title: ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice.
abstract: Rapid vascular recanalization forms the basis for successful treatment of cerebral ischemia. Currently, tissue plasminogen activator (t-PA) is the only approved thrombolytic drug for ischemic stroke. However, t-PA does not always result in efficient thrombus dissolution and subsequent blood vessel recanalization. To better understand thrombus composition, we analyzed thrombi retrieved from ischemic stroke patients and found a distinct presence of von Willebrand factor (VWF) in various samples. Thrombi contained on average 20.3% ± 10.1% VWF, and this was inversely correlated with thrombus red blood cell content. We hypothesized that ADAMTS13 can exert a thrombolytic effect in VWF-containing thrombi in the setting of stroke. To test this, we generated occlusive VWF-rich thrombi in the middle cerebral artery (MCA) of mice. Infusion of t-PA did not dissolve these MCA occlusions. Interestingly, administration of ADAMTS13 5 minutes after occlusion dose-dependently dissolved these t-PA-resistant thrombi resulting in fast restoration of MCA patency and consequently reduced cerebral infarct sizes (P < .005). Delayed ADAMTS13 administration 60 minutes after occlusion was still effective but to a lesser extent (P < .05). These data show for the first time a potent thrombolytic activity of ADAMTS13 in the setting of stroke, which might become useful in treatment of acute ischemic stroke.
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Frederik
authors.initials: F
authors.lastname: Denorme
authors.affiliation: Department of Neurology, University Clinic of Würzburg, Würzburg, Germany;
authors.forename: Friederike
authors.initials: F
authors.lastname: Langhauser
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Linda
authors.initials: L
authors.lastname: Desender
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Aline
authors.initials: A
authors.lastname: Vandenbulcke
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria;
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Rottensteiner
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria;
authors.forename: Barbara
authors.initials: B
authors.lastname: Plaimauer
authors.affiliation: Department of Medical Imaging, AZ Groeninge, Kortrijk, Belgium; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: François
authors.affiliation: Department of Medical Imaging, AZ Groeninge, Kortrijk, Belgium; and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Hans
authors.identifier: 0000-0003-3952-5501
authors.initials: H
authors.lastname: Deckmyn
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.affiliation: Department of Neurology, University Clinic of Würzburg, Würzburg, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Karen
authors.initials: K
authors.lastname: Vanhoorelbeke
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium;
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D010959:Tissue Plasminogen Activator; C502939:ADAMTS13 protein, mouse; D000071120:ADAMTS13 Protein