{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T09:44:01Z","timestamp":1792057441755,"version":"4.4.0"},"reference-count":54,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":44,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005273","name":"Natural Science Foundation of Yunnan Province","doi-asserted-by":"publisher","award":["202302AA310025"],"award-info":[{"award-number":["202302AA310025"]}],"id":[{"id":"10.13039\/501100005273","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The shortage of donor livers motivates the development of pig\u2010to\u2010non\u2010human\u2010primate liver xenotransplantation. While gene\u2010editing\u2010mediated xenoantigen knockout reliably prevents hyperacute rejection (HAR), nevertheless, the integrated in\u2010vivo phenotype and coagulation\u2010associated complications of multi\u2010gene\u2010edited porcine livers remain poorly characterized. To address this knowledge gap, we established orthotopic auxiliary partial liver xenotransplantation in non\u2010human primates using 6\u2010, 8\u2010, and 10\u2010gene\u2010edited porcine donors, and performed multi\u2010modal longitudinal phenotyping covering graft function assessment, immune\u2010coagulation profiling, PERV\/PCMV DNA screening, as well as mechanistic analyses of graft injury. Consistent with prior reports, all three transplantations succeeded; xenoantigen knockout prevented HAR, and grafts maintained basal function with only mild sinusoidal congestion and limited complement\u2010antibody deposition. Strikingly, every recipient developed severe thrombocytopenia, graft thrombosis, and thrombotic microangiopathy, which ultimately culminated in graft dysfunction. Further analyses revealed that aberrant endothelial ASGR1 and vWF expression together with porcine macrophage\u2010mediated platelet clearance constituted principal drivers of platelet depletion; meanwhile, PERV and PCMV DNA were undetectable in recipient tissues. Collectively, although xenoantigen knockout effectively averts HAR, irreversible coagulation\u2010cascade activation, thrombosis and consumptive coagulopathy still represent the principal barriers to long\u2010term xenograft survival even in the setting of donor\u2010expressed human anticoagulant transgenes hTBM, hCD39, and hEPCR. These findings provide valuable insights for future donor\u2010engineering and complication\u2010intervention strategies.<\/jats:p>","DOI":"10.1111\/xen.70175","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T08:44:14Z","timestamp":1792053854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multigene\u2010Edited Pig\u2010to\u2010Rhesus\u2010Macaque Liver Xenotransplantation: Multifaceted Profiling\u2010of\u2010Post\u2010transplant Phenotypes"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7615-5197","authenticated-orcid":false,"given":"Yao","family":"Gao","sequence":"first","affiliation":[{"name":"The Organ Transplantation Center The First Affiliated Hospital of Kunming Medical University  Kunming Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"He","sequence":"additional","affiliation":[{"name":"Guangzhou Medical Research Institute of Infectious Diseases Department of Hepatology Guangzhou Eighth People's Hospital, Guangzhou Medical University  Guangzhou Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-4871","authenticated-orcid":false,"given":"Zhong","family":"Zeng","sequence":"additional","affiliation":[{"name":"The Organ Transplantation Center The First Affiliated Hospital of Kunming Medical University  Kunming Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3302-823X","authenticated-orcid":false,"given":"Han\u2010Fei","family":"Huang","sequence":"additional","affiliation":[{"name":"The Organ Transplantation Center The First Affiliated Hospital of Kunming Medical University  Kunming Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"issue":"9","key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1016\/j.transproceed.2005.09.186","article-title":"Prevention of Hyperacute Rejection in a Model of Orthotopic Liver Xenotransplantation From Pig to Baboon Using Polytransgenic Pig Livers (CD55, CD59, and H\u2010transferase)","volume":"37","author":"Ram\u00edrez P.","year":"2005","journal-title":"Transplantation Proceedings"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11138","article-title":"Chimeric 2C10R4 Anti\u2010CD40 Antibody Therapy is Critical for Long\u2010term Survival of GTKO.HCD46.HTBM Pig\u2010to\u2010primate Cardiac Xenograft","volume":"7","author":"Mohiuddin M. M.","year":"2016","journal-title":"Nature Communications"},{"issue":"3","key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/SLA.0000000000004996","article-title":"Anti\u2010C5 Antibody Tesidolumab Reduces Early Antibody\u2010mediated Rejection and Prolongs Survival in Renal Xenotransplantation","volume":"274","author":"Adams A. B.","year":"2021","journal-title":"Annals of Surgery"},{"issue":"12","key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1111\/j.1600-6143.2009.02850.x","article-title":"Long\u2010term Controlled Normoglycemia in Diabetic Non\u2010human Primates After Transplantation with hCD46 Transgenic Porcine Islets","volume":"9","author":"Windt D. J.","year":"2009","journal-title":"American Journal of Transplantation"},{"issue":"5","key":"e_1_2_7_6_1","doi-asserted-by":"crossref","DOI":"10.1111\/xen.12814","article-title":"Auxiliary Liver Xenotransplantation Technique in a Transgenic Pig\u2010to\u2010non\u2010human Primate Model: A Surgical Approach to Prolong Survival","volume":"30","author":"Lee K. W.","year":"2023","journal-title":"Xenotransplantation"},{"issue":"3","key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/s41591-025-04196-3","article-title":"Extracorporeal Liver Cross\u2010circulation Using Transgenic Xenogeneic Pig Livers With Brain\u2010dead human Decedents","volume":"32","author":"Shaked A.","year":"2026","journal-title":"Nature Medicine"},{"issue":"8","key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1111\/ajt.14341","article-title":"Prolonged Survival Following Pig\u2010to\u2010Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade","volume":"17","author":"Shah J. A.","year":"2017","journal-title":"American Journal of Transplantation"},{"issue":"3","key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jhep.2025.08.044","article-title":"Genetically Engineered Pig\u2010to\u2010human Liver Xenotransplantation","volume":"84","author":"Zhang W.","year":"2026","journal-title":"Journal of Hepatology"},{"issue":"4","key":"e_1_2_7_10_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.trre.2021.100631","article-title":"Auxiliary Liver Transplantation for Management of Acute Liver Failure in Children\u2014Systematic Review","volume":"35","author":"Quadros J.","year":"2021","journal-title":"Transplant Rev (Orlando)"},{"issue":"2","key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1097\/JS9.0000000000003929","article-title":"A Systematic Review and Meta\u2010analysis of Liver Xenotransplantation From Genetically Modified Pigs to Nonhuman Primates","volume":"112","author":"Zhang W.","year":"2026","journal-title":"Int J Surg"},{"issue":"4","key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/lt.24361","article-title":"Longterm Outcomes of Auxiliary Partial Orthotopic Liver Transplantation in Preadolescent Children With Fulminant Hepatic Failure","volume":"22","author":"Weiner J.","year":"2016","journal-title":"Liver Transplantation"},{"issue":"9","key":"e_1_2_7_13_1","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1002\/lt.24509","article-title":"Current Status of Auxiliary Partial Orthotopic Liver Transplantation for Acute Liver Failure","volume":"22","author":"Rela M.","year":"2016","journal-title":"Liver Transplantation"},{"issue":"1","key":"e_1_2_7_14_1","doi-asserted-by":"crossref","DOI":"10.1111\/xen.70011","article-title":"Bridging Therapies\u2014Ex Vivo Liver Xenoperfusion and the Role of Machine Perfusion: An Update","volume":"32","author":"Czigany Z.","year":"2025","journal-title":"Xenotransplantation"},{"issue":"9","key":"e_1_2_7_15_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI200800","article-title":"Graft\u2010derived VWF Drives Platelet Activation and Thrombocytopenia During Porcine Liver Xenotransplantation to Brain\u2010dead human Recipients","volume":"136","author":"Zhao L.","year":"2026","journal-title":"Journal of Clinical Investigation"},{"issue":"5","key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1097\/TP.0b013e3181e98d51","article-title":"Hepatic Function After Genetically Engineered Pig Liver Transplantation in Baboons","volume":"90","author":"Ekser B.","year":"2010","journal-title":"Transplantation"},{"issue":"2","key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1600-6143.2009.02945.x","article-title":"Impact of Thrombocytopenia on Survival of Baboons With Genetically Modified Pig Liver Transplants: Clinical Relevance","volume":"10","author":"Ekser B.","year":"2010","journal-title":"American Journal of Transplantation"},{"issue":"6","key":"e_1_2_7_18_1","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1399-3089.2011.00679.x","article-title":"Thrombocytopenia After Pig\u2010to\u2010baboon Liver Xenotransplantation: Where Do Platelets Go?","volume":"18","author":"Ezzelarab M.","year":"2011","journal-title":"Xenotransplantation"},{"issue":"6","key":"e_1_2_7_19_1","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/j.1399-3089.2006.00346.x","article-title":"Selected Physiologic Compatibilities and Incompatibilities Between human and Porcine Organ Systems","volume":"13","author":"Ibrahim Z.","year":"2006","journal-title":"Xenotransplantation"},{"issue":"1","key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bcmd.2009.02.004","article-title":"Characterization of Porcine Factor VII, X and Comparison With human Factor VII, X","volume":"43","author":"Chen Y.","year":"2009","journal-title":"Blood Cells, Molecules & Diseases"},{"issue":"1","key":"e_1_2_7_21_1","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1159\/000374067","article-title":"Pig BMSCs Transfected With Human TFPI Combat Species Incompatibility and Regulate the Human TF Pathway in Vitro and in a Rodent Model","volume":"36","author":"Ji H.","year":"2015","journal-title":"Cellular Physiology and Biochemistry"},{"issue":"3","key":"e_1_2_7_22_1","doi-asserted-by":"crossref","DOI":"10.1111\/xen.12393","article-title":"Is Sensitization to Pig Antigens Detrimental to Subsequent Allotransplantation?","volume":"25","author":"Li Q.","year":"2018","journal-title":"Xenotransplantation"},{"issue":"5","key":"e_1_2_7_23_1","doi-asserted-by":"crossref","DOI":"10.1111\/xen.12884","article-title":"Is Allosensitization Detrimental to Pig Organ Xenotransplantation, and Is Xenosensitization Detrimental to Subsequent Organ Allotransplantation? A Debate Organized by the International Xenotransplantation Association (IXA)","volume":"31","author":"Knechtle S.","year":"2024","journal-title":"Xenotransplantation"},{"issue":"2","key":"e_1_2_7_24_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jhep.2023.04.010","article-title":"A Randomized\u2010controlled Trial of Ischemia\u2010free Liver Transplantation for End\u2010stage Liver Disease","volume":"79","author":"Guo Z.","year":"2023","journal-title":"Journal of Hepatology"},{"issue":"10","key":"e_1_2_7_25_1","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1111\/ajt.13909","article-title":"2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody\u2010Mediated Rejection","volume":"16","author":"Demetris A. 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J.","year":"2004","journal-title":"Journal of Infectious Diseases"},{"issue":"2","key":"e_1_2_7_50_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/xen.12153","article-title":"Expression of Recipient cytomegalovirus in Immunosuppressed and Xenotransplanted Macaca Fascicularis May be Related to More Severe Gastrointestinal Lesions","volume":"22","author":"Cavicchioli L.","year":"2015","journal-title":"Xenotransplantation"},{"issue":"24","key":"e_1_2_7_51_1","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1056\/NEJMra2207462","article-title":"Risks of Infectious Disease in Xenotransplantation","volume":"387","author":"Fishman J. 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