Letter by Brambilla et al Regarding Article, “Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report”
2021; Lippincott Williams & Wilkins; Volume: 41; Issue: 6 Linguagem: Inglês
10.1161/atvbaha.121.316188
ISSN1524-4636
AutoresMarta Brambilla, Paola Canzano, Alessia Becchetti, Elena Tremoli, Marina Camera,
Tópico(s)Inflammasome and immune disorders
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 41, No. 6Letter by Brambilla et al Regarding Article, "Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Brambilla et al Regarding Article, "Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report" Marta Brambilla, Paola Canzano, Alessia Becchetti, Elena Tremoli and Marina Camera Marta BrambillaMarta Brambilla https://orcid.org/0000-0002-7251-9106 Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., A.B., E.T., M.C.). , Paola CanzanoPaola Canzano https://orcid.org/0000-0003-4122-7853 Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., A.B., E.T., M.C.). , Alessia BecchettiAlessia Becchetti https://orcid.org/0000-0003-4478-2123 Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., A.B., E.T., M.C.). , Elena TremoliElena Tremoli https://orcid.org/0000-0002-0929-6106 Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., A.B., E.T., M.C.). and Marina CameraMarina Camera https://orcid.org/0000-0002-7814-7067 Centro Cardiologico Monzino IRCCS, Milan, Italy (M.B., P.C., A.B., E.T., M.C.). Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy (M.C.). Originally published26 May 2021https://doi.org/10.1161/ATVBAHA.121.316188Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41:e379–e380To the Editor:We read with great interest the work recently published by Rosell et al1 suggesting that increased levels of TF (tissue factor)-positive extracellular vesicles (EVs) may drive thrombosis in patients with coronavirus disease 2019 (COVID-19). The results of the study, conducted on 100 COVID-19 patients and 28 healthy subjects, show indeed that the capacity of EVs isolated from patient plasma to generate factor Xa is significantly higher than that of EVs isolated from healthy subjects. Furthermore, TF-dependent activity is associated with disease severity, thus leading the authors to propose EV TF activity as a prognostic marker in patients with COVID-19.Over the years, several studies have described the potential value of EVs as biomarkers and therapeutic targets.2,3 It is worth mentioning, however, that the ideal biomarkers should be useful not only in assessing the risk of negative outcome but should also prompt the adoption of strategies to treat the disease. To do that, biomarkers should reflect the pathological state and also provide information on the dysfunctional cellular compartment.Unfortunately, the authors do not provide any detail on EV characterization, justifying this gap with their previous failure to evaluate circulating TF-positive EVs by flow cytometry.4 It should be considered on this regard that flow cytometry analysis of EVs has been largely improved in the last 10 years mainly through the development of highly sensitive instruments.5 This has allowed a major breakthrough in identifying the molecular composition of vesicles, making them not only ideal candidates as disease biomarkers but also a useful tool for the clinician in view of an increasingly personalized pharmacological intervention.6–8 Their potential ability to provide information on pathophysiological processes has prompted several scientific societies, including the International Society of Extracellular Vesicles, International Society for Advancement of Cytometry, and International Society for Thrombosis and Haemostasis Vascular Biology Scientific Standardization Committee to draw up guidelines for EV analysis by flow cytometry.9–12 Further standardization studies by EV flow cytometry working groups are currently in progress to upgrade EV characterization from sample preparation to data analysis, ensuring that results can be compared and shared among different laboratories.10,13 While waiting for these further indications, the frameworks available today propose standard operating procedures to improve the interpretation and reproducibility of results. This has minimized the preanalytical and methodological variability also in terms of TF-positive EV analysis, and indeed, during the years, several authors have published data on TF-positive EVs.14–16Compliance to these recommendations has recently allowed us to characterize the signature of circulating EVs in COVID-19 patients through an in-depth analysis in terms of number, procoagulant phenotype, and cellular origin.8 In line with Rosell et al, our data show that the total number of TF-positive EVs is significantly higher in COVID-19 patients than in healthy subjects or in coronary syndrome patients and correlates with their thrombin generation potential (r=0.495, P=0.02). Furthermore, in contrast to Rosell's speculation, we provide evidence that the most abundant TF-positive EVs comes from platelets, being 2-fold and 4-fold higher than those from endothelium and monocytes, respectively. As expected, this profile mirrors the pattern of TF expression in circulating cells, being the number of TF-positive platelets significantly higher in SARS-CoV2 (severe acute respiratory syndrome coronavirus 2)–infected patients than in healthy subjects. Of note, TF-positive platelets and procoagulant EVs both correlate with the disease severity, being higher in COVID-19 patients requiring mechanical ventilation. The evidence of a sustained platelet activation, characterized not only by elevated TF expression and increased number of platelet-leukocyte aggregates but also by a high EV release, would support the effectiveness of a pharmacological intervention aimed at reducing the platelet activation state.8In conclusion, information on the cellular origin of circulating EVs makes these biomarkers more useful from a clinical point of view since they pose the rationale for therapeutic intervention. On this regard, results of the currently ongoing randomized clinical trials testing the efficacy of antiplatelet therapy on COVID-19 patients will provide evidence on the usefulness of platelet-EV biomarkers in this disease.Disclosures None.FootnotesThis manuscript was sent to William C. Sessa, Senior Consulting Editor, for review by expert referees, editorial decision, and final disposition.For Disclosures, see page e380.References1. Rosell A, Havervall S, von Meijenfeldt F, Hisada Y, Aguilera K, Grover SP, Lisman T, Mackman N, Thålin C. Patients with COVID-19 have elevated levels of circulating extracellular vesicle tissue factor activity that is associated with severity and mortality—brief report.Arterioscler Thromb Vasc Biol. 2021; 41:878–882. doi: 10.1161/ATVBAHA.120.315547LinkGoogle Scholar2. Konkoth A, Saraswat R, Dubrou C, Sabatier F, Leroyer AS, Lacroix R, Duchez AC, Dignat-George F. Multifaceted role of extracellular vesicles in atherosclerosis.Atherosclerosis. 2021; 319:121–131. doi: 10.1016/j.atherosclerosis.2020.11.006CrossrefMedlineGoogle Scholar3. Zacharia E, Zacharias K, Papamikroulis GA, Bertsias D, Miliou A, Pallantza Z, Papageorgiou N, Tousoulis D. Cell- derived microparticles and acute coronary syndromes: is there a predictive role for microparticles?Curr Med Chem. 2020; 27:4440–4468. doi: 10.2174/0929867327666191213104841CrossrefMedlineGoogle Scholar4. Lee RD, Barcel DA, Williams JC, Wang JG, Boles JC, Manly DA, Key NS, Mackman N. Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity.Thromb Res. 2012; 129:80–85. doi: 10.1016/j.thromres.2011.06.004CrossrefMedlineGoogle Scholar5. Groot Kormelink T, Arkesteijn GJ, Nauwelaers FA, van den Engh G, Nolte-'t Hoen EN, Wauben MH. Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution flow cytometry.Cytometry A. 2016; 89:135–147. doi: 10.1002/cyto.a.22644CrossrefMedlineGoogle Scholar6. Fernández M, Calligaris SD. Circulating microparticles in cardiovascular disease: going on stage!Biomarkers. 2019; 24:423–428. doi: 10.1080/1354750X.2019.1616822CrossrefMedlineGoogle Scholar7. Taus F, Meneguzzi A, Castelli M, Minuz P. Platelet- derived extracellular vesicles as target of antiplatelet agents. what is the evidence?Front Pharmacol. 2019; 10:1256. doi: 10.3389/fphar.2019.01256CrossrefMedlineGoogle Scholar8. Camera M, Brambilla M, Canzano P, Cavallotti L, Parolari A, Tedesco CC, Zara C, Rossetti L, Tremoli E. Association of microvesicles with graft patency in patients undergoing CABG surgery.J Am Coll Cardiol. 2020; 75:2819–2832. doi: 10.1016/j.jacc.2020.03.073CrossrefMedlineGoogle Scholar9. Lee JA, Spidlen J, Boyce K, Cai J, Crosbie N, Dalphin M, Furlong J, Gasparetto M, Goldberg M, Goralczyk EM, et al; International Society for Advancement of Cytometry Data Standards Task Force. MIFlowCyt: the minimum information about a Flow Cytometry Experiment.Cytometry A. 2008; 73:926–930. doi: 10.1002/cyto.a.20623CrossrefMedlineGoogle Scholar10. van der Pol E, Sturk A, van Leeuwen T, Nieuwland R, Coumans F; ISTH-SSC-VB Working Group. Standardization of extracellular vesicle measurements by flow cytometry through vesicle diameter approximation.J Thromb Haemost. 2018; 16:1236–1245. doi: 10.1111/jth.14009CrossrefMedlineGoogle Scholar11. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles. 2018; 7:1535750. doi: 10.1080/20013078.2018.1535750CrossrefMedlineGoogle Scholar12. Welsh JA, Van Der Pol E, Arkesteijn GJA, Bremer M, Brisson A, Coumans F, Dignat-George F, Duggan E, Ghiran I, Giebel B, et al. MIFlowCyt-EV: a framework for standardized reporting of extracellular vesicle flow cytometry experiments.J Extracell Vesicles. 2020; 9:1713526. doi: 10.1080/20013078.2020.1713526CrossrefMedlineGoogle Scholar13. Cointe S, Judicone C, Robert S, Mooberry MJ, Poncelet P, Wauben M, Nieuwland R, Key NS, Dignat-George F, Lacroix R. Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop.J Thromb Haemost. 2017; 15:187–193. doi: 10.1111/jth.13514CrossrefMedlineGoogle Scholar14. Chiva-Blanch G, Crespo J, Suades R, Arderiu G, Padro T, Vilahur G, Cubedo J, Corella D, Salas-Salvadó J, Arós F, et al. CD142+/CD61+, CD146+ and CD45+ microparticles predict cardiovascular events in high risk patients following a Mediterranean diet supplemented with nuts.Thromb Haemost. 2016; 116:103–114. doi: 10.1160/TH16-02-0130CrossrefMedlineGoogle Scholar15. Campello E, Radu CM, Duner E, Lombardi AM, Spiezia L, Bendo R, Ferrari S, Simioni P, Fabris F. Activated platelet- derived and leukocyte- derived circulating microparticles and the risk of thrombosis in heparin- induced thrombocytopenia: a role for PF4- bearing microparticles?Cytometry B Clin Cytom. 2018; 94:334–341. doi: 10.1002/cyto.b.21507CrossrefMedlineGoogle Scholar16. Thulin Å, Yan J, Åberg M, Christersson C, Kamali-Moghaddam M, Siegbahn A. Sensitive and specific detection of platelet-derived and tissue factor-positive extracellular vesicles in plasma using solid-phase proximity ligation assay.TH Open. 2018; 2:e250–e260. doi: 10.1055/s-0038-1667204CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Burrello J, Caporali E, Gauthier L, Pianezzi E, Balbi C, Rigamonti E, Bolis S, Lazzarini E, Biemmi V, Burrello A, Frigerio R, Martinetti G, Fusi-Schmidhauser T, Vassalli G, Ferrari E, Moccetti T, Gori A, Cretich M, Melli G, Monticone S and Barile L (2022) Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles, Vascular Pharmacology, 10.1016/j.vph.2022.106999, 145, (106999), Online publication date: 1-Aug-2022. Ferrari D, Rubini M and Burns J (2022) The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2, Frontiers in Immunology, 10.3389/fimmu.2022.904419, 13 June 2021Vol 41, Issue 6 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.121.316188PMID: 34038167 Originally publishedMay 26, 2021 PDF download Advertisement SubjectsBiomarkersPlateletsThrombosis
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