Thrombopoietin (Tpo), is a key regulator of megakaryocytopoiesis and thrombopoiesis. It is principally produced in the liver and is bound and internalized by the receptor Tpo R/c mpl. Defects in the Tpo Tpo R signaling pathway are associated with a variety of platelet disorders . Mature rat Tpo shares 68% and 81% aa sequence homology with human and mouse Tpo, respectively . It is an 80 85 kDa protein that consists of an N terminal domain with homology to Erythropoietin (Epo) and a C terminal domain that contains multiple N linked and O linked glycosylation sites. Tpo promotes the differentiation, proliferation, and maturation of megakaryocytes (MK) and their progenitors . Several other cytokines can also promote these functions but only in cooperation with Tpo . Notably, IL 3 independently induces MK development, although its effects are restricted to early in the MK lineage . Tpo additionally promotes platelet production, aggregation, ECM adhesion, and activation . These actions, in combination with direct effects on cardiomyocytes, can aid in the recovery of heart function following myocardial infarction . Tpo is cleaved by platelet derived thrombin following Arg191 within the C terminal domain and subsequently at other sites upon extended digestion . The C terminal domain is not required for binding to Tpo R or inducing MK growth and differentiation . Aside from its hematopoietic effects, Tpo is expressed in the brain where it promotes the apoptosis of hypoxia sensitized neurons and inhibits neuronal differentiation by blocking NGF induced signaling .