{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T10:55:05Z","timestamp":1792580105716,"version":"4.5.0"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005971","name":"Deutsche Herzstiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Neutrophils and platelets are among the most abundant cell types in peripheral blood and characterized by high plasticity and a readily available reservoir of surface proteins and secretable granule contents. Receptor-mediated activation and granule release predispose both cell types for rapid responses to various stimuli. While neutrophils provide the first line of defense to microbial infections and platelets are known for their aggregatory functions in hemostasis and thrombosis, research of the past decade has highlighted that both cell types jointly shape local and systemic immune responses and clot formation alike. Concomitant activation of neutrophils and platelets has been observed in a variety of cardiovascular diseases, including arterial and venous thrombosis, atherosclerosis as well as myocardial infarction and ischemia-reperfusion injury. In this review, we describe the mechanisms by which neutrophils and platelets interact physically, how release of granule contents and soluble molecules by either cell type affects the other and how this mutual activation supports the efficacy of immune responses. We go on to describe how activated platelets contribute to host defense by triggering neutrophil extracellular trap (NET) formation in a process termed immunothrombosis, which in turn promotes local platelet activation and coagulation. Further, we review current evidence of hazardous overactivation of either cell type and their respective role in cardiovascular disease, with a focus on thrombosis, myocardial infarction and ischemia-reperfusion injury, and describe how neutrophils and platelets shape thromboinflammation in COVID-19. Finally, we provide an overview of therapeutic approaches targeting neutrophil-platelet interactions as novel treatment strategy in cardiovascular disease.<\/jats:p>","DOI":"10.3389\/fcvm.2021.824112","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:28:37Z","timestamp":1643588917000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Neutrophil-Platelet Interactions as Novel Treatment Targets in Cardiovascular Disease"],"prefix":"10.3389","volume":"8","author":[{"given":"Rainer","family":"Kaiser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Escaig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Erber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Nicolai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1016\/j.immuni.2021.06.006","article-title":"The neutrophil","volume":"54","author":"Burn","year":"2021","journal-title":"Immunity."},{"key":"B2","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/s41569-018-0110-0","article-title":"Platelet biology and functions: new concepts and clinical perspectives","volume":"16","author":"van der Meijden","year":"2019","journal-title":"Nat Rev Cardiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"599511","DOI":"10.3389\/fimmu.2020.599511","article-title":"Damage-Associated molecular patterns in myocardial infarction and heart transplantation: the road to translational success","volume":"11","author":"Silvis","year":"2020","journal-title":"Front Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat Rev Dis Primers."},{"key":"B5","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.it.2019.08.004","article-title":"Platelets in host defense: experimental and clinical insights","volume":"40","author":"Nicolai","year":"2019","journal-title":"Trends Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/s41577-019-0202-z","article-title":"Patrolling the vascular borders: platelets in immunity to infection and cancer","volume":"19","author":"Gaertner","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.2741\/4576","article-title":"Platelet toll-like receptors in thromboinflammation","volume":"22","author":"D'Atri","year":"2017","journal-title":"Front Biosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nm1565","article-title":"Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood","volume":"13","author":"Clark","year":"2007","journal-title":"Nat Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.coph.2011.06.007","article-title":"The role of TLRs in neutrophil activation","volume":"11","author":"Prince","year":"2011","journal-title":"Curr Opin Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"15559","DOI":"10.1038\/ncomms15559","article-title":"Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbalpha","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1126\/science.1256478","article-title":"Neutrophils scan for activated platelets to initiate inflammation","volume":"346","author":"Sreeramkumar","year":"2014","journal-title":"Science."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1182\/blood.V98.5.1440","article-title":"Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin Blood","volume":"98","author":"Gardiner","year":"2001"},{"key":"B13","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1084\/jem.20020267","article-title":"The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1","volume":"196","author":"Santoso","year":"2002","journal-title":"J Exp Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1161\/ATVBAHA.115.307074","article-title":"Platelet CD40 exacerbates atherosclerosis by transcellular activation of endothelial cells and leukocytes","volume":"36","author":"Gerdes","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1182\/blood-2007-01-069195","article-title":"TREM-1 ligand expression on platelets enhances neutrophil activation","volume":"110","author":"Haselmayer","year":"2007","journal-title":"Blood."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4956","DOI":"10.4049\/jimmunol.172.8.4956","article-title":"Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: differential regulation of activation and survival","volume":"172","author":"Radsak","year":"2004","journal-title":"J Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1097\/SLA.0b013e3181bd95b7","article-title":"Platelet-derived CD40L (CD154) mediates neutrophil upregulation of Mac-1 and recruitment in septic lung injury","volume":"250","author":"Rahman","year":"2009","journal-title":"Ann Surg."},{"key":"B18","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.thromres.2007.12.019","article-title":"Neutrophil CD40 enhances platelet-mediated inflammation","volume":"122","author":"Vanichakarn","year":"2008","journal-title":"Thromb Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1182\/blood-2017-06-788067","article-title":"Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria","volume":"131","author":"Claushuis","year":"2018","journal-title":"Blood."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3105","DOI":"10.1182\/blood.2020009774","article-title":"Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis","volume":"137","author":"Weiss","year":"2021","journal-title":"Blood."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1161\/CIRCULATIONAHA.118.034600","article-title":"Functional relevance of the anaphylatoxin receptor c3ar for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis","volume":"138","author":"Sauter","year":"2018","journal-title":"Circulation."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13464","DOI":"10.1038\/ncomms13464","article-title":"Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response","volume":"7","author":"Rossaint","year":"2016","journal-title":"Nat Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1160\/TH11-12-0867","article-title":"Prasugrel inhibits platelet-leukocyte interaction, reduces inflammatory markers in a model of endotoxic shock in the mouse","volume":"107","author":"Totani","year":"2012","journal-title":"Thromb Haemost."},{"key":"B24","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1097\/SHK.0b013e3181f48987","article-title":"Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model","volume":"35","author":"Hagiwara","year":"2011","journal-title":"Shock"},{"key":"B25","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/0268-960X(93)90024-X","article-title":"Platelet alpha-granules","volume":"7","author":"Harrison","year":"1993","journal-title":"Blood Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1164\/rccm.201108-1533OC","article-title":"Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury","volume":"185","author":"Grommes","year":"2012","journal-title":"Am J Respir Crit Care Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"10647","DOI":"10.1038\/s41598-018-29026-0","article-title":"Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis","volume":"8","author":"Vajen","year":"2018","journal-title":"Sci Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1182\/blood-2017-02-770479","article-title":"Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice","volume":"130","author":"Panicker","year":"2017","journal-title":"Blood."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1182\/blood-2016-04-710632","article-title":"Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice","volume":"128","author":"Stark","year":"2016","journal-title":"Blood."},{"key":"B30","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1161\/CIRCULATIONAHA.118.033942","article-title":"Platelet serotonin aggravates myocardial ischemia\/reperfusion injury via neutrophil degranulation","volume":"139","author":"Mauler","year":"2019","journal-title":"Circulation."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-018-03925-2","article-title":"Cathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation","volume":"9","author":"Pircher","year":"2018","journal-title":"Nat Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1182\/blood.V82.1.139.bloodjournal821139","article-title":"Enhancement of cathepsin G-induced platelet activation by leukocyte elastase: consequence for the neutrophil-mediated platelet activation","volume":"82","author":"Renesto","year":"1993","journal-title":"Blood."},{"key":"B33","unstructured":"Neutrophil cathepsin g proteolysis of protease activated receptor 4 generates a novel, functional tethered ligand\n            StollerML\n            BasakI\n            DenormeF\n            RowleyJW\n            AlsobrooksJ\n            ParsawarK\n          10.1182\/bloodadvances.202100613334883511Blood Adv2021"},{"key":"B34","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1186\/s13054-020-03082-3","article-title":"Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock","volume":"24","author":"Jiao","year":"2020","journal-title":"Crit Care."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1038\/s41467-019-10360-4","article-title":"Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A\/TLR2","volume":"10","author":"Sung","year":"2019","journal-title":"Nat Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2797","DOI":"10.3389\/fimmu.2018.02797","article-title":"Differential interaction of platelet-derived extracellular vesicles with circulating immune cells: roles of TAM receptors, CD11b, and phosphatidylserine","volume":"9","author":"Fendl","year":"2018","journal-title":"Front Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/s41569-021-00552-1","article-title":"Interplay between inflammation and thrombosis in cardiovascular pathology","volume":"18","author":"Stark","year":"2021","journal-title":"Nat Rev Cardiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S1074-7613(02)00420-X","article-title":"ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1","volume":"17","author":"Urzainqui","year":"2002","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1111\/jth.12710","article-title":"Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps","volume":"12","author":"Maugeri","year":"2014","journal-title":"J Thromb Haemost."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5778","DOI":"10.1038\/s41467-020-19515-0","article-title":"Vascular surveillance by haptotactic blood platelets in inflammation and infection","volume":"11","author":"Nicolai","year":"2020","journal-title":"Nat Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science."},{"key":"B42","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1182\/blood-2015-01-624023","article-title":"P-selectin promotes neutrophil extracellular trap formation in mice","volume":"126","author":"Etulain","year":"2015","journal-title":"Blood."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1038\/s41467-019-09607-x","article-title":"The role of platelets in mediating a response to human influenza infection","volume":"10","author":"Koupenova","year":"2019","journal-title":"Nat Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.chom.2013.01.005","article-title":"Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps","volume":"13","author":"Jenne","year":"2013","journal-title":"Cell Host Microbe."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1016\/j.cell.2017.11.001","article-title":"Migrating platelets are mechano-scavengers that collect and bundle bacteria","volume":"171","author":"Gaertner","year":"2017","journal-title":"Cell."},{"key":"B46","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/nm.2184","article-title":"Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases","volume":"16","author":"Massberg","year":"2010","journal-title":"Nat Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/ni.2987","article-title":"Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens","volume":"15","author":"Branzk","year":"2014","journal-title":"Nat Immunol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.chom.2012.06.011","article-title":"Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis","volume":"12","author":"McDonald","year":"2012","journal-title":"Cell Host Microbe."},{"key":"B49","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/nri3345","article-title":"Thrombosis as an intravascular effector of innate immunity","volume":"13","author":"Engelmann","year":"2013","journal-title":"Nat Rev Immunol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1182\/blood-2011-03-343061","article-title":"Extracellular histones promote thrombin generation through platelet-dependent mechanisms, involvement of platelet TLR2 and TLR4","volume":"118","author":"Semeraro","year":"2011","journal-title":"Blood."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1182\/blood-2010-05-287623","article-title":"von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models","volume":"117","author":"Brill","year":"2011","journal-title":"Blood."},{"key":"B53","doi-asserted-by":"publisher","first-page":"15880","DOI":"10.1073\/pnas.1005743107","article-title":"Extracellular DNA traps promote thrombosis","volume":"107","author":"Fuchs","year":"2010","journal-title":"Proc Natl Acad Sci USA."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1182\/blood-2016-09-741298","article-title":"Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice","volume":"129","author":"McDonald","year":"2017","journal-title":"Blood."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1182\/blood-2016-06-722298","article-title":"In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps","volume":"129","author":"Noubouossie","year":"2017","journal-title":"Blood."},{"key":"B56","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1111\/jth.15179","article-title":"Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia","volume":"19","author":"Nicolai","year":"2021","journal-title":"J Thromb Haemost."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1161\/CIRCULATIONAHA.120.048488","article-title":"Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy","volume":"142","author":"Nicolai","year":"2020","journal-title":"Circulation"},{"key":"B58","doi-asserted-by":"publisher","first-page":"16037","DOI":"10.1038\/nrdp.2016.37","article-title":"Disseminated intravascular coagulation","volume":"2","author":"Gando","year":"2016","journal-title":"Nat Rev Dis Primers."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e150862","DOI":"10.1172\/jci.insight.150862","article-title":"Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19","volume":"6","author":"Kaiser","year":"2021","journal-title":"JCI Insight"},{"key":"B60","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1161\/CIRCULATIONAHA.114.011432","article-title":"Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets","volume":"131","author":"Jung","year":"2015","journal-title":"Circulation"},{"key":"B61","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1055\/s-0039-1678665","article-title":"Neutrophil extracellular traps enhance staphylococcus aureus vegetation formation through interaction with platelets in infective endocarditis","volume":"119","author":"Hsu","year":"2019","journal-title":"Thromb Haemost."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/S0140-6736(20)30925-9","article-title":"Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"396","year":"2020","journal-title":"Lancet."},{"key":"B63","doi-asserted-by":"publisher","first-page":"3378","DOI":"10.1172\/JCI27196","article-title":"Platelets in inflammation and atherogenesis","volume":"115","author":"Gawaz","year":"2005","journal-title":"J Clin Invest."},{"key":"B64","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nm810","article-title":"Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E","volume":"9","author":"Huo","year":"2003","journal-title":"Nat Med."},{"key":"B65","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1084\/jem.20012044","article-title":"A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation","volume":"196","author":"Massberg","year":"2002","journal-title":"J Exp Med."},{"key":"B66","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1182\/blood.2019000518","article-title":"Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps","volume":"134","author":"Marx","year":"2019","journal-title":"Blood."},{"key":"B67","doi-asserted-by":"publisher","first-page":"eaax0481","DOI":"10.1126\/scitranslmed.aax0481","article-title":"Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis","volume":"11","author":"Barrett","year":"2019","journal-title":"Sci Transl Med"},{"key":"B68","doi-asserted-by":"publisher","first-page":"658","DOI":"10.3109\/09537104.2016.1153619","article-title":"Leukocyte-platelet aggregates-a phenotypic characterization of different stages of peripheral arterial disease","volume":"27","author":"Dopheide","year":"2016","journal-title":"Platelets."},{"key":"B69","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.amjcard.2004.10.009","article-title":"Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease","volume":"95","author":"Nijm","year":"2005","journal-title":"Am J Cardiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/S0735-1097(97)00510-X","article-title":"Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease","volume":"31","author":"Furman","year":"1998","journal-title":"J Am Coll Cardiol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/j.jacc.2016.12.022","article-title":"Neutrophil counts and initial presentation of 12 cardiovascular diseases: a CALIBER cohort study","volume":"69","author":"Shah","year":"2017","journal-title":"J Am Coll Cardiol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1160\/TH11-08-0592","article-title":"Platelets in atherosclerosis","volume":"106","author":"Lievens","year":"2011","journal-title":"Thromb Haemost."},{"key":"B73","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","article-title":"Atherosclerosis","volume":"5","author":"Libby","year":"2019","journal-title":"Nat Rev Dis Primers."},{"key":"B74","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.1016\/j.ehj.2003.08.021","article-title":"The adhesion molecule P-selectin and cardiovascular disease","volume":"24","author":"Blann","year":"2003","journal-title":"Eur Heart J."},{"key":"B75","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1161\/01.CIR.103.4.491","article-title":"Soluble P-selectin and the risk of future cardiovascular events","volume":"103","author":"Ridker","year":"2001","journal-title":"Circulation."},{"key":"B76","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41569-021-00542-3","article-title":"Plaque erosion and acute coronary syndromes: phenotype, molecular characteristics and future directions","volume":"18","author":"Fahed","year":"2021","journal-title":"Nat Rev Cardiol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41569-019-0326-7","article-title":"Neutrophils as regulators of cardiovascular inflammation","volume":"17","author":"Silvestre-Roig","year":"2020","journal-title":"Nat Rev Cardiol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1161\/CIRCRESAHA.117.312494","article-title":"Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury: implications for superficial erosion","volume":"123","author":"Franck","year":"2018","journal-title":"Circ Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1038\/s41586-019-1167-6","article-title":"Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death","volume":"569","author":"Silvestre-Roig","year":"2019","journal-title":"Nature."},{"key":"B80","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1126\/science.aaa8064","article-title":"Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis","volume":"349","author":"Warnatsch","year":"2015","journal-title":"Science."},{"key":"B81","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41573-021-00198-1","article-title":"Targeting inflammation in atherosclerosis - from experimental insights to the clinic","volume":"20","author":"Soehnlein","year":"2021","journal-title":"Nat Rev Drug Discov."},{"key":"B82","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.atherosclerosis.2020.04.018","article-title":"Platelet-leukocyte interplay during vascular disease","volume":"307","author":"Schrottmaier","year":"2020","journal-title":"Atherosclerosis."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/nm.2515","article-title":"Arterial thrombosis\u2013insidious, unpredictable and deadly","volume":"17","author":"Jackson","year":"2011","journal-title":"Nat Med."},{"key":"B84","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/359848a0","article-title":"Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets","volume":"359","author":"Palabrica","year":"1992","journal-title":"Nature."},{"key":"B85","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1182\/blood-2012-06-437772","article-title":"Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation","volume":"120","author":"Darbousset","year":"2012","journal-title":"Blood."},{"key":"B86","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1182\/blood.2019002846","article-title":"Targeting myeloid-cell specific integrin alpha9beta1 inhibits arterial thrombosis in mice","volume":"135","author":"Dhanesha","year":"2020","journal-title":"Blood."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1161\/CIRCULATIONAHA.116.024790","article-title":"Cathepsin G controls arterial but not venular myeloid cell recruitment","volume":"134","author":"Ortega-Gomez","year":"2016","journal-title":"Circulation."},{"key":"B88","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.3389\/fimmu.2018.01680","article-title":"Myeloid-Specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis","volume":"9","author":"Liu","year":"2018","journal-title":"Front Immunol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"E9618","DOI":"10.1073\/pnas.1708247114","article-title":"Necroptosis controls NET generation and mediates complement activation, endothelial damage, autoimmune vasculitis","volume":"114","author":"Schreiber","year":"2017","journal-title":"Proc Natl Acad Sci USA."},{"key":"B90","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1111\/j.1538-7836.2009.03334.x","article-title":"Abnormal platelet function in C3-deficient mice","volume":"7","author":"Gushiken","year":"2009","journal-title":"J Thromb Haemost."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1093\/eurheartj\/ehv419","article-title":"Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium","volume":"37","author":"Riegger","year":"2016","journal-title":"Eur Heart J."},{"key":"B92","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1093\/eurheartj\/ehv007","article-title":"Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction","volume":"36","author":"Stakos","year":"2015","journal-title":"Eur Heart J."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1161\/CIRCRESAHA.116.304944","article-title":"Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size","volume":"116","author":"Mangold","year":"2015","journal-title":"Circ Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1084\/jem.20112322","article-title":"Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo","volume":"209","author":"von Bruhl","year":"2012","journal-title":"J Exp Med"},{"key":"B95","doi-asserted-by":"publisher","first-page":"e53353","DOI":"10.7554\/eLife.53353","article-title":"Activated alphaIIbbeta3 on platelets mediates flow-dependent NETosis via SLC44A2","volume":"9","author":"Constantinescu-Bercu","year":"2020","journal-title":"Elife"},{"key":"B96","doi-asserted-by":"publisher","first-page":"8674","DOI":"10.1073\/pnas.1301059110","article-title":"Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice","volume":"110","author":"Martinod","year":"2013","journal-title":"Proc Natl Acad Sci US A."},{"key":"B97","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.atherosclerosis.2012.02.042","article-title":"Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction","volume":"222","author":"Kim","year":"2012","journal-title":"Atherosclerosis."},{"key":"B98","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1161\/STROKEAHA.107.490128","article-title":"Early neutrophilia is associated with volume of ischemic tissue in acute stroke","volume":"39","author":"Buck","year":"2008","journal-title":"Stroke."},{"key":"B99","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1182\/blood.2019002124","article-title":"Platelet necrosis mediates ischemic stroke outcome in mice","volume":"135","author":"Denorme","year":"2020","journal-title":"Blood."},{"key":"B100","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.1182\/blood-2017-05-787259","article-title":"Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis","volume":"130","author":"Agbani","year":"2017","journal-title":"Blood."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1161\/CIRCULATIONAHA.114.015036","article-title":"Coordinated membrane ballooning and procoagulant spreading in human platelets","volume":"132","author":"Agbani","year":"2015","journal-title":"Circulation."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1182\/blood-2007-05-092684","article-title":"Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis","volume":"111","author":"Jobe","year":"2008","journal-title":"Blood."},{"key":"B103","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1182\/blood-2017-05-785253","article-title":"Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation","volume":"132","author":"Pang","year":"2018","journal-title":"Blood."},{"key":"B104","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1161\/CIRCULATIONAHA.118.039345","article-title":"Platelet function to promote resolution of inflammation","volume":"140","author":"Senchenkova","year":"2019","journal-title":"Circulation."},{"key":"B105","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.3389\/fimmu.2019.02747","article-title":"Brain-Derived microparticles (BDMPs) Contribute to neuroinflammation and lactadherin reduces BDMP induced neuroinflammation and improves outcome after stroke","volume":"10","author":"Chen","year":"2019","journal-title":"Front Immunol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1111\/eci.12633","article-title":"Cellular recruitment in myocardial ischaemia\/reperfusion injury","volume":"46","author":"Bonaventura","year":"2016","journal-title":"Eur J Clin Invest."},{"key":"B107","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1002\/hep.510290505","article-title":"P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver","volume":"29","author":"Yadav","year":"1999","journal-title":"Hepatology."},{"key":"B108","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.kint.2016.08.006","article-title":"Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps","volume":"91","author":"Jansen","year":"2017","journal-title":"Kidney Int."},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00549-8","article-title":"Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity","author":"Hirao","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B110","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1164\/rccm.201406-1086OC","article-title":"Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation","volume":"191","author":"Sayah","year":"2015","journal-title":"Am J Respir Crit Care Med."},{"key":"B111","doi-asserted-by":"publisher","first-page":"eaam5861","DOI":"10.1126\/scitranslmed.aam5861","article-title":"Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia","volume":"9","author":"Yuan","year":"2017","journal-title":"Sci Transl Med"},{"key":"B112","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41577-020-0305-6","article-title":"In the eye of the COVID-19 cytokine storm","volume":"20","author":"Vaninov","year":"2020","journal-title":"Nat Rev Immunol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"100639","DOI":"10.1016\/j.eclinm.2020.100639","article-title":"Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis","volume":"29","author":"Malas","year":"2020","journal-title":"EClinicalMedicine."},{"key":"B114","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1001\/jamacardio.2020.1105","article-title":"Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality","volume":"5","author":"Bonow","year":"2020","journal-title":"JAMA Cardiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1161\/CIRCULATIONAHA.120.050809","article-title":"Acute COVID-19 and the incidence of ischemic stroke and acute myocardial infarction","volume":"142","author":"Modin","year":"2020","journal-title":"Circulation."},{"key":"B116","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/s41577-021-00536-9","article-title":"Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19","volume":"21","author":"Bonaventura","year":"2021","journal-title":"Nat Rev Immunol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1182\/blood.2020007008","article-title":"Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome","volume":"136","author":"Middleton","year":"2020","journal-title":"Blood."},{"key":"B118","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1182\/blood.2020007214","article-title":"Platelet gene expression and function in patients with COVID-19","volume":"136","author":"Manne","year":"2020","journal-title":"Blood."},{"key":"B119","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19","volume":"383","author":"Ackermann","year":"2020","journal-title":"N Engl J Med."},{"key":"B120","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1161\/CIRCRESAHA.120.317703","article-title":"Platelets can associate with SARS-CoV-2 RNA and are hyperactivated in COVID-19","volume":"127","author":"Zaid","year":"2020","journal-title":"Circ Res."},{"key":"B121","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1182\/blood.2020008762","article-title":"Antibody-induced procoagulant platelets in severe COVID-19 infection","volume":"137","author":"Althaus","year":"2021","journal-title":"Blood."},{"key":"B122","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1111\/jth.15587","article-title":"Antibody-mediated procoagulant platelet formation in COVID-19 is AKT dependent","volume":"18","author":"Pelzl","year":"2021","journal-title":"J Thromb Haemost"},{"key":"B123","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1182\/blood-2020-140530","article-title":"Inclacumab, a fully human anti-p-selectin antibody, directly binds to PSGL-1 binding region and demonstrates robust and durable inhibition of cell adhesion","volume":"136","author":"Geng","year":"2020","journal-title":"Blood."},{"key":"B124","doi-asserted-by":"publisher","first-page":"e004255","DOI":"10.1161\/JAHA.116.004255","article-title":"Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention according to timing of infusion: insights from the SELECT-ACS trial","volume":"5","author":"St\u00e4hli","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"B125","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.1016\/j.jacc.2013.03.003","article-title":"Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial","volume":"61","author":"Tardif","year":"2013","journal-title":"J Am Coll Cardiol."},{"key":"B126","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.jacc.2015.10.071","article-title":"Effects of P-Selectin antagonist inclacumab in patients undergoing coronary artery bypass graft surgery","volume":"67","author":"St\u00e4hli Barbara","year":"2016","journal-title":"J Am Coll Cardiol."},{"key":"B127","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1056\/NEJMoa1611770","article-title":"Crizanlizumab for the prevention of pain crises in sickle cell disease","volume":"376","author":"Ataga","year":"2017","journal-title":"N Engl J Med."},{"key":"B128","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.jacbts.2018.05.005","article-title":"Ticagrelor reduces thromboinflammatory markers in patients with pneumonia","volume":"3","author":"Sexton","year":"2018","journal-title":"JACC Basic Transl Sci."},{"key":"B129","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1056\/NEJMoa0904327","article-title":"Ticagrelor versus clopidogrel in patients with acute coronary syndromes","volume":"361","author":"Wallentin","year":"2009","journal-title":"N Engl J Med."},{"key":"B130","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1111\/imm.12892","article-title":"Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbalpha","volume":"154","author":"Giles","year":"2018","journal-title":"Immunology."},{"key":"B131","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/NEJMoa1215734","article-title":"Vedolizumab as induction and maintenance therapy for ulcerative colitis","volume":"369","author":"Feagan","year":"2013","journal-title":"N Engl J Med."},{"key":"B132","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1056\/NEJMoa1215739","article-title":"Vedolizumab as induction and maintenance therapy for Crohn's disease","volume":"369","author":"Sandborn","year":"2013","journal-title":"N Engl J Med."},{"key":"B133","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/s41467-018-02896-8","article-title":"A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense","volume":"9","author":"Wolf","year":"2018","journal-title":"Nat Commun."},{"key":"B134","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1096\/fj.201902542R","article-title":"Regulation of neutrophil function by selective targeting of glycan epitopes expressed on the integrin CD11b\/CD18","volume":"34","author":"Kelm","year":"2020","journal-title":"FASEB J."},{"key":"B135","doi-asserted-by":"publisher","first-page":"e1370","DOI":"10.1038\/cddis.2014.337","article-title":"Release and activity of histone in diseases","volume":"5","author":"Chen","year":"2014","journal-title":"Cell Death Dis."},{"key":"B136","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.phrs.2016.08.008","article-title":"Low molecular weight heparins prevent the induction of autophagy of activated neutrophils and the formation of neutrophil extracellular traps","volume":"123","author":"Manfredi","year":"2017","journal-title":"Pharmacol Res."},{"key":"B137","doi-asserted-by":"publisher","first-page":"714833","DOI":"10.3389\/fimmu.2021.714833","article-title":"Non-Randomized trial of dornase alfa for acute respiratory distress syndrome secondary to Covid-19","volume":"12","author":"Holliday","year":"2021","journal-title":"Front Immunol"},{"key":"B138","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1056\/NEJMoa0803152","article-title":"Maraviroc for previously treated patients with R5 HIV-1 infection","volume":"359","author":"Gulick","year":"2008","journal-title":"N Engl J Med."},{"key":"B139","doi-asserted-by":"publisher","first-page":"ofz112","DOI":"10.1093\/ofid\/ofz112","article-title":"Maraviroc intensification modulates atherosclerotic progression in hiv-suppressed patients at high cardiovascular risk. A randomized, crossover pilot study","volume":"6","author":"Francisci","year":"2019","journal-title":"Open Forum Infect Dis."},{"key":"B140","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1161\/CIRCULATIONAHA.113.001278","article-title":"Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice","volume":"127","author":"Cipriani","year":"2013","journal-title":"Circulation."},{"key":"B141","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.cell.2019.01.044","article-title":"CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury","volume":"176","author":"Joy","year":"2019","journal-title":"Cell."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.824112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:28:41Z","timestamp":1643588921000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.824112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":141,"alternative-id":["10.3389\/fcvm.2021.824112"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.824112","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]},"article-number":"824112"}}