Thrombopoietin is the physiologically relevant regulator of platelet production. Although the concept of a platelet growth factor analogous to erythropoietin had been proposed over 40 years ago, it was not until 1994 that the existence of this hematopoietic growth factor was demonstrated and the protein purified [1-5]. Although historically called "thrombopoietin" , its discoverers also called it by several other names, including megapoietin , megakaryocyte growth and development factor (MGDF) , and c-Mpl ligand . The last name is often used instead of thrombopoietin because the receptor for thrombopoietin, called c-Mpl, was discovered prior to the identification of thrombopoietin  and was instrumental in helping to purify the ligand (ie, the c-Mpl ligand) that bound to it.
This topic will review the biology and physiology of thrombopoietin. The potential clinical applications of thrombopoietin, ranging from the management of thrombocytopenic states to improving yields from platelet apheresis, are discussed separately . (See "Clinical applications of thrombopoietic growth factors".)
STRUCTURE OF THROMBOPOIETIN
Thrombopoietin is produced primarily in liver parenchymal cells with much smaller amounts being made in the kidney and bone marrow [9,10]. It is synthesized as a 353 amino acid precursor protein with a molecular weight of 36 kDa [2,4,11]. Following the removal of the 21 amino acid signal peptide, the remaining 332 amino acids undergo glycosylation to produce a 95 kDa glycoprotein (figure 1). The glycoprotein is then released into the circulation with no apparent intracellular storage in the liver or kidney.
Thrombopoietin is an unusual hematopoietic growth factor in a number of ways:
- It is much larger than most other regulators of blood cell production such as G-CSF (granulocyte colony-stimulating factor) and erythropoietin.
- It has an unusual structure in that the first 153 amino acids of the mature protein are 23 percent homologous with human erythropoietin (figure 1)  and probably 50 percent similar if conservative amino acid substitutions are considered. This region also contains four cysteine residues just like those in erythropoietin and is highly conserved among different species. Despite these similarities, thrombopoietin does not bind the erythropoietin receptor and erythropoietin does not bind to the thrombopoietin receptor.
- Amino acids 154 to 332 comprise a novel sequence that contains six-N-linked glycosylation sites and is less well conserved among different species. Structure-function studies have demonstrated that the first 153 amino acids of the c-Mpl ligand are all that is required for its thrombopoietic effect in vitro [2,4]; however, this truncated molecule has a markedly decreased circulatory half-life compared with the 20 to 40 hour half-life of the native protein . Presumably, the glycosylated second half of the molecule confers stability and prolongs the circulatory half-life. Similar carbohydrate sequences regulate the stability of erythropoietin .