INHIBITION OF PLATELET INTEGRIN GPIIBIIIA PROLONGS SURVIVAL OF DISCORDANT CARDIAC XENOGRAFTS

The integrin GPIIbIIIa is known to be crucial to the formation of plat elet aggregates and potentiates adhesion to subendothelial matrices vi a fibrin(ogen), von Willebrand factor, and vitronectin, Given the demo nstration by us and others of widespread platelet aggregation during x enograft rejection, we hypothesized that platelet thrombi might contri bute to graft dysfunction during development of hyperacute rejection ( HAR), as well as during what we have termed delayed xenograft rejectio n (DXR), e.g., as seen in complement-depleted rat recipients of guinea pig cardiac xenografts, We therefore tested the effects of a specific GPIIbIIIa antagonist (SDZ GPI 562) during xenograft rejection. Lewis rats received heterotopic guinea pig cardiac xenografts and were treat ed with GPI 562 alone (HAR model) or in combination with cobra venom f actor (CVF) (DXR model), A high (0.5 mg/kg) or a low dose (0.1 mg/kg) of GPI 562 was administered perioperatively and then given twice daily in the same dose until rejection, CVF was given daily until rejection , Plasma drawn after the first dose of GPI 562 and at the time of reje ction was tested for the ability to inhibit ADP-stimulated platelet ag gregation in vitro, Rejected grafts were analyzed by immunohistology. Plasma hom animals in the high-dose group completely inhibited platele t aggregation in vitro, whereas plasma from the low-dose group resulte d in only partial inhibition, Similarly, whereas low-dose GPI 562 fail ed to prolong graft survival, high-dose GPI 562 showed a statistically significant increase in graft survival in both HAR and DXR groups, Im munohistologic studies of HAR showed little effect of GPI 562 on plate let aggregation or activation and no effect on fibrin deposition. Howe ver, the combination of high-dose GPI 562 and CVF resulted in a signif icant decrease in intragraft platelet aggregation, P-selectin expressi on, and leukocyte infiltration compared with CVF alone. In conclusion, GPIIbIIIa antagonist therapy can inhibit platelet aggregation in vitr o and prolong xenograft survival, The diminution of intragraft platele t microthrombi formation and leukocyte infiltration suggests an import ant role for platelet-dependent mechanisms in leukocyte recruitment du ring DXR.