Graft-derived VWF drives platelet activation and thrombocytopenia during porcine liver xenotransplantation to brain-dead human recipients

作者：Linda Zhao, Sokratis A. Apostolidis, Aae Suzuki, Amrita Sarkar, Qian Guo, F. Li, Alex Sagar, John I. Fallon, Mohamed Elzawahry, Syed Hussain Abbas, Leanne Lanieri, Kristen Getchell, Susan C. Low, Kim M. Olthoff, E E Furth, Brendan J. Keating, Peter J. Friend, Mortimer Poncz, Abraham Shaked, Charles S. Abrams · 发表于：Journal of Clinical Investigation · 年份：2026 · DOI：10.1172/jci200800 · 被引用次数：3 · 研究领域：Xenotransplantation and immune response、Organ Transplantation Techniques and Outcomes、Liver physiology and pathology

BACKGROUNDGenetically engineered porcine livers are being developed as a bridge therapy for acute liver failure, providing detoxification and restoration of hepatic protein synthesis. Severe xenograft-associated thrombocytopenia remains a major limitation, and human mechanistic data are scarce.METHODSPlatelet kinetics were characterized in 3 human decedents undergoing extracorporeal cross-circulation with transgenic porcine livers. Platelet counts, transfusion requirements, and clearance patterns were assessed to distinguish consumption from marrow suppression or hypersplenism. Antibody- and complement-directed inhibitors were administered to test immune-mediated mechanisms. Mechanistic studies focused on porcine von Willebrand factor-dependent (pVWF-dependent) platelet activation, including ex vivo blockade with the anti-VWF nanobody caplacizumab, a VWF-directed antibody fragment that prevents VWF-platelet binding. A fourth decedent received caplacizumab during porcine liver perfusion.RESULTSIn all 3 initial cases, 80%-90% of circulating and transfused platelets were rapidly cleared, a pattern inconsistent with marrow suppression or hypersplenism. Antibody and complement inhibition failed to ameliorate thrombocytopenia. Recipient plasma induced robust pVWF-mediated platelet activation analogous to human type IIb von Willebrand disease, which was completely abrogated ex vivo by caplacizumab. In a fourth decedent treated with caplacizumab, aberrant platelet activation was prev...