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SUMMARY
The three major pathophysiologic causes of thrombocytosis are (1) clonal, including essential (or primary) thrombocythemia and other myeloproliferative neoplasms; (2) familial, including rare cases of nonclonal myeloproliferation resulting from thrombopoietin and thrombopoietin receptor mutations; and (3) reactive, in which thrombocytosis occurs secondary to a variety of acute and chronic clinical conditions. This chapter deals with the latter two causes of thrombocytosis.
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Acronyms and Abbreviations
EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; FGF, fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; LIF, leukemia inhibitory factor; MHC, major histocompatibility complex; NF, nuclear factor; ORF, open reading frame; SDF, stromal cell-derived factor; STAT, signal transducer and activator of transcription; TPO, thrombopoietin.
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The upper limit of the normal platelet count in most clinical laboratories is between 350 × 109/L and 450 × 109/L. In a sample of 10,000 healthy individuals 18 to 65 years of age, 1% had platelet counts greater than 400 × 109/L. Only in eight of these 99 individuals was thrombocytosis confirmed 6 months to 1 year later.1 Nevertheless, it is clear that thrombocytosis is a feature of several important disorders, including cancer and numerous, serious inflammatory disorders, and that even a high normal platelet count is associated with morbidity and mortality. In a longitudinal study of healthy Norwegian men, a platelet count in the top quartile of the normal range (from 275 × 109/L to 350 × 109/L) was associated with a twofold increase in cardiovascular mortality over a 12-year follow-up.2 Whether the platelet count per se or an underlying inflammatory condition resulting in both thrombocytosis and accelerated atherogenesis is responsible for these observations is not certain.
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The causes of thrombocytosis in which the platelet count exceeds the upper limit can be broadly categorized as (1) clonal, including essential thrombocythemia and other myeloproliferative neoplasms; (2) familial; and (3) reactive, or secondary. This chapter focuses on the causes and molecular mechanisms that underlie reactive and hereditary thrombocytosis. A full discussion of neoplastic thrombocytosis, termed essential thrombocythemia, is found in Chap. 84.
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NORMAL THROMBOPOIESIS
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The regulation of platelet production is discussed extensively in Chap. 110, but a brief discussion here provides the appropriate background for discussion of reactive and hereditary thrombocytosis. Thrombopoietin (TPO), the ligand for the megakaryocytic growth factor receptor c-MPL, is the major humoral regulator of megakaryocyte survival, growth, and development, although it does not stimulate the final step in thrombopoiesis: platelet release from megakaryocyte proplatelet processes. Although TPO supports the entire continuum of megakaryocyte development from stem cell to mature megakaryocyte,3 other cytokines including interleukin (IL)-6,4 IL-3,5,6 IL-11,7 leukemia inhibitory factor,8,9 fibroblast growth factor–4,10 stromal cell–derived factor–1,10,11 interferon (IFN)-γ,12 and granulocyte-macrophage colony-stimulating factor13 also affect thrombopoiesis, both in ...