Background: Xenogeneic pig lung perfusion with human blood leads to the initiation of rejection mechanisms that are associated with the immediate sequestration of circulating platelets. Here we ask whether blockade of platelet GPIb and GPIIb/IIIa receptors modulates platelet sequestration and activation during xenogeneic perfusion of GalTKO.hCD46 pig lungs. Methods: Pig lungs were perfused with heparinized fresh human blood until failure or elective termination at 4h. The blood was treated with αGPIb Fab (6B4, 10mg/L blood, n=6), αGPIIb/IIIa (ReoPro, 3.5mg/L blood, n=6), or both drugs (n=4). In 2 additional groups the donor pig received 1-deamino-8-d-arginine vasopressin (DDAVP, 3μg/kg) and the perfusate was left untreated or treated with αGPIb (n=6 each). 37 previously published GalTKO.hCD46 lung perfusions with human blood served as reference. Results: Platelet sequestration was significantly delayed in αGPIb, aGPIb+DDAVP and aGPIb+aGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162min reference, p=0.016), and platelet (as CD62P and βTG) and coagulation cascade activation (as F1+2) were significantly inhibited, when pigs were pre-treated with DDAVP, with or without aGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration. Conclusion: We confirm that the GPIb-VWF axis plays an important role in xenogeneic coagulation cascade activation and platelet sequestration. Blocking this interaction by αGPIb significantly reduces platelet activation and delayed platelet sequestration, effects amplified by adding αGPIIb/IIIa or DDAVP pre-treatment of the donor pig. Mechanisms driving residual coagulation cascade activation, inflammation, and platelet and neutrophil sequestration, and their contribution to lung xenograft injury, remain to be elucidated.

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