title: Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke.
abstract: Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Haihao
authors.initials: H
authors.lastname: Zhu
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.forename: Zhanyang
authors.initials: Z
authors.lastname: Yu
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Liu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Murata
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000494:pharmacology* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D017306:Annexin A2; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin