Endothelial Injury-Induced Shedding of Thrombomodulin as a Biomarker for Predicting Adverse Prognosis in Sepsis.

PURPOSE: Sepsis-associated endothelial injury drives thrombomodulin (TM) shedding and severe coagulopathy. We hypothesized that plasma TM levels predict sepsis severity and prognosis. This study investigated the prognostic association of plasma TM as a sepsis biomarker and validated it in a murine model. PATIENTS AND METHODS: In a prospective cohort (Gongli Hospital, Shanghai; July 2024-January 2025), 68 sepsis patients (45 survivors, 23 nonsurvivors) and 50 controls underwent plasma TM, CD64 index, procalcitonin (PCT), C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score assessments. Survival analysis, multivariable regression, and receiver operating characteristic (ROC) curve modeling were performed. Mechanistic validation utilized Cecal Ligation and Puncture (CLP) mice with plasma/aortic TM quantification. RESULTS: Elevated plasma TM and CD64 index correlated with poor prognosis (p<0.05). The combined TM/CD64 Index ROC model achieved superior predictive performance (AUC=0.9671, p<0.05) compared with TM alone (AUC=0.9333) or CD64 alone (AUC=0.8628). The multiple linear regression model indicated a positive correlation between TM levels in sepsis patients and SOFA and APACHE II scores. In vivo, experiments indicate plasma TM increased while aortic endothelial TM expression decreased. CONCLUSION: This study demonstrates that the combined plasma TM and CD64 index assessment enhances early prediction of adverse sepsis outcomes, with strong correlations to clinical severity scores. The paradoxical TM dynamics (plasma elevation vs endothelial depletion) suggest endothelial injury as a key mechanism. Future research should focus on multicenter validation, and mechanistic studies are warranted to optimize clinical translation.