Physiologic role of TPO in thrombopoiesis.

Recombinant human thrombopoietin (rHuTPO) serves as a megakaryocyte colony-stimulating factor and predominantly acts on GPIIb/IIIa+ rat late megakaryocyte progenitor cells, colony forming units-megakaryocyte (CFU-MK). The GPIIb/IIIa+ fraction of CFU-MK differentiates into mature megakaryocytes and further into proplatelets in liquid culture containing rHuTPO. rHuTPO stimulates cultured megakaryocytes generated from rat GPIIb/IIIa+ CFU-MK to enhance proplatelet formation and to increase megakaryocyte size. rHuTPO also induces a big size of megakaryocyte colonies from human cord blood CD34+ cells. rHuTPO does not cause aggregation of platelets from normal mice and mice made thrombocytotic by consecutive administration of rHuTPO, but preincubation with rHuTPO enhances adenosine diphosphate-induced aggregation, suggesting that platelets induced by rHuTPO administration may have a normal function. Administration of rHuTPO to normal mice daily for five days causes a dose-dependent thrombocytosis. On the other hand, rHuTPO induces a significant decrease in hemoglobin concentration and does not affect white blood cell counts. rHuTPO increases the size and number of marrow megakaryocytes and the number of marrow CFU-MK, and also influences the development of other hematopoietic progenitor cells. The effects of rHuTPO on thrombocytopenia associated with myelosuppression were examined in animal models. Following treatment with mitomycin C, mice received daily injections of various doses of rHuTPO. rHuTPO reduced the severity of thrombocytopenia, accelerated the recovery of platelets and improved neutropenia. Similar therapeutic efficacy was observed in cynomolgus monkeys treated with nimustine. These results suggest the clinical usefulness of rHuTPO for the treatment of thrombocytopenia.