Damage-associated Molecular Patterns, Immunothrombosis, and Intravascular Inflammation in Sepsis: A Narrative Integrative Review

Abstract

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 in pattern recognition (Toll-like receptors, receptor for advanced glycation end products) 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 convert 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.

Keywords

HMGB1 protein - histones - mitochondrial DNA - receptor for advanced glycation end products - thromboinflammation

Contributors' Statement

T.I.: conceptualization; J.H.: investigation; H.O.: investigation; K.N.: writing—review and editing; K.S.: writing—review and editing; R.F.: writing—review and editing; J.H.L.: writing—review and editing.

Publikationsverlauf

Eingereicht: 02. Dezember 2025

Angenommen: 18. Dezember 2025

Accepted Manuscript online:
19. Dezember 2025

Artikel online veröffentlicht:
31. Dezember 2025

• References

• 1 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
• 2 Iba T, Helms J, Maier CL, Ferrer R, Levy JH. Mitochondrial dysfunction is a major cause of thromboinflammation and inflammatory cell death in critical illnesses. Inflamm Res 2025; 74 (01) 17
• 3 Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017; 149: 38-44
• 4 Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 2011; 29: 139-162
• 5 Magna M, Pisetsky DS. The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med 2014; 20 (01) 138-146
• 6 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
• 7 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
• 8 Ferrer R, Iba T. Mitochondrial damage in sepsis. Juntendo Iji Zasshi 2024; 70 (04) 269-272
• 9 Zuo Y, Yalavarthi S, Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight 2020; 5 (11) e138999
• 10 Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129 (03) 290-295
• 11 Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers 2016; 2: 16045
• 12 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369 (09) 840-851
• 13 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 14 Rudd KE, Johnson SC, Agesa KM. et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395 (10219): 200-211
• 15 Fleischmann C, Scherag A, Adhikari NK. et al; International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 2016; 193 (03) 259-272
• 16 Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. JAMA 2018; 319 (01) 62-75
• 17 Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost 2018; 16 (02) 231-241
• 18 Schmidt EP, Yang Y, Janssen WJ. et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 2012; 18 (08) 1217-1223
• 19 Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 2019; 23 (01) 16
• 20 Ostrowski SR, Gaïni S, Pedersen C, Johansson PI. Sympathoadrenal activation and endothelial damage in patients with varying degrees of acute infectious disease: an observational study. J Crit Care 2015; 30 (01) 90-96
• 21 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140 (06) 805-820
• 22 Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418 (6894) 191-195
• 23 Xu J, Zhang X, Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15 (11) 1318-1321
• 24 Nakahira K, Kyung SY, Rogers AJ. et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 2013; 10 (12) e1001577 , discussion e1001577
• 25 Murao A, Aziz M, Wang H, Brenner M, Wang P. Release mechanisms of major DAMPs. Apoptosis 2021; 26 (3-4): 152-162
• 26 Xu J, Gao Y, Huang X. et al. S100A9 in sepsis: a biomarker for inflammation and a mediator of organ damage. Biochem Biophys Res Commun 2025; 752: 151484
• 27 Raymond SL, Holden DC, Mira JC. et al. Microbial recognition and danger signals in sepsis and trauma. Biochim Biophys Acta Mol Basis Dis 2017; 1863 (10 Pt B): 2564-2573
• 28 Li Y, Liu M, Zuo Z. et al. TLR9 regulates the NF-κB-NLRP3-IL-1β pathway negatively in Salmonella-induced NKG2D-mediated intestinal inflammation. J Immunol 2017; 199 (02) 761-773
• 29 Hofer S, Uhle F, Fleming T. et al. RAGE-mediated inflammation in patients with septic shock. J Surg Res 2016; 202 (02) 315-327
• 30 Yoo H, Im Y, Ko RE, Lee JY, Park J, Jeon K. Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes. Sci Rep 2021; 11 (01) 9512
• 31 Su F, Moreau A, Savi M. et al. Circulating nucleosomes as a novel biomarker for sepsis: a scoping review. Biomedicines 2024; 12 (07) 1385
• 32 Wang L, Zhou W, Wang K, He S, Chen Y. Predictive value of circulating plasma mitochondrial DNA for sepsis in the emergency department: observational study based on the Sepsis-3 definition. BMC Emerg Med 2020; 20 (01) 25
• 33 Iba T, Maier CL, Helms J, Ferrer R, Thachil J, Levy JH. Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines. Ann Intensive Care 2024; 14 (01) 64
• 34 Ito T, Thachil J, Asakura H, Levy JH, Iba T. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential. Crit Care 2019; 23 (01) 280
• 35 Esmon CT. The protein C pathway. Chest 2003; 124 (03) 26S-32S
• 36 Lehner GF, Tobiasch AK, Perschinka F. et al. Associations of tissue factor and tissue factor pathway inhibitor with organ dysfunctions in septic shock. Sci Rep 2024; 14 (01) 14468
• 37 Manz XD, Bogaard HJ, Aman J. Regulation of VWF (von Willebrand factor) in inflammatory thrombosis. Arterioscler Thromb Vasc Biol 2022; 42 (11) 1307-1320
• 38 Yung S, Chan TM. Endothelial cell activation and glycocalyx shedding—potential as biomarkers in patients with lupus nephritis. Front Immunol 2023; 14: 1251876
• 39 Inoda A, Suzuki K, Tomita H, Okada H. Glycocalyx shedding as a clinical biomarker in critical illness. Exp Mol Pathol 2025; 144: 104997
• 40 Iba T, Levy JH. Derangement of the endothelial glycocalyx in sepsis. J Thromb Haemost 2019; 17 (02) 283-294
• 41 Riewald M, Ruf W. Science review: role of coagulation protease cascades in sepsis. Crit Care 2003; 7 (02) 123-129
• 42 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
• 43 Cognasse F, Nguyen KA, Damien P. et al. The inflammatory role of platelets via their TLRs and Siglec receptors. Front Immunol 2015; 6: 83
• 44 Xu X, Wang Y, Tao Y, Dang W, Yang B, Li Y. The role of platelets in sepsis: a review. Biomol Biomed 2024; 24 (04) 741-752
• 45 Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011; 108 (10) 1284-1297
• 46 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
• 47 Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (08) 1777-1783
• 48 Yang J, Wu Z, Long Q. et al. Insights into immunothrombosis: the interplay among neutrophil extracellular trap, von Willebrand factor, and ADAMTS13. Front Immunol 2020; 11: 610696
• 49 Iba T, Ogura H. Role of extracellular vesicles in the development of sepsis-induced coagulopathy. J Intensive Care 2018; 6: 68
• 50 Jiang M, Wu W, Xia Y, Wang X, Liang J. Platelet-derived extracellular vesicles promote endothelial dysfunction in sepsis by enhancing neutrophil extracellular traps. BMC Immunol 2023; 24 (01) 22
• 51 Wei X, Tu Y, Bu S, Guo G, Wang H, Wang Z. Unraveling the intricate web: complement activation shapes the pathogenesis of sepsis-induced coagulopathy. J Innate Immun 2024; 16 (01) 337-353
• 52 Mollnes TE, Castellheim A, Lindenskov PH, Salvesen B, Saugstad OD. The role of complement in meconium aspiration syndrome. J Perinatol 2008; 28 (Suppl. 03) S116-S119
• 53 Gultom M, Rieben R. Complement, coagulation, and fibrinolysis: the role of the endothelium and its glycocalyx layer in xenotransplantation. Transpl Int 2024; 37: 13473
• 54 Gressner OA, Koch A, Sanson E, Trautwein C, Tacke F. High C5a levels are associated with increased mortality in sepsis patients—no enhancing effect by actin-free Gc-globulin. Clin Biochem 2008; 41 (12) 974-980
• 55 Krisinger MJ, Goebeler V, Lu Z. et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood 2012; 120 (08) 1717-1725
• 56 Hippensteel JA, LaRiviere WB, Colbert JF, Langouët-Astrié CJ, Schmidt EP. Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol 2020; 319 (02) L211-L217
• 57 Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M. Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019; 17 (11) 1989-1994
• 58 Girardis M, David S, Ferrer R. et al. Understanding, assessing and treating immune, endothelial and haemostasis dysfunctions in bacterial sepsis. Intensive Care Med 2024; 50 (10) 1580-1592
• 59 Iba T, Helms J, Levi M, Levy JH. Thromboinflammation in acute injury: infections, heatstroke, and trauma. J Thromb Haemost 2024; 22 (01) 7-22
• 60 Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the management of sepsis. Ann Intensive Care 2024; 14 (01) 148
• 61 Ince C. The microcirculation is the motor of sepsis. Crit Care 2005; 9 (Suppl 4): S13-S19
• 62 Iba T, Helms J, Maier CL, Levi M, Scarlatescu E, Levy JH. The role of thromboinflammation in acute kidney injury among patients with septic coagulopathy. J Thromb Haemost 2024; 22 (06) 1530-1540
• 63 Vincent JL, De Backer D. Microvascular dysfunction as a cause of organ dysfunction in severe sepsis. Crit Care 2005; 9 (Suppl 4): S9-S12
• 64 Bernard GR, Vincent JL, Laterre PF. et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
• 65 Ranieri VM, Thompson BT, Barie PS. et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366 (22) 2055-2064
• 66 Warren BL, Eid A, Singer P. et al; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286 (15) 1869-1878
• 67 Longstaff C, Hogwood J, Gray E. et al. Neutralisation of the anti-coagulant effects of heparin by histones in blood plasma and purified systems. Thromb Haemost 2016; 115 (03) 591-599
• 68 Zarychanski R, Abou-Setta AM, Kanji S. et al; Canadian Critical Care Trials Group. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med 2015; 43 (03) 511-518
• 69 Iba T, Helms J, Totoki T, Levy JH. Heparins may not be the optimal anticoagulants for sepsis and sepsis-associated disseminated intravascular coagulation. Semin Thromb Hemost 2024; 50 (07) 1012-1018
• 70 Saito H, Maruyama I, Shimazaki S. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5 (01) 31-41
• 71 Vincent JL, Francois B, Zabolotskikh I. et al; SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA 2019; 321 (20) 1993-2002
• 72 Kienast J, Juers M, Wiedermann CJ. et al; KyberSept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 4 (01) 90-97
• 73 Sharma S, Tyagi T, Antoniak S. Platelet in thrombo-inflammation: unraveling new therapeutic targets. Front Immunol 2022; 13: 1039843
• 74 Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23 (12) 2131-2137
• 75 Medeiros SK, Sharma N, Dwivedi D. et al. The effect of DNase I and low-molecular-weight heparin in a murine model of polymicrobial abdominal sepsis. Shock 2023; 59 (04) 666-672
• 76 Liu X, Li T, Chen H, Yuan L, Ao H. Role and intervention of PAD4 in NETs in acute respiratory distress syndrome. Respir Res 2024; 25 (01) 63
• 77 Deng C, Zhao L, Yang Z. et al. Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury. Acta Pharmacol Sin 2022; 43 (03) 520-528
• 78 Chi Y, Yu S, Yin J, Liu D, Zhuo M, Li X. Role of angiopoietin/Tie2 system in sepsis: a potential therapeutic target. Clin Appl Thromb Hemost 2024; 30: 10 760296241238010
• 79 Keshari RS, Silasi R, Popescu NI. et al. Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proc Natl Acad Sci U S A 2017; 114 (31) E6390-E6399
• 80 Seymour CW, Kennedy JN, Wang S. et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019; 321 (20) 2003-2017
• 81 Zhao QY, Liu LP, Luo JC. et al. A machine-learning approach for dynamic prediction of sepsis-induced coagulopathy in critically ill patients with sepsis. Front Med (Lausanne) 2021; 7: 637434
• 82 Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost 2020; 18 (07) 1559-1561
• 83 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
• 84 Epstein Y, Yanovich R. Heatstroke. N Engl J Med 2019; 380 (25) 2449-2459
• 85 Levy JH, Iba T. Fibrinolytic changes in critical illnesses: is fibrinolysis shutdown a specific concept?. Juntendo Iji Zasshi 2024; 70 (06) 416-419
• 86 Hayakawa M, Sawamura A, Gando S, Jesmin S, Naito S, Ieko M. A low TAFI activity and insufficient activation of fibrinolysis by both plasmin and neutrophil elastase promote organ dysfunction in disseminated intravascular coagulation associated with sepsis. Thromb Res 2012; 130 (06) 906-913
• 87 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5 (04) 331-342
• 88 Zhang Q, Raoof M, Chen Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464 (7285) 104-107
• 89 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 2007; 104 (15) 6388-6393
• 90 Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007; 81 (01) 28-37
• 91 Jiang D, Liang J, Fan J. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 2005; 11 (11) 1173-1179
• 92 Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol 2002; 168 (10) 5233-5239
• 93 Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 2018; 18 (02) 134-147