Unfractionated Heparin and Low‐Molecular‐Weight Heparin in Sepsis: Anti‐Inflammatory and Anticoagulant Effects Versus No Anticoagulation—A Propensity Score‐Matched Analysis

BACKGROUND: Given the controversy surrounding anticoagulation therapy in sepsis, this study evaluated the efficacy of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) compared with no anticoagulation in sepsis management, considering their potential benefits beyond anticoagulation. METHODS: In this retrospective cohort study, 1362 sepsis patients were stratified into no anticoagulation, UFH, or LMWH groups. Propensity score matching balanced baseline characteristics. UFH was administered intravenously and LMWH subcutaneously at standard doses. Twenty-two biomarkers were assessed at baseline and days 1, 3, and 7 post-anticoagulation. Survival and bleeding were evaluated using Kaplan-Meier curves. Generalized linear mixed models identified treatment-associated biomarkers, and mediation analysis evaluated their role in survival benefit. RESULTS: After matching, 109 and 394 patients were included in the UFH and LMWH comparisons, respectively. Both UFH and LMWH were associated with significantly improved survival versus the no anticoagulation group (p < 0.001), without increased 90-day bleeding risk. UFH was associated with significant reductions in FDP, D-dimer, IL-6, IL-8, and CRP (FDR-adjusted p < 0.001), whereas LMWH was associated with significant reductions only in FDP and D-dimer. Mediation analysis demonstrated that UFH's survival benefit was partly mediated by IL-6 and IL-8 reduction, accounting for 30.9% (p = 0.012) and 29.6% (p = 0.045) of the total effect. LMWH's survival benefit was not significantly mediated by any measured biomarker. CONCLUSIONS: Both UFH and LMWH improved survival in sepsis patients without increasing bleeding risk. However, UFH demonstrated broader anti-inflammatory effects, with survival benefit partially explained by IL-6/IL-8 suppression. LMWH's benefit appeared primarily anticoagulant-mediated. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100045167. Registered 06 April 2021, retrospectively registered.