Immunothrombosis as a bridge between innate immunity and hemostasis

A narrative review of emerging mechanisms

Penulis

  • Anang Rizky Maulana Institut Kesehatan Hermina
  • Cici Nuriah Institut Kesehatan Hermina
  • Faradiyan Kencana Institut Kesehatan Hermina

DOI:

https://doi.org/10.54957/ijhs.v6i1.1993

Kata Kunci:

Immunothrombosis, Innate immunity, Hemostasis, NETs, Thrombo-inflammation

Abstrak

Background: Immunothrombosis is an evolutionarily conserved host defense mechanism integrating innate immunity and hemostasis to limit pathogen dissemination through localized thrombus formation. While physiologically protective, dysregulated immunothrombosis contributes to thrombo-inflammatory diseases. Objective: This narrative review summarizes emerging cellular and molecular mechanisms linking innate immunity and coagulation, with emphasis on their pathological and therapeutic implications. Methods: A narrative literature review was conducted using Scopus-indexed journals retrieved from PubMed, Scopus, and ScienceDirect, prioritizing review articles and landmark original studies published between 2013 and 2025. Main Findings: Immunothrombosis is orchestrated by neutrophils, platelets, monocytes, endothelial cells, and complement systems through mechanisms including neutrophil extracellular trap (NET) formation, tissue factor expression, inflammasome activation, and immune–coagulation crosstalk. Conclusion: Immunothrombosis represents a fundamental biological bridge between innate immunity and hemostasis, offering novel therapeutic targets in thrombo-inflammatory disorders.

Referensi

Engelmann, B., & Massberg, S. (2013). Thrombosis as an intravascular effector of innate immunity. Nature Reviews Immunology, 13(1), 34–45. https://doi.org/10.1038/nri3345

Levi, M., & van der Poll, T. (2017). Coagulation and sepsis. New England Journal of Medicine, 377(12), 1177–1187. https://doi.org/10.1056/NEJMra1607438

Gaertner, F., & Massberg, S. (2016). Blood coagulation in immunothrombosis—At the frontline of intravascular immunity. Thrombosis and Haemostasis, 116(6), 1048–1057. https://doi.org/10.1160/TH16-06-0460

Iba, T., & Levy, J. H. (2020). Sepsis-induced coagulopathy and immunothrombosis. Journal of Thrombosis and Haemostasis, 18(10), 2421–2434. https://doi.org/10.1111/jth.15054

Nicolai, L., & Massberg, S. (2020). Platelets as key players in inflammation and infection. Journal of Thrombosis and Haemostasis, 18(8), 1897–1904. https://doi.org/10.1111/jth.14890

Delabranche, X., Helms, J., & Meziani, F. (2017). Immunothrombosis: A new target for sepsis therapy. Annals of Intensive Care, 7(1), Article 1. https://doi.org/10.1186/s13613-016-0221-8

Aklilu, A., Lai, M. S.-L., Jiang, Z., et al. (2025). Immunothrombosis in sepsis: Cellular crosstalk, molecular triggers, and therapeutic opportunities. International Journal of Molecular Sciences, 26(13), 6114. https://doi.org/10.3390/ijms26136114

Loof, T. G., Mörgelin, M., Johansson, L., et al. (2018). Coagulation, an ancestral serine protease cascade, exerts antibacterial effects. Blood, 131(18), 1936–1947. https://doi.org/10.1182/blood-2017-10-810200

Doolittle, R. F. (2012). Evolution of vertebrate blood coagulation. Cold Spring Harbor Perspectives in Biology, 4(2), a008278. https://doi.org/10.1101/cshperspect.a008278

Esmon, C. T. (2012). Molecular circuits in thrombosis and inflammation. Nature Medicine, 18(6), 846–854. https://doi.org/10.1038/nm.2795

Brinkmann, V., Reichard, U., Goosmann, C., et al. (2004). Neutrophil extracellular traps kill bacteria. Science, 303(5663), 1532–1535. https://doi.org/10.1126/science.1092385

Fuchs, T. A., Brill, A., & Wagner, D. D. (2010). Neutrophil extracellular trap impact on deep vein thrombosis. Proceedings of the National Academy of Sciences of the United States of America, 107(36), 15880–15885. https://doi.org/10.1073/pnas.1005743107

Martinod, K., & Wagner, D. D. (2014). Thrombosis: Tangled up in NETs. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(8), 1741–1749. https://doi.org/10.1161/ATVBAHA.114.303395

Thålin, C., Hisada, Y., Lundström, S., et al. (2019). Neutrophil extracellular traps: Villains and targets in arterial, venous, and cancer-associated thrombosis. Blood, 134(5), 381–390. https://doi.org/10.1182/blood.2019000510

Semple, J. W., Italiano, J. E., Jr., & Freedman, J. (2011). Platelets and the immune continuum. Nature Reviews Immunology, 11(4), 264–274. https://doi.org/10.1038/nri2956

Koupenova, M., Clancy, L., Corkrey, H. A., & Freedman, J. E. (2018). Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circulation Research, 122(2), 337–351. https://doi.org/10.1161/CIRCRESAHA.117.310795

Clark, S. R., Ma, A. C., Tavener, S. A., et al. (2007). Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Medicine, 13(4), 463–469. https://doi.org/10.1038/nm1565

Zarbock, A., Singbartl, K., & Ley, K. (2006). Complete reversal of acid-induced acute lung injury by blocking of platelet–neutrophil aggregation. Blood, 107(11), 4481–4489. https://doi.org/10.1182/blood-2005-09-3776

Østerud, B. (2012). Tissue factor expression in blood cells. Thrombosis Research, 129(Suppl 1), S10–S14. https://doi.org/10.1016/S0049-3848(12)70004-3

Pober, J. S., & Sessa, W. C. (2007). Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology, 7(10), 803–815. https://doi.org/10.1038/nri2171

Mackman, N. (2009). Triggers, targets and treatments for thrombosis. Thrombosis and Haemostasis, 102(5), 858–865.

Pawlinski, R., & Mackman, N. (2010). Cellular sources of tissue factor in endotoxemia and sepsis. Thrombosis Research, 125(Suppl 1), S70–S73. https://doi.org/10.1016/S0049-3848(10)70018-3

Fidler, T. P., Xue, C., Yalcinkaya, M., et al. (2021). The AIM2 inflammasome exacerbates atherosclerosis in clonal hematopoiesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(8), 2447–2459. https://doi.org/10.1161/ATVBAHA.120.315721

Yang, X., Cheng, X., Tang, Y., et al. (2022). Bacterial endotoxin activates the coagulation cascade through inflammasome-dependent tissue factor release. Nature Immunology, 23(2), 220–232. https://doi.org/10.1038/s41590-021-01093-4

Markiewski, M. M., & Lambris, J. D. (2007). The role of complement in inflammatory diseases from behind the scenes into the spotlight. Nature Reviews Immunology, 7(7), 528–538. https://doi.org/10.1038/nri2137

Conway, E. M. (2018). Reincarnation of ancient links between coagulation and complement. Nature Reviews Immunology, 18(1), 62–72. https://doi.org/10.1038/nri.2017.113

Iba, T., Levy, J. H., Raj, A., & Warkentin, T. E. (2019). Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation. Thrombosis Research, 178, 92–100. https://doi.org/10.1016/j.thromres.2019.04.010

Levi, M. (2018). Pathogenesis and diagnosis of disseminated intravascular coagulation. Critical Care, 22(1), 32. https://doi.org/10.1186/s13054-018-1959-5

Ackermann, M., Verleden, S. E., Kuehnel, M., et al. (2020). Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. New England Journal of Medicine, 383(2), 120–128. https://doi.org/10.1056/NEJMoa2015432

Middleton, E. A., He, X. Y., Denorme, F., et al. (2020). Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood, 136(10), 1169–1179. https://doi.org/10.1182/blood.2020007008

Bonaventura, A., Vecchié, A., Dagna, L., et al. (2021). Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. European Heart Journal, 42(32), 3100–3111. https://doi.org/10.1093/eurheartj/ehab271

Knight, J. S., Caricchio, R., Casanova, J.-L., et al. (2021). The intersection of COVID-19, autoimmunity, and immunothrombosis. Nature Reviews Rheumatology, 17(9), 560–575. https://doi.org/10.1038/s41584-021-00653-3

Yalavarthi, S., Gould, T. J., Rao, A. N., et al. (2015). Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies. Arthritis & Rheumatology, 67(11), 2990–3003. https://doi.org/10.1002/art.39247

Connors, J. M., & Levy, J. H. (2020). COVID-19 and its implications for thrombosis and anticoagulation. Blood, 135(23), 2033–2040. https://doi.org/10.1182/blood.2020006000

Barnes, B. J., Adrover, J. M., Baxter-Stoltzfus, A., et al. (2020). Targeting potential drivers of COVID-19: Neutrophil extracellular traps. Journal of Experimental Medicine, 217(6), e20200652. https://doi.org/10.1084/jem.20200652

Skendros, P., Mitsios, A., Chrysanthopoulou, A., et al. (2020). Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. Journal of Clinical Investigation, 130(11), 6151–6157. https://doi.org/10.1172/JCI141374

Flick, M. J., Chauhan, A. K., Frederick, M., et al. (2014). The development of inflammatory thrombi requires fibrinogen binding to integrin αIIbβ3. Blood, 123(23), 3636–3644. https://doi.org/10.1182/blood-2013-12-545228

Rauch, P. J., et al. (2019). Loss of hematopoietic stem cell quiescence promotes pathological thrombosis. Circulation, 139(19), 2381–2395. https://doi.org/10.1161/CIRCULATIONAHA.118.037764

Unduhan

Diterbitkan

17-01-2026

Cara Mengutip

Maulana, A. R., Nuriah, C., & Kencana, F. (2026). Immunothrombosis as a bridge between innate immunity and hemostasis: A narrative review of emerging mechanisms. Indonesian Journal of Health Science, 6(1), 46–51. https://doi.org/10.54957/ijhs.v6i1.1993

Terbitan

Bagian

Articles