INHIBITION OF PLATELET GPIIBIIA IN AN EX-VIVO MODEL OF HYPERACUTE XENOGRAFT REJECTION DOES NOT PROLONG CARDIAC SURVIVAL-TIME

Discordant cardiac xenografts are rapidly rejected in a process charac terized by platelet activation with microvascular thrombosis, termed h yperacute rejection (HAR). The fibrinogen receptor GPIIbIIIa is crucia l for the formation of platelet aggregates and potentiates platelet ad hesion to subendothelial matrix, We have studied the effects of a spec ific GPIIbIIIa antagonist (GPI 562) in an ex vivo working heart model using discordant porcine hearts perfused with fresh, heparinized human blood. Stable plasma GPI 562 inhibitory levels were confirmed by inhi bition of human platelet aggregation in vitro. Biopsies from the left ventricle of rejected hearts were analyzed by immunopathology. Control porcine hearts (n=8) underwent HAR and ceased functioning at around 6 0 min. Hearts perfused with human blood containing GPI 562 at 0.5 mu M (n=5) appeared to show an initial increase in coronary blood flow rel ative to controls, but neither this difference nor survival times of t he hearts reached significance. Mean cardiac output values were 7.3 ml /g (SEM 2.5) in the experimental group and 5 ml/g (SEM 0.6) in the con trol group following 5 min of working mode and were comparable at othe r timepoints. Platelet counts in the perfusate were maintained in the presence of GPI 562, unlike the reduction of over 50% in control sampl es. Immunohistochemistry suggested decreased platelet vascular pluggin g as determined by P-selectin staining in the GPI 562 group, with asso ciated reduction in neutrophil adherence and fibrin deposition. The us e of GPI 562 in this ex vivo model conferred no marked benefits with r espect to cardiac function and explant survival despite some positive differences on histological comparison. Further studies of this agent, in association with modalities of complement inhibition, are warrante d in other models of discordant xenograft rejection.