{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:20:21Z","timestamp":1787016021477,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFC3406800"],"award-info":[{"award-number":["2024YFC3406800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Severe thrombocytopenia and coagulation dysregulation remain major barriers to survival in pig\u2010to\u2010primate liver xenotransplantation models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Porcine livers with five genetic modifications (GTKO, CMAHKO, \u03b24GalNT2KO, hCD55, and hTBM) were orthotopically transplanted into four Tibetan macaques under two conventional immunosuppressive protocols. Longitudinal monitoring included graft and multi\u2010organ function, hematology, coagulation, and immune responses. Histopathological and immunohistochemical analyses were performed to characterize graft and recipient pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High expression of human thrombomodulin (hTBM) in donor livers effectively prevented early rapid and severe thrombocytopenia, with three of four recipients maintaining platelets &gt;100 \u00d7 10\n                      <jats:sup>9<\/jats:sup>\n                      \/L. Thrombotic microangiopathy (TMA) was absent in grafts and recipient organs despite transient hypercoagulability. No spontaneous bleeding occurred in three of four cases. However, porcine livers failed to synthesize functional coagulation factor II, protein C, and protein S, contributing to progressive coagulopathy. While early graft function and coagulation remained stable for four posttransplant days, late dysfunction ensued, characterized by impaired coagulation factor synthesis and progressive graft failure. Antibody\u2010mediated rejection, accompanied by IgM\/IgG\/C4b deposition, anti\u2010TKO antibody increase, and pvWF upregulation, triggered injury that was amplified by innate and T cell\u2013mediated responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GTKO\/CMAHKO\/\u03b24GalNT2KO\/hCD55\/hTBM donor liver transplantation was associated with an absence of early severe thrombocytopenia, transfusion requirement, and TMA, but long\u2010term survival was limited by immune\u2010mediated rejection and cross\u2010species incompatibilities in coagulation factor synthesis. Optimizing (i) donor genetic modifications and (ii) immunosuppressive therapy, with (iii) replacement of targeted coagulation factors will be crucial for achieving durable survival in pig liver xenotransplantation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/xen.70120","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:06:16Z","timestamp":1774271176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expression of Human Thrombomodulin Prevents Early Thrombocytopenia and Thrombotic Microangiopathy in Pig\u2010to\u2010Nonhuman Primate Orthotopic Liver Xenotransplantation"],"prefix":"10.1111","volume":"33","author":[{"given":"Zhongqiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9366-7116","authenticated-orcid":false,"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinger","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shali","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinchun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Operation Room The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Deng","sequence":"additional","affiliation":[{"name":"Operation Room The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Xenotransplantation and Regeneration Key Laboratory of Sichuan Province Chengdu ClonOrgan Biotechnology Co. 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