Anticoagulants beyond coagulation: repurposing heparin to mitigate immunothrombosis and inflammatory cascades in sepsis.
- 1Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- 2Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
- 3Hubei Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment of Digestive System, Wuhan, China.
Abstract
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.
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BibTeX
@article{ren2026anticoagulants,
title = {{Anticoagulants beyond coagulation: repurposing heparin to mitigate immunothrombosis and inflammatory cascades in sepsis.}},
author = {Yanming Ren and Hongqi Meng and Beibei Li and Yuhao Wang and Lulu Gu and Ruyue Lv and Letian Xue and Li Xu and Hao Zhang and Dinghang Wang and Peng Sun},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1901895},
url = {https://europepmc.org/article/MED/42903397},
note = {CC BY},
}
RIS
TY - JOUR
TI - Anticoagulants beyond coagulation: repurposing heparin to mitigate immunothrombosis and inflammatory cascades in sepsis.
AU - Yanming Ren
AU - Hongqi Meng
AU - Beibei Li
AU - Yuhao Wang
AU - Lulu Gu
AU - Ruyue Lv
AU - Letian Xue
AU - Li Xu
AU - Hao Zhang
AU - Dinghang Wang
AU - Peng Sun
PY - 2026
DA - 2026/10/06
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1901895
UR - https://europepmc.org/article/MED/42903397
AB - 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.
SN - 1663-9812
ER -