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Fibrin degradation products (FDPs) are generated during hyperfibrinolysis; however, the mechanism with which they contribute to endotheliopathy and blood\u2013brain barrier (BBB) dysfunction in TBI-C remains unknown. Here, we performed comprehensive structural, functional and transcriptional analysis of human primary endothelial cells (ECs) treated with isolated human FDPs (D-dimer, Fragments D\/E [FragD, FragE]) and a human primary co-culture consisting of ECs and astrocytes treated with plasma from patients with severe TBI with high FDP levels or healthy subjects. Exposure of ECs to FragD and FragE resulted in increased permeability of the EC barrier. While ECs treated with FragD and FragE maintained expression and membrane localization patterns of junctional proteins VE-Cadherin and ZO-1, super-resolution imaging showed a higher degree of intracellular localization of these proteins in vesicles. FragD and FragE exposure increased the formation of actin stress fibers and F\/G-actin ratio. At the transcriptional level, FragD and FragE affected genes related to cell adhesion, cell migration and angiogenesis. A co-culture of ECs and astrocytes treated with human TBI plasma showed increased formation of actin stress fibers and F\/G-actin ratio, and &gt;300 differentially expressed genes, including genes governing cell-cell interactions and mechanotransduction. This study shows that FDPs mediate endothelial barrier dysfunction through disruption of the actin cytoskeleton and its interaction with junctional proteins. The positioning of FDPs at the molecular link between hyperfibrinolysis and endotheliopathy makes them therapeutic targets in TBI-C. Further work is needed to fully delineate the mechanistic framework of TBI-C.<\/jats:p>","DOI":"10.1177\/2689288x261469553","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:47:10Z","timestamp":1787809630000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fibrin Degradation Products Regulate Endothelial Barrier Function in Traumatic Brain Injury via the Actin Cytoskeleton"],"prefix":"10.1177","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-8893","authenticated-orcid":false,"given":"Ayhan","family":"Atmanli","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA."},{"name":"Division of Emergency Medicine, Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan Michael","family":"Collier","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott Douglas","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Charles Samuel","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_3_3_2_1","unstructured":"1.Centers for Disease Control and Prevention. 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