Thrombopoietin

Human TPO is a 332 amino acid, 60 kDa glycoprotein, containing six potential N-linked glycosylation sites. These are all localized towards the C-terminus of the molecule. The N-terminal half exhibits a high degree of amino acid homology with EPO and represents the biologically active domain of the molecule.

TPO is the haemopoietic growth factor now shown to be the primary physiological regulator of platelet production. This molecule may, therefore, represent an important future therapeutic agent in combating thrombocytopenia, a condition characterized by reduced blood platelet levels. The most likely initial TPO therapeutic target is thrombocytopenia induced by cancer chemo- or

Figure 10.6 Simplified representation of the production of platelets from stem cells. CFU-megakaryocytes and in particular, mature megakaryocytes, are most sensitive to the stimulatory actions of TPO. These two cell types also display a limited response to IL-6, IL-11 and LIF

radio-therapy. This indication generally accounts for up to 80 per cent of all platelet transfusions undertaken. In the USA alone, close to 2 million people receive platelet transfusions annually.

Platelets (thrombocytes) carry out several functions in the body, all of which relate to the arrest of bleeding. They are disc-shaped structures 1-2 |m in diameter, and are present in the blood of healthy individuals at levels of approximately 250 x 109 T1. They are formed by a lineage-specific stem cell differentiation process, as depicted in Figure 10.6. The terminal stages of this process entail the maturation of large progenitor cells termed 'megakaryocytes'. Platelets represent small vesicles that bud off from the megakaryocyte cell surface and enter the circulation.

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