Primate Recipients of Porcine Livers Develop Fatal Coagulopathy Despite Prevention of Thrombocytopenia

Abstract

Background: While allogeneic liver transplantation has evolved to the standard of care for end-stage cirrhosis, it is severely limited by organ shortage. Previous attempts to pursue xenogeneic transplantation, placing GalT-KO swine livers into non-human primates, have yielded only short-term survival primarily ascribed to the immediate post-implantation thrombocytopenia observed leading to subsequent fatal coagulopathy. We have shown that aminocaproic acid (Amicar) dramatically preserves platelet levels, but that fatal hemorrhage still prevails. Methods: Three baboons received orthotropic hepatic xenografts from size-matched miniature swine under immunosuppression, proven adequate for xenotransplantation of other organs. Two baboons received, in addition, treatment with Amicar starting on POD 0 or 5 following transplantation. Results: The recipients survived, with good liver function, for 6, 8, and 9 days respectively. The platelet counts plummeted shortly after transplantation. In the first animal (B274), progressive platelet loss was unresponsive to transfusion of allogeneic platelets. In the second recipient (B291) Amicar was started on POD 5, following which platelet counts stabilized in the 30-60 k/μl range throughout a 9-day survival period, the longest reported to date. The third animal (B317) survived for 8 days with platelet numbers rescued to > 100 k/μl during continuous Amicar treatment started before reperfusion. Serial xenograft biopsies did not show any signs of rejection at any time point. Liver function parameters were within normal limits and the recipient animals appeared clinically well. Nevertheless, all animals eventually developed internal hemorrhage. The causes of death were therapy refractory coagulopathy, which in B291 and B317 possibly was exacerbated by enterococcal infection, detected in ascites cultures. Conclusions: These observations indicate for the first time that thrombocytopenia after liver xenotransplantation can be controlled by Amicar. The finding that fatal hemorrhage occurred despite satisfactory platelet levels, suggests that other incompatibilities between porcine and primate coagulation pathways may exist. Our results suggest that improved immunosuppressive regimens to reduce the risk of infection and additional measures to address coagulation factor incompatibilities will likely be required to achieve long-term survival of xenogeneic livers.Table: [Platelet count]