Beyond conventional immunosuppression: tailoring perioperative management protocols for clinical xenotransplantation.

Clinical xenotransplantation offers a conceptually unlimited supply of donor organs, owing to transformative advances in gene-editing technologies. However, the pharmacological and physiological distinctions between allo- and xenotransplantation pose a major challenge. Unlike allografts, xenografts simultaneously trigger complement-amplified humoral rejection, thromboregulatory incompatibility driven by porcine-human molecular mismatch, and species-specific innate inflammatory cascades. However, conventional calcineurin-based immunosuppression provides no meaningful coverage for these pathways. We analyzed these differences to provide the mechanistic foundation for a dedicated perioperative framework. The proposed framework encompasses immunologic assessment; porcine cytomegalovirus (PCMV)/roseolovirus-free donor certification; intensified induction; third-generation anti-CD154 monoclonal antibodies with pharmacokinetically verified trough targets; normothermic machine perfusion with anti-inflammatory perfusate supplementation; and thromboregulatory rescue protocols incorporating tranexamic acid, heparin, and antiplatelet agents. Furthermore, we aimed to address consumptive coagulopathy; targeted suppression of macrophage- and neutrophil-driven innate inflammatory cascades, alongside activation of xenoreactive natural killer cells; and multimodal surveillance integrating flow cytometry, donor-derived cell-free DNA, and metagenomic sequencing for porcine endogenous retrovirus and PCMV monitoring. By combining compassionate-use failure analysis with prospective trial design aligned with the 2026 International Society for Heart and Lung Transplantation consensus statement, this review proposes a standardized perioperative management protocol that is applicable to clinical xenotransplantation.