Background: Sepsis-induced coagulopathy (SIC) is a life-threatening complication of sepsis characterized by dysregulated coagulation, hyperinflammation, and microvascular thrombosis. Despite advancements in its pathophysiology, therapeutic strategies remain controversial, and clinical trials have yielded inconsistent outcomes.
Methods: This study conducts a bibliometric analysis (1995-2024) to map research trends, identify knowledge gaps, and evaluate the translational challenges in SIC management. A systematic search of the Web of Science Core Collection (6382 articles) and Scopus (8423 articles) retrieved on sepsis-related coagulation dysfunction. VOSviewer and Bibliometrix analyzed publication trends, citation networks, international collaborations, and keyword co-occurrence. Metrics included annual growth rates, total link strength, and relative research interest. We visualized temporal and thematic trends to highlight emerging frontiers and interdisciplinary linkages.
Results: Global research output exhibited exponential growth (annual rate: 18.4%), peaking during the coronavirus disease 2019 pandemic. The United States and China dominated research contributions, with the University of Texas MD Anderson Cancer Center leading in citation impact. Van Der Poll, Tom (Netherlands), and Toshiaki Iba (Japan) emerged as pivotal figures, focusing on molecular mechanisms and diagnostic standardization, respectively. Keyword clustering revealed 4 pillars: (1) etiology and clinical management, (2) molecular mechanisms, (3) biomarkers and prognostics, and (4) pathophysiology and syndromes. Coronavirus disease 2019-associated coagulopathy and artificial intelligence-driven diagnostics emerged as recent hotspots.
Conclusions: This analysis reveals the exponential but heterogeneous expansion of SIC research, driven by mechanistic discoveries and pandemic-related demands. Persistent challenges include the standardization of diagnostic criteria, patient heterogeneity in clinical trials, and geographic disparities in research capacity. Future priorities include integrating precision medicine and adopting artificial intelligence for patient stratification. Bridging mechanistic insights with clinical translation will be critical to improving outcomes in SIC.
Conflict of interest statement
The authors declare no conflict of interest.
Author contributions
Song B and Chen G contributed to conceptualization, methodology, formal analysis, investigation, data curation, writing the original draft, review and editing, visualization, and software. Kang H contributed to writing, review, and editing.
Funding
None.
Ethical approval of studies and informed consent
All studies included in this study followed the principles of the Declaration of Helsinki as revised in 2013.
Acknowledgements
The authors thank VOS viewer and R-bibliometrix techniques for their support. The authors utilized DeepSeek AI (
https://www.deepseek.com) for language polishing and grammatical refinement of the manuscript. The AI tool helped improve readability while maintaining scientific accuracy. All content remains the sole responsibility of the authors.
| [1] |
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. doi:10.1016/s0140-6736(19)32989-7
|
| [2] |
van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017; 17(7):407-420. doi:10.1038/nri.2017.36
|
| [3] |
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. doi:10.1007/s00134-024-07586-2
|
| [4] |
Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017; 7(9):e017046. doi:10.1136/bmjopen-2017-017046
|
| [5] |
Iba T, Helms J, Connors JM, Levy JH. The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2023; 11(1):24. doi:10.1186/s40560-023-00672-5
|
| [6] |
Salomão R, Martins PS, Brunialti MK, et al. TLR signaling pathway in patients with sepsis. Shock. 2008; 30(Suppl 1):73-77. doi:10.1097/SHK.0b013e318181af2a
|
| [7] |
Tejada S, Clemente A, Socias A, et al. Circulating NETs enable early identification of thrombotic risk in sepsis at emergency care onset. Front Immunol. 2025; 16:1664108. doi:10.3389/fimmu.2025.1664108
|
| [8] |
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(1):64. doi:10.1186/s13613-024-01301-6
|
| [9] |
Assinger A, Schrottmaier WC, Salzmann M, Rayes J. Platelets in sepsis: an update on experimental models and clinical aata. Front Immunol. 2019; 10:1687. doi:10.3389/fimmu.2019.01687
|
| [10] |
Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial responses in sepsis. Am J Respir Crit Care Med. 2020; 202(3):361-370. doi:10.1164/rccm.201910-1911tr
|
| [11] |
McDonald B, Davis RP, Kim SJ, et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood. 2017; 129(10):1357-1367. doi:10.1182/blood-2016-09-741298
|
| [12] |
Zhang H, Wang Y, Qu M, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med. 2023; 13(1):e1170. doi:10.1002/ctm2.1170
|
| [13] |
Gando S, Saitoh D, Ogura H, et al.; Japanese Association for Acute Medicine Sepsis Registry Study Group. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care. 2013; 17(3):R111. doi:10.1186/cc12783
|
| [14] |
Iba T, Levi M, Thachil J, Helms J, Scarlatescu E, Levy JH. Communication from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis on sepsis-induced coagulopathy in the management of sepsis. J Thromb Haemost. 2023; 21(1):145-153. doi:10.1016/j.jtha.2022.10.022
|
| [15] |
Yamakawa K, Yoshimura J, Ito T, Hayakawa M, Hamasaki T, Fujimi S. External validation of the two newly proposed criteria for assessing coagulopathy in sepsis. Thromb Haemost. 2019; 119(02):203-212. doi:10.1055/s-0038-1676610
|
| [16] |
Wang B, Zhang B, Shen Y, Li J, Yuan X, Tang N. Validation of two revised, simplified criteria for assessing sepsis-associated disseminated intravascular coagulation in ICU patients with sepsis-3: a retrospective study. Lab Med. 2023; 54(3):291-298. doi:10.1093/labmed/lmac112
|
| [17] |
Iba T. History of disseminated intravascular coagulation (DIC) research and my personal research history. Juntendo Med J. 2025; 71(4):218-221. doi:10.14789/ejmj.JMJ25-0011-P
|
| [18] |
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344(10):699-709. doi:10.1056/nejm200103083441001
|
| [19] |
Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001; 286(15):1869-1878. doi:10.1001/jama.286.15.1869
|
| [20] |
Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353(13):1332-1341. doi:10.1056/NEJMoa050935
|
| [21] |
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(1):31-41. doi:10.1111/j.1538-7836.2006.02267.x
|
| [22] |
Williams B, Zou L, Pittet JF, Chao W. Sepsis-induced coagulopathy: a comprehensive narrative review of pathophysiology, clinical presentation, diagnosis, and management strategies. Anesth Analg. 2024; 138(4):696-711. doi:10.1213/ane.0000000000006888
|
| [23] |
Vincent JL, Francois B, Zabolotskikh I, et al.; for the SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with aepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA. 2019; 321(20):1993-2002. doi:10.1001/jama.2019.5358
|
| [24] |
Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021; 47(11):1181-1247. doi:10.1007/s00134-021-06506-y
|
| [25] |
Egi M, Ogura H, Yatabe T, et al. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020). Acute Med Surg. 2021; 8(1):e659. doi:10.1002/ams2.659
|
| [26] |
Crowther MA, Marshall JC. Continuing challenges of sepsis research. JAMA. 2001; 286(15):1894-1896. doi:10.1001/jama.286.15.1894
|
| [27] |
Wong F, Bernardi M, Balk R, et al. Sepsis in cirrhosis: report on the 7th meeting of the international ascites club. Gut. 2005; 54(5):718-725. doi:10.1136/gut.2004.038679
|
| [28] |
Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999; 341(8):586-592. doi:10.1056/nejm199908193410807
|
| [29] |
Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost. 1999; 82(2):695-705.
|
| [30] |
Abraham E, Anzueto A, Gutierrez G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II study group. Lancet. 1998; 351(9107):929-933.
|
| [31] |
Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995; 273(2):117-123. doi:10.1001/jama.1995.03520260039030
|
| [32] |
Gando S, Meziani F, Levi M. What’s new in the diagnostic criteria of disseminated intravascular coagulation? Intensive Care Med. 2016; 42(6):1062-1064. doi:10.1007/s00134-016-4257-z
|
| [33] |
Kienast J, Juers M, Wiedermann CJ, et al. 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(1):90-97. doi:10.1111/j.1538-7836.2005.01697.x
|
| [34] |
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020; 18(5):1094-1099. doi:10.1111/jth.14817
|
| [35] |
Man C, An Y, Wang GX, Mao EQ, Ma L. Recent advances in pathogenesis and anticoagulation treatment of sepsis-induced coagulopathy. J Inflamm Res. 2025; 18:737-750. doi:10.2147/jir.s495223
|
| [36] |
Zhu L, Dong H, Li L, Liu X. The mechanisms of sepsis induced coagulation dysfunction and its treatment. J Inflamm Res. 2025; 18:1479-1495. doi:10.2147/jir.S504184
|
| [37] |
Scicluna BP, van Vught LA, Zwinderman AH, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017; 5(10):816-826. doi:10.1016/s2213-2600(17)30294-1
|
| [38] |
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-810. doi:10.1001/jama.2016.0287
|
| [39] |
van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. 2021; 54(11):2450-2464. doi:10.1016/j.immuni.2021.10.012
|
| [40] |
Wada H, Asakura H, Okamoto K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010; 125(1):6-11. doi:10.1016/j.thromres.2009.08.017
|
| [41] |
Gando S, Wada H, Asakura H, et al. Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients. Clin Appl Thromb Hemost. 2005; 11(1):71-76. doi:10.1177/107602960501100108
|
| [42] |
Asakura H, Wada H, Okamoto K, et al. Evaluation of haemostatic molecular markers for diagnosis of disseminated intravascular coagulation in patients with infections. Thromb Haemost. 2006; 95(2):282-287. doi:10.1160/th05-04-0286
|
| [43] |
Okamoto K, Wada H, Hatada T, et al. Frequency and hemostatic abnormalities in pre-DIC patients. Thromb Res. 2010; 126(1):74-78. doi:10.1016/j.thromres.2010.03.017
|
| [44] |
Iba T, Gando S, Saitoh D, Wada H, Di Nisio M, Thachil J. Antithrombin supplementation and risk of bleeding in patients with sepsis-associated disseminated intravascular coagulation. Thromb Res. 2016; 145:46-50. doi:10.1016/j.thromres.2016.07.016
|
| [45] |
Yamakawa K, Umemura Y, Mochizuki K, et al. Proposal and validation of a clinically relevant modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis. Thromb Haemost. 2024; 124(11):1003-1012. doi:10.1055/s-0044-1786808
|
| [46] |
Yamakawa K, Okamoto K, Seki Y, et al.; Committee of the Clinical Practice Guidelines for Management of Disseminated Intravascular Coagulation 2024, the Japanese Society on Thrombosis and Hemostasis. Clinical practice guidelines for management of disseminated intravascular coagulation in Japan 2024. Part 1: sepsis. Int J Hematol. 2024; 121(5):592-604. doi:10.1007/s12185-024-03896-9
|
| [47] |
Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020; 46(6):1089-1098. doi:10.1007/s00134-020-06062-x
|
| [48] |
Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020; 135(23):2033-2040. doi:10.1182/blood.2020006000
|
| [49] |
Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagulation in COVID-19. Blood Rev. 2021; 47:100761. doi:10.1016/j.blre.2020.100761
|
| [50] |
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395(10234):1417-1418. doi:10.1016/s0140-6736(20)30937-5
|
| [51] |
Sadeghipour P, Talasaz AH, Rashidi F, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION Randomized Clinical Trial. JAMA. 2021; 325(16):1620-1630. doi:10.1001/jama.2021.4152
|
| [52] |
Fanaroff AC, Lopes RD. COVID-19 thrombotic complications and therapeutic strategies. Annu Rev Med. 2023; 74(1):15-30. doi:10.1146/annurev-med-042921-110257
|
| [53] |
Wang R, Han Q, Fan J, et al. Sepsis-induced endothelial barrier dysfunction: mechanisms, pathology, and therapeutic advances. Research (Wash D C). 2025; 8:0997. doi:10.34133/research.0997
|
| [54] |
Colling ME, Tourdot BE, Kanthi Y. Inflammation, infection and venous thromboembolism. Circ Res. 2021; 128(12):2017-2036. doi:10.1161/circresaha.121.318225
|
| [55] |
Delabranche X, Helms J, Meziani F. Immunohaemostasis: a new view on haemostasis during sepsis. Ann Intensive Care. 2017; 7(1):117. doi:10.1186/s13613-017-0339-5
|
| [56] |
Retter A, Singer M, Annane D. “The NET effect”: neutrophil extracellular traps-a potential key component of the dysregulated host immune response in sepsis. Crit Care. 2025; 29(1):59. doi:10.1186/s13054-025-05283-0
|
| [57] |
Lipinska-Gediga M. Neutrophils, NETs, NETosis—old or new factors in sepsis and septic shock? Anaesthesiol Intensive Ther. 2017; 49(3):235-240. doi:10.5603/AIT.2017.0041
|
| [58] |
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. doi:10.3389/fimmu.2020.610696
|
| [59] |
Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019; 23(1):16. doi:10.1186/s13054-018-2292-6
|
| [60] |
Kravitz MS, Kattouf N, Stewart IJ, Ginde AA, Schmidt EP, Shapiro NI. Plasma for prevention and treatment of glycocalyx degradation in trauma and sepsis. Crit Care. 2024; 28(1):254. doi:10.1186/s13054-024-05026-7
|
| [61] |
Iba T, Levy JH, Raj A, Warkentin TE. Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Clin Med. 2019; 8(5):728. doi:10.3390/jcm8050728
|
| [62] |
Zhan JH, Wei J, Liu YJ, Wang PX, Zhu XY. Sepsis-associated endothelial glycocalyx damage: a review of animal models, clinical evidence, and molecular mechanisms. Int J Biol Macromol. 2025; 295:139548. doi:10.1016/j.ijbiomac.2025.139548
|
| [63] |
Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013; 13(1):34-45. doi:10.1038/nri3345
|
| [64] |
Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol. 2021; 18(9):666-682. doi:10.1038/s41569-021-00552-1
|
| [65] |
De Caterina R, D’Ugo E, Libby P. Inflammation and thrombosis—testing the hypothesis with anti-inflammatory drug trials. Thromb Haemost. 2016; 116(6):1012-1021. doi:10.1160/TH16-03-0246
|
| [66] |
Ryan TAJ, O’Neill LAJ. Innate immune signaling and immunothrombosis: new insights and therapeutic opportunities. Eur J Immunol. 2022; 52(7):1024-1034. doi:10.1002/eji.202149410
|
| [67] |
Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the management of sepsis. Ann Intensive Care. 2024; 14(1):148. doi:10.1186/s13613-024-01380-5
|
| [68] |
Curtiaud A, Iba T, Angles-Cano E, Meziani F, Helms J. Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications. Ann Intensive Care. 2025; 15(1):12. doi:10.1186/s13613-025-01434-2
|
| [69] |
Tan R, Ge C, Wang J, et al. Interpretable machine learning model for early morbidity risk prediction in patients with sepsis-induced coagulopathy: a multi-center study. Front Immunol. 2025; 16:1552265. doi:10.3389/fimmu.2025.1552265
|
| [70] |
Scully M, Hunt BJ, Benjamin S, et al.; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012; 158(3):323-335. doi:10.1111/j.1365-2141.2012.09167.x
|
| [71] |
Kruijt M, Cobbaert CM, Ruhaak LR. Antithrombin: deficiency, diversity, and the future of diagnostics. Mass Spectrom Rev. 2025:1-24. doi:10.1002/mas.21929
|