Trombocitosis

The

new england journal

of

medicine

review article

current concepts

Thrombocytosis
Andrew I. Schafer, M.D. hrombocytosis is typically discovered as an incidental laboratory abnormality when the complete blood count is obtained for some unrelated reason. When found, however, it creates an important diagnostic challenge. Thrombocytosis generally either is a reactive process(secondary thrombocytosis) or is caused by a clonal bone marrow (myeloproliferative) disorder; the latter category includes essential thrombocythemia. It is often exceedingly difficult to differentiate between the reactive and clonal types of thrombocytosis on the basis of clinical findings or laboratory test results. Yet there are fundamental differences between them in terms of cause,pathophysiological features, and clinical implications.

t

From the Department of Medicine, University of Pennsylvania School of Medicine and University of Pennsylvania Health System, Philadelphia. Address reprint requests to Dr. Schafer at the University of Pennyslvania Health System, 100 Centrex, 3400 Spruce St., Philadelphia, PA 19104, or at andrew. schafer@uphs.upenn.edu. N Engl J Med 2004;350:1211-9.Copyright © 2004 Massachusetts Medical Society.

mechanisms of thrombocytosis
Thrombopoietin is the key hormone in the regulation of megakaryocyte differentiation and proliferation, although various cytokines (e.g., interleukin-6 and interleukin-11) may play an accessory role in the process.1 Megakaryocytes and their platelet progeny have receptors for thrombopoietin (referred to as c-Mplreceptors). Thrombopoietin in plasma binds to c-Mpl on the surfaces of circulating platelets; the remaining, unbound thrombopoietin in plasma is available to promote megakaryocyte proliferation. Thus, when the platelet count drops, increased plasma levels of free thrombopoietin stimulate megakaryocytopoiesis; conversely, when the platelet count rises, reduced levels of free thrombopoietin slowmegakaryocytopoiesis. In this way, the total mass of platelets (and megakaryocytes) can regulate platelet production and maintain it at a steady state (Fig. 1A). In some cases of reactive thrombocytosis, an underlying inflammatory stimulus may up-regulate the production of thrombopoietin by the liver.2 Plasma levels of thrombopoietin are high or inappropriately normal in reactive (secondary)thrombocytosis.3,4 In cases of acute inflammation, this elevation precedes an increase in the platelet count.5,6 Plasma levels of interleukin-6 are also elevated in reactive thrombocytosis: this interleukin, which plays a prominent role in the acute-phase response of inflammatory and neoplastic diseases, up-regulates the expression of thrombopoietin messenger RNA (mRNA) in the liver.7 Thus, interleukin-6 maybe a key mediator of the increased synthesis of thrombopoietin and the consequent reactive thrombocytosis (Fig. 1B). Thrombopoietin levels are also elevated or inappropriately normal in clonal thrombocytosis, but in this case the mechanism involves abnormalities in the regulation of c-Mpl receptor–mediated uptake of constitutively synthesized thrombopoietin (Fig. 1C). In essential thrombocythemia,a clonal defect in platelet and megakaryocyte expression of c-Mpl causes impaired binding of thrombopoietin and leads to higher-than-expected levels of plasma free thrombopoietin.8-11 This situation contrasts with that in other myeloproliferative disorders, in which clonal proliferation of a hematopoietic lineage leads, by a physiological feedback mechanism, to the suppression of the specificgrowth factors that normally control the differentiation and proliferation of individual hematopoi-

n engl j med 350;12

www.nejm.org

march 18, 2004

1211

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Rare cases of familial...