Inhibition of platelet aggregation in baboons: therapeutic implications for xenotransplantation

Activation of endothelial cells and platelet sequestration play major roles in rejection of xenografts. The histopathology of both hyperacute and acut e vascular or delayed rejection of vascularized discordant xenografts is ch aracterized by interstitial hemorrhage and intravascular thrombosis. Agents that prevent platelet activation and consequent microthrombus formation ha ve proven beneficial in xenograft rejection but do not fully preclude vascu lar thrombosis. Recently, several new anti-platelet therapies have undergon e extensive clinical testing for atherosclerotic thrombotic vascular disord ers; other putative therapies are undergoing pre-clinical evaluation. We ha ve investigated the effect of several of these novel agents on platelet agg regation in baboons in order to screen for future potential in xenograft re jection models. Methods: Drugs tested in these experiments were aurintricarboxylic acid (AT A, von Willebrand Factor-GPIb inhibitor), fucoidin (a selectin-inhibitor), 1-benzylimidazole (1-BI, thromboxane synthase antagonist), prostacyclin (PG I(2), endothelial stabilizer), heparin (thrombin antagonist), nitroprusside sodium or nicotinamide (NPN or NA, both NO-donors), and eptifibatide (EFT, GPIIb/IIIa receptor antagonist). These were infused intravenously to nine baboons. Coagulation parameters and platelet counts were monitored and babo ons were observed for adverse side-effects. The efficacy of these agents in inhibiting platelet aggregation was assayed in a platelet aggregometer. Results. Treatment with ATA and fucoidin resulted in complete inhibition of platelet aggregation but also in major perturbation of coagulation paramet ers. 1-BI and PGI2 had no effect when administered alone, but in combinatio n resulted in moderate inhibition of aggregation without disturbance in PT or PTT. NPN and NA had no substantive effects on platelet aggregation. Hepa rin resulted in specific inhibition of thrombin-induced platelet aggregatio n and, as anticipated, was associated with moderate prolongation of PTT. Im portantly, EFT caused complete inhibition of platelet aggregation without c hanges in coagulation. Platelet counts, fibrinogen levels, and fibrinogen d egradation products remained within the normal ranges in all experiments. Conclusions: Although excellent inhibition of platelet activation was obtai ned with ATA and fucoidin, clinical use may be precluded by concomitant dis turbances of coagulation. Combinations of heparin and EFT may prove benefic ial in preventing the thrombotic disorders associated with xenograft reject ion while maintaining adequate hemostatic responses. These agents are to be evaluated in our pig-to-primate xenotransplantation models.