Pig thrombomodulin cannot activate human protein C

Pig thrombomodulin is structurally incompatible with human protein C, meaning the natural anti-clotting mechanism that should protect a transplanted organ's blood vessels does not function across species. In a normal human transplant, thrombomodulin on the donor endothelium activates protein C, which breaks down clots before they damage the graft. In a pig-to-human transplant, this pathway is broken. The result is consumptive coagulopathy and thrombotic microangiopathy (TMA): microscopic blood clots form throughout the graft's vasculature, destroying it from the inside. This is what happened in a pig-to-human liver xenotransplant in May 2024, where the patient showed improving liver function for 31 days before xenotransplantation-associated TMA emerged and destroyed the graft. Genetic engineers have responded by inserting human thrombomodulin (hTBM) and human endothelial protein C receptor (hEPCR) transgenes into donor pigs, but these transgenes must be expressed at the right level, in the right cells, at the right time, and current gene-editing approaches cannot guarantee uniform expression across all endothelial cells in an organ.