The vascular and coagulation issues in xenotransplantation

Vascular injury is a complex process that is central to the rejection of solid-organ xenografts in the preclinical pig-to-primate model of xenotransplantation. This review summarizes recent work that provides insights into the mechanisms of vascular injury in GalT KO pig xenografts.

Several groups have reported further evidence for the importance of preexisting and elicited non-GalT antibodies, which are capable of fixing complement and activating graft endothelial cells. One important study showed that without complete suppression of these antibodies, there is a progressive activation and injury of xenograft endothelium, resulting in the development of thrombotic microangiopathy and graft loss. The mechanism of molecular incompatibilities affecting the control of coagulation across the species barrier has been examined in finer detail. The failure of pig thrombomodulin to promote activation of human protein C was found to be due to a deficiency in cofactor activity rather than to its capacity to bind human thrombin. On a positive note, pig tissue factor pathway inhibitor appears to be capable of efficiently regulating the human tissue factor pathway, contrary to earlier reports. We and others remain optimistic that overexpressing complement regulators anticoagulant proteins or both on the GalT knockout background will provide a significant protective effect, but definitive testing of this approach in the preclinical model is still forthcoming.

Preventing the activation of xenograft endothelium and consequent intravascular coagulation is critical to the future success of solid-organ xenotransplantation.