LAUSR

Tissue plasminogen activator (r-tPA) therapy followed by thrombectomy-mediated, mechanical reperfusion profoundly reduces neurologic disability in appropriately selected patients. Nevertheless, a high proportion of these patients (20-37%) develop brain hemorrhage. We examined the contribution of α2-antiplasmin, a fast-acting plasmin inhibitor, to brain hemorrhage and ischemic injury following r-tPA treatment and mechanical reperfusion. Methods: Mice (C57Bl6) underwent 1 to 4 h of middle cerebral artery occlusion followed by treatment with r-tPA alone (10 mg/kg), r-tPA (10 mg/kg) plus an α2AP inhibitor (α2AP-I, 10 mg/kg) antibody or saline, followed by reperfusion. Mice were assessed by neurobehavioral measures (Bederson score and corner test) and histology 24 h post-ischemic stroke. Analyses were performed in a blinded fashion. Time course studies in r-tPA-treated mice showed that intracerebral hemorrhage (p<0.05), brain infarct volume (p<0.001) and brain swelling (p<0.01) increased progressively with ischemic time, with a plateau at 3 h of ischemia, as compared to saline treated controls. Mice treated at 3 h with r r-tPA + α2AP-I showed significantly (p<0.05) reduced brain hemorrhage, brain infarct volume (p<0.01) and brain swelling (p<0.05). Treatment with r-tPA + α2AP-I also significantly improved neurobehavioral deficits (p<0.01) and sensory motor dysfunction (p<0.01) at 24h of reperfusion. Conclusion: α2AP contributes to the increased brain hemorrhage and ischemic brain injury associated with r-tPA treatment followed by mechanical reperfusion. Targeting a2AP appears beneficial, because specific, monoclonal antibody-mediated inhibition of α2AP markedly reduced brain hemorrhage, infarction, swelling and neurobehavioral disability.