJ, Van Schilfgaarde M, Van Oerle R, Renn ET, Ten Cate H, Spronk HMH (2012) Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 10:1355–1362CrossRefGoogle Scholar
  100. 100.
    Furie B, Furie BC (2004) Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 10:171–178PubMedCrossRefGoogle Scholar
  101. 101.
    Jensen MK, de Nully Brown P, Lund BV, Nielsen OJ, Hasselbalch HC (2000) Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol 110:116–124PubMedCrossRefGoogle Scholar
  102. 102.
    André P (2004) P-selectin in haemostasis. Br J Haematol 126:298–306PubMedCrossRefGoogle Scholar
  103. 103.
    Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, Villamor N, Colomer D, Cervantes F (2006) Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 91:169–175PubMedGoogle Scholar
  104. 104.
    Panova-Noeva M, Marchetti M, Russo L et al (2013) ADP-induced platelet aggregation and thrombin generation are increased in Essential Thrombocythemia and Polycythemia Vera. Thromb Res 132:88–93PubMedCrossRefGoogle Scholar
  105. 105.
    Panova-Noeva M, Marchetti M, Spronk HM et al (2011) Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera. Am J Hematol 86:337–342PubMedCrossRefGoogle Scholar
  106. 106.
    Gadomska G, Stankowska K, Boinska J, Bartoszewska-Kubiak A, Haus O, Rość D (2016) Activation of the tissue factor-dependent extrinsic pathway and its relation to JAK2 V617F mutation status in patients with essential thrombocythemia. Blood Coagul Fibrinolysis 27:817–821PubMedCrossRefGoogle Scholar
  107. 107.
    Mackman N (2009) The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 108:1447–1452PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Presseizen K, Friedman Z, Shapiro H, Radnay J, Ellis MH (2002) Phosphatidylserine expression on the platelet membrane of patients with myeloproliferative disorders and its effect on platelet-dependent thrombin formation. Clin Appl Thromb Hemost 8:33–39PubMedCrossRefGoogle Scholar
  109. 109.
    Marchetti M, Castoldi E, Spronk HM et al (2008) Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 112:4061–4068PubMedCrossRefGoogle Scholar
  110. 110.
    Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC et al (2009) Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol 84:102–108PubMedCrossRefGoogle Scholar
  111. 111.
    Smalberg JH, Arends LR, Valla DC, Kiladjian JJ, Janssen HL, Leebeek FW (2012) Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 120:4921–4928PubMedCrossRefGoogle Scholar
  112. 112.
    Dentali F, Squizzato A, Brivio L et al (2009) JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 113:5617–5623PubMedCrossRefGoogle Scholar
  113. 113.
    De Stefano V, Za T, Rossi E et al; GIMEMA Chronic Myeloproliferative Neoplasms Working Party (2010) Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617Fmutation. Ann Hematol 89:141–146PubMedCrossRefGoogle Scholar
  114. 114.
    Vannucchi AM, Antonioli E, Guglielmelli P et al (2007) Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 110:840–846PubMedCrossRefGoogle Scholar
  115. 115.
    Bertozzi I, Bogoni G, Biagetti G et al (2017) Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. Ann Hematol 96:1297–1302PubMedCrossRefGoogle Scholar
  116. 116.
    Panova-Noeva M, Marchetti M, Buoro S et al (2011) JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood 118:2599–2601PubMedCrossRefGoogle Scholar
  117. 117.
    Kogan I, Chap D, Hoffman R et al (2016) JAK-2 V617F mutation increases heparanase procoagulant activity. Thromb Haemost 115:73–80PubMedCrossRefGoogle Scholar
  118. 118.
    Rosti V, Villani L, Riboni R et al (2013) Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation. Blood 121:360–368PubMedCrossRefGoogle Scholar
  119. 119.
    Verstovsek S, Kantarjian H, Mesa RA et al (2010) Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363:1117–1127PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Verstovsek S, Passamonti F, Rambaldi A et al (2012) Long-term efficacy and safety results from a phase II study of Ruxolitinib in patients with polycythemia vera. ASH Annual Meeting. Abstract 120(21):804Google Scholar
  121. 121.
    Rumi E, Pietra D, Ferretti V et al (2014) JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 123:1544–1551PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Rotunno G, Mannarelli C, Guglielmelli P et al (2014) Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123:1552–1555PubMedCrossRefGoogle Scholar
  123. 123.
    Finazzi G, Carobbio A, Guglielmelli P et al (2014) Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood 124:2611–2612PubMedCrossRefGoogle Scholar
  124. 124.
    Rumi E, Pietra D, Pascutto C et al (2014) Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 124:1062–1069PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Finazzi MC, Carobbio A, Cervantes F et al (2015) CALR mutation, MPL mutation, and triple negativity identify patients with the lowest vascular risk in primary myelofibrosis. Leukemia 29:1209–1210PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Somedeb Ball
    • 1
    • 3
  • Kyaw Zin Thein
    • 1
  • Abhishek Maiti
    • 2
  • Kenneth Nugent
    • 1
  1. 1.Texas Tech. University Health Sciences CenterLubbockUSA
  2. 2.University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Internal MedicineTexas Tech. University Health Sciences CenterLubbockUSA

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