PEG-rHuMGDF has been given to healthy volunteers (99) and healthy apheresis donors (100-102). Treatment of apheresis donors with a single dose of PEG-rHuMGDF on d 1 produces a dose-dependent increase in the platelet count that begins on d 5 and peaks after 10-12 d (Fig. 11). A clear dose-response effect is seen. Compared with placebo-treated donors who had platelet counts of 225 x 109/L, donors treated with 1 or 3 |g/kg of PEG-rHuMGDF had median platelet counts of 336 x 109/L and 599 x 109/L, respectively. The donors experienced no adverse effects. The platelets produced had normal platelet aggregation responses in vitro and, when transfused into thrombocytopenic recipients, produced a dose-dependent increase in platelet count (101).
In addition to increasing the number of megakaryocytes and platelets, TPO affects the function of platelets. When TPO binds to its platelet receptor, it induces phosphorylation of the c-mpl receptor and a number of other molecules in several signal transduction pathways (103-105) but does not directly cause platelet activation. Such TPO treatment reduces by 50% the threshold for activation by other platelet agonists such ADP and collagen (51). It is unclear whether this is a clinically relevant effect.
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