Thrombi and Neutrophils
2015; Lippincott Williams & Wilkins; Volume: 116; Issue: 7 Linguagem: Inglês
10.1161/circresaha.115.306050
ISSN1524-4571
AutoresJean‐Baptiste Michel, Benoît Ho‐Tin‐Noé,
Tópico(s)Vasculitis and related conditions
ResumoHomeCirculation ResearchVol. 116, No. 7Thrombi and Neutrophils Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThrombi and Neutrophils Jean-Baptiste Michel and Benoît Ho-Tin-Noé Jean-Baptiste MichelJean-Baptiste Michel From the UMR 1148, Inserm-Laboratory for Vascular Translation Science, Denis Diderot Université, Paris, France. and Benoît Ho-Tin-NoéBenoît Ho-Tin-Noé From the UMR 1148, Inserm-Laboratory for Vascular Translation Science, Denis Diderot Université, Paris, France. Originally published27 Mar 2015https://doi.org/10.1161/CIRCRESAHA.115.306050Circulation Research. 2015;116:1107–1108More than a century ago, in 1881, Bizzozero1 discovered platelets and their role in primary hemostasis. Since this founding study, it has been shown that, in addition to the scaffold of platelets and fibrin, other proteins and cells play an important role in thrombus formation and stabilization. One can already observe in the previous drawings of Bizzozero1 that leukocytes and red blood cells are trapped within the thrombus. We know now that thrombi are actually heterogeneous and can take on multiple forms both in the arterial and venous systems. As a consequence of this diversity, thrombi can have a variable effect on the development and outcome of cardiovascular diseases. In fact, whereas occlusive thrombi can abruptly cause dramatic acute ischemic events, nonobstructive thrombi, like those found in abdominal aortic aneurysms, can slowly and progressively degrade the vessel wall via convection of blood-borne and leukocyte-derived proteases.2 Furthermore, thrombus heterogeneity bears important clinical implications because the efficacy of thrombolysis in the treatment of acute ischemic events is highly dependent on thrombus composition and structure. For example, both platelet-rich thrombi and aged thrombi are known to be more resistant to the gold-standard thrombolytic agent, recombinant tissue plasminogen activator (r-tPA).3 Because of these barriers to r-tPA–induced thrombolysis and given that r-tPA targets the fibrin scaffold, it has been proposed that targeting other thrombus components (eg, Von Willebrand factor4) could help to improve the efficacy of thrombolysis.Article, see p 1182In recent years, neutrophil extracellular traps (NETs) have been identified as major triggers and structural factors of various forms of thrombosis, including infection-induced thrombosis,5 deep vein thrombosis,6 and cancer-associated thrombosis.7 NETs are extracellular webs primarily composed of DNA from neutrophils that ensnare pathogens but also cause platelet activation and aggregation.8,9 It should be noted that the discovery of NETs and of their role in thrombosis somewhat rehabilitates the theories of Schmidt10 and Mantegazza11, who both attributed triggering and structural roles of leukocytes and leukocyte destruction in thrombus formation before being eclipsed by Bizzozero1 and his discovery of platelets a few years later. Although most of the work on NETs has been focused on the venous compartment, NETs have also been identified in the arterial compartment, such as in the thrombus of human aortic aneurysms.12 Therefore, the contribution of NETs to thrombus formation and to thrombotic events is likely far from being restricted to venous thrombosis, and NETs could, in consequence, be promising targets for improved thrombolysis under various thrombotic conditions. The results of Mangold e al13 presented in this issue of Circulation Research strongly support this hypothesis. In this translational clinical investigation, the authors explored the relationship between the presence of neutrophils and NETs in human obstructive coronary thrombi and postmyocardial infarction evolution. Precisely, this study shows that the NET burden in culprit coronary thrombi is positively correlated with the infarct size and negatively correlated with ST-segment resolution. They further show that, on the contrary, DNase activity correlates negatively with coronary thrombus NET burden and with infarct size. This study therefore points to an aggravating role of neutrophils and NETs in ST-elevation acute coronary syndrome, an effect that could be because of the increased resistance of the NET-loaded thrombus to fibrinolysis. The authors indeed show that DNase accelerates the lysis of coronary thrombi by tPA in vitro. Interestingly, a deleterious action of NETs was recently shown in a mouse model of myocardial ischemia/reperfusion.14 Together, this study and that by Mangold et al13 thus suggest that targeting NETs with DNase could be beneficial both to increase the efficacy of thrombolysis and to reduce the ischemia-related cardiac damage. NETs are indeed coated with neutrophil proteolytic and oxidative enzymes that can seriously damage host tissues. We have previously demonstrated that neutrophil invasion and activation within the thrombus of human aortic abdominal aneurysms are the main biological impediments to the repair process that shifts the thrombus phenotype from a potential healing substrate to an aggressive neotissue.15One of the strengths of the study by Mangold et al13 resides in the use of human biological material. When compared with mice, in which the blood count is low in granulocytes (<20%), polymorphonuclear neutrophils are the predominant type of circulating leukocytes (50%–70%) in humans and are therefore systematically present in human thrombi.16 Concordantly, important ancillary results of Mangold et al13 highlight the fact that neutrophils and NETs are significant components of human coronary thrombi that do not only represent new therapeutic targets for thrombolysis but also provide a source of new biomarkers to define the biological process of acute coronary syndrome. In fact, the authors show that measurement of free double-stranded DNA can be used as a plasma biomarker of coronary thrombus NET burden, in addition to the more classical markers of neutrophil activation (neutrophil elastase and myeloperoxidase).Because pathogens are one of the strongest triggers of NET formation17 and to explain the observed activation of neutrophils at the culprit lesion site, the authors explored the thrombus content in bacterial species from the bucodental microbiote. Their results confirm the high frequency of contamination of coronary thrombi by weak bucodental pathogens, such as Streptococcus species. Oral bacteria have been detected in carotid endarterectomy samples18,19 and in thrombectomy samples.20 If one considers the effect that bacteria can have on the deleterious biological activities of thrombi, one can imagine that thrombus contamination also fosters thrombus- and neutrophil-dependent injury in ST-elevation acute coronary syndrome. Human abdominal aortic aneurysms, intracerebral aneurysms, and infective endocarditis nicely illustrate how interactions between bacteria and the thrombus can fuel thrombus-dependent injury, notably by promoting neutrophil recruitment and activation.12,21Conclusions and PerspectivesIntravascular thrombi, whatever their initial cause and localization, are highly pathogenic because they not only induce downstream tissue ischemia by occluding arteries but also participate in injury of the surrounding tissue by releasing proteolytic and oxidative enzymes. Because of the various mechanisms of resistance to thrombolysis by r-tPA, new therapeutic approaches for the treatment of occlusive thrombosis are being actively investigated. In this context, the study of Mangold et al13 is of critical interest as it designates NETs as a source of new biomarkers to define the biological process of acute coronary syndrome and DNA as a therapeutic target for increasing the efficacy of r-tPA–induced thrombus lysis. Furthermore, this study strengthens the idea that periodontal diseases can affect the development and evolution of atherothrombotic diseases.AcknowledgmentsWe are indebted to Mary Osborne-Pellegrin and Richard Bayles for help in editing the article.Sources of FundingThis study was supported by grants from Fondation de France (no. 2012-29500) and Fondation pour la Recherche Médicale.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jean-Baptiste Michel, MD, PhD, UMR 1148, Inserm-Denis Diderot Université, CHU Xavier Bichat, 46 rue Henri Huchard, 75018 Paris. E-mail [email protected]References1. Bizzozero G. 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Role of leukocyte elastase in preventing cellular re-colonization of the mural thrombus.Am J Pathol. 2004; 164:2077–2087.CrossrefMedlineGoogle Scholar16. Arakawa K, Yasuda S, Hao H, Kataoka Y, Morii I, Kasahara Y, Kawamura A, Ishibashi-Ueda H, Miyazaki S. Significant association between neutrophil aggregation in aspirated thrombus and myocardial damage in patients with ST-segment elevation acute myocardial infarction.Circ J. 2009; 73:139–144.CrossrefMedlineGoogle Scholar17. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin?J Cell Biol. 2012; 198:773–783. doi: 10.1083/jcb.201203170.CrossrefMedlineGoogle Scholar18. Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE, Bäckhed F. Human oral, gut, and plaque microbiota in patients with atherosclerosis.Proc Natl Acad Sci U S A. 2011; 108(suppl 1):4592–4598. doi: 10.1073/pnas.1011383107.CrossrefMedlineGoogle Scholar19. 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Predominant role of host proteases in myocardial damage associated with infectious endocarditis induced by Enterococcus faecalis in a rat model.Infect Immun. 2013; 81:1721–1729. doi: 10.1128/IAI.00775-12.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Michel J (2020) Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells, Physiological Reviews, 10.1152/physrev.00022.2019, 100:4, (1779-1837), Online publication date: 1-Oct-2020. Salhi L, Rompen E, Sakalihasan N, Laleman I, Teughels W, Michel J and Lambert F (2018) Can Periodontitis Influence the Progression of Abdominal Aortic Aneurysm? A Systematic Review, Angiology, 10.1177/0003319718821243, 70:6, (479-491), Online publication date: 1-Jul-2019. Ouk T, Potey C, Maestrini I, Petrault M, Mendyk A, Leys D, Bordet R and Gautier S (2019) Neutrophils in tPA-induced hemorrhagic transformations: Main culprit, accomplice or innocent bystander?, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2018.09.005, 194, (73-83), Online publication date: 1-Feb-2019. Kaesmacher J, Boeckh-Behrens T, Simon S, Maegerlein C, Kleine J, Zimmer C, Schirmer L, Poppert H and Huber T (2017) Risk of Thrombus Fragmentation during Endovascular Stroke Treatment, American Journal of Neuroradiology, 10.3174/ajnr.A5105, 38:5, (991-998), Online publication date: 1-May-2017. Berezin A (2016) Is the neutrophil extracellular trap-driven microvascular inflammation essential for diabetes vasculopathy?, Biomedical Research and Therapy, 10.7603/s40730-016-0021-9, 3:5, Online publication date: 1-Jun-2016. Pende A, Artom N, Bertolotto M, Montecucco F and Dallegri F (2016) Role of neutrophils in atherogenesis: an update, European Journal of Clinical Investigation, 10.1111/eci.12566, 46:3, (252-263), Online publication date: 1-Mar-2016. Rinaldi I, Hamonangan R, Azizi M, Cahyanur R, Wirawan F, Fatya A, Budiananti A and Winston K (2021) Diagnostic Value of Neutrophil Lymphocyte Ratio and D-Dimer as Biological Markers of Deep Vein Thrombosis in Patients Presenting with Unilateral Limb Edema, Journal of Blood Medicine, 10.2147/JBM.S291226, Volume 12, (313-325) He G, Huang Y, Liu L, Huang J, Lo K, Yu Y, Chen C, Zhang B and Feng Y (2021) Association of Circulating, Inflammatory-Response Exosomal mRNAs With Acute Myocardial Infarction, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.712061, 8 March 27, 2015Vol 116, Issue 7 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.115.306050PMID: 25814679 Originally publishedMarch 27, 2015 Keywordsinfectionblood plateletsleukocytesEditorialshemoglobinsPDF download Advertisement SubjectsPathophysiology
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