Which anti‐platelet therapies might be beneficial in xenotransplantation?

Abstract

Xenotransplantation could provide an unlimited and elective supply of grafts, once mechanisms of graft loss and vascular injury are better understood. The development of α-1,3-galactosyltransferase gene-knockout (GalT-KO) swine with the removal of a dominant xeno-antigen has been an important advance; however, delayed xenograft and acute vascular reaction in GalT-KO animals persist. These occur, at least in part, because of humoral reactions that result in vascular injury. Intrinsic molecular incompatibilities in the regulation of blood clotting and extracellular nucleotide homeostasis between discordant species may also predispose to thrombophilia within the vasculature of xenografts. Although limited benefits have been achieved with currently available pharmacological anti-thrombotics and anti-coagulants, the highly complex mechanisms of platelet activation and thrombosis in xenograft rejection also require potent immunosuppressive interventions. We will focus on recent thromboregulatory approaches while elucidating appropriate anti-platelet mechanisms. We will discuss potential benefits of additional anti-thrombotic interventions that are possible in transgenic swine and review recent developments in pharmacological anti-platelet therapy.

Thrombocytopenia after pig‐to‐baboon liver xenotransplantation: where do platelets go?

“…Consequently, therapeutic intervention to prevent coagulation dysregulation in xenograft recipients will most likely encompass anti-platelet agents or the genetic engineering of the pigs to inhibit platelet activation and/or aggregation. Careful assessment of the fate of circulating platelets in xenograft recipients and their possible interaction with WBC will be needed to determine the anti-platelet agent of choice [11], thus inhibiting aggregation but minimizing the risk of bleeding, or the genetic manipulation that might be beneficial. Our group has reported that aggregation of platelets with WBC begins as early as day 2 in baboons after receiving pig kidney xenografts [1].…”

Kidney xenotransplantation

“…Administration of recombinant human antithrombin was clearly protective in the first week after pig-to-baboon renal xenotransplantation ( 98 ), but had no apparent long-term benefit in the pig-to-macaque renal model ( 142 ), even when combined with human activated protein C ( 143 ). Other reagents have also produced mixed results, and it would be reasonable to conclude that both genetic modification and pharmacotherapy will be necessary to fully control inflammation and coagulation in renal xenotransplantation ( 144 ).…”

Xenotransplantation literature update, March – April 2011

“…In addition, Schmelzle et al. [9] discussed potential benefits of additional antithrombotic interventions in transgenic pigs and recent developments in pharmacological anti‐platelet therapy.…”