RSS-Feed abonnieren
DOI: 10.1055/s-0039-1693477
Pathogenesis and Management of Thrombotic Disease in Myeloproliferative Neoplasms
Publikationsverlauf
Publikationsdatum:
05. August 2019 (online)
![](https://www.thieme-connect.de/media/sth/201906/lookinside/thumbnails/10-1055-s-0039-1693477_02669-1.jpg)
Abstract
Chronic myeloproliferative neoplasms (MPN) are characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Venous thrombosis, often at unusual sites, including splanchnic vein thrombosis and arterial thrombosis, as well as a hemorrhagic tendency and a propensity to transform into myelofibrosis or acute leukemia are common complications in patients with MPNs. The pathogenesis of thrombosis in MPN patients is complex and multifactorial. Disease related factors, such as an increase in blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), and more importantly presence of JAK2 mutation can interact with non-disease patient related factors such as age, previous history of thrombotic events, obesity, hypertension, hyperlipidemia, and presence of thrombophilic defects. The overall rate of recurrent thrombosis after venous thromboembolism (VTE) is 6.0 to 6.5 per 100 patient-years in patients with MPN compared to 2.7 to 3.7 per 100 patient-years in patients without MPN, and antithrombotic therapy with vitamin K antagonists (VKAs) is associated with a clear benefit, reducing the incidence of recurrence by 48 to 69%. Life-long oral anticoagulation with VKAs is the cornerstone of the antithrombotic treatment for splanchnic vein thrombosis (SVT). Patients with MPN-related cerebral venous thrombosis (CVT) should also be treated with long-term anticoagulation with VKAs. The role of direct acting oral anticoagulants in patients with thrombosis and MPN is not established and the use of these anticoagulants should be considered on an individual basis according to the risk of recurrent of VTE and bleeding.
Keywords
polycythemia vera - essential thrombocythemia - thrombosis - anticoagulation - antiplatelet treatmentAuthors' Contribution
D.R.J.A. performed the literature search and wrote the first draft. M.L. and D.R.J.A. reviewed and approved the final manuscript
-
References
- 1 McMullin MF, Harrison CN, Ali S. , et al; BSH Committee. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol 2019; 184 (02) 176-191
- 2 Arber DA, Orazi A, Hasserjian R. , et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
- 3 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 (06) 2446-2452
- 4 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8
- 5 Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost 2007; 33 (04) 313-320
- 6 Michiels JJ, Berneman Z, Gadisseur A, Lam KH, De Raeve H, Schroyens W. Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera. Acta Haematol 2015; 133 (01) 56-63
- 7 Michiels JJ, Abels J, Steketee J, van Vliet HH, Vuzevski VD. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med 1985; 102 (04) 466-471
- 8 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
- 9 Sekhar M. Prevention and management of thrombosis in myeloproliferative neoplasms. Clin Adv Hematol Oncol 2017; 15 (03) 178-181
- 10 McMullin MFF, Mead AJ, Ali S. , et al; British Society for Haematology Guideline. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: a British Society for Haematology Guideline. Br J Haematol 2019; 184 (02) 161-175
- 11 Barbui T, Thiele J, Vannucchi AM, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J 2015; 5: e337
- 12 James C, Ugo V, Casadevall N, Constantinescu SN, Vainchenker W. A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. Trends Mol Med 2005; 11 (12) 546-554
- 13 Scott LM, Tong W, Levine RL. , et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356 (05) 459-468
- 14 Rumi E, Pietra D, Ferretti V. , et al; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014; 123 (10) 1544-1551
- 15 Klampfl T, Gisslinger H, Harutyunyan AS. , et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369 (25) 2379-2390
- 16 Guy A, Gourdou-Latyszenok V, Le Lay N. , 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 (01) 70-81
- 17 Lowe GD, Lee AJ, Rumley A, Price JF, Fowkes FG. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96 (01) 168-173
- 18 Marchioli R, Finazzi G, Specchia G, Masciulli A, Mennitto MR, Barbui T. The CYTO-PV: a large-scale trial testing the intensity of CYTO reductive therapy to prevent cardiovascular events in patients with polycythemia vera. thrombosis 2011; 2011: 794240
- 19 Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013; 122 (13) 2176-2184
- 20 Wu Z, Zhang C, Ma X, Guan M. Clinical relevance between CALR mutation and myeloproliferative neoplasms. Stem Cell Investig 2015; 2: 4
- 21 Finazzi G. ; low-dose aspirin in polycythemia (ECLAP). A prospective analysis of thrombotic events in the European collaboration study on low-dose aspirin in polycythemia (ECLAP). Pathol Biol (Paris) 2004; 52 (05) 285-288
- 22 Tiede A. Diagnosis and treatment of acquired von Willebrand syndrome. Thromb Res 2012; 130 (Suppl. 02) S2-S6
- 23 Tiede A, Priesack J, Werwitzke S. , et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008; 6 (04) 569-576
- 24 Cervantes F, Alvarez-Larrán A, Arellano-Rodrigo E, Granell M, Domingo A, Montserrat E. Frequency and risk factors for thrombosis in idiopathic myelofibrosis: analysis in a series of 155 patients from a single institution. Leukemia 2006; 20 (01) 55-60
- 25 Barbui T, Carobbio A, Cervantes F. , et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 2010; 115 (04) 778-782
- 26 Cerquozzi S, Barraco D, Lasho T. , et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J 2017; 7 (12) 662
- 27 Marchioli R, Finazzi G, Specchia G. , et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368 (01) 22-33 . Epub 2012 Dec 8
- 28 Barbui T, Masciulli A, Ghirardi A, Carobbio A. ACE inhibitors and cytoreductive therapy in polycythemia vera. Blood 2017; 129 (09) 1226-1227
- 29 De Stefano V, Finazzi G, Barbui T. Antithrombotic therapy for venous thromboembolism in myeloproliferative neoplasms. Blood Cancer J 2018; 8 (07) 65
- 30 Vučković BA, Cannegieter SC, van Hylckama Vlieg A, Rosendaal FR, Lijfering WM. Recurrent venous thrombosis related to overweight and obesity: results from the MEGA follow-up study. J Thromb Haemost 2017; 15 (07) 1430-1435
- 31 Ianotto JC, Couturier MA, Galinat H. , et al. Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms. Int J Hematol 2017; 106 (04) 517-521
- 32 Martinelli I, De Stefano V, Carobbio A. , et al. Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia Net study. Am J Hematol 2014; 89 (11) E200-E205
- 33 Miranda B, Ferro JM, Canhão P. , et al; ISCVT Investigators. Venous thromboembolic events after cerebral vein thrombosis. Stroke 2010; 41 (09) 1901-1906
- 34 Gangat N, Wolanskyj AP, Tefferi A. Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications. Eur J Haematol 2006; 77 (04) 327-333
- 35 Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost 2013; 11 (07) 1215-1227
- 36 Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013; 162 (06) 730-747
- 37 De Stefano V, Qi X, Betti S, Rossi E. Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment. Thromb Haemost 2016; 115 (02) 240-249
- 38 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
- 39 Ageno W, Riva N, Schulman S. , et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med 2015; 175 (09) 1474-1480
- 40 De Stefano V, Vannucchi AM, Ruggeri M. , et al. Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients. Blood Cancer J 2016; 6 (11) e493
- 41 Pieri L, Paoli C, Arena U. , et al. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms. Am J Hematol 2017; 92 (02) 187-195
- 42 Finazzi G, De Stefano V, Barbui T. Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018. Blood Cancer J 2018; 8 (07) 64
- 43 Skeith L, Carrier M, Robinson SE, Alimam S, Rodger MA. Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. Blood 2017; 129 (08) 934-939