Essential Thrombocytosis

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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  ^[1] (see the images below). Mutations in JAK2, CALR, or MPL are found in approximately 90% of patients with essential thrombocytosis.

Essential thrombocytosis was first described by Epstein and Goedel in 1934 ^[2] and was traditionally considered a clonal disorder that involved pluripotent stem cells. However, studies have indicated that some patients may have polyclonal hematopoiesis. ^[3]

Essential thrombocytosis is characterized by the following ^{[4, 5, 6, 7, 8, 9, 10]} :

A persistently elevated platelet count greater than 450,000/µL

Megakaryocytic hyperplasia

Splenomegaly

A clinical course complicated by thrombotic or hemorrhagic episodes or both

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:

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). ^[11]

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. ^[11]

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. ^[12]

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. ^{[13, 14]} Some reports show patients with an acquired deficiency of antithrombin III, protein C, and protein S. ^[7]

United States

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. ^[15]

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 during the first decade and increases significantly in subsequent decades. ^[16] Risk factors include advanced age, anemia (hemoglobin less than 12 g/dL in females and less than 13.5 g/dL in males), leukocytosis, platelet count of >1,000,000/μL, and sequence variants/mutations involving TP53 and EZH2. ^[17]  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.

Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018 Oct 3. [Medline]. [Full Text].

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].

Rumi E, Cazzola M. How we treat essential thrombocythemia. Blood. 2016 Aug 25. [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].

Kwon M, Osorio S, Muñoz C, Sánchez JM, Buno I, Díez-Martín JL. Essential thrombocythemia in patients with platelet counts below 600×10(9)/L: applicability of the 2008 World Health Organization diagnostic criteria revision proposal. Am J Hematol. 2009 Jul. 84(7):452-4. [Medline].

Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017 Jan. 92 (1):94-108. [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].

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].

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].

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].

Shrestha R, Giri S, Pathak R, Bhatt VR. Risk of second primary malignancies in a population-based study of adult patients with essential thrombocythemia. World J Clin Oncol. 2016 Aug 10. 7 (4):324-30. [Medline].

Yogarajah M, Tefferi A. Leukemic Transformation in Myeloproliferative Neoplasms: A Literature Review on Risk, Characteristics, and Outcome. Mayo Clin Proc. 2017 Jul. 92 (7):1118-1128. [Medline].

Rospond-Kubiak I, Oszkinis G, Kociecki J. Retinal Intra-arterial Thrombocytic Material Revealing Essential Thrombocythemia. JAMA Ophthalmol. 2016 Aug 11. 134 (8):e161111. [Medline].

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].

Appleby N, Angelov D. Clinical and laboratory assessment of a patient with thrombocytosis. Br J Hosp Med (Lond). 2017 Oct 2. 78 (10):558-564. [Medline].

[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].

Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017 Feb 9. 129 (6):680-692. [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].

Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J. 2018 Jan 10. 8 (1):2. [Medline]. [Full Text].

Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995 Apr 27. 332(17):1132-6. [Medline]. [Full Text].

Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7. 353(1):33-45. [Medline]. [Full Text].

Aruch D, Mascarenhas J. Contemporary approach to essential thrombocythemia and polycythemia vera. Curr Opin Hematol. 2016 Mar. 23 (2):150-60. [Medline].

Kanakura Y, Shirasugi Y, Yamaguchi H, Koike M, Chou T, Okamoto S, et al. A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia. Int J Hematol. 2018 Nov. 108 (5):491-498. [Medline].

Godfrey AL, Campbell PJ, MacLean C, et al. Hydroxycarbamide Plus Aspirin Versus Aspirin Alone in Patients With Essential Thrombocythemia Age 40 to 59 Years Without High-Risk Features. J Clin Oncol. 2018 Aug 28. JCO2018788414. [Medline]. [Full Text].

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 JAK2^V617F -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].

Pieri L, Pancrazzi A, Pacilli A, Rabuzzi C, Rotunno G, Fanelli T, et al. JAK2V617F complete molecular remission in polycythemia vera/essential thrombocythemia patients treated with ruxolitinib. Blood. 2015 May 21. 125 (21):3352-3. [Medline]. [Full Text].

Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017 Oct 26. 130 (17):1889-1897. [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.

Asheesh Lal, MBBS, MD Physician, Department of Internal Medicine, Lexington Medical Center

Asheesh Lal, MBBS, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Wadie F Bahou, MD Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Essential Thrombocytosis

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