Overcoming Coagulation Dysregulation in Pig Solid Organ Transplantation in Nonhuman Primates

Abstract

There has recently been considerable progress in the results of pig organ transplantation in nonhuman primates, largely associated with the availability of (i) pigs genetically engineered to overcome coagulation dysregulation, and (ii) novel immunosuppressive agents. The barriers of thrombotic microangiopathy and/or consumptive coagulation were believed to be associated with (i) activation of the graft vascular endothelial cells by a low level of antipig antibody binding and/or complement deposition and/or innate immune cell activity, and (ii) molecular incompatibilities between the nonhuman primate and pig coagulation-anticoagulation systems. The introduction of a human coagulation-regulatory transgene, for example, thrombomodulin, endothelial protein C receptor, into the pig vascular endothelial cells has contributed to preventing a procoagulant state from developing, resulting in a considerable increase in graft survival. In the heterotopic (non-life-supporting) heart transplant model, graft survival has increased from a maximum of 179 days in 2005 to 945 days. After life-supporting kidney transplantation, survival has been extended from 90 days in 2004 to 499 days. In view of the more complex coagulation dysfunction seen after pig liver and, particularly, lung transplantation, progress has been less dramatic, but the maximum survival of a pig liver has been increased from 7 days in 2010 to 29 days, and of a pig lung from 4 days in 2007 to 9 days. There is a realistic prospect that the transplantation of a kidney or heart, in combination with a conventional immunosuppressive regimen, will enable long-term recipient survival.