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The evolving role of heparin in sepsis: therapeutic potential in the age of immunothrombosis
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DOI：10.1016/j.jtha.2026.06.017.png)
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Abstract
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Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and remains a leading cause of global morbidity and mortality. Despite decades of research, most biologically targeted therapies have failed to improve survival, highlighting the need for new treatment strategies that address the complex pathophysiology of sepsis. A defining feature of sepsis is immunothrombosis, characterized by widespread activation of inflammation and coagulation, endothelial injury, platelet activation, and neutrophil extracellular trap (NET) formation, resulting in both macrovascular thrombosis and microvascular occlusion. Heparin is commonly used as an anticoagulant and has re-emerged as a potential therapeutic agent for sepsis due to its pleiotropic properties that extend beyond anticoagulant effects. Heparin exhibits anti-inflammatory and antimicrobial activities, inhibits immune activation, neutralizes damage-associated molecular patterns, and modulates NET-mediated pathology. Clinical evidence for efficacy in sepsis remains limited, and no adequately powered randomized trials have confirmed a net survival benefit of therapeutic-dose heparin. This may reflect historical challenges with trial methodology and the heterogeneous nature of human sepsis. Data from COVID-19-associated sepsis suggest that severity may influence outcomes, with potential benefits in earlier disease stages and possible harm in advanced stages. Emerging interest in nonanticoagulant heparin derivatives and biomarker-guided patient selection may offer scientific opportunities to optimize therapeutic benefit while minimizing bleeding, but these approaches remain investigational. This review synthesized current mechanistic, preclinical, and clinical evidence supporting heparin-based strategies in sepsis and emphasizes that therapeutic use beyond standard thromboprophylaxis should be evaluated in clinical trials before being applied in practice.
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