Controlling coagulation dysregulation in xenotransplantation

Abstract

Purpose of review Deletion of the α1,3-galactosyltransferase (GalT) gene in pigs has removed a major xenoantigen but has not eliminated the problem of dysregulated coagulation and vascular injury. Rejecting GalT KO organ xenografts almost invariably show evidence of thrombosis and platelet sequestration, and primate recipients frequently develop consumptive coagulopathy (CC). This review examines recent findings that illuminate potential mechanisms of this current barrier to successful xenotransplantation. Recent findings The coagulation response to xenotransplantation differs depending on the type of organ and quite likely the distinct vasculatures. Renal xenografts appear more likely to initiate CC than cardiac xenografts, possibly reflecting differential transcriptional responses. Liver xenografts induce rapid and profound thrombocytopenia resulting in recipient death within days due to bleeding; ex vivo data suggest that liver endothelial cells and hepatocytes are responsible for platelet consumption by a coagulation-independent process. It has been proposed that expression of recipient tissue factor on platelets and monocytes is an important trigger of CC. Finally, pigs transgenic for human anticoagulants and antithrombotics are slowly but surely coming on line, but have not yet been rigorously tested to date. Summary Successful control of coagulation dysregulation in xenotransplantation may require different combinatorial pharmacological and genetic strategies for different organs.

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

“…For example, coagulation is exacerbated during inflammation by the down-regulation and degradation of critical endothelial anticoagulant and antiplatelet systems. This is best illustrated by the influence of inflammatory TNF-α and IFN-γ on thrombomodulin gene expression and mRNA stability, [57][58][59] as well as proteolytic inactivation of endothelial protein C receptor (EPCR) by neutrophil proteinase-3. [60] Our data provide a basic perspective for understanding molecular incompatibilities that may relate to excessive platelet activity in pig-to-primate xenotransplantation, and also provide a clue for strategies to control excessive platelet function in prevention of thrombosis.…”

Modifiers of complement activation for prevention of antibody-mediated injury to allografts

“…One such example is the coagulation pathway whose action is often intertwined with that of the complement system [117,118], and which is usually activated in the setting of AbMR [5, 68,69]. A large body of research has been performed examining the role of disordered coagulation, and its interaction with complement in the hyperacute and early phases of xenotransplant rejection [114,117,119,120].…”

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

“…This was believed to be related to activation of the vascular endothelium, converting its usual anticoagulant state into a procoagulant state, which was in part associated with molecular incompatibilities between the pig and primate coagulation-anticoagulation systems [17]. These complications could be largely prevented by expression in the organ-source pig of one or more human coagulation-regulatory proteins, for example, thrombomodulin or endothelial protein C receptor.…”