Thrombopoietin (Mpl-ligand) and the regulation of platelet production

Thrombopoietin is the primary physiological regulator of platelet production. TPO stimulates both early and late megakaryocyte (MK) progenitors, and acts additively or synergistically with several cytokines on various progenitors including the most primitive stem cells. Much has been learn about the physiology of the endogenous TPO production and its regulation. TPO is constantly produced by the liver and kidney; its plasmatic clearance occurs by binding to the Mpl receptor expressed on MKs and platelets. TPO binding is followed by internalization and catabolism. The factor is a potent thrombopoietic agent in vivo and accelerates platelet recovery in several models of marrow suppression. Phase I clinical trials have begun. The lack of adverse effects suggests that TPO may join other cytokines in the clinical armamentarium. Nevertheless, several important areas of basic or clinical haematology remain to be explored to fully understand the biology of this new cytokine. For example, is TPO needed for the terminal stage of platelet formation? What genetic events are involved in the process of endomitosis? What are the physiopathological mechanisms underlying thrombocytopenia or thrombocytemia in human?