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Essential thrombocythemia is a clonal stem cell disorder characterized by an overproduction of platelets and associated with mutations in JAK2 or MPL. Complications include thrombosis (predominantly arterial), hemorrhage, and progression to myelofibrosis or acute myeloid leukemia. Diagnosis requires exclusion of reactive thrombocytosis and other myeloid malignancies associated with a raised platelet count. Therapy is aimed at reducing thrombotic complications and includes modification of known cardiovascular risk factors and antiplatelet therapy for the majority of patients. Those at high risk of thrombosis are also considered for cytoreductive therapy with agents such as hydroxyurea, anagrelide, or interferon-α. Although survival in the first decade following diagnosis appears similar to controls, mortality rates increase thereafter as a consequence of disease complications.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AML, acute myeloid leukemia; CML, chronic myeloid leukemia; ET, essential thrombocythemia; JAK2, Janus family of tyrosine kinases type 2; PMF, primary myelofibrosis; PV, polycythemia vera; RARS-t, refractory anemia with ringed sideroblasts and thrombocytosis.

Essential thrombocythemia (ET), one of the myeloproliferative neoplasms, is a clonal hematopoietic stem cell disorder characterized by an isolated thrombocytosis and associated with thrombotic and hemorrhagic complications. First recognized as a specific disease entity in 1934,1 ET shares clinical and pathologic similarities with other myeloproliferative neoplasms, particularly polycythemia vera (PV) and primary myelofibrosis (PMF).

The annual incidence of ET is in the order of 1 to 2.5 per 100,000 population and appears slightly more common in females.2,3 Patients may present at any age, although ET is largely a disorder of later life with a peak incidence between the ages of 50 and 70 years. Presentation in childhood is rare but well recognized.

Little is known about the precise etiology of this disorder, although environmental factors such as exposure to radiation have been implicated in the genesis of other myeloproliferative neoplasms.4 Both registry data and kindred studies suggest a familial tendency to develop myeloproliferative neoplasms, including ET.5–7 This predisposition appears to be explained in part by inheritance of a specific haplotype that contains the JAK2 gene.8–10

Although shown to be a clonal disorder in 1981,11 little was known about the molecular pathogenesis of ET until 2005, when an acquired mutation in the JAK2 gene (JAK2 V617F) was identified in approximately 50 percent of patients with ET or PMF and the majority of those with PV.12–15 JAK2, one of the JAK family of cytoplasmic tyrosine kinases, is essential for signaling by the erythropoietin and thrombopoietin receptors,16,17 and also contributes to signaling by the granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor,18 and interferon- receptors.19 Studies of the erythropoietin receptor have demonstrated that erythropoietin binding leads to a conformation change in the JAK2-receptor complex,20 with consequent activation of JAK2 kinase activity and recruitment of downstream signaling pathways.16 The JAK2 V617F mutation alters ...

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