Title : Coagulopathy, a hidden enemy in persistent organ dysfunction in post-septic rats
Abstract:
Background: Post-sepsis syndrome (PSS) affects up to 50% of survivors, with a mortality exceeding 82% at 5 years and annual costs exceeding $100 billion only in the United States. While immune dysregulation has dominated PSS research, coagulopathy emerges as a silent but critical driver of post-sepsis sequelae. However, mechanisms, biomarkers, and subsequently, therapies targeting PSS remain poorly characterized.
Objective: To evaluate the contribution of coagulopathy to organ dysfunction during the post-sepsis period.
Methods: Male Sprague-Dawley rats received Salmonella enterica serovar Typhi outer membrane vesicles (OMVs) (n=17) or saline solution (n=11). Animals were euthanized at three temporal phases: acute (6h), survivor (6d), and post-sepsis (20d) periods. Thirty-two parameters, including coagulation, renal, hepatic, immune, and metabolic markers were normalized as Z-scores against reference intervals from thirty untreated rats. An adapted SOFA score was used to define organ dysfunction. The predictive role of coagulopathy and associated markers was analyzed through relative risk (Fisher's exact), ROC/AUC, and logistic regression.
Results: OMVs induced organ dysfunction in 100% of animals at 6h (p=0.029) and 80% at 20d (p=0.048) versus 0% saline. SOFA trajectory showed a non-linear pattern, with 100% of animals presenting organ dysfunction at 6h, then a partial recovery at 6d, and re-emergence at 20d. INR independently predicted organ dysfunction (OR=6.6 [95%CI: 1.0–43.4], p=0.049; AUC=0.903). Thrombocytopenia was the most persistent alteration on post-sepsis period (Cliff's δ=−1.0 at 20d), suggesting active platelet consumption by ongoing thrombus formation. Immune markers (LYMPHO% AUC=0.938; SEGMEN% AUC=0.920) and glucose (AUC=0.912) emerged as strong predictors of organ dysfunction, potentially attributable to NET formation, lymphocyte exhaustion, and hyperglycemia, possibly amplifying endothelial dysfunction and perpetuating the coagulopathic state.
Conclusions: Coagulopathy, specifically through elevated INR and thrombocytopenia, is associated with organ dysfunction during the post-sepsis period. Immune and metabolic dysregulation could act as amplifiers of these alterations. The S. Typhi OMVs model represents a robust platform for evaluating biomarkers and therapeutic strategies in post-sepsis syndrome.
