Background.The influence of platelet von Willebrand factor (vWF)–glycoprotein (GP)Ib-V-IX and GPIIb–IIIa receptor interactions in the context of hyperacute rejection (HAR) of pulmonary xenografts has not previously been explored.Methods.Aurintricarboxylic acid (ATA, an inhibitor of platelet-GPIb interactions with vWF), SC52012A (SC, a synthetic GPIIb/IIIa inhibiting peptide), or both were added to heparinized whole human blood before perfusion of isolated piglet lungs. Results were compared with unmodified blood (“unmodified”).Results.Perfusion of porcine lungs with unmodified human blood resulted in an immediate rise in pulmonary vascular resistance (PVR), fluid and platelet sequestration in the lung, and, without exception, cessation of function within 15 minutes with a mean survival of 8 minutes. Addition of ATA or SC before lung perfusion significantly decreased the rise in PVR, diminished histamine release, and prolonged survival to 31±11 and 31±22 minutes, respectively. When the therapies were combined, mean survival was 156±77 minutes (P<0.05 vs. either monotherapy). Complement activation was synergistically attenuated only when the drugs were used together.Conclusions.Platelet protein receptor adhesive interactions play an important role in amplification of complement activation during hyperacute lung rejection. Inhibiting recruitment of platelets at the site of initial immunologic injury to endothelial cells may protect porcine organs against thrombosis and inflammation during the initial exposure to human blood.