The effect of MGDF on platelet function and thrombosis in animal models.
Recombinant human megakaryocyte growth and development factor (rHuMGDF) is a recombinant form of the endogenous c-mpl ligand, thrombopoietin (TPO). rHuMGDF (and c-mpl ligands in general) can produce a measurable sensitization of platelets to known platelet agonists. Our laboratory has observed this sensitization in vitro in both platelet-rich plasma and whole blood and ex vivo in platelets from animals receiving rHuMGDF. Concurrently, clear increases in the tyrosine phosphorylation of Jak2 and c-mpl receptor can be observed both in vitro and ex vivo. To assess the in vivo prothrombotic potential of rHuMGDF, a rabbit carotid artery model of cyclic flow reduction (CFR) was used. Intravenous administration of platelet-sensitizing dosages of rHuMGDF had no effect on the CFR pattern, whereas control experiments demonstrated that the CFR pattern can be modulated by both platelet sensitizing (epinephrine) and antithrombotic (aspirin and ketanserin) agents. We conclude that thrombopoiesis can be observed at dosages that do not sensitize platelets, and further, that platelet-sensitizing dosages of rHuMGDF do not necessarily enhance platelet-dependent thrombosis in this model.
Toombs
C F
CF
Department of Pharmacology, Amgen, Inc., Thousand Oaks, California, USA.
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013926:Thrombopoietin / Q000378:metabolism* / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology*
D011994:Recombinant Proteins; D013926:Thrombopoietin