{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T17:25:52Z","timestamp":1769707552925,"version":"3.49.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>During the COVID-19 pandemic, it became evident that an infection with SARS-CoV-2 is associated with an increased predisposition for thrombembolic events. Recent studies suggest an excessive neutrophil extracellular trap (NET)-formation in response to SARS-CoV-2, which is considered a hallmark in immunothrombosis. A better understanding of the (dys)regulation of NET-formation in COVID-19 may provide the basis for new therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a pilot study with a total of 84 patients in three groups matched in a 1:1:1 fashion: Group 1: patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and SARS-CoV-2 infection, Group 2: patients with AIS and no SARS-CoV-2 infection and Group 3: patients with SARS-CoV-2 infection and no AIS or TIA. Venous blood samples were collected from all patients and subsequently analyzed for NET-specific markers, NET regulators (Deoxyribonuclease (DNase) activity) and a panel of cytokines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Citrullinated histone3 (H3cit) and elastase levels were higher in groups with SARS-CoV-2 infection (Groups 1 and 3) compared to patients without ((group 1: H3cit = 2.9 (1.11\u20136.89) ng\/mL, elastase = 312.1 (162\u2013435.4) ng\/mL and group 3: H3cit = 3.31 (2.03\u20137.97) ng\/mL and elastase = 433.1 (281\u2013783.8) ng\/mL) vs. group 2: H3cit = 1.17 (0.61\u20132.15) ng\/mL), elastase = 195.1 (91.99\u2013386.9) ng\/mL). No relevant differences were found regarding other measured NET-marker (myeloperoxidase, LL-37). DNase activity was lower in group 1 (6.12 (4.97\u20136.78) pmol\/mL\/min) compared to both other groups (group 2: (7.16 (5.88\u20137.85) pmol\/mL\/min) (p=0.018) and group 3 (7.19 (5.52\u20138.54) pmol\/mL\/min) (p=0.013).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This pilot data suggest that a disturbed regulation of NETs in patients with SARS-CoV-2 infection may play a role in SARS-CoV-2 associated cerebral ischemia. These results highlight the importance of further investigating the role of NETs in immunothrombosis in the context of viral infections, to better understand its potential as a target for therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1662418","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:23:04Z","timestamp":1769664184000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Disturbed regulation of immunothrombosis in cerebral ischemia associated with SARS-CoV-2 infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Richard","family":"Plem","sequence":"first","affiliation":[{"name":"Department of Neurology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"de Buhr","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]},{"name":"Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabea","family":"Imker","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]},{"name":"Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Akhdar","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]},{"name":"Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marita","family":"Meurer","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]},{"name":"Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine S.","family":"Falk","sequence":"additional","affiliation":[{"name":"Institute of Transplant Immunology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria M.","family":"Gabriel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Keil","sequence":"additional","affiliation":[{"name":"Institute of Transplant Immunology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Kopfnagel","sequence":"additional","affiliation":[{"name":"Hannover Unified Biobank, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Illig","sequence":"additional","affiliation":[{"name":"Hannover Unified Biobank, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Weissenborn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Blaschke","sequence":"additional","affiliation":[{"name":"Emergency Department, University Medical Center Goettingen","place":["Goettingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Br\u00f6hl","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Faculty of Medicine, Institute for Digital Medicine and Clinical Data Sciences","place":["Frankfurt, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"R\u00f6mmele","sequence":"additional","affiliation":[{"name":"Internal Medicine III \u2013 Gastroenterology and Infectious Diseases, University Hospital of Augsburg","place":["Augsburg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"NAPKON Investigators","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerrit M.","family":"Grosse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramona","family":"Schuppner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School","place":["Hannover, Germany"]},{"name":"Department of Neurology and Stroke Center, University Hospital Basel","place":["Basel, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1182\/blood.2020006520","article-title":"COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection","volume":"136","author":"Al-Samkari","year":"2020","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e217498","DOI":"10.1001\/jamanetworkopen.2021.7498","article-title":"Acute ischemic stroke during the convalescent phase of asymptomatic COVID-2019 infection in men","volume":"4","author":"Tu","year":"2021","journal-title":"JAMA Netw Open"},{"key":"B3","doi-asserted-by":"publisher","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":"B4","doi-asserted-by":"publisher","DOI":"10.1159\/000521594","article-title":"Impaired degradation of neutrophil extracellular traps: a possible severity factor of elderly male COVID-19 patients","volume":"14","author":"de Buhr","year":"2022","journal-title":"J Innate Immun"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242115805","article-title":"Role of neutrophil extracellular traps in health and disease pathophysiology: recent insights and advances","volume":"24","author":"Islam","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix475","article-title":"High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection","volume":"217","author":"Zhu","year":"2018","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e138999","DOI":"10.1172\/jci.insight.138999","article-title":"Neutrophil extracellular traps in COVID-19","volume":"5","author":"Zuo","year":"2020","journal-title":"JCI Insight"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005743107","article-title":"Extracellular DNA traps promote thrombosis","volume":"107","author":"Fuchs","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","first-page":"e0178","DOI":"10.1097\/CCE.0000000000000178","article-title":"Role for anti-cytokine therapies in severe coronavirus disease 2019","volume":"2","author":"Buckley","year":"2020","journal-title":"Crit Care Explor"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2007.11.008","article-title":"STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"61","author":"von Elm","year":"2008","journal-title":"J\u00a0Clin Epidemiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213747","article-title":"Circulating inflammatory biomarkers in early prediction of stroke-associated infections","volume":"23","author":"Hasse","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30483-7","article-title":"A minimal common outcome measure set for COVID-19 clinical research","volume":"20","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.19.5.604","article-title":"Interobserver agreement for the assessment of handicap in stroke patients","volume":"19","author":"van Swieten","year":"1988","journal-title":"Stroke"},{"key":"B17","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1161\/01.STR.24.1.35","article-title":"Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment","volume":"24","author":"Adams","year":"1993","journal-title":"Stroke"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e042670","DOI":"10.1161\/JAHA.125.042670","article-title":"Viral infections and risk of cardiovascular disease: systematic review and meta-analysis","volume":"14","author":"Kawai","year":"2025","journal-title":"J Am Heart Assoc"},{"key":"B19","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1055\/s-0038-1677040","article-title":"Neutrophil extracellular traps in arterial and venous thrombosis","volume":"45","author":"Laridan","year":"2019","journal-title":"Semin Thromb Hemost"},{"key":"B20","doi-asserted-by":"publisher","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":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.036299","article-title":"Endogenous deoxyribonuclease activity and cell-free deoxyribonucleic acid in acute ischemic stroke: a cohort study","volume":"53","author":"Grosse","year":"2022","journal-title":"Stroke"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12796","article-title":"Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies","volume":"13","author":"Jim\u00e9nez-Alc\u00e1zar","year":"2015","journal-title":"J Thromb Haemost"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07803-4","article-title":"DNA-sensing inflammasomes cause recurrent atherosclerotic stroke","volume":"633","author":"Cao","year":"2024","journal-title":"Nature"},{"key":"B26","unstructured":"Improving early reperfusion with adjuvant dornase alfa in large vessel ischemic stroke (EXTEND-IA DNase)"},{"key":"B27","unstructured":"Reduction of systemic inflammation after ischemic stroke by intravenous DNase administration (ReSCInD)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/945861","article-title":"Impaired deoxyribonuclease I activity in patients with inflammatory bowel diseases","volume":"2011","author":"Mal\u00ed\u010dkov\u00e1","year":"2011","journal-title":"Autoimmune Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1325269","article-title":"Impact of bronchoalveolar lavage from influenza A virus diseased pigs on neutrophil functions and growth of co-infecting pathogenic bacteria","volume":"15","author":"Lassnig","year":"2024","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.44.181","article-title":"Tissue distribution of deoxyribonuclease I (DNase I) activity level in mice and its sexual dimorphism","volume":"44","author":"Koizumi","year":"1995","journal-title":"Exp Anim"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.018595","article-title":"Herpesvirus infections and childhood arterial ischemic stroke: results of the VIPS study","volume":"133","author":"Elkind","year":"2016","journal-title":"Circulation"},{"key":"B32","doi-asserted-by":"publisher","first-page":"26112618","DOI":"10.1056\/NEJMoa041747","article-title":"Risk of myocardial infarction and stroke after acute infection or vaccination","volume":"351","author":"Smeeth","year":"2004","journal-title":"N Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/irv.12470","article-title":"The hidden burden of influenza: a review of the extra-pulmonary complications of influenza infection","volume":"11","author":"Sellers","year":"2017","journal-title":"Influenza Other Respir Viruses"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.545","article-title":"Influenza-like illness as a trigger for ischemic stroke","volume":"5","author":"Boehme","year":"2018","journal-title":"Ann Clin Transl Neurol"},{"key":"B35","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":"B36","doi-asserted-by":"publisher","DOI":"10.1055\/a-1544-5431","article-title":"Circulating cytokines and growth factors in acute cerebral large vessel occlusion-association with success of endovascular treatment","volume":"122","author":"Grosse","year":"2022","journal-title":"Thromb Haemost"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1172\/jci110509","article-title":"Chemotaxis of monocytes and neutrophils to platelet-derived growth factor","volume":"69","author":"Deuel","year":"1982","journal-title":"J Clin Invest"},{"key":"B38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/rth2.12266","article-title":"The dual role of platelet-innate immune\u00a0cell interactions in thrombo-inflammation","volume":"4","author":"Rayes","year":"2019","journal-title":"Res Pract Thromb Haemost"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3988\/jcn.2021.17.1.70","article-title":"Platelet-derived growth factor is associated with progression of symptomatic intracranial atherosclerotic stenosis","volume":"17","author":"Kim","year":"2021","journal-title":"J Clin Neurol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/medicina60030353","article-title":"Evaluation of the levels of selected cytokines and their possible influence on the development of cardiovascular and pulmonary complications in patients after COVID-19","volume":"60","author":"Stanjek-Cichoracka","year":"2024","journal-title":"Med (Kaunas)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.895216","article-title":"Diverse roles of NETosis in the pathogenesis of lupus","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70101","article-title":"The emerging role of neutrophil extracellular traps in autoimmune and autoinflammatory diseases","volume":"6","author":"Zeng","year":"2025","journal-title":"MedComm"},{"key":"B43","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil extracellular traps in homeostasis and disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1159\/000489829","article-title":"Neutrophil extracellular traps in the second decade","volume":"10","author":"Brinkmann","year":"2018","journal-title":"J Innate Immun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1662418\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:23:05Z","timestamp":1769664185000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1662418\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2026.1662418"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1662418","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]},"article-number":"1662418"}}