Coagulation, platelet activation and thrombosis in xenotransplantation

Abstract

Xenotransplantation may become clinically feasible once the mechanisms of graft loss and rejection are better understood. Inflammatory reactions to vasculature of grafted pig organs and pancreatic islets have been linked to procoagulant activation and consumption with resulting thrombosis that precludes long-term function. Although development of alpha-1,3-galactosyltransferase gene-knockout swine with removal of a dominant xenoantigen has been an important advance, major problems still persist. Consumptive coagulopathy and platelet sequestration are initiated by immune responses associated with xenograft rejection and are exacerbated by putative intrinsic functional incompatibilities. Thrombotic processes together with progressive xenograft microangiopathy and infarction are intertwined with humoral immune reactions that may be secondary, at least in part, to 'natural' or elicited nongalactosyl antibodies. These immune responses are further exacerbated by the documented intrinsic molecular incompatibilities in the vascular regulation of blood clotting and extracellular nucleotide homeostasis between discordant species. Hence, limited benefits have been achieved with currently available pharmacological antithrombotics and anticoagulants. Proposed strategies to tackle this problem will include optimal immunosuppressive interventions, attempts to induce tolerance, judicious and more effective use of anti-thrombotics with development of mutant swine either transgenic for human anticoagulants and thromboregulatory factors or null for defined porcine procoagulants.