When administered to normal animals, TPO increases bone marrow and peripheral blood Meg-CFC, increases bone marrow megakaryocyte number size and ploidy, and increases platelet count. Interestingly, both erythroid and multipotential precursor cells are also increased in the bone marrow and peripheral blood, but not the erythro-cytes or neutrophils.
After daily administration of a recombinant form of TPO (PEG-rHuMGDF) to normal baboons (Fig. 2), a predictable response occurs (4,50,51). During the first 4 d of administration, bone marrow megakaryocyte ploidy increases to a maximum without change in platelet count. On d 5, the platelet count begins to increase and does so at a dose-dependent rate. With continued administration of TPO, a dose-dependent plateau platelet count is reached on d 8-12. A log-linear relationship exists between TPO dose and the plateau platelet count, with a maximum sixfold increase in the rate of platelet production (Fig. 2, inset). Upon stopping the growth factor, the platelet count returns to its baseline value over 10 d without a rebound thrombocytopenia. White and red blood cell counts are not affected.
Although TPO does not directly cause platelet activation, at pharmacologically high doses it does have a modest effect on mature platelets by increasing their reactivity to some aggregation stimuli; TPO-treated platelets require half as much adenosine diphosphate (ADP) for a response (50,52). Other HGFs also reduce the threshold for platelet activation, but the clinical relevance is uncertain. This effect may be mediated by TPO-dependent activation of phosphatidylinositide 3-kinase (PI3K), which in turn phosphorylates Thr306 and Ser473 of platelet protein kinase Ba, an important anti-apoptotic protein (53). However, TPO does not prevent apoptosis of platelets during ex vivo storage (54,55).
Fig. 2. The effect of recombinant thrombopoietin on the platelet count in vivo. Baboons were injected daily for 28 d with pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF; horizontal bar) at doses of 0.05 (■; n = 3), 0.10 (▲; n = 3), 0.50 (•; n = 4), or 2.50 (O; n = 6) |J,g/kg/d. The inset shows the log-linear relationship between the administered dose and the fold-increase in platelet counts. White cell and red cell counts were not affected. (Reproduced with permission from ref. 51.)
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