Integrated Multi‐Omics Analysis of Coagulation Dysregulation and Immune Pathway Alterations in 10‐Gene Pig‐to‐Monkey Liver Xenotransplantation: A Case Report

Liver xenotransplantation has the potential to address the global shortage of donor organs; however, coagulation dysregulation remains a predominant barrier to long-term liver xenograft survival. In this study, orthotopic liver xenotransplantation was performed using a 10-gene-edited (GTKO/CMAHKO/β4GalNT2KO/hCD46/hCD55/hCD59/hTBM/hCD39/hEPCR/hCD47) porcine donor liver transplanted into a nonhuman primate recipient. Independent of graft function, which remained stable, an unexpected interruption of the oxygen supply on POD 3 triggered a terminal event, leading to death on POD 4. Despite technical success, rapid consumptive coagulopathy developed within 24 h, characterized by severe thrombocytopenia, fibrinogen depletion, and prolongation of coagulation times. Declining plasma von Willebrand factor activity (vWF) and reduced graft vWF expression accompanied these changes. Integrated longitudinal hematologic monitoring, histopathology, transcriptomics, and proteomics were used to define early graft injury. Histological analysis demonstrated microvascular injury with macrophage and B cell infiltration and immunoglobulin deposition, without T cell involvement. Molecular profiling revealed a dominant recipient innate immune response enriched for macrophage-mediated phagocytosis, adhesion, and proteasome pathways, alongside activation of complement and coagulation cascades. Concurrently, the donor graft showed downregulation of key metabolic enzymes, indicating early metabolic stress. These findings indicate that macrophage-driven innate immunity and systemic coagulation exhaustion represent principal early challenges in liver xenotransplantation, highlighting the complement-coagulation axis and macrophage activation as critical therapeutic targets for improving xenograft outcomes. However, given the intense induction immunosuppression and early severe systemic inflammation, these multi-omics findings reflect a complex interplay of graft injury and pharmacological intervention, requiring cautious interpretation.