{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:44:28Z","timestamp":1785437068795,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL092750"],"award-info":[{"award-number":["HL092750"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL158376"],"award-info":[{"award-number":["HL158376"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["UH3NS125023"],"award-info":[{"award-number":["UH3NS125023"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ANRF, Government of India","award":["RJF\/2020\/000070"],"award-info":[{"award-number":["RJF\/2020\/000070"]}]},{"award":["RJF\/2020\/000070"],"award-info":[{"award-number":["RJF\/2020\/000070"]}],"id":[{"id":"https:\/\/ror.org\/036h6g940","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>A bioengineered version of recombinant tissue plasminogen activator, i.e., tenecteplase (TNK-tPA), was designed to have a longer half-life, resistance to plasminogen activator inhibitor-1, and fibrin-targeted plasminogen activation. By comparison to tPA, clinical trials suggest that TNK-tPA may be less susceptible to the effects of alpha2-antiplasmin (\u03b12AP), the primary inhibitor of thrombus dissolution. However, preclinical studies are limited, and whether \u03b12AP affects TNK-tPA\u2019s fibrinolytic activity or efficacy in experimental ischemic stroke is unknown. We examined the effects of TNK-tPA and \u03b12AP on the dissolution of human plasma clots (in vitro) and experimental ischemic brain injury from stroke induced by transient middle cerebral artery ischemia. TNK-tPA induced a dose-dependent increase in plasma clot dissolution; inhibition of \u03b12AP with a specific monoclonal antibody caused a synergistic increase in TNK-tPA-mediated clot dissolution. In experimental ischemic stroke with ischemia and reperfusion, TNK-tPA treatment of \u03b12AP\u2212\/\u2212 mice significantly reduced ischemic infarct volume, brain swelling, brain hemorrhage, and neurobehavioral disability vs. TNK-tPA-treated \u03b12AP+\/+ (C57BL\/6 background) mice with normal \u03b12AP levels (p &lt; 0.05 to p &lt; 0.0001). \u03b12AP impairs the dissolution of human clots in vitro by TNK-tPA and significantly exacerbates ischemic brain injury, swelling, hemorrhage, and neurobehavioral disability after experimental stroke, even with reperfusion. Targeting \u03b12AP may improve the efficacy of TNK-tPA and reduce hemorrhagic complications.<\/jats:p>","DOI":"10.3390\/ijms27156558","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"6558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alpha2-Antiplasmin Limits Fibrinolysis by Tenecteplase and Enhances Brain Injury After Reperfusion in Ischemic Stroke"],"prefix":"10.3390","volume":"27","author":[{"given":"Satish","family":"Singh","sequence":"first","affiliation":[{"name":"Translational Cardiovascular Research Center, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"},{"name":"CSIR\u2014Institute of Himalayan Bioresource Technology, Palampur 176061, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofiyan","family":"Saleem","sequence":"additional","affiliation":[{"name":"Translational Cardiovascular Research Center, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7633-2210","authenticated-orcid":false,"given":"Ryan D.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Translational Cardiovascular Research Center, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy L.","family":"Reed","sequence":"additional","affiliation":[{"name":"Translational Cardiovascular Research Center, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1161\/STROKEAHA.120.029749","article-title":"Tenecteplase Thrombolysis for Acute Ischemic Stroke","volume":"51","author":"Warach","year":"2020","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e250548","DOI":"10.1001\/jamanetworkopen.2025.0548","article-title":"Short-Term Safety and Effectiveness for Tenecteplase and Alteplase in Acute Ischemic Stroke","volume":"8","author":"Rousseau","year":"2025","journal-title":"JAMA Netw. 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