{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T12:13:04Z","timestamp":1778933584318,"version":"3.51.4"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400166"],"award-info":[{"award-number":["82400166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270142"],"award-info":[{"award-number":["82270142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82570159"],"award-info":[{"award-number":["82570159"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Thrombosis is a common complication in paroxysmal nocturnal haemoglobinuria (PNH) patients, but primary prevention remains controversial. Identifying high\u2010risk individuals could enable risk\u2010stratified prophylactic anticoagulation strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed clinical data from PNH patients with or without thrombosis, including\n                      <jats:italic>MUC4<\/jats:italic>\n                      mutation status and serum complement C5b\u20109 levels. Complement deposition assays and a murine lower limb deep vein thrombosis model were used to investigate the role of\n                      <jats:italic>MUC4<\/jats:italic>\n                      mutation in thrombotic risk and explore the underlying mechanism involving terminal complement activation in PNH patients. Therapeutic interventions with low molecular weight heparin (LMWH) were tested in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that PNH patients with\n                      <jats:italic>MUC4<\/jats:italic>\n                      mutations have a higher incidence of thrombotic events (TEs) and\n                      <jats:italic>MUC4<\/jats:italic>\n                      mutation is an independent risk factor for TE in PNH patients. Additionally, PNH patients with acute thrombosis had elevated serum complement C5b\u20109 levels, and complement deposition experiments further confirmed the abnormal activation and excessive deposition of C5b\u20109 as the basis for the thrombotic tendency in PNH patients. By constructing a mouse model of lower limb deep vein thrombosis, we confirmed the thrombotic tendency in a PNH mouse model and that MUC4 deficiency further promoted the thrombotic phenotype of the mice. Moreover, we found that MUC4 knockdown promoted the deposition of C5b\u20109 on the cell surface, indicating that a lack of MUC4 expression facilitates the deposition of C5b\u20109. Finally, in vivo drug administration experiments demonstrated that prophylactic anticoagulation with LMWH significantly reduced both the incidence of thrombosis and thrombus length in murine models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>MUC4<\/jats:italic>\n                      mutations promote the thrombotic phenotype in PNH patients by increasing the deposition of terminal complement. In PNH patients with concomitant MUC4 mutations, the risk of TEs is further elevated. The potential role of early complement inhibitor therapy in reducing this heightened thrombotic risk, as well as the value of prophylactic LMWH therapy as a potential option for patients who are unable to receive complement inhibitor treatment, warrants further study and prospective validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>MUC4<\/jats:italic>\n                            gene mutation increases the deposition of abnormally activated terminal complement in patients with PNH, thereby promoting the thrombotic phenotype in these patients. Consequently, the risk of thrombosis is further elevated in PNH patients with concurrent\n                            <jats:italic>MUC4<\/jats:italic>\n                            mutations.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            In patients with PNH who have concurrent\n                            <jats:italic>MUC4<\/jats:italic>\n                            mutations, the potential role of early complement inhibitor therapy in reducing thrombosis risk, as well as the value of prophylactic LMWH therapy as a potential alternative for those who are unable to receive complement inhibitor treatment, may warrant further study and prospective validation.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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