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Chronic myeloproliferative neoplasms

Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms


Thrombosis, both in arterial and venous territories, is the major complication of myeloproliferative neoplasms and is responsible for a high rate of morbidity and mortality. The currently accepted risk factors are an age over 60 years and a history of thrombosis. However, many complex mechanisms contribute to this increased prothrombotic risk, with involvement of all blood cell types, plasmatic factors, and endothelial cells. Besides, some cardiovascular events may originate from arterial vasospasm that could contribute to thrombotic complications. In this review, we discuss recent results obtained in mouse models in the light of data obtained from clinical studies. We emphasize on actors of thrombosis that are currently not targeted with current therapeutics but could be promising targets, i.e, neutrophil extracellular traps and vascular reactivity.

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Fig. 1: Main pathways involved during hemostasis.
Fig. 2: Main mechanisms involved in the pathophysiology of thrombosis during MPNs.
Fig. 3: Main mechanisms specifically involved in the pathophysiology of arterial cardiovascular events during MPNs.
Fig. 4: Potential novel therapies in the treatment or the prevention of thrombosis during MPN.


  1. 1.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    CAS  PubMed  Google Scholar 

  2. 2.

    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;19:184.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224–32.

    PubMed  Google Scholar 

  4. 4.

    Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol. 2013;162:730–47.

    CAS  PubMed  Google Scholar 

  5. 5.

    Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368:22–33.

    CAS  PubMed  Google Scholar 

  6. 6.

    Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117:5857–9.

    CAS  PubMed  Google Scholar 

  7. 7.

    Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128–33.

    CAS  PubMed  Google Scholar 

  8. 8.

    Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95:1599–613.

  9. 9.

    Maslah N, Soret J, Dosquet C, Vercellino L, Belkhodja C, Schlageter M-H, et al. Masked polycythemia vera: analysis of a single center cohort of 2480 red cell masses. Haematologica. 2020;105:e95–7.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hultcrantz M, Björkholm M, Dickman PW, Landgren O, Derolf ÅR, Kristinsson SY, et al. Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: a population-based cohort study. Ann Intern Med. 2018;168:317.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    De Stefano V, Ruggeri M, Cervantes F, Alvarez-Larrán A, Iurlo A, Randi ML, et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia. 2016;30:2032–8.

    PubMed  Google Scholar 

  12. 12.

    Stein BL, Martin K. From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2019;2019:397–406.

  13. 13.

    Weisel JW, Litvinov RI. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost. 2019;17:271–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss D, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.

    CAS  PubMed  Google Scholar 

  15. 15.

    Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci. 2010;107:15880–5.

    CAS  PubMed  Google Scholar 

  16. 16.

    von Brühl M-L, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209:819–35.

    Google Scholar 

  17. 17.

    Massberg S, Grahl L, von Bruehl M-L, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887–96.

    CAS  PubMed  Google Scholar 

  18. 18.

    Campbell PJ, MacLean C, Beer PA, Buck G, Wheatley K, Kiladjian J-J, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood. 2012;120:1409–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Jensen MK, Brown PDN, Lund BV, Nielsen OJ, Hasselbalch HC. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol. 2000;110:116–24.

    CAS  PubMed  Google Scholar 

  20. 20.

    Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol. 2005;33:523–30.

    CAS  PubMed  Google Scholar 

  21. 21.

    Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, 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;169:75.

    Google Scholar 

  22. 22.

    Falanga A, Marchetti M, Vignoli A, Balducci D, Russo L, Guerini V, et al. V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. Exp Hematol. 2007;35:702–11.

    CAS  PubMed  Google Scholar 

  23. 23.

    Arellano‐Rodrigo E, Alvarez‐Larrán A, Reverter J-C, Colomer D, Villamor N, Bellosillo B, et al. 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. 2008;84:102–8.

    Google Scholar 

  24. 24.

    Panova-Noeva M, Marchetti M, Buoro S, Russo L, Leuzzi A, Finazzi G, et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood. 2011;118:2599–601.

    CAS  PubMed  Google Scholar 

  25. 25.

    Landolfi R, Ciabattoni G, Patrignani P, Bizzi B, Patrono C. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood. 1992;8:1965–71.

  26. 26.

    Pareti FI, Gugliotta L, Mannucci L, Guarini A, Mannucci PM. Biochemical and metabolic aspects of platelet dysfunction in chronic myeloproliferative disorders. Thromb Haemost. 1982;47:84–9.

    CAS  PubMed  Google Scholar 

  27. 27.

    Landolfi R, Rocca B, Patrono C. Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment. Crit Rev Oncol Hematol. 1995;20:203–22.

    CAS  PubMed  Google Scholar 

  28. 28.

    Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood. 1984;64:1–12.

    CAS  PubMed  Google Scholar 

  29. 29.

    Panova‐Noeva M, Marchetti M, Spronk HM, Russo L, Diani E, Finazzi G, et al. Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera. Am J Hematol. 2011;86:337–42.

    PubMed  Google Scholar 

  30. 30.

    Tiedt R, Schomber T, Hao-Shen H, Skoda RC. Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. Blood. 2007;109:1503–6.

    CAS  PubMed  Google Scholar 

  31. 31.

    Mansier O, Kilani B, Guitart AV, Guy A, Gourdou-Latyszenok V, Marty C, et al. Description of a knock-in mouse model of JAK2V617F MPN emerging from a minority of mutated hematopoietic stem cells. Blood. 2019;134:2383–7.

    PubMed  Google Scholar 

  32. 32.

    Calaminus SDJ, Guitart A, Sinclair A, Schachtner H, Watson SP, Holyoake TL, et al. Lineage tracing of Pf4-Cre marks hematopoietic stem cells and their progeny. PLoS One. 2012;7:e51361.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Lamrani L, Lacout C, Ollivier V, Denis CV, Gardiner E, Ho Tin Noe B, et al. Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. Blood. 2014;124:1136–45.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Etheridge SL, Roh ME, Cosgrove ME, Sangkhae V, Fox NE, Chen J, et al. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. Proc Natl Acad Sci. 2014;111:2295–300.

    CAS  PubMed  Google Scholar 

  35. 35.

    Strassel C, Kubovcakova L, Mangin PH, Ravanat C, Freund M, Skoda RC, et al. Haemorrhagic and thrombotic diatheses in mouse models with thrombocytosis. Thromb Haemost. 2015;113:414–25.

    PubMed  Google Scholar 

  36. 36.

    Hobbs CM, Manning H, Bennett C, Vasquez L, Severin S, Brain L, et al. JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Blood. 2013;122:3787–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Pearson T. Hemorheologic considerations in the pathogenesis of vascular occlusive events in polycythemia vera. Semin Thromb Hemost. 1997;23:433–9.

    CAS  PubMed  Google Scholar 

  38. 38.

    Zhao B, Keerthivasan G, Mei Y, Yang J, McElherne J, Wong P, et al. Targeted shRNA screening identified critical roles of pleckstrin-2 in erythropoiesis. Haematologica. 2014;99:1157–67.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Zhao B, Mei Y, Cao L, Zhang J, Sumagin R, Yang J, et al. Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J Clin Investig. 2017;128:125–40.

    PubMed  Google Scholar 

  40. 40.

    Wautier M-P, El Nemer W, Gane P, Rain J-D, Cartron J-P, Colin Y, et al. Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin 5 chain and Lu/BCAM. Blood. 2007;110:894–901.

    CAS  PubMed  Google Scholar 

  41. 41.

    De Grandis M, Cambot M, Wautier M-P, Cassinat B, Chomienne C, Colin Y, et al. JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway. Blood. 2013;121:658–65.

    PubMed  Google Scholar 

  42. 42.

    Poisson J, Tanguy M, Davy H, Camara F, Mdawar M-BE, Kheloufi M, et al. Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm. J Clin Invest. 2020;130:2630–43.

  43. 43.

    Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24:1574–9.

    CAS  PubMed  Google Scholar 

  44. 44.

    Carobbio A, Ferrari A, Masciulli A, Ghirardi A, Barosi G, Barbui T. Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2019;3:1729–37.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Ronner L, Podoltsev N, Gotlib J, Heaney ML, Kuykendall AT, O’Connell C, et al. Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis. Blood. 2020;135:1696–703.

  46. 46.

    Alvarez-Larrán A, Arellano-Rodrigo E, Reverter JC, Domingo A, Villamor N, Colomer D, et al. Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis. Ann Hematol. 2008;87:269–76.

    PubMed  Google Scholar 

  47. 47.

    Wang W, Liu W, Fidler T, Wang Y, Tang Y, Woods B, et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 V617F mice. Circ Res. 2018;123:e35–47.

  48. 48.

    Falanga A, Marchetti M, Evangelista V, Vignoli A, Licini M, Balicco M, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96:7.

    Google Scholar 

  49. 49.

    Marchetti M, Castoldi E, Spronk HMH, van Oerle R, Balducci D, Barbui T, et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood. 2008;112:4061–8.

    CAS  PubMed  Google Scholar 

  50. 50.

    Guy A, Favre S, Labrouche-Colomer S, Deloison L, Gourdou-Latyszenok V, Renault M-A, et al. High circulating levels of MPO-DNA are associated with thrombosis in patients with MPN. Leukemia. 2019;33:2544–8.

    PubMed  Google Scholar 

  51. 51.

    Gupta N, Edelmann B, Schnoeder TM, Saalfeld FC, Wolleschak D, Kliche S, et al. JAK2-V617F activates β1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1. Leukemia. 2017;31:1223–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Edelmann B, Gupta N, Schnöder TM, Oelschlegel AM, Shahzad K, Goldschmidt J, et al. JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation. J Clin Invest. 2018;128:4359–71.

  53. 53.

    Marin Oyarzún CP, Carestia A, Lev PR, Glembotsky AC, Castro Ríos MA, Moiraghi B, et al. Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms. Sci Rep. 2016;6:38738.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Wolach O, Sellar RS, Martinod K, Cherpokova D, McConkey M, Chappell RJ, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med. 2018;10:eaan8292.

  55. 55.

    Craver BM, Ramanathan G, Hoang S, Chang X, Mendez Luque LF, Brooks S, et al. N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm. Blood Adv. 2020;4:312–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Boulanger CM, Loyer X, Rautou P-E, Amabile N. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol. 2017;14:259–72.

    CAS  PubMed  Google Scholar 

  57. 57.

    Charpentier A, Lebreton A, Rauch A, Bauters A, Trillot N, Nibourel O, et al. Microparticle phenotypes are associated with driver mutations and distinct thrombotic risks in essential thrombocythemia. Haematologica. 2016;101:e365–8.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Duchemin J, Ugo V, Ianotto J-C, Lecucq L, Mercier B, Abgrall J-F. Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms. Thromb Res. 2010;126:238–42.

    CAS  PubMed  Google Scholar 

  59. 59.

    Marchetti M, Tartari CJ, Russo L, Panova-Noeva M, Leuzzi A, Rambaldi A, et al. Phospholipid-dependent procoagulant activity is highly expressed by circulating microparticles in patients with essential thrombocythemia. Am J Hematol. 2014;89:68–73.

    CAS  PubMed  Google Scholar 

  60. 60.

    Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk HM, Cate HT, Leyte A, et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94:911–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Moles-Moreau M-P, Ternisien C, Tanguy-Schmidt A, Boyer F, Gardembas M, Dib M, et al. Flow cytometry-evaluated platelet CD36 expression, reticulated platelets and platelet microparticles in essential thrombocythaemia and secondary thrombocytosis. Thromb Res. 2010;126:e394–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Kissova J, Ovesna P, Bulikova A, Zavřelova J, Penka M. Increasing procoagulant activity of circulating microparticles in patients with Philadelphia-negative myeloproliferative neoplasms: a single-centre experience. Blood Coagul Fibrinolysis. 2015;26:448–53.

    CAS  PubMed  Google Scholar 

  63. 63.

    Zhang W, Qi J, Zhao S, Shen W, Dai L, Han W, et al. Clinical significance of circulating microparticles in Ph- myeloproliferative neoplasms. Oncol Lett. 2017;14:2531–6.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Baccouche H, Jemaa MB, Chakroun A, Chadi S, Mahjoub S, Sfar I, et al. The evaluation of the relevance of thrombin generation and procoagulant activity in thrombotic risk assessment in BCR-ABL-negative myeloproliferative neoplasm patients. Int J Lab Hematol. 2017;39:502–7.

    CAS  PubMed  Google Scholar 

  65. 65.

    Tong D, Yu M, Guo L, Li T, Li J, Novakovic VA, et al. Phosphatidylserine-exposing blood and endothelial cells contribute to the hypercoagulable state in essential thrombocythemia patients. Ann Hematol. 2018;97:605–16.

    CAS  PubMed  Google Scholar 

  66. 66.

    Wieczorek I, MacGregor IR, Prescott RJ, Ludlam CA. The fibrinolytic system and proteins C and S in treated polycythaemia rubra vera. Blood Coagul Fibrinolysis. 1992;3:823–6.

    CAS  PubMed  Google Scholar 

  67. 67.

    Bucalossi A, Marotta G, Bigazzi C, Galieni P, Dispensa E. Reduction of antithrombin III, protein C, and protein S levels and activated protein C resistance in polycythemia vera and essential thrombocythemia patients with thrombosis. Am J Hematol. 1996;52:14–20.

    CAS  PubMed  Google Scholar 

  68. 68.

    Cella G, Marchetti M, Vianello F, Panova-Noeva M, Vignoli A, Russo L, et al. Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb Haemost. 2010;104:151–6.

    CAS  PubMed  Google Scholar 

  69. 69.

    Belotti A, Elli E, Speranza T, Lanzi E, Pioltelli P, Pogliani E. Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment—flow cytometry and soluble E-selectin detection. Am J Hematol. 2011;87:319–20.

    PubMed  Google Scholar 

  70. 70.

    Torres C, Fonseca AM, Leander M, Matos R, Morais S, Campos M, et al. Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. PLoS One. 2013;8:e81574.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    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;113:5246–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Rosti V, Villani L, Riboni R, Poletto V, Bonetti E, Tozzi L, et al. Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation. Blood. 2013;121:360–8.

    CAS  PubMed  Google Scholar 

  73. 73.

    Guy A, Gourdou-Latyszenok V, Lay NL, Peghaire C, Kilani B, Dias JV, et al. Vascular endothelial cell expression of JAK2V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin expression. Haematologica. 2019;104:70–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Guadall A, Lesteven E, Letort G, Awan Toor S, Delord M, Pognant D, et al. Endothelial cells harbouring the JAK2V617F mutation display pro-adherent and pro-thrombotic features. Thromb Haemost. 2018;118:1586–99.

    PubMed  Google Scholar 

  75. 75.

    Pósfai É, Marton I, Borbényi Z, Nemes A. Myocardial infarction as a thrombotic complication of essential thrombocythemia and polycythemia vera. Anatol J Cardiol. 2016;16:397–402.

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Larsen AI, Galbraith PD, Ghali WA, Norris CM, Graham MM, Knudtson ML. Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries. Am J Cardiol. 2005;95:261–3.

    PubMed  Google Scholar 

  77. 77.

    Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio ALP, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017;38:143–53.

    PubMed  Google Scholar 

  78. 78.

    Neunteufl T, Heher S, Stefenelli T, Pabinger I, Gisslinger H. Endothelial dysfunction in patients with polycythaemia vera. Br J Haematol. 2001;115:354–9.

    CAS  PubMed  Google Scholar 

  79. 79.

    Hasselbalch HC. Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms. Expert Rev Hematol. 2014;7:203–16.

    CAS  PubMed  Google Scholar 

  80. 80.

    Vrtovec M, Anzic A, Zupan IP, Zaletel K, Blinc A. Carotid artery stiffness, digital endothelial function, and coronary calcium in patients with essential thrombocytosis, free of overt atherosclerotic disease. Radio Oncol. 2017;51:203–10.

    CAS  Google Scholar 

  81. 81.

    Akpan IJ, Stein BL. Splanchnic vein thrombosis in the myeloproliferative neoplasms. Curr Hematol Malig Rep. 2018;13:183–90.

    PubMed  Google Scholar 

  82. 82.

    How J, Trinkaus KM, Oh ST. Distinct clinical, laboratory and molecular features of myeloproliferative neoplasm patients with splanchnic vein thrombosis. Br J Haematol. 2018;183:310–3.

    PubMed  Google Scholar 

  83. 83.

    Smalberg JH, Arends LR, Valla DC, Kiladjian J-J, Janssen HLA, Leebeek FWG. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood. 2012;120:4921–8.

    CAS  PubMed  Google Scholar 

  84. 84.

    Kiladjian J-J, Cervantes F, Leebeek FWG, Marzac C, Cassinat B, Chevret S, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood. 2008;111:4922–9.

    CAS  PubMed  Google Scholar 

  85. 85.

    Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–64.

    CAS  PubMed  Google Scholar 

  86. 86.

    Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007;100:174–90.

    CAS  PubMed  Google Scholar 

  87. 87.

    Poisson J, Hilscher MB, Tanguy M, Hammoutene A, Boulanger CM, Villeval J-L, et al. Endothelial JAK2V617F does not enhance liver lesions in mice with Budd-Chiari syndrome. J Hepatol. 2018;68:1086–7.

    PubMed  Google Scholar 

  88. 88.

    Piaggio G, Rosti V, Corselli M, Bertolotti F, Bergamaschi G, Pozzi S, et al. Endothelial colony-forming cells from patients with chronic myeloproliferative disorders lack the disease-specific molecular clonality marker. Blood. 2009;114:3127–30.

    CAS  PubMed  Google Scholar 

  89. 89.

    Teofili L, Martini M, Iachininoto MG, Capodimonti S, Nuzzolo ER, Torti L, 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;117:2700–7.

    CAS  PubMed  Google Scholar 

  90. 90.

    Guy A, Danaee A, Paschalaki K, Boureau L, Rivière E, Etienne G, et al. Absence of JAK2V617F mutated endothelial colony-forming cells in patients with JAK2V617F myeloproliferative neoplasms and splanchnic vein thrombosis. Hemasphere. 2020;4:e364.

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376:429–39.

    CAS  PubMed  Google Scholar 

  92. 92.

    Lapponi MJ, Carestia A, Landoni VI, Rivadeneyra L, Etulain J, Negrotto S, et al. Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J Pharmacol Exp Therapeutics. 2013;345:430–7.

    CAS  Google Scholar 

  93. 93.

    Perdomo J, Leung HHL, Ahmadi Z, Yan F, Chong JJH, Passam FH, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10:1322.

  94. 94.

    De Meyer SF, Suidan GL, Fuchs TA, Monestier M, Wagner DD. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler Thromb Vasc Biol. 2012;32:1884–91.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Santilli F, Romano M, Recchiuti A, Dragani A, Falco A, Lessiani G, et al. Circulating endothelial progenitor cells and residual in vivo thromboxane biosynthesis in low-dose aspirin-treated polycythemia vera patients. Blood. 2008;112:1085–90.

    CAS  PubMed  Google Scholar 

  96. 96.

    Tan X, Shi J, Fu Y, Gao C, Yang X, Li J, et al. Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation. Thromb Haemost. 2013;109:1025–32.

    CAS  PubMed  Google Scholar 

  97. 97.

    Dienava-Verdoold I, Marchetti MR, te Boome LCJ, Russo L, Falanga A, Koene HR, et al. Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies. Thromb Haemost. 2012;107:468–76.

    PubMed  Google Scholar 

  98. 98.

    Alonci A, Allegra A, Bellomo G, Penna G, D’Angelo A, Quartarone E, et al. Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases. Hematol Oncol. 2008;26:235–9.

    CAS  PubMed  Google Scholar 

  99. 99.

    Treliński J, Wierzbowska A, Krawczyńska A, Sakowicz A, Pietrucha T, Smolewski P, et al. Plasma levels of angiogenic factors and circulating endothelial cells in essential thrombocythemia: correlation with cytoreductive therapy and JAK2–V617F mutational status. Leuk Lymphoma. 2010;51:1–7.

    Google Scholar 

  100. 100.

    Shi K, Zhao W, Chen Y, Ho W, Yang P, Zhao Z. Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice. J Hematol Oncol. 2014;7:25.

    PubMed  PubMed Central  Google Scholar 

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The authors are especially thankful to Pierre Emmanuel Rautou, Martine Jandrot Perrus, Jean Luc Villeval, William Vainchenker, and the French Intergroup Myeloproliferative (FIM) network. The authors received research grants from ANR-DFG JAKPOT (no. ANR-14-CE35-0022-02), INSERM, Force Hemato, The Fondation Bettencourt Schueller, and the Aquitaine Region.

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Correspondence to Chloe James.

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AG and JP have nothing to disclose. CJ consulted for Novartis and received funding for travel and accommodation expenses from Novartis.

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Guy, A., Poisson, J. & James, C. Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms. Leukemia 35, 935–955 (2021).

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