Clin Transplant Res.  2025 Mar;39(1):12-23. 10.4285/ctr.24.0044.

Addressing glycan and hematological barriers in pig-to-nonhuman primate liver xenotransplantation: challenges and future directions

• Kim JY

• KMID: 2566576
• DOI: http://doi.org/10.4285/ctr.24.0044

Abstract

Achieving long-term survival in pig-to-primate liver xenotransplantation has proven highly challenging due to significant hematological issues. This paper investigates the primary obstacles from a hematological perspective, focusing on coagulation disorders caused by molecular incompatibility between species. It also examines the mismatched glycan structures on the surfaces of platelets and red blood cells, which lead to sequestration and phagocytosis by recipient macrophages. These mismatches underscore the need for improved glycan and molecular compatibility to overcome im- munological and physiological barriers. Moreover, the liver's unique role in synthesizing a wide array of proteins, especially those involved in blood coagulation, introduces additional challenges of molecular incompatibility compared to other organs, such as the heart and kidneys. This study highlights the importance of addressing these challenges to improve the outcomes of liver xenotransplantation and suggests the necessity of strategies like glycan matching and the development of gene-edited pigs specifically tailored for liver transplantation.

Keyword

Xenotransplantation; Liver; Hematology; Coagulation; Platelet

Figure

• 

  Fig. 1 Proposed mechanisms of coagulation dysregulation in liver xenotransplantation. The molecular incompatibility of coagulation factors leads to excessive thrombin generation, fibrin formation, and consumptive coagulopathy. Activation of the coagulation cascade via tissue factor (TF) and Factor VIIa is highlighted, with regulatory pathways such as antithrombin (AT) and activated protein C (aPC)/protein S (PS) shown as inhibitory mechanisms. Platelet overactivation arises from interactions between recipient platelet glycoprotein Ib (GPIb) and pig von Willebrand factor (vWF), triggering platelet aggregation and fibrin adhesion. Additionally, platelet sequestration and phagocytosis by Kupffer cells and sinusoidal endothelial cells contribute to thrombocytopenia, exacerbating the imbalance between thrombosis and bleeding. These interactions underscore the multifaceted challenges in maintaining hemostatic balance in xenotransplantation settings. PBMC, peripheral blood mononuclear cell; TFPI, tissue factor pathway inhibitor.

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