Koroner Aterotrombozda S100A8/A9'un Trombosit Yanıtları Üzerindeki Etkileri

Mustafa Orhan Tunçel

doi:10.5281/zenodo.23043976

Authors

Mustafa Orhan Tunçel İnönü University https://orcid.org/0000-0002-8999-2223

DOI:

https://doi.org/10.5281/zenodo.23043976

Keywords:

Coronary Atherothrombosis, Platelet Activation, S100A8/A9, Thromboinflammation

Abstract

Coronary atherothrombosis is a multicomponent process resulting from the interplay of structural changes within the atherosclerotic plaque, vascular inflammation, and platelet responses. The S100A8/A9 heterodimer, primarily released by myeloid cells, is one of the protein complexes involved in the link between inflammation and thrombosis. This review evaluates the potential role of S100A8/A9 in platelet functions and coronary atherothrombosis, based on studies published between 2021 and 2026. Research indicates that S100A8/A9 can promote the formation of procoagulant platelets via GPIbα, and that signaling pathways involving CD36 and EGFR may also contribute to platelet responses. Interactions among neutrophils, endothelial cells, and platelets suggest that these effects cannot be assessed independently of the inflammatory environment. However, experimental findings regarding aggregation, phosphatidylserine exposure, and thrombus formation under flow conditions are not always consistent. Clinical studies have associated elevated circulating S100A8/A9 levels with acute coronary syndrome and subsequent cardiovascular events. Furthermore, there is evidence suggesting that S100A8/A9 may influence the durability of the response to aspirin. While current data suggest that S100A8/A9 may establish a functional link between inflammatory and platelet-driven processes in coronary atherothrombosis, they do not definitively establish a causal role in human coronary thrombus formation. Clinical studies simultaneously examining S100A8/A9 levels, the various functional responses of platelets, and antiplatelet treatment status are needed to clarify this relationship.

References

1. Sun Y, Xu H, Gao W, Deng J, Song X, Li J, et al. S100a8/A9 proteins: critical regulators of inflammation in cardiovascular diseases. Frontiers in Cardiovascular Medicine. 2024;11:1394137.

2. Lee Y-J, Lee S-J, Kim JW, Lee S-H, Kim G-S, Park JH, et al. Intensive LDL cholesterol targeting in atherosclerotic cardiovascular disease. New England Journal of Medicine. 2026;394(14):1365-75.

3. Baaten CC, Nagy M, Bergmeier W, Spronk HM, van der Meijden PE. Platelet biology and function: plaque erosion vs. rupture. European heart journal. 2024;45(1):18-31.

4. Badimon L, Vilahur G, Mendieta G. A new era in atherothrombosis. Atherosclerosis. 2026:120777.

5. Huilcaman R, Venturini W, Fuenzalida L, Cayo A, Segovia R, Valenzuela C, et al. Platelets, a key cell in inflammation and atherosclerosis progression. Cells. 2022;11(6):1014.

6. Scherlinger M, Richez C, Tsokos GC, Boilard E, Blanco P. The role of platelets in immune-mediated inflammatory diseases. Nature Reviews Immunology. 2023;23(8):495-510.

7. Chen S, Chen H, Dong P, Wang Y, Huang J, Wang J. Mechanistic insights and clinical implications of the S100 protein family in breast cancer. Biomedicine & Pharmacotherapy. 2026;198:119358.

8. Rastrygina VA, Vologzhannikova AA, Chaplygina AV, Bobrova LA, Zemskova MY, Deryusheva EI, et al. Activity of epidermal growth factor is directly affected by S100 proteins. Cell Calcium. 2026:103153.

9. Joshi A, Schmidt LE, Burnap SA, Lu R, Chan MV, Armstrong PC, et al. Neutrophil-derived protein S100A8/A9 alters the platelet proteome in acute myocardial infarction and is associated with changes in platelet reactivity. Arteriosclerosis, thrombosis, and vascular biology. 2022;42(1):49-62.

10. Wang J, Chen G, Li L, Luo S, Hu B, Xu J, et al. Sustained induction of IP-10 by MRP8/14 via the IFNβ–IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice. Burns & Trauma. 2023;11:tkad006.

11. Wang S, Ni Y, Feng J, Zhang W, Zhou M, Zhao C. S100A8/A9 as a central hub in inflammaging: Cross-system mechanisms. Ageing Research Reviews. 2026:103108.

12. Colicchia M, Schrottmaier WC, Perrella G, Reyat JS, Begum J, Slater A, et al. S100A8/A9 drives the formation of procoagulant platelets through GPIbα. Blood, The Journal of the American Society of Hematology. 2022;140(24):2626-43.

13. Feng Y, Zhao W, Fang S, Zhao J, Wang W, Zhou S, et al. Low-Molecular-weight fucoidan inhibits thromboinflammation and ameliorates deep vein thrombosis via targeting S100A8/A9. Marine drugs. 2025;23(5):180.

14. Feng J, Qin Y, Zhao H, Liu Y. The mechanism of S100A8/A9 heterodimer promoting atherosclerotic thrombosis. Clinical and Experimental Medicine. 2026;26(1):70.

15. Zhou H, Zhao C, Shao R, Xu Y, Zhao W. The functions and regulatory pathways of S100A8/A9 and its receptors in cancers. Frontiers in pharmacology. 2023;14:1187741.

16. Kulkarni AJ, Rai V. S100A8/A9 and S100A12 Proteins and Macrophage Polarization: Therapeutic Targets in Atherosclerosis. Biomolecules. 2026;16(8):1115.

17. Sprenkeler EG, Zandstra J, van Kleef ND, Goetschalckx I, Verstegen B, Aarts CE, et al. S100A8/A9 is a marker for the release of neutrophil extracellular traps and induces neutrophil activation. Cells. 2022;11(2):236.

18. Revenstorff J, Ludwig N, Hilger A, Mersmann S, Lehmann M, Grenzheuser JC, et al. Role of S100A8/A9 in platelet–neutrophil complex formation during acute inflammation. Cells. 2022;11(23):3944.

19. Liani R, Simeone PG, Alfonsetti M, Lattanzio S, Ricci A, Frezza M, et al. Circulating S100A8/A9 drives faster platelet COX-1 recovery via MRP4, impairing the duration of aspirin response. Blood advances. 2026;10(4):1236-49.

20. Chen Y-C, Smith M, Ying Y-L, Makridakis M, Noonan J, Kanellakis P, et al. Quantitative proteomic landscape of unstable atherosclerosis identifies molecular signatures and therapeutic targets for plaque stabilization. Communications biology. 2023;6(1):265.

21. Rao RS, Panbhukarasu S, Waleed M, Raichel CRC, Rahman K, Sivakumar K, et al. Neutrophil-derived S100a8/A9 in cardiovascular disease and beyond. Current Pharmacology Reports. 2023;9(5):353-63.

22. Kwon H-W, Shin J-H, Rhee MH, Park C-E, Lee D-H. Anti-thrombotic effects of ginsenoside Rk3 by regulating cAMP and PI3K/MAPK pathway on human platelets. Journal of Ginseng Research. 2023;47(6):706-13.

23. Zhou X, Zhou X, Zhu R, Ming Z, Cheng Z, Hu Y. The mechanism of oleic acid inhibiting platelet activation stimulated by collagen. Cell Communication and Signaling. 2023;21(1):278.

24. Luo S, Xu R, Xie P, Liu X, Ling C, Liu Y, et al. EGFR of platelet regulates macrophage activation and bacterial phagocytosis function. Journal of Inflammation. 2024;21(1):10.

25. Guo Y, Gao Z, Zhang R, Long H, Zhang M, Liu L, et al. Neutrophil–endothelium interaction mediated by S100A9 promotes pulmonary vascular remodeling during pulmonary hypertension. Advanced Science. 2025;12(31):e04397.

26. Barrett TJ, Cornwell M, Myndzar K, Rolling CC, Xia Y, Drenkova K, et al. Platelets amplify endotheliopathy in COVID-19. Science Advances. 2021;7(37):eabh2434.

27. Blasco A, Rosell A, Castejón R, Coronado MJ, Royuela A, Ramil E, et al. Analysis of NETs (neutrophil extracellular traps) in coronary thrombus and peripheral blood of patients with ST-segment elevation myocardial infarction. Thrombosis Research. 2024;235:18-21.

28. Gerhardt T, Seppelt C, Abdelwahed YS, Meteva D, Wolfram C, Stapmanns P, et al. Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome. European Heart Journal. 2023;44(38):3911-25.

29. Kiełbowski K, Skórka P, Plewa P, Bakinowska E, Pawlik A. The role of alarmins in the pathogenesis of atherosclerosis and myocardial infarction. Current issues in molecular biology. 2024;46(8):8995-9015.

30. Cozac D-A, Halațiu V-B, Scridon A. The alarmin tandem: unraveling the complex effect of S100A8/A9–from atherosclerosis to cardiac arrhythmias. Frontiers in Immunology. 2025;16:1630410.

31. Reshadmanesh T, Behnoush AH, Farajollahi M, Khalaji A, Ghondaghsaz E, Ahangar H. Circulating Levels of Calprotectin as a Biomarker in Patients With Coronary Artery Disease: A Systematic Review and Meta‐Analysis. Clinical Cardiology. 2024;47(7):e24315.

32. Berg DD, Yeh RW, Mauri L, Morrow DA, Kereiakes DJ, Cutlip DE, et al. Biomarkers of platelet activation and cardiovascular risk in the DAPT trial. Journal of thrombosis and thrombolysis. 2021;51(3):675-81.

33. Pi J, Geng L, Fan C, Xu J, Wang X, Zhang Q, et al. Plasma alarmin S100A8/A9 serves as a potential biomarker of major adverse cardiovascular events after acute myocardial infarction. Cardiovascular Diagnosis and Therapy. 2026;16(3):47.