{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:16:04Z","timestamp":1788009364732,"version":"build-2784847793"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RICORS-Ictus (RD21\/0006\/0002 and RD24\/0009\/0008)"],"award-info":[{"award-number":["RICORS-Ictus (RD21\/0006\/0002 and RD24\/0009\/0008)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n Hospital Nacional de Parapl\u00e9jicos-IDISCAM","award":["Refuerzo de la actividad investigadora de Castilla\u2011La Mancha (EMER)"],"award-info":[{"award-number":["Refuerzo de la actividad investigadora de Castilla\u2011La Mancha (EMER)"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"DOI":"10.1007\/s00401-026-03074-7","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T12:25:59Z","timestamp":1788006359000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2\u2013induced prothrombotic state"],"prefix":"10.1007","volume":"152","author":[{"given":"Mar\u00eda","family":"Pay\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Alcahut-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa A.","family":"Barbella-Aponte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Hern\u00e1ndez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan D.","family":"Molina-Nuevo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Barroso-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Castro-Robles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"L\u00f3pez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Arias-Salazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Ayo-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Garc\u00eda-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Y\u00e9lamos-Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Garc\u00eda-Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba G.","family":"Arandilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Moreno-Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Aliena-Valero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Vielba-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 I.","family":"Tembl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan B.","family":"Salom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9368-4832","authenticated-orcid":false,"given":"Gemma","family":"Serrano-Heras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Segura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"3074_CR1","doi-asserted-by":"publisher","first-page":"10267","DOI":"10.26355\/eurrev_202010_23251","volume":"24","author":"N Akhter","year":"2020","unstructured":"Akhter N, Ahmad S, Alzahrani FA, Dar SA, Wahid M, Haque S et al (2020) Impact of COVID-19 on the cerebrovascular system and the prevention of RBC lysis. Eur Rev Med Pharmacol Sci 24:10267\u201310278. https:\/\/doi.org\/10.26355\/eurrev_202010_23251","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"3074_CR2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s40134-021-00379-1","volume":"9","author":"AS Al-Smadi","year":"2021","unstructured":"Al-Smadi AS, Mach JC, Abrol S, Luqman A, Chamiraju P, Abujudeh H (2021) Endovascular thrombectomy of COVID-19-related large vessel occlusion: a systematic review and summary of the literature. Curr Radiol Rep 9:4. https:\/\/doi.org\/10.1007\/s40134-021-00379-1","journal-title":"Curr Radiol Rep"},{"key":"3074_CR3","doi-asserted-by":"publisher","first-page":"205031212110029","DOI":"10.1177\/20503121211002996","volume":"9","author":"W Alam","year":"2021","unstructured":"Alam W (2021) Hypercoagulability in COVID-19: A review of the potential mechanisms underlying clotting disorders. SAGE Open Med 9:205031212110029. https:\/\/doi.org\/10.1177\/20503121211002996","journal-title":"SAGE Open Med"},{"key":"3074_CR4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1599639","volume":"16","author":"LM Almskog","year":"2025","unstructured":"Almskog LM, \u00c5gren A (2025) Thromboinflammation vs. immunothrombosis: strategies for overcoming anticoagulant resistance in COVID-19 and other hyperinflammatory diseases. Is ROTEM helpful or not? Front Immunol 16:1599639. https:\/\/doi.org\/10.3389\/fimmu.2025.1599639","journal-title":"Front Immunol"},{"key":"3074_CR5","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1159\/000522498","volume":"145","author":"T Alnima","year":"2022","unstructured":"Alnima T, Mulder MMG, Van Bussel BCT, Cate HT (2022) COVID-19 coagulopathy: from pathogenesis to treatment. Acta Haematol 145:282\u2013296. https:\/\/doi.org\/10.1159\/000522498","journal-title":"Acta Haematol"},{"key":"3074_CR6","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1182\/blood.2020008762","volume":"137","author":"K Althaus","year":"2021","unstructured":"Althaus K, Marini I, Zlamal J, Pelzl L, Singh A, H\u00e4berle H et al (2021) Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood 137:1061\u20131071. https:\/\/doi.org\/10.1182\/blood.2020008762","journal-title":"Blood"},{"key":"3074_CR7","first-page":"1052","volume":"4","author":"GK Annarapu","year":"2016","unstructured":"Annarapu GK, Singhal R, Chawla S, Ojha A, Guchhait P (2016) Hemoglobin mediated regulation of platelet functions. J Hematol Transfus 4:1052","journal-title":"J Hematol Transfus"},{"key":"3074_CR8","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1093\/cvr\/cvae049","volume":"120","author":"A Battistoni","year":"2024","unstructured":"Battistoni A, Volpe M, Morisco C, Piccinocchi G, Piccinocchi R, Fini M (2024) Persistent increase of cardiovascular and cerebrovascular events in COVID-19 patients: a 3-year population-based analysis. Cardiovasc Res 120:623\u2013629. https:\/\/doi.org\/10.1093\/cvr\/cvae049","journal-title":"Cardiovasc Res"},{"key":"3074_CR9","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1159\/000438964","volume":"42","author":"S Berentsen","year":"2015","unstructured":"Berentsen S (2015) Role of complement in autoimmune hemolytic anemia. Transfus Med Hemother 42:303\u2013310. https:\/\/doi.org\/10.1159\/000438964","journal-title":"Transfus Med Hemother"},{"key":"3074_CR10","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","volume":"16","author":"S Berg","year":"2019","unstructured":"Berg S, Kutra D, Kroeger T, Straehle CN, Kausler BX, Haubold C et al (2019) Ilastik: interactive machine learning for (bio)image analysis. Nat Methods 16:1226\u20131232. https:\/\/doi.org\/10.1038\/s41592-019-0582-9","journal-title":"Nat Methods"},{"key":"3074_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01323","volume":"11","author":"MT Bozza","year":"2020","unstructured":"Bozza MT, Jeney V (2020) Pro-inflammatory actions of heme and other hemoglobin-derived DAMPs. Front Immunol 11:1323. https:\/\/doi.org\/10.3389\/fimmu.2020.01323","journal-title":"Front Immunol"},{"key":"3074_CR12","doi-asserted-by":"publisher","DOI":"10.4081\/cp.2020.1271","volume":"10","author":"A Cavezzi","year":"2020","unstructured":"Cavezzi A, Troiani E, Corrao S (2020) COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract (Abingdon) 10:1271. https:\/\/doi.org\/10.4081\/cp.2020.1271","journal-title":"Clin Pract (Abingdon)"},{"key":"3074_CR13","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/labinvest.2016.116","volume":"97","author":"DA Chistiakov","year":"2017","unstructured":"Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobryshev YV (2017) CD68\/macrosialin: not just a histochemical marker. Lab Invest 97:4\u201313. https:\/\/doi.org\/10.1038\/labinvest.2016.116","journal-title":"Lab Invest"},{"key":"3074_CR14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001109","volume":"19","author":"SP Comer","year":"2021","unstructured":"Comer SP, Cullivan S, Szklanna PB, Weiss L, Cullen S, Kelliher S et al (2021) COVID-19 induces a hyperactive phenotype in circulating platelets. PLoS Biol 19:e3001109. https:\/\/doi.org\/10.1371\/journal.pbio.3001109","journal-title":"PLoS Biol"},{"key":"3074_CR15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043419","volume":"24","author":"G Costamagna","year":"2023","unstructured":"Costamagna G, Bonato S, Corti S, Meneri M (2023) Advancing stroke research on cerebral thrombi with omic technologies. Int J Mol Sci 24:3419. https:\/\/doi.org\/10.3390\/ijms24043419","journal-title":"Int J Mol Sci"},{"key":"3074_CR16","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1182\/blood-2015-05-648030","volume":"126","author":"Q Da","year":"2015","unstructured":"Da Q, Teruya M, Guchhait P, Teruya J, Olson JS, Cruz MA (2015) Free hemoglobin increases von Willebrand factor-mediated platelet adhesion in vitro. Blood 126:2338\u20132341. https:\/\/doi.org\/10.1182\/blood-2015-05-648030","journal-title":"Blood"},{"key":"3074_CR17","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13045-022-01329-w","volume":"15","author":"M De Michele","year":"2022","unstructured":"De Michele M, d\u2019Amati G, Leopizzi M, Iacobucci M, Berto I, Lorenzano S et al (2022) Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients. J Hematol Oncol 15:108. https:\/\/doi.org\/10.1186\/s13045-022-01329-w","journal-title":"J Hematol Oncol"},{"key":"3074_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2021.100834","volume":"50","author":"L Delvasto\u2011Nu\u00f1ez","year":"2021","unstructured":"Delvasto\u2011Nu\u00f1ez L, Jongerius I, Zeerleder S (2021) It takes two to thrombosis: hemolysis and complement. Blood Rev 50:100834. https:\/\/doi.org\/10.1016\/j.blre.2021.100834","journal-title":"Blood Rev"},{"issue":"4","key":"3074_CR19","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1111\/jth.15646","volume":"20","author":"JP Desilles","year":"2022","unstructured":"Desilles JP, Solo Nomenjanahary M, Consoli A, Ollivier V, Faille D, Bourrienne M-C et al (2022) Impact of COVID-19 on thrombus composition and response to thrombolysis. J Thromb Haemost 20(4):919\u2013928. https:\/\/doi.org\/10.1111\/jth.15646","journal-title":"J Thromb Haemost"},{"key":"3074_CR20","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1136\/jnis-2023-020489","volume":"16","author":"SR Ferrone","year":"2024","unstructured":"Ferrone SR, Sanmartin MX, Ohara J, Jimenez JC, Feizullayeva C, Lodatoet Z et al (2024) Acute ischemic stroke outcomes in patients with COVID-19: a systematic review and meta-analysis. J Neurointerv Surg 16:333\u2013341. https:\/\/doi.org\/10.1136\/jnis-2023-020489","journal-title":"J Neurointerv Surg"},{"key":"3074_CR21","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1182\/blood-2013-03-489245","volume":"122","author":"M Frimat","year":"2013","unstructured":"Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs-Mecarelli L, Fremeaux-Bacch V et al (2013) Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 122:282\u2013292. https:\/\/doi.org\/10.1182\/blood-2013-03-489245","journal-title":"Blood"},{"key":"3074_CR22","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40478-022-01313-y","volume":"10","author":"A Genchi","year":"2022","unstructured":"Genchi A, Semerano A, Schwarz G, Dell\u2019Acqua B, Gullotta GS, Sampaolo M et al (2022) Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients. Acta Neuropathol Commun 10:14. https:\/\/doi.org\/10.1186\/s40478-022-01313-y","journal-title":"Acta Neuropathol Commun"},{"key":"3074_CR23","doi-asserted-by":"publisher","first-page":"2340392","DOI":"10.1155\/2019\/2340392","volume":"2019","author":"H He","year":"2019","unstructured":"He H, Qiao Y, Zhou Q, Wang Z, Chen X, Liu D et al (2019) Iron overload damages the endothelial mitochondria via the ROS\/ADMA\/DDAHII\/eNOS\/NO pathway. Oxid Med Cell Longev 2019:2340392. https:\/\/doi.org\/10.1155\/2019\/2340392","journal-title":"Oxid Med Cell Longev"},{"key":"3074_CR24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0313582","volume":"20","author":"Y He","year":"2025","unstructured":"He Y, Wang B, Qian Y, Liu D, Wu Q (2025) Extraction of coronary thrombus-derived exosomes from patients with acute myocardial infarction and its effect on the function of adventitial cells. PLoS ONE 20:e0313582. https:\/\/doi.org\/10.1371\/journal.pone.0313582","journal-title":"PLoS ONE"},{"key":"3074_CR25","doi-asserted-by":"publisher","first-page":"3089","DOI":"10.1093\/brain\/awaa239","volume":"143","author":"F Hernandez\u2011Fernandez","year":"2020","unstructured":"Hernandez\u2011Fernandez F, Sandoval Valencia H, Barbella\u2011Aponte RA, Collado-Jim\u00e9nez R, Ayo-Mart\u00edn O, Barrena C et al (2020) Cerebrovascular disease in patients with COVID\u201119: neuroimaging, histological and clinical description. Brain 143:3089\u20133103. https:\/\/doi.org\/10.1093\/brain\/awaa239","journal-title":"Brain"},{"key":"3074_CR26","doi-asserted-by":"publisher","first-page":"4985","DOI":"10.1182\/blood-2012-09-311381","volume":"121","author":"A Hill","year":"2013","unstructured":"Hill A, Kelly RJ, Hillmen P (2013) Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 121:4985\u20134996. https:\/\/doi.org\/10.1182\/blood-2012-09-311381","journal-title":"Blood"},{"key":"3074_CR27","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10030427","volume":"10","author":"MT Hopp","year":"2021","unstructured":"Hopp MT, Imhof D (2021) Linking labile heme with thrombosis. J Clin Med 10:427. https:\/\/doi.org\/10.3390\/jcm10030427","journal-title":"J Clin Med"},{"key":"3074_CR28","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.1038\/s41598-018-21387-w","volume":"8","author":"E Karsten","year":"2018","unstructured":"Karsten E, Breen E, Herbert BR (2018) Red blood cells are dynamic reservoirs of cytokines. Sci Rep 8:3101. https:\/\/doi.org\/10.1038\/s41598-018-21387-w","journal-title":"Sci Rep"},{"issue":"2","key":"3074_CR29","doi-asserted-by":"publisher","DOI":"10.1177\/03000605261416675","volume":"54","author":"EH Koumans","year":"2026","unstructured":"Koumans EH, Raykin J, Coronado F, Saydah S, Boehmer TK, Wiltz J et al (2026) Acute ischemic stroke incidence after influenza or coronavirus disease 2019 among older US adults: a cross-sectional study using electronic health records. J Int Med Res 54(2):03000605261416675. https:\/\/doi.org\/10.1177\/03000605261416675","journal-title":"J Int Med Res"},{"key":"3074_CR30","doi-asserted-by":"publisher","DOI":"10.1111\/cns.70340","volume":"31","author":"TJ Kim","year":"2025","unstructured":"Kim TJ, Woo JW, Kim Y-J, Yoon B-W, Han D, Ko S-B (2025) Proteomic analyses of clots identify stroke etiologies in patients undergoing endovascular therapy. CNS Neurosci Ther 31:e70340. https:\/\/doi.org\/10.1111\/cns.70340","journal-title":"CNS Neurosci Ther"},{"key":"3074_CR31","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1161\/CIRCRESAHA.121.319117","volume":"129","author":"M Koupenova","year":"2021","unstructured":"Koupenova M, Corkrey HA, Vitseva O, Tanriverdi K, Somasundaran M, Liu P et al (2021) SARS\u2011CoV\u20112 initiates programmed cell death in platelets. Circ Res 129:631\u2013646. https:\/\/doi.org\/10.1161\/CIRCRESAHA.121.319117","journal-title":"Circ Res"},{"key":"3074_CR32","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.1093\/brain\/awac151","volume":"145","author":"M Lee","year":"2022","unstructured":"Lee M, Perl DP, Steiner J, Pasternack N, Li W, Maric D et al (2022) Neurovascular injury with complement activation and inflammation in COVID-19. Brain 145:2555\u20132568. https:\/\/doi.org\/10.1093\/brain\/awac151","journal-title":"Brain"},{"key":"3074_CR33","unstructured":"Liu W, Li H (2020) COVID\u201119 attacks the I\u2011beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv 12:31. https:\/\/chemrxiv.org\/articles\/COVID19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin\/11938173"},{"key":"3074_CR34","doi-asserted-by":"publisher","first-page":"16290","DOI":"10.1038\/s41598-021-95397-6","volume":"11","author":"R Litvinov","year":"2021","unstructured":"Litvinov R, Evtugina N, Peshkova A, Safiullina SI, Andrianova IA, Khabirova AI et al (2021) Altered platelet and coagulation function in moderate-to-severe COVID-19. Sci Rep 11:16290. https:\/\/doi.org\/10.1038\/s41598-021-95397-6","journal-title":"Sci Rep"},{"key":"3074_CR35","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1007\/s00415-021-10837-7","volume":"269","author":"W Luo","year":"2022","unstructured":"Luo W, Liu X, Bao K, Huang C (2022) Ischemic stroke associated with COVID-19: a systematic review and meta-analysis. J Neurol 269:1731\u20131740. https:\/\/doi.org\/10.1007\/s00415-021-10837-7","journal-title":"J Neurol"},{"key":"3074_CR36","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1161\/ATVBAHA.123.320144","volume":"44","author":"N Mackman","year":"2024","unstructured":"Mackman N (2024) Tissue factor and COVID-19 associated thrombosis. Arterioscler Thromb Vasc Biol 44:523\u2013529. https:\/\/doi.org\/10.1161\/ATVBAHA.123.320144","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"3074_CR37","doi-asserted-by":"publisher","first-page":"3908","DOI":"10.1161\/STROKEAHA.121.034883","volume":"52","author":"J Mart\u00ed\u2011F\u00e0bregas","year":"2021","unstructured":"Mart\u00ed\u2011F\u00e0bregas J, Guisado\u2011Alonso D, Delgado\u2011Mederos R, Mart\u00ednez-Dome\u00f1o A, Prats-S\u00e1nchez L, Guasch-Jim\u00e9nez M et al (2021) Impact of COVID\u201119 infection on the outcome of patients with ischemic stroke. Stroke 52:3908\u20133917. https:\/\/doi.org\/10.1161\/STROKEAHA.121.034883","journal-title":"Stroke"},{"key":"3074_CR38","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.96910","volume":"3","author":"NS Merle","year":"2018","unstructured":"Merle NS, Grunenwald A, Rajaratnam H, Gnemmi V, Frimat M, Figueres M-L et al (2018) Intravascular hemolysis activates complement via cell\u2011free heme and heme\u2011loaded microvesicles. JCI Insight 3:e96910. https:\/\/doi.org\/10.1172\/jci.insight.96910","journal-title":"JCI Insight"},{"key":"3074_CR39","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1177\/1747493020972922","volume":"16","author":"S Nannoni","year":"2021","unstructured":"Nannoni S, de Groot R, Bell S, Markus HS (2021) Stroke in COVID-19: a systematic review and meta-analysis. Int J Stroke 16:137\u2013149. https:\/\/doi.org\/10.1177\/1747493020972922","journal-title":"Int J Stroke"},{"key":"3074_CR40","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/b978-1-4377-0134-0.10075-7","volume-title":"Avery\u2019s diseases of the newborn","author":"A Nguyen-Vermillion","year":"2012","unstructured":"Nguyen-Vermillion A, Juul SE (2012) Developmental biology of the hematologic system. Avery\u2019s diseases of the newborn. Elsevier, pp 1047\u20131055. https:\/\/doi.org\/10.1016\/b978-1-4377-0134-0.10075-7"},{"key":"3074_CR41","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1186\/s12879-020-05678-0","volume":"20","author":"SM Ouyang","year":"2020","unstructured":"Ouyang SM, Zhu HQ, Xie YN, Zou Z-S, Zuo H-M, Rao Y-W et al (2020) Temporal changes in laboratory markers of survivors and non-survivors of adult inpatients with COVID-19. BMC Infect Dis 20:952. https:\/\/doi.org\/10.1186\/s12879-020-05678-0","journal-title":"BMC Infect Dis"},{"key":"3074_CR42","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.medcli.2024.05.027","volume":"163","author":"JA P\u00e1ramo","year":"2024","unstructured":"P\u00e1ramo JA, Marcos-Jubilar M (2024) Immunothrombosis: a key mechanism in the COVID-19 pandemic. Med Clin (Barc) 163:517\u2013521. https:\/\/doi.org\/10.1016\/j.medcli.2024.05.027","journal-title":"Med Clin (Barc)"},{"key":"3074_CR43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105307","volume":"29","author":"TJ Pisano","year":"2020","unstructured":"Pisano TJ, Hakkinen I, Rybinnik I (2020) Large vessel occlusion secondary to COVID-19 hypercoagulability in a young patient: case report and literature review. J Stroke Cerebrovasc Dis 29:105307. https:\/\/doi.org\/10.1016\/j.jstrokecerebrovasdis.2020.105307","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"3074_CR44","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/j.jacbts.2023.03.017","volume":"8","author":"N Potere","year":"2023","unstructured":"Potere N, Abbate A, Kanthi Y, Carrier M, Toldo S, Porreca E et al (2023) Inflammasome signaling, thromboinflammation, and venous thromboembolism. JACC Basic Transl Sci 8:1245\u20131261. https:\/\/doi.org\/10.1016\/j.jacbts.2023.03.017","journal-title":"JACC Basic Transl Sci"},{"key":"3074_CR45","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2025.1563371","volume":"16","author":"L Rojas\u2011Bartolom\u00e9","year":"2025","unstructured":"Rojas\u2011Bartolom\u00e9 L, Pay\u00e1 M, Barbella\u2011Aponte R, Restrepo Carvajal L, Garc\u00eda-Garc\u00eda J, Ayo-Mart\u00edn O et al (2025) Histopathological composition of thrombus material in a large cohort of patients with acute ischemic stroke: a study of atypical clots. Front Neurol 16:1563371. https:\/\/doi.org\/10.3389\/fneur.2025.1563371","journal-title":"Front Neurol"},{"key":"3074_CR46","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1111\/ijlh.13516","volume":"43","author":"R Rolla","year":"2021","unstructured":"Rolla R, Puricelli C, Bertoni A, Boggio E, Gigliotti CL, Chiocchetti A et al (2021) Platelets: \u2018multiple choice\u2019 effectors in the immune response and their implication in COVID-19 thromboinflammatory process. Int J Lab Hematol 43:895\u2013906. https:\/\/doi.org\/10.1111\/ijlh.13516","journal-title":"Int J Lab Hematol"},{"key":"3074_CR47","doi-asserted-by":"publisher","first-page":"e1060","DOI":"10.1212\/WNL.0000000000009937","volume":"95","author":"CM Romero-S\u00e1nchez","year":"2020","unstructured":"Romero-S\u00e1nchez CM, D\u00edaz-Maroto I, Fern\u00e1ndez-D\u00edaz E, S\u00e1nchez-Larsen A, Layos-Romero A, Jorge Garc\u00eda-Garc\u00eda J et al (2020) Neurologic manifestations in hospitalized patients with COVID-19: the ALBACOVID registry. Neurology 95:e1060\u2013e1070. https:\/\/doi.org\/10.1212\/WNL.0000000000009937","journal-title":"Neurology"},{"key":"3074_CR48","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.molmed.2016.01.004","volume":"22","author":"LT Roumenina","year":"2016","unstructured":"Roumenina LT, Rayes J, Lacroix-Desmazes S, Dimitrov JD (2016) Heme: modulator of plasma systems in hemolytic diseases. Trends Mol Med 22:200\u20132013. https:\/\/doi.org\/10.1016\/j.molmed.2016.01.004","journal-title":"Trends Mol Med"},{"key":"3074_CR49","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676\u2013682. https:\/\/doi.org\/10.1038\/nmeth.2019","journal-title":"Nat Methods"},{"key":"3074_CR50","doi-asserted-by":"publisher","first-page":"e117","DOI":"10.1161\/STROKEAHA.120.032927","volume":"52","author":"S Shahjouei","year":"2021","unstructured":"Shahjouei S, Tsivgoulis G, Farahmand G, Koza E, Mowla A, Vafaei Sadr A (2021) SARS-CoV-2 and stroke characteristics: a report from the multinational COVID-19 stroke study group. Stroke 52:e117\u2013e130. https:\/\/doi.org\/10.1161\/STROKEAHA.120.032927","journal-title":"Stroke"},{"key":"3074_CR51","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1074\/mcp.T600050-MCP200","volume":"6","author":"IV Shilov","year":"2007","unstructured":"Shilov IV, Seymour SL, Patel AA, Loboda A, Tang WH, Keating SP et al (2007) The Paragon algorithm: a next-generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra. Mol Cell Proteomics 6:1638\u20131655. https:\/\/doi.org\/10.1074\/mcp.T600050-MCP200","journal-title":"Mol Cell Proteomics"},{"key":"3074_CR52","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.3324\/haematol.2015.132183","volume":"100","author":"R Singhal","year":"2015","unstructured":"Singhal R, Annarapu GK, Pandey A, Chawla S, Ojha A, Gupta A et al (2015) Hemoglobin interaction with GP1b\u03b1 induces platelet activation and apoptosis. Haematologica 100:1526\u20131533. https:\/\/doi.org\/10.3324\/haematol.2015.132183","journal-title":"Haematologica"},{"key":"3074_CR53","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1080\/17474086.2016.1255142","volume":"9","author":"O Sripichai","year":"2016","unstructured":"Sripichai O, Fucharoen S (2016) Fetal hemoglobin regulation in \u03b2\u2011thalassemia: heterogeneity, modifiers and therapeutic approaches. Expert Rev Hematol 9:1129\u20131137. https:\/\/doi.org\/10.1080\/17474086.2016.1255142","journal-title":"Expert Rev Hematol"},{"key":"3074_CR54","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1007\/s10654-020-00678-5","volume":"35","author":"PE Taneri","year":"2020","unstructured":"Taneri PE, G\u00f3mez\u2011Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-D\u00edaz ZM et al (2020) Anemia and iron metabolism in COVID\u201119: a systematic review and meta\u2011analysis. Eur J Epidemiol 35:763\u2013773. https:\/\/doi.org\/10.1007\/s10654-020-00678-5","journal-title":"Eur J Epidemiol"},{"key":"3074_CR55","doi-asserted-by":"publisher","first-page":"4455","DOI":"10.1021\/acs.jproteome.0c00606","volume":"19","author":"T Thomas","year":"2020","unstructured":"Thomas T, Stefanoni D, Dzieciatkowska M, Issaian A, Nemkov T, Hill RC et al (2020) Evidence of structural protein damage and membrane lipid remodeling in red blood cells from COVID\u201119 patients. J Proteome Res 19:4455\u20134469. https:\/\/doi.org\/10.1021\/acs.jproteome.0c00606","journal-title":"J Proteome Res"},{"key":"3074_CR56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105325","volume":"29","author":"N Valencia-Enciso","year":"2020","unstructured":"Valencia-Enciso N, Ortiz-Pereira M, Zafra-Sierra MP, Espinel-G\u00f3mez L, Bayona H (2020) Time of stroke onset in COVID-19 patients around the globe: a systematic review and analysis. J Stroke Cerebrovasc Dis 29:105325. https:\/\/doi.org\/10.1016\/j.jstrokecerebrovasdis.2020.105325","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"3074_CR57","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","volume":"395","author":"Z Varga","year":"2020","unstructured":"Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS et al (2020) Endothelial cell infection and endotheliitis in COVID-19. Lancet 395:1417\u20131418. https:\/\/doi.org\/10.1016\/S0140-6736(20)30937-5","journal-title":"Lancet"},{"key":"3074_CR58","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/s41392-020-00426-x","volume":"5","author":"K Wang","year":"2020","unstructured":"Wang K, Chen W, Zhang Z, Deng Y, Lian J-Q, Du P et al (2020) CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther 5:283. https:\/\/doi.org\/10.1038\/s41392-020-00426-x","journal-title":"Signal Transduct Target Ther"},{"key":"3074_CR59","unstructured":"World Health Organization (2025) COVID-19 Epidemiological update, 177th edn. WHO, Geneva. Available from: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports"},{"key":"3074_CR60","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3892\/ijmm.2021.4854","volume":"47","author":"S Zhang","year":"2021","unstructured":"Zhang S, Zhang J, Wang C, Chen X, Zhao X, Jinget H et al (2021) COVID-19 and ischemic stroke: Mechanisms of hypercoagulability (Review). Int J Mol Med 47:21. https:\/\/doi.org\/10.3892\/ijmm.2021.4854","journal-title":"Int J Mol Med"},{"key":"3074_CR61","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.ijid.2022.01.008","volume":"116","author":"Z Zhang","year":"2022","unstructured":"Zhang Z, Lin F, Liu F, Li Q, Li Y, Zhu Z et al (2022) Proteomic profiling reveals a distinctive molecular signature for critically ill COVID-19 patients compared with asthma and chronic obstructive pulmonary disease. Int J Infect Dis 116:258\u2013267. https:\/\/doi.org\/10.1016\/j.ijid.2022.01.008","journal-title":"Int J Infect Dis"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03074-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-026-03074-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03074-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T12:26:01Z","timestamp":1788006361000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-026-03074-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,29]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3074"],"URL":"https:\/\/doi.org\/10.1007\/s00401-026-03074-7","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,29]]},"assertion":[{"value":"1 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors report no conflicts of interest.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained from all participants prior to inclusion in the study, in accordance with the principles outlined in the 1964 Declaration of Helsinki and its subsequent amendments. The study protocol, which included the collection of remaining thrombus material retrieved during mechanical thrombectomy, was reviewed and approved by the Ethics Committee of the General University Hospital of Albacete (approval no. 2019\/03\/031) and the Ethics Committee of Hospital Universitario y Polit\u00e9cnico La Fe (approval nos. ICC1_2016 and 2021-577-1). At all times, sufficient material was preserved for routine diagnostic purposes, and only remaining tissue was used for research analysis. All procedures complied with national regulations and institutional guidelines for research involving human subjects. Patient confidentiality was strictly maintained, and all data were anonymized prior to analysis. No additional interventions beyond standard clinical care were performed, and participation did not entail any foreseeable risk to the patients.","order":2,"name":"Ethics","label":"Ethical approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"26"}}