{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:13Z","timestamp":1790189953220,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Several members of the PDI (protein disulfide isomerase) family have been shown to regulate platelet function and thrombosis. TMX3 (thioredoxin-related transmembrane protein 3), the sole transmembrane member of the PDI family containing catalytically inactive thioredoxin-like domains, has been implicated in thrombotic diseases, but its role in hemostasis and thrombosis remains uninvestigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We generated hematopoietic and endothelial cell-specific (Tie2-Cre) and platelet-specific (Pf4-Cre) TMX3 conditional knockout mice to assess the contribution of TMX3 to hemostasis and thrombosis. The functions of TMX3 in platelet aggregation, granule secretion, spreading, clot retraction, and calcium mobilization were examined. Wild-type and catalytically inactive TMX3 proteins were produced to determine the catalytic capacity of TMX3 toward \u03b1IIb\u03b23. Calcium ionophore, eptifibatide, ADP, and apyrase were used to investigate the regulatory mechanisms of TMX3 in platelet granule secretion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Expression of TMX3 on the platelet surface increased with convulxin stimulation. TMX3 knockout mice exhibited prolonged tail-bleeding times and decreased platelet accumulation in both FeCl\n                      <jats:sub>3<\/jats:sub>\n                      - and laser-induced thrombosis models. TMX3-deficient platelets had decreased P-selectin expression, \u03b1IIb\u03b23 activation, platelet aggregation, and ATP release, while maintaining normal platelet spreading, clot retraction, granule biogenesis, and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization. Mechanistically, TMX3 bound tightly to \u03b1IIb\u03b23 and generated thiols in \u03b1IIb and \u03b23, particularly in \u03b1IIb. Meanwhile, TMX3 regulated calcium mobilization-triggered platelet dense granule secretion, independent of \u03b1IIb\u03b23-mediated outside-in signaling. The impaired aggregation of TMX3-deficient platelets resulted from defective ADP release. Recombinant catalytically inactivated TMX3 protein inhibited platelet aggregation and ATP release and significantly reduced platelet accumulation and fibrin deposition in the laser-induced thrombosis model, whereas recombinant wild-type TMX3 protein neither enhanced human platelet aggregation and ATP release nor rescued the impaired aggregation and ATP release of TMX3-deficient platelets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our data highlight a critical role for TMX3 in platelet function and thrombus formation by interacting with \u03b1IIb\u03b23 integrin and directly regulating platelet granule secretion.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323282","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:00:56Z","timestamp":1787216456000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Transmembrane Protein Disulfide Isomerase TMX3 Potentiates Platelet Aggregation and Arterial Thrombosis in Mice"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-3388","authenticated-orcid":true,"given":"Fengwu","family":"Chen","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Soochow University, Suzhou, China (F.C., X.Y., Z.Z., A.Y., Y.L., Y.W.)."},{"name":"The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China (F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3814-9957","authenticated-orcid":true,"given":"Xiaofeng","family":"Yan","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Soochow University, Suzhou, China (F.C., X.Y., Z.Z., A.Y., Y.L., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3941-8422","authenticated-orcid":true,"given":"Yuxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Key Laboratory of Hematology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, China (Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5855-8914","authenticated-orcid":true,"given":"Zhenzhen","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Soochow University, Suzhou, China (F.C., X.Y., Z.Z., A.Y., Y.L., Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8067-4771","authenticated-orcid":true,"given":"Aizhen","family":"Yang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Soochow University, Suzhou, China (F.C., 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