Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor necessary for 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.[2]
Thrombopoietin is produced in the liver by both parenchymal cells and sinusoidal endothelial cells, as well as in the kidney by proximal convoluted tubule cells. Small amounts are also made by striated muscle and bone marrow stromal cells.[1] In the liver, its production is augmented by interleukin 6 (IL-6).[1] However, the liver and the bone marrow stromal cells are the primary sites of thrombopoietin production.
Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile.[1]
Its negative feedback is different from that of most hormones in endocrinology: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.[1] 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 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,[4] and recovery of platelet counts after myelosuppressive chemotherapy.[1]
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.[5]Romiplostim and Eltrombopag, structurally different compounds that stimulate the same pathway, are used instead.[6]
A quadrivalent peptide analogue is being investigated, as well as several small-molecule agents,[1] and several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.[7][8]
Discovery
Thrombopoietin was cloned by five independent teams in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the cell surface receptorc-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.[1]
↑Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ (December 2001). "Thrombocytopenia caused by the development of antibodies to thrombopoietin". Blood. 98 (12): 3241–8. doi:10.1182/blood.V98.12.3241. PMID11719360.
↑Imbach P, Crowther M (August 2011). "Thrombopoietin-receptor agonists for primary immune thrombocytopenia". N. Engl. J. Med. 365 (8): 734–41. doi:10.1056/NEJMct1014202. PMID21864167.
↑Nakamura T, Miyakawa Y, Miyamura A, et al. (2006). "A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis". Blood. 107 (11): 4300–7. doi:10.1182/blood-2005-11-4433. PMID16484588.
↑Jenkins JM, Williams D, Deng Y, et al. (2007). "Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist". Blood. 109 (11): 4739–41. doi:10.1182/blood-2006-11-057968. PMID17327409.
Further reading
Hitchcock IS, Kaushansky K (2014). "Thrombopoietin from beginning to end". Br. J. Haematol. 165 (2): 259–68. doi:10.1111/bjh.12772. PMID24499199.
Kuter DJ (2013). "The biology of thrombopoietin and thrombopoietin receptor agonists". Int. J. Hematol. 98 (1): 10–23. doi:10.1007/s12185-013-1382-0. PMID23821332.
Liebman HA, Pullarkat V (2011). "Diagnosis and management of immune thrombocytopenia in the era of thrombopoietin mimetics". Hematology Am Soc Hematol Educ Program. 2011: 384–90. doi:10.1182/asheducation-2011.1.384. PMID22160062.
