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Essential Thrombocytosis

  • Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Nov 06, 2015
 

Background

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[1] and was traditionally considered a clonal disorder that involved pluripotent stem cells; however, studies have indicated that some patients may have polyclonal hematopoiesis.[2]

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
  • Megakaryocytic hyperplasia
  • Splenomegaly
  • A clinical course complicated by thrombotic or hemorrhagic episodes or both

See the images below.

Peripheral blood smear in essential thrombocytosis Peripheral blood smear in essential thrombocytosis showing increased platelet numbers. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
Bone marrow biopsy in essential thrombocytosis sho Bone marrow biopsy in essential thrombocytosis showing increased megakaryocytes. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
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Pathophysiology

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:

  • Autonomous production
  • 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).[16]

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.[16]

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.[17]

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.[7]

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Epidemiology

Frequency

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.[18]

Mortality/Morbidity

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.

Sex

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.

Age

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.

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Contributor Information and Disclosures
Author

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.

Specialty Editor Board

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.

Chief Editor

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.

Acknowledgements

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.

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Peripheral blood smear in essential thrombocytosis showing increased platelet numbers. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
Bone marrow biopsy in essential thrombocytosis showing increased megakaryocytes. Courtesy Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
 
 
 
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