Mpl-ligands stimulate platelet production by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication in vivo. Log-linear responses are produced when pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is administered to baboons over the dose range of 0.05-2.5 g/kg/day with respect to a) trough blood levels; b) peak peripheral platelet counts and mass turnover; and c) marrow megakaryocyte volume, ploidy, number and mass. Other Mpl-ligands are reported to produce similar effects in various species using different dosing regimens. Whereas Mpl-ligands do not induce platelet aggregation in vitro, they transiently enhance aggregatory responsiveness of platelets from several different species to physiologic agonists both in vitro and ex vivo. However, platelet recruitment into forming thrombus is not augmented by Mpl-ligands when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration per se. These findings indicate that appropriate dosing of Mpl-ligands following marrow suppression will prevent thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications. P51RR00165-36 1/1/96 - 12/31/96 Yerkes Regional Primate Research Center
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