Intravascular Thrombosis in Discordant Xenotransplantation

Abstract

A series of immunological and physiological barriers must be overcome for the successful clinical application of xenotransplantation. The acute phases of xenograft rejection have been prevented or at least attenuated by a variety of interventions including treatment of the recipient and genetic modification of the donor. However, recent data suggest that xenografts have a heightened susceptibility to intravascular thrombosis, a process that is emerging as a major contributor to xenograft loss. Current data strongly suggest that thrombosis is primarily a direct consequence of the rejection process, but it may also be facilitated by the failure of porcine regulators of coagulation to efficiently regulate the primate coagulation cascade. Systemic anticoagulant therapy has met with limited success and poses significant risks. Genetic strategies to express antithrombotic agents on xenograft endothelium appear to be more promising and achievable, with candidate molecules including human and leech anticoagulants and the antiplatelet enzyme CD39. Deletion of porcine procoagulants may also prove to be a useful approach.

Heparin nanomodification improves biocompatibility and biomechanical stability of decellularized vascular scaffolds

“…[5][6][7]13 To prevent early thrombosis after vascular xenograft implantation, systemic anticoagulant therapy is commonly used and this increases the risk of bleeding complications. 13 A thromboresistant surface or endothelialization of a vascular graft can effectively prevent thrombosis. Establishing a thromboresistant surface is crucial to prevent formation of blood clots in the initial phase of graft implantation.…”

Immunological Challenges and Therapies in Xenotransplantation

“…A similar picture can be seen after heart xenotransplantation (Shimizu et al 2008), in which case, AHXR is characterized by antibody and complement deposition on the capillary walls, multiple microthrombi in the capillaries, myocardial ischemia, and necrosis. The pathogenesis of AHXR is assumed to be multifactorial, but preformed and induced antibodies directed against the endothelium are believed to be the primary factors triggering AHXR, resulting in endothelial activation and orienting the anticoagulative properties of the endothelium toward a procoagulative phenotype favoring thrombosis (Crikis et al 2006).…”

Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

“…M icrovascular thrombosis is the major feature of rejection of porcine solid organ xenografts, regardless of the immunosuppressive regimen or donor type (1,2). The pathogenic mechanism of early (hyperacute rejection) and delayed humoral xenograft rejection (acute vascular rejection, also called acute humoral xenograft rejection) includes a distortion of endothelial shape caused by the binding of antibodies to the endothelium and activation of the complement cascade (3).…”