Therapeutic timing and molecular properties influence low-molecular-weight heparin (LMWH) efficacy in murine sepsis

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Beyond anticoagulation, heparin has anti-inflammatory, anti-chemotactic, and cytoprotective properties which may provide therapeutic benefits in sepsis. In COVID-19-associated sepsis, therapeutic-dose heparin improved outcomes in moderately but not critically ill patients, highlighting the importance of treatment timing. The study objectives are: (1) To identify the therapeutic window for initiating therapeutic-dose low molecular weight heparin (LMWH) in a murine model of sepsis. (2) To determine whether the protective effects of LMWH extend beyond systemic anticoagulation by comparing LMWH with a chemically-modified LMWH with reduced anticoagulant activity (Vasoflux). Sepsis was induced in 10- to 12-week old C57BL/6J mice via intraperitoneal injection of rat-derived fecal slurry. LMWH , Vasoflux, or saline was administered at 2, 8, or 16 hours post-infection, alongside analgesia, fluids, and antibiotics. Mice were monitored for 48 hours. Survival, physiological parameters, hematology, organ histology, and plasma biomarkers of inflammation, chemotaxis, coagulation, and cell death were evaluated. Compared with saline, LMWH administered at 2, 8, or 16 hours post-infection improved survival and physiological parameters, and reduced biomarkers of inflammation, chemotaxis, and cell death. LMWH remained effective when administered after organ injury was established at 16 hours post-infection. Vasoflux produced a comparable survival benefit as LMWH. Overall, LMWH administration improved outcomes when initiated between 2 and 16 hours after infection, demonstrating a therapeutic window extending beyond the onset of organ injury. The protective effects observed with Vasoflux suggest that non-anticoagulant mechanisms contribute to the beneficial effects of LMWH in sepsis.