c-Mpl ligand

Thrombopoietin is a glycoprotein that primarily regulates thrombopoiesis, that is, platelet production. Produced constitutively in the liver and inductively in the bone marrow to promote the proliferation and differentiation of megakaryocytes and their progenitors, and maintain hematopoietic stem cells. After the nature of platelets was described by Donne, Addison, Osler, and Bizzozero in the 1800s, Wright reported that the origin of human platelets (thrombocytes) was the bone marrow. The tentative name thrombopoietin (TPO) was proposed for a humoral factor of platelet production, independently by Komiya and by Kelemen. It was not apparent whether TPO activity was identical to in vitro activity defined as a megakaryocyte colony stimulating factor. TPO molecules were finally identified simultaneously by independent research groups. Concurrently, c-Mpl (Mpl) expressing megakaryocytes was confirmed as the TPO receptor.

The clinical trials of a first generation of recombinant TPO molecules (i.e., PEG-rhMGDF and rhTPO) started in 1995, and proved the increase of platelet counts in humans for the first time, but were discontinued due to the development of a neutralizing antibody to endogenous TPO in 13 human subjects in the PEG-MGDF study. The second generation of synthetic TPO-Mpl agonists (romiplostim and eltrombopag) followed, and was approved throughout the world for the treatment of immune thrombocytopenia (ITP). Other indications are further considered.

TPO stimulates the proliferation and maturation of megakaryocytes and promotes increased circulating levels of platelets in vivo. TPO signals through the c-mpl receptor and acts as an important regulator of circulating platelets