Description
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.
Uses
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.
Uses
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
Biochem/physiol Actions
Thrombopoeitin is a primary regulatory factor for megakaryocytopoiesis and thrombopoiesis. The mature form of TPO is a highly conserved glycoprotein, showing homology among various mammals. It is produced by liver and kidney cells. TPO stimulates growth and maturation of megakaryocytes and megakaryocytic colonies from bone marrow cultures. TPO binds and activates an 68-78 kDa glycoprotein receptor belonging to the GH family of cytokine receptors, a family that includes receptors to growth hormone (GH), erythropoietin (EPO), and prolactin (PRL). Like GH and EPO, TPO may bind to its receptor at two distinct sites, initiating receptor dimerization and activation. Analysis of mRNA indicates also the existence of a novel truncated and potentially soluble form of TPO receptor. The viral oncogene v-mlp of the myeloproliferative leukemia virus (MPLV) contains the gene sequence for the entire cytoplasmic and transmembrane domains and a portion of the extracellular domain of c-mlp (TPO receptor).
