Abstract
Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic modifications in pigs and intensive pharmacological support. Transfusion of human coagulation factors and complex immunosuppressive regimens have resulted in substantial improvements in recipient survival. The fundamental biological mechanisms of thrombocytopenia and coagulation dysregulation remain incompletely understood. Current studies demonstrate that porcine von Willebrand Factor binds more tightly to human platelet GPIb receptors due to increased O-linked glycosylation, resulting in increased human platelet activation. Porcine liver sinusoidal endothelial cells and Kupffer cells phagocytose human platelets in an asialoglycoprotein receptor 1-dependent and CD40/CD154-dependent manner, respectively. Porcine Kupffer cells phagocytose human platelets via a species-incompatible SIRPα/CD47 axis. Key drivers of coagulation dysregulation include constitutive activation of the extrinsic clotting cascade due to failure of porcine tissue factor pathway inhibitor to repress recipient tissue factor. Additionally, porcine thrombomodulin fails to activate human protein C when bound by human thrombin, leading to a hypercoagulable state. Combined genetic modification of these key genes may mitigate liver xenotransplantation-induced thrombocytopenia and coagulation dysregulation, leading to greater recipient survival in pig-to-nonhuman primate liver xenotransplantation and, potentially, the first pig-to-human clinical trial.
Highlights
Substantial infiltration by recipient macrophages and neutrophils was noted within the graft. These findings suggest that an integrated immune response involving both the innate and adaptive immune systems likely continues to exacerbate the consumptive coagulopathy and thrombocytopenia characteristic of species-discordant liver xenotransplantation
All xenoperfusion groups demonstrated significantly lower platelet counts when compared to alloperfusion controls. These findings suggest that porcine von Willebrand Factor (vWF)/primate GpIb interspecies incompatibilities, increased O-linked glycosylation, increase platelet activation and consumption, and contribute to liver xenotransplantation-induced thrombocytopenia
Degraded human platelets were observed inside porcine hepatocytes. These findings provide strong evidence for liver sequestration of recipient platelets by porcine liver sinusoidal endothelial cell (LSEC), Kupffer cells, and hepatocytes as a key mechanism of liver xenotransplantation-induced thrombocytopenia
Summary
End-stage organ failure currently plagues over 106,000 people in the United States [1]. A non-life-supporting pig-to-NHP heart xenograft survived for almost three years (945 days) [5] Despite such promising advances in the field, the success of liver xenotransplantation has historically lagged behind its solid-organ counterparts. The primary barriers to successful liver xenotransplantation have consistently been the severe and rapid thrombocytopenia [10, 11] combined with uncontrollable coagulation dysregulation [11–13] that inevitably results in fatal hemorrhage of the recipient [9, 11, 13]. The resolution of these major barriers may allow for the first pig-to-human liver xenotransplantation clinical trials as a bridge to allotransplantation, and potentially as definitive therapy for endstage liver disease. 2010 GTKO 2010 GTKO.hCD46 2010 GTKO.hCD46 2012 GTKO 2012 MGH MS, GTKO 2014 MGH MS, GTKO 2015 WZ MS, GTKO 2016 MGH MS, GTKO 2016 MGH MS, GTKO 2017 MGH MS, GTKO 2020 GTKO, CMAH-KO, B4GALNT2-KO, PERV-KO, hCD46, hCD55, hCD59, hTHBD, hTFPI, hCD39, hB2M, HLA-E, hCD47-TG
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