Thrombopoietin: from theory to reality.

Much is now known about the physiology of platelets and their role in primary hemostasis; however, until recently far less was understood about their immediate precursors, marrow megakaryocytes (MKs). With the cloning and characterization of thrombopoietin (TPO), the principle regulator of the growth and development of MKs, research has been rapid and broad-based. In several laboratories TPO was cloned based on it's binding to the product of the proto-oncogene c-mpl, at the time an orphan cytokine receptor, and was subsequently found to affect nearly all aspects of thrombopoiesis. Many of the molecular pathways that mediate TPO action have been explored. Like all other members of the hematopoietic cytokine receptor family upon hormone binding members of the JAK family of kinases are activated, which, in turn, phosphorylate the TPO receptor, generating docking sites for second messengers that affect multiple signaling pathways. Ultimately, cellular proliferative and anti-apoptotic mechanisms are initiated, increasing MK numbers, and a process termed endomitosis (EnM) begins, generating large, highly polyploid cells. The net result is the expansion of cells that give rise to mature platelets, a process that can be accentuated by the therapeutic administration of the hormone to thrombocytopenic patients.