Thrombopoietin

Thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and development factor), also known as THPO, is a glycoprotein hormone produced mainly by the liver and the kidney that regulates the production of platelets by the bone marrow. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets.

Genetics
The thrombopoietin gene is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis (high platelet count) and in some cases of leukemia. Thrombopoietin shares its first 153 amino acids with erythropoietin.

Function and regulation
In the liver it is produced by parenchymal cells and sinusoidal endothelial cells. In the kidney it is made by proximal convoluted tubule cells. Along with these it is made by striated muscle and stromal cells in the bone marrow. In the liver, its production is augmented by interleukin 6 (IL-6).

Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoeitin receptor show that its effects on hematopoiesis are more versatile.

Its negative feedback is different from most hormones in endocrinology: the effector regulates the hormone directly. Thrombopoeitin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.

Therapeutic use
Despite numerous trials, thrombopoeitin is not used therapeutically. Theoretical uses include the procurement of platelets for donation, recovery of platelet counts after myelosuppressive chemotherapy.

A modified recombinant form, termed "megakaryocyte growth and differentiation factor" (MGDF), caused a paradoxical reaction, delaying the development of therapeutic thrombopoietin. A quadrivalent peptide analogue is undergoing development, as well as several small molecule agents, including several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.

History
Thrombopoietin was cloned by five independent groups in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the cell surface receptor c-Mpl, and in older publications thrombopoietin is described as c-Mpl ligand (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.