Biologic Aspects of Thrombopoietins and the Development of Therapeutic Agents

Thrombopoiesis is a multistage process beginning with pluripotent hematopoietic stem cells, progressing through proliferating cells committed to megakaryocytopoiesis, to megakaryocytes, and eventually ending with the shedding of platelets from megakaryocytes. Many growth factors stimulate thrombopoiesis; this review addresses those that act through binding to the thrombopoietin receptor. The cloning of thrombopoietin in 1994 greatly accelerated progress in understanding the biology of thrombopoiesis and of hematopoiesis in general. Detailed structural and functional studies of the thrombopoietin receptor, coupled with novel molecular pharmacology approaches, have led to new classes of thrombopoietic mimetics. Initial clinical trials with recombinant thrombopoietins faltered as they encountered significant neutralizing antibodies or difficulty finding a significant clinical niche in support of chemotherapy. Ongoing studies with the new thrombopoietic agents have invigorated the field, with positive results now reported in idiopathic thrombocytopenic purpura.