Neutrophil extracellular traps (NETs): Relevance to thrombosis and hemostasis. A narrative review
By: Amin A. Alamin
References
- Ashorobi D, Ameer MA, Fernandez R. Thrombosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Updated 2024 Feb 12. https://www.ncbi.nlm.nih.gov/books/NBK538430/
- Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938-949. DOI: 10.1056/NEJMra0801082
- Bhattarai A, Shah S, Bagherieh S, et al. Endothelium, platelets, and coagulation factors as the three vital components for diagnosing bleeding disorders: a simplified perspective with clinical relevance. Int J Clin Pract. 2022;2022:5369001. DOI: 10.1155/2022/5369001
- Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-15885. DOI: 10.1073/pnas.1005743107
- Zhou Y, Xu Z, Liu Z. Impact of Neutrophil Extracellular Traps on Thrombosis Formation: New Findings and Future Perspective. Front Cell Infect Microbiol. 2022;12:910908. Published 2022 May 31. DOI: 10.3389/fcimb.2022.910908
- Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-1535. DOI: 10.1126/science.1092385
- Nauseef WM. How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev. 2007;219:88-102. DOI: 10.1111/j.1600-065X.2007.00550.x
- Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-147. DOI: 10.1038/nri.2017.105
- Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007;5(8):577-582. DOI: 10.1038/nrmicro1710
- Demers M, Wagner DD. NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost. 2014;40(3):277-283. DOI: 10.1055/s-0034-1370765
- Zucoloto AZ, Jenne CN. Platelet-Neutrophil Interplay: Insights Into Neutrophil Extracellular Trap (NET)-Driven Coagulation in Infection. Front Cardiovasc Med. 2019;6:85. Published 2019 Jun 20. DOI: 10.3389/fcvm.2019.00085
- de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol. 2019;16(1):19-27. DOI: 10.1038/s41423-018-0024-0
- Stakos DA, Kambas K, Konstantinidis T, Mitroulis I, Apostolidou E, Arelaki S, et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J. 2015;36(22):1405-1414. DOI: 10.1093/eurheartj/ehv007
- Misra DP, Thomas KN, Gasparyan AY,, Zimba O. Mechanisms of thrombosis in ANCA-associated vasculitis. Clin Rheumatol. 2021;40:4807-4815. DOI: 10.1007/s10067-021-05790-9
- Laridan E, Denorme F, Desender L, François O, Andersson T, Deckmyn H, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol. 2017;82(2):223-232. DOI: 10.1002/ana.24993
- Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109(32):13076-13081. DOI: 10.1073/pnas.1200419109
- Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc). 2020;85:1178-1190. DOI: 10.1134/S0006297920100065
- Manda A, Pruchniak MP, Araźna M, Demkow UA. Neutrophil extracellular traps in physiology and pathology. Cent Eur J Immunol. 2014;39(1):116-121. DOI: 10.5114/ceji.2014.42136
- Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 2011;18(4):581-588. DOI: 10.1038/cdd.2011.1
- Dömer D, Walther T, Möller S, Behnen M, Laskay T. Neutrophil Extracellular Traps Activate Proinflammatory Functions of Human Neutrophils. Front Immunol. 2021;12:636954. Published 2021 Jun 8. DOI: 10.3389/fimmu.2021.636954
- Wienkamp AK, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol. 2022;13:953129. DOI: 10.3389/fimmu.2022.953129
- Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349(6245):316-320. DOI: 10.1126/science.aaa8064
- Magán-Fernández A, Rasheed Al-Bakri SM, O’Valle F, Benavides-Reyes C, Abadía-Molina F, Mesa F. Neutrophil Extracellular Traps in Periodontitis. Cells. 2020;9(6):1494. Published 2020 Jun 19. DOI: 10.3390/cells9061494
- Gupta S, Chan DW, Zaal KJ, Kaplan MJ. A High-Throughput Real-Time Imaging Technique To Quantify NETosis and Distinguish Mechanisms of Cell Death in Human Neutrophils. J Immunol. 2018;200(2):869-879. DOI: 10.4049/jimmunol.1700905
- Manley HR, Keightley MC, Lieschke GJ. The neutrophil nucleus: an important influence on neutrophil migration and function. Front Immunol. 2018;9:2867. DOI: 10.3389/fimmu.2018.02867
- Santocki M, Kolaczkowska E. On Neutrophil Extracellular Trap (NET) Removal: What We Know Thus, Far and Why So Little. Cells. 2020; 9(9):2079. DOI: 10.3390/cells9092079 DOI: 10.3390/cells9092079
- Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Hemost. 2012;10(1):136-144. DOI: 10.1111/j.1538-7836.2011.04544.x
- Han T, Tang H, Lin C, Shen Y, Yan D, Tang X, Guo D. Extracellular traps and the role in thrombosis. Front Cardiovasc Med. 2022;9:951670. DOI: 10.3389/fcvm.2022.951670
- Prével R, Dupont A, Labrouche-Colomer S, Garcia G, Dewitte A, Rauch A, et al. Plasma markers of neutrophil extracellular trap are linked to survival but not to pulmonary embolism in COVID-19-related ARDS patients. Front Immunol. (2022) 13:851497. DOI: 10.3389/fimmu.2022.851497
- Rosazza T, Warner J, Sollberger G. NET formation - mechanisms and how they relate to other cell death pathways. FEBS J. 2021;288(11):3334-3350. DOI: 10.1111/febs.15589
- Xu X, Wu Y, Xu S, Yin Y, Ageno W, De Stefano V., et al. Clinical significance of neutrophil extracellular traps biomarkers in thrombosis. Thrombosis J. 2022;20:63. DOI: 10.1186/s12959-022-00421-y
- Yao M, Ma J, Wu D, Fang C, Wang Z, Guo T, et al. Neutrophil extracellular traps mediate deep vein thrombosis: from mechanism to therapy. Front Immunol. 2023 Aug 23;14:1198952. DOI: 10.3389/fimmu.2023.1198952
- Vu TT, Leslie BA, Stafford AR, Zhou J, Fredenburgh JC, Weitz JI. Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway. Blood. 2017;129(8):1021-1029. DOI: 10.1182/blood-2016-06-722298
- Maugeri N, Campana L, Gavina M, Covino C, De Metrio M, Panciroli C, et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Hemost. 2014;12(12):2074-2088. DOI: 10.1111/jth.12710
- Noubouossie DF, Whelihan MF, Yu YB, Sparkenbaugh E, Pawlinski R, Monroe DM, et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood. 2017;129(8):1021-1029. DOI: 10.1182/blood-2016-06-722298
- Varjú I, Longstaff C, Szabó L, Farkas ÁZ, Varga-Szabó VJ, Tanka-Salamon A, et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Hemost. 2015;113(6):1289-1298. DOI: 10.1160/TH14-08-0669
- Longstaff C, Varjú I, Sótonyi P, Szabó L, Krumrey M, Hoell A, et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288(10):6946-6956. DOI: 10.1074/jbc.M112.404301
- Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon N, et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952-1961. DOI: 10.1182/blood-2011-03-343061
- Glaser CB, Morser J, Clarke JH, Blasko E, McLean K, Kuhn I, et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J Clin Invest. 1992;90(6):2565-2573. DOI: 10.1172/JCI116151
- Barranco-Medina S, Pozzi N, Vogt AD, Di Cera E. Histone H4 promotes prothrombin autoactivation. J Biol Chem. 2013;288(50):35749-35757. DOI: 10.1074/jbc.M113.509786
- Machovich R, Owen WG. An elastase-dependent pathway of plasminogen activation. Biochemistry. 1989;28(10):4517-4522. DOI: 10.1021/bi00436a059
- Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-2776. DOI: 10.1182/blood-2013-10-463646
- Wohner N, Keresztes Z, Sótonyi P, Szabó L, Komorowicz E, Machovich R, et al. Neutrophil granulocyte-dependent proteolysis enhances platelet adhesion to the arterial wall under high-shear flow. J Thromb Hemost. 2010;8(7):1624-1631. DOI: 10.1111/j.1538-7836.2010.03890.x
- Moir E, Robbie LA, Bennett B, Booth NA. Polymorphonuclear leucocytes have two opposing roles in fibrinolysis. Thromb Hemost. 2002;87(6):1006-1010. DOI: 10.1055/s-0037-1613125
- Thålin C, Hisada Y, Lundström S, Mackman N, Wallén H. NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. Thromb Res. 2016;139:56-64. DOI: 10.1016/j.thromres.2016.01.009
- Zhou Y, Tao W, Shen F, Du W, Xu Z, Liu Z. The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis. Front Cardiovasc Med. 2021;8:786387. DOI: 10.3389/fcvm.2021.786387
- Zaiema SE, Elwafa MA, Hassan SG, El Adwey RH, Ghorab RM, Galal RE. Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation. Thromb J. 2024;22(1):32. Published 2024 Mar 28. DOI: 10.1186/s12959-024-00598-4
- Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481-3488. DOI: 10.1161/CIRCULATIONAHA.105.537878
- Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16(8):887-896. DOI: 10.1038/nm.2184
- Hofbauer TM, Ondracek AS, Lang IM. Neutrophil extracellular traps in atherosclerosis and thrombosis. In: von Eckardstein A, Binder CJ, eds. Prevention and Treatment of Atherosclerosis: Improving State-of-the-Art Management and Search for Novel Targets. Cham, Switzerland: Springer; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK584303/
- Ferré-Vallverdú M, Latorre AM, Fuset MP, Sánchez E, Madrid I, Ten F, Vallés J, et al. Neutrophil extracellular traps (NETs) in patients with STEMI. Association with percutaneous coronary intervention and antithrombotic treatments. Thromb Res. 2022;213:78-83. DOI: 10.1016/j.thromres.2022.03.002
- Bonaventura A, Vecchié A, Abbate A, Montecucco F. Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update. Cells. 2020;9(1):231. Published 2020 Jan 17. DOI: 10.3390/cells9010231
- Badimon L, Vilahur G. Neutrophil extracellular traps: a new source of tissue factor in atherothrombosis. Eur Heart J. 2015;36(22):1364-1366. DOI: 10.1093/eurheartj/ehv105
- Natorska J, Ząbczyk M, Undas A. Neutrophil extracellular traps (NETs) in cardiovascular diseases: From molecular mechanisms to therapeutic interventions. Kardiol Pol. 2023;81(12):1205-1216. DOI: 10.33963/v.kp.98520
- Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28(3):370-372. DOI: 10.1161/ATVBAHA.108.162545
- Kimball AS, Obi AT, Diaz JA, Henke PK. The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Front Immunol. 2016;7:236. Published 2016 Jun 27. DOI: 10.3389/fimmu.2016.00236
- Li W, Wang Z, Su C, Liao Z, Pei Y, Wang J., et al. The effect of neutrophil extracellular traps in venous thrombosis. Thrombosis J. 2023;21:67. DOI: 10.1186/s12959-023-00512-4
- Pfeiler S, Stark K, Massberg S, Engelmann B. Propagation of thrombosis by neutrophils and extracellular nucleosome networks. Hematologica. 2017;102(2):206-213. DOI: 10.3324/haematol.2016.142471
- Folco EJ, Mawson TL, Vromman A, Bernardes-Souza B, Franck G, Persson O, et al. Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1α and Cathepsin G. Arterioscler Thromb Vasc Biol. 2018;38(8):1901-1912. DOI: 10.1161/ATVBAHA.118.311150
- Borissoff JI, ten Cate H. From neutrophil extracellular traps release to thrombosis: an overshooting host-defense mechanism?. J Thromb Haemost. 2011;9(9):1791-1794. DOI: 10.1111/j.1538-7836.2011.04425.x
- Rosell A, Martinod K, Mackman N, Thålin C. Neutrophil extracellular traps and cancer-associated thrombosis. Thromb Res. 2022;213 Suppl 1:S35-S41. DOI: 10.1016/j.thromres.2021.12.018
- Scarlatescu E, Tomescu D, Arama SS. Anticoagulant Therapy in Sepsis. The Importance of Timing. J Crit Care Med (Targu Mures). 2017;3(2):63-69. Published 2017 May 11. DOI: 10.1515/jccm-2017-0011
- Zhu D, Lu Y, Wang Y, Wang Y. PAD4 and Its Inhibitors in Cancer Progression and Prognosis. Pharmaceutics. 2022;14(11):2414. Published 2022 Nov 8. DOI: 10.3390/pharmaceutics14112414
- Du M, Yang W, Schmull S, Gu J, Xue S. Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction. Int Immunopharmacol. 2019;78:106055. DOI: 10.1016/j.intimp.2019.106055
- Leinweber J, Mizurini DM, Francischetti IMB, Fleischer M, Hermann DM, Kleinschnitz C, et al. Elastase inhibitor agaphelin protects from acute ischemic stroke in mice by reducing thrombosis, blood-brain barrier damage, and inflammation. Brain Behav Immun. 2021;93:288-298. DOI: 10.1016/j.bbi.2020.12.027
- Sule G, Mazza LF, Kazzaz NM, Yalavarthi S, Meng H, Knight JS. Inhibition of neutrophil elastase protects against glomerulonephritis and thrombosis in a mouse model of lupus [abstract]. Arthritis Rheumatol. 2017;69(suppl 10). Available from: https://acrabstracts.org/abstract/inhibition-of-neutrophil-elastase-protects-against-glomerulonephritis-and-thrombosis-in-a-mouse-model-of-lupus/. Accessed July 21, 2024.
- Carminita E, Crescence L, Brouilly N, Altié A, Panicot-Dubois L, Dubois C. DNAse dependent, NET-independent pathway of thrombus formation in vivo. Proc Natl Acad Sci U S A. 2021;118(28):e2100561118. DOI: 10.1073/pnas.2100561118
- Kumar R, Sonkar VK, Swamy J, Ahmed A, Sharathkumar AA, Pierce GL, et al. DNase 1 protects from increased thrombin generation and venous thrombosis during aging: cross-sectional study in mice and humans. J Am Heart Assoc. 2022;11. DOI: 10.1161/JAHA.121.021188
- Stanger L, Holinstat M, Lambert S, Yalavarthi P, Bergh N, Dahlof B. HDAC Inhibitor CS014 Attenuates Thrombosis Alone and in Combination with Rivaroxaban without Increased Risk of Bleeding. Blood. 2023;142(Supplement 1):1195. DOI: 10.1182/blood-2023-186602
Language: English
Page range: 79 - 86
Submitted on: Jan 24, 2025
Accepted on: Feb 21, 2025
Published on: May 15, 2025
Published by: Romanian Association of Laboratory Medicine
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year
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© 2025 Amin A. Alamin, published by Romanian Association of Laboratory Medicine
This work is licensed under the Creative Commons Attribution 4.0 License.