- Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD more...
Essential thrombocytosis (primary thrombocythemia) is a nonreactive, chronic myeloproliferative disorder in which sustained megakaryocyte proliferation leads to an increase in the number of circulating platelets. Essential thrombocytosis was first described by Epstein and Goedel in 1934 and was traditionally considered a clonal disorder that involved pluripotent stem cells; however, studies have indicated that some patients may have polyclonal hematopoiesis.
Essential thrombocytosis is characterized by the following[3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] :
A persistently elevated platelet count greater than 450,000/µL
A clinical course complicated by thrombotic or hemorrhagic episodes or both
See the images below.
Platelet survival is normal in essential thrombocytosis. Instead, the elevated counts result from increased production of platelets by megakaryocytes. The cause of this increase in platelet production remains unclear, but possibilities include the following:
Increased sensitivities to cytokines (eg, interleukin-3 [IL-3])
Decreased effect of platelet-inhibiting factors (eg, transforming growth factor [TGF] beta)
Defects in the accessory cell microenvironment
Bone marrow megakaryocytic precursors (colony-forming unit–megakaryocyte [CFU-Meg]) from patients with essential thrombocytosis form colonies in the absence of exogenous thrombopoietin (Tpo). There is no evidence for mutations in the genes for Tpo, and patients with essential thrombocytosis have normal or even decreased plasma Tpo levels, possibly reflecting increased Tpo clearance due to the elevated circulating platelet mass.
The majority of patients with essential thrombocytosis have mutations in one of three genes: Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Rare cases involve mutations in the thrombopoietin gene (THPO), which are associated with autosomal dominant hereditary thrombocytosis, and somatic mutations in tet methylcytosine dioxygenase 2 (TET2).
MPL mutations have been associated with only about 3-5% of essential thrombocytosis cases. MPL codes for the thrombopoietin receptor protein, which promotes the growth and proliferation of megakaryocytes. The mutations consist of amino acid substitutions at position 505 in familial cases or 515 in sporadic cases These result in constitutive activation of the thrombopoietin receptor protein.
JAK2 mutations possibly turn the thrombopoietin receptor on permanently, leading to overproduction of megakaryocytes. JAK2 mutation is seen in approximately 50-60% of patients.
Somatic mutations in CALR are detected in peripheral blood in the approximately 25% of essential thrombocythemia cases. CALR mutations are mutually exclusive with JAK2 or MPL mutations.
One study found that patients with JAK2 mutations tend to be older than patients with CALR mutations and to have a higher hemoglobin level and white blood cell count, as well as a lower platelet count and serum erythropoietin level. Risk of thrombosis was twice as high in patients with JAK2 mutations than in those with CALR mutations. Transformation to polycythemia was not observed in patients with CALR mutations, whereas the cumulative risk of polycythemic transformation was 29% at 15 years in those with JAK2 mutations.
The mechanism by which thrombocythemia produces hemorrhage or thrombosis is not well defined. Several defects have been described, including a decrease in aggregation, hyperaggregation, and intracellular concentration of various chemicals. In addition, reports show a decrease in von Willebrand ristocetin cofactor activity and high molecular weight von Willebrand factor multimers. Some reports show patients with an acquired deficiency of antithrombin III, protein C, and protein S.
Clinicians diagnose approximately 6000 cases of essential thrombocytosis (primary thrombocythemia) each year. Some researchers speculate that the incidence rate may be several times higher. A study from southeastern Minnesota reported an incidence of 2.38 cases per 100,000 population per year.
Patients with essential thrombocytosis (primary thrombocythemia) have a 10-year survival rate of 64-80%, which may not be significantly different from that of the age-matched general population. Death occurs from thrombotic complications.
Transformation to acute myelogenous leukemia (AML) occurs in 0.6-5% of patients. Risk factors include anemia (hemoglobin less than 12 g/dL in females and less than 13.5 g/dL in males), platelet count of >1,000,000/μ L, and increased age. Treatment with alkylating agents or radiophosphorus may be associated with higher risk of leukemic transformation.
Morbidity in patients with essential thrombocytosis may involve large-vessel or microvascular thrombosis and bleeding.
In older patients with essential thrombocytosis, the frequency is similar in both sexes. In younger patients, however, essential thrombocytosis occurs more often in women than in men.
Essential thrombocytosis (primary thrombocythemia) is more frequent in older patients, although younger patients may develop the disease. The median age at diagnosis is 60 years, and perhaps up to 20% of patients are younger than 40 years. The disease is rare in children.
Epstein E, Goedel A. Hammorhagische thrombocythamie bei vascularer schrumpfmilz. Virch Arch (Pathol Anat). 1934. 292:233.
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 Jan 15. 93(2):417-24. [Medline]. [Full Text].
Barbui T, Finazzi G. Treatment indications and choice of a platelet-lowering agent in essential thrombocythemia. Curr Hematol Rep. 2003 May. 2(3):248-56. [Medline].
Ruggeri M, Gisslinger H, Tosetto A, et al. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol. 2002 Sep. 71(1):1-6. [Medline]. [Full Text].
Harrison CN, Donohoe S, Carr P, et al. Patients with essential thrombocythaemia have an increased prevalence of antiphospholipid antibodies which may be associated with thrombosis. Thromb Haemost. 2002 May. 87(5):802-7. [Medline].
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 May. 52(1):14-20. [Medline].
Colombi M, Radaelli F, Zocchi L, Maiolo AT. Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients. Cancer. 1991 Jun 1. 67(11):2926-30. [Medline].
Fenaux P, Simon M, Caulier MT, et al. Clinical course of essential thrombocythemia in 147 cases. Cancer. 1990 Aug 1. 66(3):549-56. [Medline].
Chistolini A, Mazzucconi MG, Ferrari A, et al. Essential thrombocythemia: a retrospective study on the clinical course of 100 patients. Haematologica. 1990 Nov-Dec. 75(6):537-40. [Medline].
Hehlmann R, Jahn M, Baumann B, Köpcke W. Essential thrombocythemia. Clinical characteristics and course of 61 cases. Cancer. 1988 Jun 15. 61(12):2487-96. [Medline].
Bellucci S, Janvier M, Tobelem G, et al. Essential thrombocythemias. Clinical evolutionary and biological data. Cancer. 1986 Dec 1. 58(11):2440-7. [Medline].
Kwon M, Osorio S, Muñoz C, Sánchez JM, Buno I, Díez-Martín JL. Essential thrombocythemia in patients with platelet counts below 600x10(9)/L: applicability of the 2008 World Health Organization diagnostic criteria revision proposal. Am J Hematol. 2009 Jul. 84(7):452-4. [Medline].
Cervantes F. Management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2011. 2011:215-21. [Medline].
Lee HS, Park LC, Lee EM, Lee SJ, Shin SH, Im H, et al. Incidence Rates and Risk Factors for Vascular Events in Patients With Essential Thrombocythemia: A Multicenter Study From Korea. Clin Lymphoma Myeloma Leuk. 2011 Nov 14. [Medline].
Genetics Home Reference. Essential Thrombocythemia. U.S. National Library of Medicine. Available at http://ghr.nlm.nih.gov/condition/essential-thrombocythemia. November 2, 2015; Accessed: November 5, 2015.
Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014 Mar 6. 123 (10):1544-51. [Medline].
Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999 May. 61(1):10-5. [Medline]. [Full Text].
Tefferi A, Fonseca R, Pereira DL, Hoagland HC. A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc. 2001 Jan. 76(1):22-8. [Medline].
Girodon F, Bonicelli G, Schaeffer C, Mounier M, Carillo S, Lafon I, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica. 2009 Jun. 94(6):865-9. [Medline]. [Full Text].
[Guideline] Harrison CN, Butt N, Campbell P, Conneally E, Drummond M, Green AR, et al. Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia. Br J Haematol. 2014 Nov. 167 (3):421-3. [Medline]. [Full Text].
Spanoudakis E, Margaritis D, Kotsianidis I, et al. Long-term bone marrow cultures (LTBMC) from essential thrombocythemia (ET) patients with or without JAK2617V>F mutation. Leuk Res. 2008 Oct. 32(10):1593-6. [Medline].
Teofili L, Martini M, Cenci T, et al. Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases. Int J Cancer. 2008 Oct 1. 123(7):1586-92. [Medline].
Ohyashiki K, Kodama A, Ohyashiki JH. Recurrent der(9;18) in essential thrombocythemia with JAK2 V617F is highly linked to myelofibrosis development. Cancer Genet Cytogenet. 2008 Oct. 186(1):6-11. [Medline].
Zhan H, Spivak JL. The diagnosis and management of polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the JAK2 V617F era. Clin Adv Hematol Oncol. 2009 May. 7(5):334-42. [Medline].
Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G, et al. Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy. J Clin Oncol. 2009 Jun 20. 27(18):2991-9. [Medline].
Riley CH, Brimnes MK, Hansen M, Jensen MK, Hasselbalch HC, Kjaer L, et al. Interferon-α induces marked alterations in circulating regulatory T cells, NK cell subsets and dendritic cells in patients with JAK2V617F -positive essential thrombocythemia and polycythemia vera. Eur J Haematol. 2015 Sep 19. [Medline].
Verger E, Cassinat B, Chauveau A, Dosquet C, Giraudier S, Schlageter MH, et al. Clinical and molecular response to interferon alpha therapy in essential thrombocythemia patients with CALR mutations. Blood. 2015 Oct 20. [Medline].
[Guideline] Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004 Feb. 89 (2):215-32. [Medline]. [Full Text].
Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015 Feb. 90 (2):162-73. [Medline].
Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015 Sep 3. 373 (10):908-19. [Medline].
Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood. 2009 May 14. 113(20):4829-33. [Medline].
Gugliotta L, Marchioli R, Fiacchini M, et al. Epidemiological, diagnostic, therapeutic and prognostic aspects of essential thrombocythemia in a retrospective study of the GIMMC group in two thousand patients [abstract]. Blood. 1997. 90(suppl 1):348a.
Besses C, Cervantes F, Pereira A, et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia. 1999 Feb. 13(2):150-4. [Medline].
Cervantes F, Tassies D, Salgado C, et al. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991. 85(3):124-7. [Medline].
Chistolini A, Filoni V, Dragoni F, et al. Hepatitis C virus antibody in coagulopathic patients: ELISA and RIBA methods. Haematologica. 1993 Jul-Aug. 78(4):252-4. [Medline].
el-Kassar N, Hetet G, Brière J, Grandchamp B. Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood. 1997 Jan 1. 89(1):128-34. [Medline]. [Full Text].
Elliott MA, Tefferi A. Interferon-alpha therapy in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 1997. 23(5):463-72. [Medline].
Emilia G, Sacchi S, Temperani P. Progression of essential thrombocythemia to blastic crisis via idiopathic myelofibrosis. Leuk Lymphoma. 1993 Mar. 9(4-5):423-6. [Medline].
Fabris F, Casonato A, Grazia del Ben M, De Marco L, Girolami A. Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis. Br J Haematol. 1986 May. 63(1):75-83. [Medline].
Jantunen R, Juvonen E, Ikkala E, et al. The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia. Ann Hematol. 2001 Feb. 80(2):74-8. [Medline].
Kobayashi S, Teramura M, Hoshino S, et al. Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3. Br J Haematol. 1993 Apr. 83(4):539-44. [Medline].
Randi ML, Barbone E, Zerbinati P, et al. Essential thrombocythemia following polycythemia vera: an unusual sequence. J Med. 1996. 27(5-6):363-8. [Medline].
Shabbad E, Cassel A, Froom P, Aghai E. Effect of adherent cells on the regulation of BFU-E in patients with myeloproliferative disease. Am J Hematol. 1990 Apr. 33(4):225-9. [Medline].
van Genderen PJ, Michiels JJ, van der Poel-van de Luytgaarde SC, van Vliet HH. Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: relationship with platelet count. Ann Hematol. 1994 Aug. 69(2):81-4. [Medline].
Zauli G, Visani G, Catani L, et al. Reduced responsiveness of bone marrow megakaryocyte progenitors to platelet-derived transforming growth factor beta 1, produced in normal amount, in patients with essential thrombocythaemia. Br J Haematol. 1993 Jan. 83(1):14-20. [Medline].