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Semin Thromb Hemost
DOI: 10.1055/a-2776-5999
Review Article

Damage-associated molecular patterns, immunothrombosis, and intravascular inflammation in sepsis: A narrative integrative review

Authors

  • Toshiaki Iba

    1   Emergency and Disaster Medicine, Juntendo University, Bunkyo, Japan (Ringgold ID: RIN12847)

  • Julie Helms

    2   Intensive Care Unit, Strasbourg University Hospitals, Strasbourg, France (Ringgold ID: RIN36604)

  • Hideshi Okada

    3   Department of Emergency and Disaster Medicine, Gifu Daigaku, Gifu, Japan (Ringgold ID: RIN12785)

  • Kunihiko Nagakari

    4   Surgery, Juntendo Daigaku Igakubu Fuzoku Urayasu Byoin, Urayasu, Japan (Ringgold ID: RIN37069)

  • Koichi Sato

    5   Surgery, Juntendo Daigaku Igakubu Fuzoku Shizuoka Byoin, Izunokuni, Japan (Ringgold ID: RIN73832)

  • Ricard Ferrer

    6   Intensive Care Department, Hospital Infantil y el Hospital de la Mujer de Vall d’Hebron, Barcelona, Spain (Ringgold ID: RIN96692)

  • Jerrold Levy

    7   Anesthesiology and Critcal Care, Duke University, Durham, United States (Ringgold ID: RIN3065)

Supported by: Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan
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Sepsis is now considered a dysregulated host response in which inflammation, coagulation, and endothelial injury converge to create a self-amplifying network of thromboinflammation. This definition reflects maladaptive immunothrombosis—a defense mechanism that becomes pathogenic when excessive, rather than an isolated inflammatory process. This review integrates recent mechanistic advances linking damage-associated molecular patterns (DAMPs), endothelial dysfunction, and intravascular coagulation. Endogenous alarmins, such as high-mobility group box 1, histones, and mitochondrial DNA, engage pattern-recognition (Toll-like receptors, receptor for advanced glycation endproducts) to propagate leukocyte activation, platelet aggregation, and endothelial disruption. The resulting loss of critical endothelial anticoagulant molecules (thrombomodulin, endothelial cell protein C receptor, antithrombin) and glycocalyx degradation converts the vascular endothelium into a procoagulant interface. Complement activation and protease-activated receptor signaling reinforce this loop, producing microvascular thrombosis, capillary leakage, and organ ischemia. Platelet–leukocyte aggregates and neutrophil extracellular traps (NETs) serve as intravascular scaffolds for fibrin deposition, thereby propagating disseminated intravascular coagulation (DIC). Targeted interventions, including recombinant thrombomodulin, antithrombin supplementation, neutralization of NETs and DAMPs, complement blockade, and endothelial-protective strategies, seek to restore vascular homeostasis. A multidomain biomarker approach integrating DAMPs, endothelial markers, and coagulation indices, combined with machine-learning-based phenotyping, may enable precision stratification of sepsis endotypes. The convergence of DAMP signaling, immune activation, and coagulation underlies the pathophysiologic continuum from sepsis-induced coagulopathy to DIC. Therapeutically interrupting this axis represents the most promising avenue toward personalized, mechanism-driven treatment in sepsis.



Publication History

Received: 01 December 2025

Accepted after revision: 18 December 2025

Accepted Manuscript online:
19 December 2025

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