Disordered regulation of coagulation and platelet activation in xenotransplantation

Abstract

Rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation (DIC). Similarly, bone marrow-derived cellular xenotransplantation procedures are associated with endothelial cell activation and thrombotic microangiopathic injury. These complications generally develop despite the best available measures for depletion of xenoreactive natural antibody, inhibition of complement activation and suppression of T- and B-cell mediated immune responses. The mechanisms underlying the DIC and thrombotic microangiopathy associated with xenotransplantation are unclear. A proposed primary biological dysfunction of xenografts with respect to regulation of clotting could amplify vascular injury, promote immunological responses and independently contribute to graft failure. Disordered thromboregulation could have deleterious effects, comparable to unregulated complement activation, in the pathogenesis of xenograft rejection and may therefore represent a substantive barrier to xenotransplantation.

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

“…Porcine TFPI does not efficiently neutralize human factor Xa (12). Finally, in addition to initiating clotting, thrombin may stabilize clots and can trigger further endothelial cell activation and platelet aggregation and activation (8,9).…”

“…Additional intravascular TF is expressed by monocytes adhering to activated platelets and endothelial cells at the site of injury, as well as by the activated endothelial cells themselves (7,8). Endothelial cell activation also results in the loss of heparan sulfate and its associated molecules ATIII and TFPI, the disappearance of TM from the cell surface (9), and the expression of inflammatory mediators such as platelet-activating factor (10). Cross-species molecular incompatibilities between activated coagulation components and their inhibitors may further tip the balance towards activation of coagulation (9).…”

“…Endothelial cell activation also results in the loss of heparan sulfate and its associated molecules ATIII and TFPI, the disappearance of TM from the cell surface (9), and the expression of inflammatory mediators such as platelet-activating factor (10). Cross-species molecular incompatibilities between activated coagulation components and their inhibitors may further tip the balance towards activation of coagulation (9). Porcine TM fails to efficiently bind human thrombin and hence fails to catalyze the generation of the activated human protein C, which is a Antithrombin Protects Pig-To-Primate Xenografts Figure 1: Proposed events leading to vascular rejection of a pig-to-primate xenograft.…”

Thrombotic Microangiopathy

“…This is not surprising as there are several molecular incompatibilities between human clotting factors and thromboregulatory molecules present on pig EC. In particular, thrombomodulin and tissue factor pathway inhibitor are incompatible with human clotting factors, and as a result pig EC is naturally prothrombotic when exposed to the human circulation (16). If we are to overcome this problem and bring renal xenotransplantation to the clinic, then we need to develop a pig whose EC lacks ␣Gal and expresses both human complement regulatory and thromboregulatory molecules.…”

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

“…Diffuse hemorrhage occurs in renal and cardiac xenotransplantation only after hyperacute rejection has been prevented. [10][11][12][13][14] Discordant hepatic xenotransplantation will not move toward the clinic until this hemorrhage can be prevented. No published reports analyze the mechanism of the hemorrhage that follows discordant hepatic xenotransplantation.…”