The molecular mechanisms that control thrombopoiesis

Abstract

Our understanding of thrombopoiesis -the formation of blood platelets -has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process.Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells.The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances. Overview of platelets and thrombopoiesisAn adequate supply of platelets is essential to repair the minute vascular damage that occurs with daily life, and to initiate thrombus formation in the event of overt vascular injury.Accumulating evidence also indicates vital roles for platelets in wound repair, the innate immune response, and metastatic tumor cell biology.The average platelet count in humans ranges from 150 × 10 9 to 400 × 10 9 per liter, although the level for any individual is maintained within fairly narrow limits from day to day.While 150 × 10 9 to 400 × 10 9 per liter is considered "normal," the values derived from the mean ± 2 SDs of a group of "healthy" individuals, epidemiological evidence indicates that individuals who display platelet counts in the highest quartile of the normal range have a 2-fold increased risk of adverse cardiovascular events (1), and, in both experimental animal models of metastatic cancer and patients with tumors, higher platelet levels carry an unfavorable prognosis (2).With a lifespan of approximately 10 days, a blood volume of 5 liters, and one-third of platelets pooled in the spleen, the average adult must produce each day approximately 1 × 10 11 platelets to maintain a normal platelet count under steady-state conditions, a level of production that can increase more than 10-fold under conditions of increased demand.The primary regulator of platelet production is thrombopoietin, an acidic glycoprotein produced primarily in the liver, kidney, and BM.The biochemistry and structure-activity relationships of thrombopoietin have been carefully evaluated, as have the binding sites to its receptor, the product of the cellular protooncogene c-Mpl (3, 4).This Review will focus on the regulation of platelet production, how thrombopoietin stimulates thrombopoiesis under normal and pathological conditions, and the molecular mechanisms through which the hormone produces its biological effects.In addition to providing an understanding of normal physiology, the discovery of the biological effects of thrombopoietin and its receptor provides a platform on which to understand a number of clinical disorders of hematopoiesis and serves to suggest novel therapeutic approaches to several diseases.