Thrombopoietin

Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a is_associated_with::protein that in humans is encoded by the THPO is_associated_with::gene.

Thrombopoietin is a is_associated_with::glycoprotein is_associated_with::hormone produced by the is_associated_with::liver and is_associated_with::kidney which regulates the production of is_associated_with::platelets. It stimulates the production and differentiation of is_associated_with::megakaryocytes, the bone marrow cells that bud off large numbers of is_associated_with::platelets.

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor necessary for is_associated_with::megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.

Genetics
The thrombopoietin is_associated_with::gene is located on the long arm of is_associated_with::chromosome 3 (q26.3-27). Abnormalities in this gene occur in some is_associated_with::hereditary forms of is_associated_with::thrombocytosis (high platelet count) and in some cases of is_associated_with::leukemia. The first 155 is_associated_with::amino acids of the protein share homology with is_associated_with::erythropoietin.

Function and regulation
Thrombopoietin is produced in the liver by both parenchymal cells and is_associated_with::sinusoidal endothelial cells, in the kidney by proximal convoluted tubule cells. Small amounts are also made by is_associated_with::striated muscle and bone marrow stromal cells. In the liver, its production is augmented by is_associated_with::interleukin 6 (IL-6). However, the liver and the bone marrow stromal cells are the primary sites of thrombopoietin production.

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

Its negative feedback is different from that of most hormones in is_associated_with::endocrinology: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets by the mpl receptor (is_associated_with::CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone. Therefore, the rising and dropping platelet concentrations regulate the thrombopoietin levels. Low platelets lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells, leading to differentiation into is_associated_with::megakaryocytes and further maturation of these cells. On the other hand, high platelet concentrations lead to less availability of thrombopoietin to megakaryocytes.

Therapeutic use
Despite numerous trials, thrombopoietin has not been found to be useful therapeutically. Theoretical uses include the procurement of platelets for donation, recovery of platelet counts after myelosuppressive is_associated_with::chemotherapy.

Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia. is_associated_with::Romiplostim and is_associated_with::Eltrombopag, structurally different compounds that stimulate the same pathway, are used instead.

A quadrivalent peptide analogue is being investigated, as well as several small-molecule agents, and several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.

Discovery
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 is_associated_with::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.