Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation-A narrative review

Abstract

The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation-anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease.

FIGURE 1

Overview of coagulation and fibrinolytic systems, basic regulatory mechanisms including primary and secondary hemostasis. These mechanisms are functionally similar in both humans and NHP. Including the procoagulant intrinsic, extrinsic, and common pathways and clot dissolving fibrinolytic pathway. AT‐III, antithrombin‐III; PAI, plasminogen activator inhibitor; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; uPA, urokinase‐type plasminogen activator.

FIGURE 2

Proposed mechanisms of coagulation dysregulation in kidney xenotransplantation. The broad range of these mechanisms, including graft rejection, complement activation, and coagulation system incompatibilities and regulation, highlights the abundance of issues that may cause coagulation dysregulation in kidney xenotransplantation. Thus, failure to overcome these challenges may lead to undesirable outcomes during and after xenotransplantation. (Created with BioRender.com.). [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Mechanisms of rhAT and rhAPC in overcoming coagulation dysregulation in pig kidney xenotransplantation. RhAT and rhAPC are shown inhibiting key steps in the cascade, particularly the activities of Factor Xa and Va, thereby regulating thrombin generation and preventing excessive clot formation. RhAT, recombinant human antithrombin; rhAPC, recombinant human‐activated protein C.