Internal and Emergency Medicine

, Volume 5, Issue 3, pp 177–184 | Cite as

Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia

  • Alessandro M. VannucchiEmail author
IM - Review


The classic myeloproliferative neoplasms (MPNs) include polycythemia vera and essential thrombocythemia; their molecular basis has been described only recently with the demonstration of recurrent mutations in JAK2 or MPL. While life expectancy may not be significantly shortened, arterial and venous thrombosis constitute the major causes of morbidity and mortality, together with disease evolution to myelofibrosis or transformation to acute leukemia. Therapy is currently aimed at reducing the rate of thrombosis without increasing the risk of hematologic transformation by inappropriate exposure to cytotoxic drugs. Nevertheless, the mechanism(s) finally responsible for the increased thrombotic tendency have not been clearly elucidated, although risk factors for thrombosis have been identified, and are currently employed for stratifying patients to the most appropriate therapeutic options. Abnormalities of blood cells, activation of neutrophils and platelets, and a hypercoagulability state, can all act in conjunction to lead to thrombosis. Intriguing data also point to the JAK2V617F mutation as both a marker and a mechanism for thrombosis. Better knowledge in the pathophysiology of these disorders, and the introduction of molecularly targeted drugs in clinical trials, anticipate the possibility of more specific and efficacious treatment of classic MPN, particularly as concerns the reduction of risk associated with vascular events.


Thrombosis Myeloproliferative neoplasms JAK2V617F mutation Leukocytosis Platelet activation 



This work was supported by Institutional Funds from University of Florence (ex-60%) and Istituto Toscano Tumori. The author apologizes to many eminent colleagues whose work in the field can not be cited because of space limitations.

Conflict of interest statement

The authors declare that they have no conflict of interest related to the publication of this manuscript.


  1. 1.
    Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW (2007) Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 110:1092–1097CrossRefPubMedGoogle Scholar
  2. 2.
    Vannucchi AM, Guglielmelli P, Tefferi A (2009) Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin 59:171–191CrossRefPubMedGoogle Scholar
  3. 3.
    Tefferi A (2008) The history of myeloproliferative disorders: before and after Dameshek. Leukemia 22:3–13CrossRefPubMedGoogle Scholar
  4. 4.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (ed) (2008) WHO classification of tumors of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, LyonGoogle Scholar
  5. 5.
    Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, Edwards BK, List AF (2008) Epidemiology of Myelodysplastic Syndromes and Chronic Myeloproliferative Disorders in the United States, 2001–2004: utilizing Data from the NAACCR and SEER Programs. Blood 112:45–52CrossRefPubMedGoogle Scholar
  6. 6.
    Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, Dupriez B, Levine RL, Passamonti F, Gotlib J, Reilly JT, Vannucchi AM, Hanson CA, Solberg LA, Orazi A, Tefferi A (2008) Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the international working group for myelofibrosis research and treatment. Leukemia 22:437–438CrossRefPubMedGoogle Scholar
  7. 7.
    Levine RL, Pardanani A, Tefferi A, Gilliland DG (2007) Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7:673–683CrossRefPubMedGoogle Scholar
  8. 8.
    James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148CrossRefPubMedGoogle Scholar
  9. 9.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790CrossRefPubMedGoogle Scholar
  10. 10.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and Myeloid Metaplasia with myelofibrosis. Cancer Cell 7:387–397CrossRefPubMedGoogle Scholar
  11. 11.
    Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356:459–468CrossRefPubMedGoogle Scholar
  12. 12.
    Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, Steensma DP, Elliott MA, Wolanskyj AP, Hogan WJ, McClure RF, Litzow MR, Gilliland DG, Tefferi A (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108:3472–3476CrossRefPubMedGoogle Scholar
  13. 13.
    Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I, DeAngelo DJ, Clark JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270CrossRefPubMedGoogle Scholar
  14. 14.
    Guglielmelli P, Pancrazzi A, Bergamaschi G, Rosti V, Villani L, Antonioli E, Bosi A, Barosi G, Vannucchi AM (2007) Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol 137:244–247CrossRefPubMedGoogle Scholar
  15. 15.
    Vannucchi AM, Antonioli E, Guglielmelli P, Pancrazzi A, Guerini V, Barosi G, Ruggeri M, Specchia G, Lo Coco F, Delaini F, Villani L, Finotto S, Ammatuna E, Alterini R, Carrai V, Capaccioli G, Di Lollo S, Liso V, Rambaldi A, Bosi A, Barbui T (2008) Characteristics and clinical correlates of MPL 515 W > L/K mutation in essential thrombocythemia. Blood 112:844–847CrossRefPubMedGoogle Scholar
  16. 16.
    Beer PA, Campbell P, Scott LM, Bench AJ, Erber WN, Bareford D, Wilkins B, Reilly JT, Hasselbalch HC, Bowman R, Wheatley K, Buck G, Harrison C, Green AR (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112:141–149CrossRefPubMedGoogle Scholar
  17. 17.
    Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301CrossRefPubMedGoogle Scholar
  18. 18.
    Vannucchi AM, Guglielmelli P (2008) Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations. Haematologica 93:972–976CrossRefPubMedGoogle Scholar
  19. 19.
    Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T (1995) Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332:1132–1136CrossRefPubMedGoogle Scholar
  20. 20.
    Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T (2004) Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350:114–124CrossRefPubMedGoogle Scholar
  21. 21.
    Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T (2005) Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23:2224–2232CrossRefPubMedGoogle Scholar
  22. 22.
    Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR (2005) Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353:33–45CrossRefPubMedGoogle Scholar
  23. 23.
    De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, Mico C, Tieghi A, Cacciola RR, Santoro C, Gerli G, Vianelli N, Guglielmelli P, Pieri L, Scognamiglio F, Rodeghiero F, Pogliani EM, Finazzi G, Gugliotta L, Marchioli R, Leone G, Barbui T (2008) Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 93:372–380CrossRefPubMedGoogle Scholar
  24. 24.
    Kiladjian JJ, Cervantes F, Leebeek FW, Marzac C, Cassinat B, Chevret S, Cazals-Hatem D, Plessier A, Garcia-Pagan JC, Murad SD, Raffa S, Janssen HL, Gardin C, Cereja S, Tonetti C, Giraudier S, Condat B, Casadevall N, Fenaux P, Valla DC (2008) The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 111:4922–4929CrossRefPubMedGoogle Scholar
  25. 25.
    Cervantes F, Passamonti F, Barosi G (2008) Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia 22:905–914CrossRefPubMedGoogle Scholar
  26. 26.
    Finazzi G, Barbui T (2005) Risk-adapted therapy in essential thrombocythemia and polycythemia vera. Blood Rev 19:243–252CrossRefPubMedGoogle Scholar
  27. 27.
    Marchetti M, Falanga A (2008) Leukocytosis, JAK2V617F mutation, and hemostasis in myeloproliferative disorders. Pathophysiol Haemost Thromb 36:148–159CrossRefPubMedGoogle Scholar
  28. 28.
    Di Nisio M, Barbui T, Di Gennaro L, Borrelli G, Finazzi G, Landolfi R, Leone G, Marfisi R, Porreca E, Ruggeri M, Rutjes AW, Tognoni G, Vannucchi AM, Marchioli R (2007) The haematocrit and platelet target in polycythemia vera. Br J Haematol 136:249–259CrossRefPubMedGoogle Scholar
  29. 29.
    Pearson TC, Wetherley-Mein G (1978) Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 2:1219–1222CrossRefPubMedGoogle Scholar
  30. 30.
    Tefferi A, Gangat N, Wolanskyj AP (2006) Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? Blood 108:2493–2494CrossRefPubMedGoogle Scholar
  31. 31.
    Barbui T, Carobbio A, Rambaldi A, Finazzi G (2009) Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood 114:759–763PubMedGoogle Scholar
  32. 32.
    Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M, Ponziani V, Longo G, Bosi A, Vannucchi AM (2005) Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 19:1847–1849CrossRefPubMedGoogle Scholar
  33. 33.
    Antonioli E, Guglielmelli P, Poli G, Bogani C, Pancrazzi A, Longo G, Ponziani V, Tozzi L, Pieri L, Santini V, Bosi A, Vannucchi AM (2008) Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 93:41–48CrossRefPubMedGoogle Scholar
  34. 34.
    Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, Gilliland DG, Tefferi A (2005) JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 131:208–213CrossRefPubMedGoogle Scholar
  35. 35.
    Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, Marfisi RM, Finazzi G, Guerini V, Fabris F, Randi ML, De Stefano V, Caberlon S, Tafuri A, Ruggeri M, Specchia G, Liso V, Rossi E, Pogliani E, Gugliotta L, Bosi A, Barbui T (2007) Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 110:840–846CrossRefPubMedGoogle Scholar
  36. 36.
    Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V, Bogani C, Ferrini PR, Rambaldi A, Guerini V, Bosi A, Barbui T (2007) Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 21:1952–1959CrossRefPubMedGoogle Scholar
  37. 37.
    Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A (2008) Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 22:1299–1307CrossRefPubMedGoogle Scholar
  38. 38.
    Ziakas PD (2008) Effect of JAK2 V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain. Haematologica 93:1412–1414CrossRefPubMedGoogle Scholar
  39. 39.
    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 33:67–73CrossRefPubMedGoogle Scholar
  40. 40.
    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 Mar 17 (epub ahead of print)Google Scholar
  41. 41.
    De Stefano V, Fiorini A, Rossi E, Za T, Farina G, Chiusolo P, Sica S, Leone G (2007) Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost 5:708–714CrossRefPubMedGoogle Scholar
  42. 42.
    Dentali F, Squizzato A, Brivio L, Appio L, Campiotti L, Crowther M, Grandi AM, Ageno W (2009) JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 113:5617–5623CrossRefPubMedGoogle Scholar
  43. 43.
    Passamonti F, Rumi E, Pietra D, Della Porta MG, Boveri E, Pascutto C, Vanelli L, Arcaini L, Burcheri S, Malcovati L, Lazzarino M, Cazzola M (2006) Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34 + cells into peripheral blood in myeloproliferative disorders. Blood 107:3676–3682CrossRefPubMedGoogle Scholar
  44. 44.
    Falanga A, Marchetti M, Evangelista V, Vignoli A, Licini M, Balicco M, Manarini S, Finazzi G, Cerletti C, Barbui T (2000) Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 96:4261–4266PubMedGoogle Scholar
  45. 45.
    Falanga A, Marchetti M, Vignoli A, Balducci D, Russo L, Guerini V, Barbui T (2007) V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. Exp Hematol 35:702–711CrossRefPubMedGoogle Scholar
  46. 46.
    Marchetti M, Castoldi E, Spronk HM, van Oerle R, Balducci D, Barbui T, Rosing J, Ten Cate H, Falanga A (2008) Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 112:4061–4068CrossRefPubMedGoogle Scholar
  47. 47.
    De Stefano V, Za T, Rossi E, Fiorini A, Ciminello A, Luzzi C, Chiusolo P, Sica S, Leone G (2009) Influence of the JAK2 V617F mutation and inherited thrombophilia on the thrombotic risk among patients with essential thrombocythemia. Haematologica 94:733–737CrossRefPubMedGoogle Scholar
  48. 48.
    Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, Bellucci S, Grandchamp B, Chomienne C, Fenaux P (2008) Pegylated interferon-alfa-2a induces complete hematological and molecular responses with low toxicity in polycythemia vera. Blood 112:3065–3072CrossRefPubMedGoogle Scholar
  49. 49.
    Barbui T, Finazzi G (2006) Myeloproliferative disease in pregnancy and other management issues. In: Hematology. American Society of Hematology Education Program, pp 246–252Google Scholar
  50. 50.
    Pardanani A (2008) JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 22:23–30CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2009

Authors and Affiliations

  1. 1.Unità Funzionale di Ematologia, Dipartimento di Area CriticaUniversità degli StudiFlorenceItaly
  2. 2.Istituto Toscano TumoriFlorenceItaly

Personalised recommendations