{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:12:02Z","timestamp":1790604722390,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Reperfusion therapies have revolutionized the treatment of acute ischemic stroke (AIS), but target-artery recanalization, downstream angiographic reperfusion, microvascular tissue reperfusion, and functional recovery are distinct endpoints. Patients may have persistent occlusion or early reocclusion, incomplete modified Thrombolysis in Cerebral Infarction (mTICI) reperfusion, microvascular no-reflow despite high-grade mTICI\/eTICI reperfusion, hemorrhagic transformation (HT), or poor 90-day functional outcome. Neutrophil extracellular traps (NETs) form a mechanistic link between thrombus structure, innate immune activation, endothelial injury, and antithrombotic responses. NETs provide a DNA-histone scaffold that stabilizes fibrin-rich thrombi, recruits platelets and coagulation factors, and exposes the neurovascular unit to cytotoxic granular proteins. The biological characteristics of NETs nevertheless vary among patients. Differences in neutrophil priming, platelet activation, monocyte-endothelial signaling, thrombus composition, collateral status, concurrent inflammation, and reperfusion injury create distinct thrombo-immune microenvironments. This article reviews how NET-driven immunothrombosis affects arterial recanalization, angiographic and tissue reperfusion, HT, and emerging antithrombotic strategies. It also proposes an operational immune-phenotyping framework with candidate biomarkers, assay-dependent research thresholds, sampling time points, and trial-level decision rules.<\/jats:p>","DOI":"10.3389\/fneur.2026.1918580","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:53:33Z","timestamp":1790603613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NETs and the thrombo-immune microenvironment: immune heterogeneity in recanalization, reperfusion, hemorrhagic transformation, and antithrombotic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Fangfang","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of General Practice, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Affiliated Hospital of Shandong Academy of Chinese Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Jinan Maternal and Child Health Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shandong Second Provincial General Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shandong Second Provincial General Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e344","DOI":"10.1161\/STR.0000000000000211","article-title":"Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association\/American Stroke Association","volume":"50","author":"Powers","year":"2019","journal-title":"Stroke"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1016\/S0140-6736(16)00163-X","article-title":"Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials","volume":"387","author":"Goyal","year":"2016","journal-title":"Lancet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2650","DOI":"10.1161\/STROKEAHA.113.001972","article-title":"Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement","volume":"44","author":"Zaidat","year":"2013","journal-title":"Stroke"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1136\/neurintsurg-2018-014127","article-title":"eTICI reperfusion: defining success in endovascular stroke therapy","volume":"11","author":"Liebeskind","year":"2019","journal-title":"J Neurointerv Surg"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/S0140-6736(20)31179-X","article-title":"Stroke","volume":"396","author":"Campbell","year":"2020","journal-title":"Lancet"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3071","DOI":"10.1161\/STROKEAHA.118.022015","article-title":"Ischemia-reperfusion injury after endovascular thrombectomy for ischemic stroke","volume":"49","author":"Gauberti","year":"2018","journal-title":"Stroke"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e790","DOI":"10.1212\/WNL.0000000000013210","article-title":"Prevalence and significance of impaired microvascular tissue reperfusion despite macrovascular angiographic reperfusion (no-reflow)","volume":"98","author":"Ng","year":"2022","journal-title":"Neurology"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.3390\/life13101965","article-title":"Comprehensive meta-analysis of futile recanalization in acute ischemic stroke patients undergoing endovascular thrombectomy: prevalence, factors, and clinical outcomes","volume":"13","author":"Shen","year":"2023","journal-title":"Life (Basel)"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/jcbfm.2013.203","article-title":"Hemorrhagic transformation after ischemic stroke in animals and humans","volume":"34","author":"Jickling","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3324\/haematol.2019.219881","article-title":"Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance","volume":"105","author":"Staessens","year":"2020","journal-title":"Haematologica"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1161\/STROKEAHA.117.016590","article-title":"Ischemic stroke: what does the histological composition tell us about the origin of the thrombus?","volume":"48","author":"Sporns","year":"2017","journal-title":"Stroke"},{"key":"ref12","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":"ref13","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":"ref14","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1161\/STROKEAHA.117.019896","article-title":"Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke","volume":"49","author":"Ducroux","year":"2018","journal-title":"Stroke"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1002\/ana.24993","article-title":"Neutrophil extracellular traps in ischemic stroke thrombi","volume":"82","author":"Laridan","year":"2017","journal-title":"Ann Neurol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1864","DOI":"10.1161\/STROKEAHA.116.013105","article-title":"Thrombus histology suggests cardioembolic cause in cryptogenic stroke","volume":"47","author":"Boeckh-Behrens","year":"2016","journal-title":"Stroke"},{"key":"ref17","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 USA"},{"key":"ref18","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":"ref19","doi-asserted-by":"publisher","first-page":"e154225","DOI":"10.1172\/JCI154225","article-title":"Neutrophil extracellular traps regulate ischemic stroke brain injury","volume":"132","author":"Denorme","year":"2022","journal-title":"J Clin Invest"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2768","DOI":"10.1182\/blood-2013-10-463646","article-title":"Thrombosis: tangled up in NETs","volume":"123","author":"Martinod","year":"2014","journal-title":"Blood"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"3228","DOI":"10.1161\/STROKEAHA.119.026848","article-title":"Pharmacological modulation of neutrophil extracellular traps reverses thrombotic stroke tPA (tissue-type plasminogen activator) resistance","volume":"50","author":"Pe\u00f1a-Mart\u00ednez","year":"2019","journal-title":"Stroke"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"102671","DOI":"10.1016\/j.ebiom.2020.102671","article-title":"Interactions between neutrophil extracellular traps and activated platelets enhance procoagulant activity in acute stroke patients with ICA occlusion","volume":"53","author":"Zhou","year":"2020","journal-title":"EBioMedicine"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"4115","DOI":"10.1113\/jphysiol.2011.212886","article-title":"Ischaemic stroke: a thrombo-inflammatory disease?","volume":"589","author":"Nieswandt","year":"2011","journal-title":"J Physiol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/nm.2399","article-title":"The immunology of stroke: from mechanisms to translation","volume":"17","author":"Iadecola","year":"2011","journal-title":"Nat Med"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1161\/STROKEAHA.111.628867","article-title":"von Willebrand factor: an emerging target in stroke therapy","volume":"43","author":"De Meyer","year":"2012","journal-title":"Stroke"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"8418820","DOI":"10.1155\/2022\/8418820","article-title":"The role of oxidative stress in acute ischemic stroke-related thrombosis","volume":"2022","author":"Li","year":"2022","journal-title":"Oxidative Med Cell Longev"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1152\/physrev.00012.2018","article-title":"The neutrophil's role during health and disease","volume":"99","author":"Liew","year":"2019","journal-title":"Physiol Rev"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1177\/1747493017709671","article-title":"Analyses of thrombi in acute ischemic stroke: a consensus statement on current knowledge and future directions","volume":"12","author":"De Meyer","year":"2017","journal-title":"Int J Stroke"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.3390\/cells8121477","article-title":"The brain entangled: the contribution of neutrophil extracellular traps to the diseases of the central nervous system","volume":"8","author":"Manda-Handzlik","year":"2019","journal-title":"Cells"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1160\/TH17-02-0130","article-title":"Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance","volume":"117","author":"Vall\u00e9s","year":"2017","journal-title":"Thromb Haemost"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.hjc.2024.09.001","article-title":"Association of neutrophil extracellular traps burden with clinical and angiographic characteristics in patients with ST-elevation myocardial infarction","volume":"88","author":"Stalikas","year":"2026","journal-title":"Hell J Cardiol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e2346","DOI":"10.1212\/WNL.0000000000009532","article-title":"Thrombus NET content is associated with clinical outcome in stroke and myocardial infarction","volume":"94","author":"Novotny","year":"2020","journal-title":"Neurology"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1182\/blood.2020008913","article-title":"Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke","volume":"138","author":"Wang","year":"2021","journal-title":"Blood"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e32366","DOI":"10.1371\/journal.pone.0032366","article-title":"Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones","volume":"7","author":"Saffarzadeh","year":"2012","journal-title":"PLoS One"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s12035-021-02635-z","article-title":"Neutrophil extracellular traps exacerbate ischemic brain damage","volume":"59","author":"Li","year":"2022","journal-title":"Mol Neurobiol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1161\/STROKEAHA.107.500868","article-title":"MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke","volume":"39","author":"Rosell","year":"2008","journal-title":"Stroke"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"6060","DOI":"10.1007\/s12035-024-03959-2","article-title":"SIRT1-mediated HMGB1 deacetylation suppresses neutrophil extracellular traps related to blood-brain barrier impairment after cerebral venous thrombosis","volume":"61","author":"Mu","year":"2024","journal-title":"Mol Neurobiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cytogfr.2024.12.001","article-title":"Cytokine signalling in formation of neutrophil extracellular traps: implications for health and diseases","volume":"81","author":"Manoj","year":"2025","journal-title":"Cytokine Growth Factor Rev"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa1603060","article-title":"Ticagrelor versus aspirin in acute stroke or transient ischemic attack","volume":"375","author":"Johnston","year":"2016","journal-title":"N Engl J Med"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1056\/NEJMoa1916870","article-title":"Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA","volume":"383","author":"Johnston","year":"2020","journal-title":"N Engl J Med"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.jcmg.2017.08.013","article-title":"Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: a CT coronary angiography study","volume":"11","author":"Vaidya","year":"2018","journal-title":"JACC Cardiovasc Imaging"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e2308719","DOI":"10.1002\/advs.202308719","article-title":"Neutrophil targeting platform reduces neutrophil extracellular traps for improved traumatic brain injury and stroke theranostics","volume":"11","author":"Mu","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.3390\/cells12232709","article-title":"NLRP3-induced NETosis: a potential therapeutic target for ischemic thrombotic diseases?","volume":"12","author":"Kumar","year":"2023","journal-title":"Cells"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1084\/jem.20052458","article-title":"Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis","volume":"203","author":"Kleinschnitz","year":"2006","journal-title":"J Exp Med"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.3390\/neurolint15040076","article-title":"Targeting neutrophil extracellular traps for stroke prognosis: a promising path","volume":"15","author":"Liaptsi","year":"2023","journal-title":"Neurol Int"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e045163","DOI":"10.1161\/JAHA.125.045163","article-title":"Neutrophil extracellular traps are associated with early neurological deterioration in patients with acute ischemic stroke receiving intravenous thrombolysis: a prospective cohort study","volume":"15","author":"Pei","year":"2026","journal-title":"J Am Heart Assoc"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1918580\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:53:35Z","timestamp":1790603615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1918580\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":46,"alternative-id":["10.3389\/fneur.2026.1918580"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1918580","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"article-number":"1918580"}}