Anticoagulants beyond coagulation: repurposing heparin to mitigate immunothrombosis and inflammatory cascades in sepsis.

Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection, in which inflammation, coagulation, endothelial injury, and immune dysfunction interact to drive organ failure and death. Accumulating evidence identifies immunothrombosis as a central mechanism in this process, linking neutrophil extracellular traps, platelet activation, tissue factor expression, circulating histones, and glycocalyx degradation to microvascular collapse and multiple organ dysfunction. Although heparin has traditionally been used as an anticoagulant, its highly sulfated structure also permits interactions that are independent of antithrombin. In addition to inhibiting thrombin generation, heparin can neutralize extracellular histones, interfere with HMGB1- and lipopolysaccharide-related inflammatory signaling, inhibit heparanase, preserve endothelial glycocalyx integrity, and modulate leukocyte trafficking through selectin-related pathways. Most of these non-anticoagulant actions have been demonstrated in cell systems, animal models, human endotoxemia, or diseases other than sepsis, and should therefore be read as biological plausibility rather than as an established clinical effect. The clinical literature addresses three questions that should not be conflated: routine venous thromboembolism prophylaxis in critically ill patients, anticoagulation directed at sepsis-induced coagulopathy or disseminated intravascular coagulation, and experimental immunomodulatory repurposing. The most recent meta-analysis restricted to randomized trials found no significant mortality reduction with heparin across three trials and 426 patients (risk ratio 0.86, 95% confidence interval 0.60-1.24), and the disseminated intravascular coagulation subgroup was also inconclusive. Favorable associations reported in retrospective sepsis-induced coagulopathy cohorts justify prospective phenotype-enriched trials but do not identify established responders. This review summarizes the pathophysiological rationale, mechanistic basis, current clinical evidence, and major safety considerations of heparin use in sepsis, and highlights future directions including precision phenotyping, biomarker-guided therapy, and non-anticoagulant heparin derivatives. At present no heparin preparation, salt, dose, or biomarker threshold is validated for sepsis-specific immunomodulation.