ESSENTIAL THROMBOCYTHEMIA: UPDATE ON PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT

Year 2014, Volume: 77 Issue: 1, 14 - 20, 16.06.2014

İpek Yönal , Fatma Sargın

https://doi.org/10.18017/iuitfd.13056441.2014.77/1.14-20

Abstract

Essential thrombocythemia (ET), a member of the family of myeloproliferative neoplasms (MPN), is characterized by an overproduction of platelets and usually accompanied by thrombotic or hemorrhagic symptoms. JAK2V617F mutation is present in about one-half of patients with ET. Mutations in MPL exon 10 are present in a further 4% of patients, with MPL W515L being the most common mutation. The diagnosis is made by exclusion of reactive thrombocytosis and other myeloid malignancies. Bone marrow examination reveals an increase in megakaryocyte frequency with megakaryocyte clustering and nuclear hyperlobulation in the absence of significant reticulin fibrosis and significant increase in granulopoiesis and erythropoiesis. Survival of patients with ET had been similar to population controls during the first decade of the disease. Yet, survival became significantly worse thereafter due to disease complications such as thrombosis and transformation to myelofibrosis or acute myeloid leukemia (AML). Management paradigms have changed significantly over the last 20 years. This review aims to highlight the pathogenesis, diagnosis and current management in ET.

Keywords

Acute myeloid leukemia, Essential thrombocythemia, Myeloproliferative neoplasms, Thrombosis

ESANSİYEL TROMBOSİTEMİ: PATOGENEZ, TEŞHİS VE TEDAVİNİN GÜNCELLEMESİ

Abstract

Miyeloproliferatif neoplazi (MPN) ailesinin bir üyesi olan esansiyel trombositemi (ET), trombositlerin aşırı üretimi ve sıklıkla eşlik eden trombotik veya hemorajik semptomlarla karakterize bir hastalıktır. ET tanılı hastaların yaklaşık yarısında JAK2V617F mutasyonu ve %4’ünde MPL exon 10’da mutasyonlar görülmektedir. MPL exon 10 mutasyonları içinde en sık mutasyon MPL W515L’dir. ET tanısı, reaktif trombositoz ve diğer miyeloid malignitelerin dışlanması ile konmaktadır. Kemik iliği incelemesi, anlamlı bir retikülin fibrozis ve granülopoez ve eritropoezde anlamlı bir artış olmaksızın megakaryosit kümelenmesi ve nükleer hiperlobülasyon ile karakterizedir. ET’de yaşam süresi, hastalığın ilk dekadında kontrol grubu ile benzer olmasına rağmen, sonraki dönemlerde tromboz ve miyelofibroz veya akut miyeloid lösemiye (AML) dönüşüm gibi hastalık komplikasyonları nedeniyle kısalmaktadır. ET’de tedavi algoritması, son 20 yılda önemli derecede değişiklik göstermiştir. Bu derlemenin amacı, ET tanılı olgularda patogenez, tanı yöntemleri ve güncel tedaviyi özetlemektir.

Keywords

Akut miyeloid lösemi, Esansiyel trombositemi, Miyeloproliferatif neoplaziler, Tromboz

References

• Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, Heguy A, Bueso-Ramos C, Kantarjian H, Levine RL, Verstovsek S.Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Cancer Res. 2010;70(2):447-52.
• Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, Beran M, Gilliland DG, Levine RL, Tefferi A.Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms.Leukemia. 2011;25(7):1200-2.
• Abdel-Wahab O, Tefferi A, Levine RL. Role of TET2 and ASXL1 mutations in the pathogenesis of myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012;26(5):1053-64.
• Anger BR, Seifried E, Scheppach J, Heimpel H.Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases.Klin Wochenschr. 1989;67(16):818-25.
• .Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D, Wilkins BS, Reilly JT, Hasselbalch HC, Bowman R, Wheatley K, Buck G, Harrison CN, Green AR. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008;112(1):141-9.
• Beer P, Erber W, Campbell P, Green A. How I treat essential thrombocythemia. Blood. 2011;117(5):1472-82.
• Besses C, Cervantes F, Pereira A, Florensa L, Solé F, Hernández-Boluda JC, Woessner S, SansSabrafen J, Rozman C, Montserrat E.Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia. 1999;13(2):150-4.
• Bittencourt RI, Vassallo J, Chauffaille Mde L, Xavier SG, Pagnano KB, Nascimento AC, De Souza CA, Chiattone CS. Philadelphia-negative chronic myeloproliferative neoplasms. Rev Bras Hematol Hemoter. 2012;34(2):140-9.
• Budde U, van Genderen PJ.Acquired von Willebrand disease in patients with high platelet counts. Semin Thromb Hemost. 1997;23(5):425-31.
• Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G, Wheatley K, Harrison CN, Green AR. Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. J Clin Oncol. 2009;27(18):2991-9..
• Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2005:201-8.
• Carobbio A, Antonioli E, Guglielmelli P, Vannucchi AM, Delaini F, Guerini V, Finazzi G, Rambaldi A, Barbui T.Leukocytosis and risk stratification assessment in essential thrombocythemia.J Clin Oncol. 2008;26(16):2732-6.
• Carobbio A, Finazzi G, Antonioli E, Guglielmelli P, Vannucchi AM, Delaini F, Guerini V, Ruggeri M, Rodeghiero F, Rambaldi A, Barbui T. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. Blood. 2008;112(8):3135-7.
• Cervantes F, Alvarez-Larrán A, Talarn C, Gómez M, Montserrat E.Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients.Br J Haematol. 2002;118(3):786-90.
• Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995;332(17):1132-6.
• 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(3):556-62.
• De Sanctis V, Mazzucconi MG, Spadea A, Alfò M, Mancini M, Bizzoni L, Peraino M, Mandelli F.Longterm evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution. Br J Haematol. 2003;123(3):517-21.
• Elliott MA, Tefferi A.Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.Br J Haematol. 2005;128(3):275
• Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica. 2007;92(1):135-6.
• Finazzi G, Ruggeri M, Rodeghiero F, Barbui T. Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis. Blood. 2003;101(9):3749.
• Finazzi G, Ruggeri M, Rodeghiero F, Barbui T. Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol. 2000;110(3):577-83.
• Girodon F, Bonicelli G, Schaeffer C, Mounier M, Carillo S, Lafon I, Carli PM, Janoray I, Ferrant E, Maynadié M.Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study.Haematologica. 2009;94(6):865-9.
• Gisslinger H, Gotic M, Holowiecki J, et al: Final results of the ANAHYDRET study: Non-inferiority of anagrelide compared to hydroxyurea in newly diagnosed WHO-essential thrombocythemia patients. ASH Annu Meet Abstr 112:661, 2008.
• Harrison C.Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br J Haematol. 2005;129(3):293-306.
• 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; United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33-45.
• Harrison CN, Gale RE, Machin SJ, Linch DC.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(2):417-24.
• Kiladjian JJ, Chomienne C, Fenaux P. Interferonalpha therapy in bcr-abl-negative myeloproliferative neoplasms.Leukemia. 2008;22(11):1990-8.
• Kiladjian JJ, Rain JD, Bernard JF, Briere J, Chomienne C, Fenaux P.Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia.Semin Thromb Hemost. 2006;32(4 Pt 2):417-21.
• Kobayashi S, Teramura M, Hoshino S, Motoji T, Oshimi K, Mizoguchi H. Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3. Br J Haematol. 1993;83(4):539-44.
• Landolfi R, Gennaro L. Prevention of thrombosis in polycythemia vera and essential thrombocythemia. Haematologica. 2008;93(3):331-5.
• Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350(2):114-24.
• Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Buller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res. 2009; 124(4):409-17.
• Michiels JJ, van Genderen PJ, Lindemans J, van Vliet HH.Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia. Leuk Lymphoma. 1996 Sep;22 Suppl 1:47-56. Review.
• Mohamed A, McLeod JG, Hallinan J.Superior sagittal sinus thrombosis.Clin Exp Neurol. 1991;28:23-36.
• Nielsen I, Hasselbalch HC: Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan. Am J Hematol 74:26, 200 Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, Orlandi E, Arcaini L, Brusamolino E, Pascutto C, Cazzola M, Morra E, Lazzarino M. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755-61.
• Schafer AI.Bleeding and thrombosis in the myeloproliferative disorders. Blood. 1984;64(1):1
• Schafer AI. Essential Thrombocythemia and Thrombocytosis. In: Lichtman MA, Beutler E, Kipps TJ, Seligshon U, Kaushansky K, Prchal JT, Eds. Williams Hematology, New York: McGraw-Hill, 2006:1785-1794.
• Steensma DP, Tefferi A.Cytogenetic and molecular genetic aspects of essential thrombocythemia. Acta Haematol. 2002;108(2):55-65.
• Tache JE, Saffra N, Marshak H, Aithal S, Novetsky A, Huang YW.Retinal vein thrombosis as the presenting symptom of essential thrombocythemia.Am J Med Sci. 2005;329(3):139
• Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and pointof-care diagnostic algorithms. Leukemia. 2008; 22(1):14-22. Comment in: Leukemia. 2008;22(11):2118-9.
• 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. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood. 2008;112(3):844-7.
• Wang JC, Chen C, Novetsky AD, Lichter SM, Ahmed F, Friedberg NM.Blood thrombopoietin levels in clonal thrombocytosis and reactive thrombocytosis. Am J Med. 1998;104(5):451-5.
• Watson KV, Key N.Vascular complications of essential thrombocythaemia: a link to cardiovascular risk factors.Br J Haematol. 1993;83(2):198-203.
• Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: Life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006;81:159–166.
• Zahavi J, Zahavi M, Firsteter E, Frish B, Turleanu R, Rachmani R. An abnormal pattern of multiple platelet function abnormalities and increased thromboxane generation in patients with primary thrombocytosis and thrombotic complications. Eur J Haematol. 1991;47(5):326-32.