Modifying consumptive coagulopathy following discordant porcine xenotransplantation - In vitro and in vivo analysis of enhanced HO-I expression on native and modified porcine cells and kidneys

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The aim of project IV is to analyse the aberrant activation of the human coagulation system following contact with porcine endothelium. For this purpose ex vivo porcine kidney and lung perfusion systems were modified to allow for analysis of coagulation activation parameters. The project will focus on the identification of potential targets for pharmacological abrogation of aberrant coagulation. Pharmacological intervention will be performed using different drugs acting at various levels of the coagulation process like Hirulog, activated protein C (APC), prostacyclin and nitroprusside. The administration of exogenous recombinant APC shall serve as a substitute for the non-functional porcine thrombomodulin to human thrombin interaction, which physiologically generates APC. Prostacyclin as well as Nitroprusside are aimed to cause inhibition of human platelet aggregation. Following identification of major incompatibilities susceptible to exogenous pharmacological intervention, alteration of these defects should be possible by introduction of appropriate human regulators of the coagulation cascade by rAAV mediated gene transfer or by genetic engineering. Finally, multi-transgenic porcine organs that had been engineered in a way to express human regulators of the coagulation system such as e.g. human thrombomodulin or HO-I will be tested in the perfusion circuits as to their ability to interfere with the aberrant coagulation activation in these systems.