Thrombopoetin

Thrombopoietin (TPO) is a glycoprotein hormone that regulates the production of platelets (thrombocytes). It is produced primarily by the liver, with smaller contributions from the kidneys and bone marrow stromal cells. TPO functions as the principal regulator of megakaryopoiesis by binding to the thrombopoietin receptor, c-Mpl (CD110), on megakaryocyte progenitors and mature megakaryocytes, stimulating their proliferation, differentiation, and maturation and thereby increasing platelet output.

TPO is secreted constitutively at low but steady levels. Its circulating concentration is tightly controlled by receptor-mediated clearance: platelets and megakaryocytes express c-Mpl and bind TPO, which is internalized and degraded. Consequently, this creates an inverse relationship between platelet mass and free TPO levels. The THPO gene encodes the protein; it is primarily expressed in the liver.

Signaling occurs through the MPL receptor, activating JAK2 and downstream pathways such as STAT, PI3K/AKT, and MAPK, leading to megakaryocyte growth and maturation.

Clinical relevance: In immune thrombocytopenia, endogenous TPO levels may be insufficient to compensate; TPO receptor agonists, such as romiplostim and eltrombopag, are used to stimulate platelet production. Thrombopoietin and its agonists carry risks including thrombosis and, with long-term use, possible marrow reticulin fibrosis or dysplasia.

History: Thrombopoietin was identified in the 1990s, and its discovery clarified the regulation of platelet production and spurred development of TPO receptor agonists.