{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:06:51Z","timestamp":1792206411052,"version":"4.4.0"},"reference-count":39,"publisher":"American Society of Hematology","issue":"10","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in\u00a0vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia\/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA\/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in\u00a0vitro and in\u00a0vivo activities that result from its constitutively active conformation.<\/jats:p>","DOI":"10.1182\/blood.2021012787","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T16:01:31Z","timestamp":1636992091000},"page":"1575-1587","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":36,"title":["Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9141-3438","authenticated-orcid":false,"given":"Kieron","family":"South","sequence":"first","affiliation":[{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of 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Salford Royal NHS Foundation Trust, Salford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9599-6194","authenticated-orcid":false,"given":"Ingo","family":"Schiessl","sequence":"additional","affiliation":[{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom;"},{"name":"Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Group\u2013University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-4456","authenticated-orcid":false,"given":"Stuart M.","family":"Allan","sequence":"additional","affiliation":[{"name":"Division of Neuroscience and Experimental Psychology, School 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