Abstract W P258: Alpha-2-antiplasmin Inactivation Reduces Brain Injury, Hemorrhage and Death Following Ischemic Stroke
INTRODUCTION: High levels of a2-antiplasmin (a2AP) have been linked to failure of tissue plasminogen activator therapy, but the overall role of a2AP in ischemic stroke is poorly understood. HYPOTHESIS: We examined the hypothesis that a2AP may contribute to the pathogenesis of ischemic stroke. METHODS: The effects of a2AP blood levels and a2AP inactivation on stroke outcomes were examined in a model of middle cerebral artery thromboembolism. RESULTS: There was a dose-dependent relationship between a2AP blood levels and stroke outcomes. Deficiency of circulating a2AP had protective effects in ischemic stroke; it increased dissolution of the culprit middle cerebral artery thromboembolus (p<0.001), enhanced hemispheric blood flow and markedly reduced brain injury (p<0.001). Increased a2AP levels had opposite and harmful effects; it reduced middle cerebral artery thrombus dissolution (p<0.001), worsened brain injury (p<0.001) and swelling (p<0.001). Higher levels of a2AP significantly increased, and a2AP deficiency significantly reduced, microvascular thrombosis in the ischemic hemisphere. Treatment of mice with a monoclonal antibody that inactivated a2AP, either in the form of whole IgG or Fab, significantly reduced brain infarction, swelling and hemorrhage by comparison to controls, or to treatment with tissue plasminogen activator. Treatment with an a2AP inactivating antibody after cerebral thromboembolism also prevented death and disability. CONCLUSIONS: In cerebral thromboembolism, a2AP has dose-related, injurious effects that increase ischemic brain injury, hemorrhage, microvascular thrombosis and brain swelling. Therapeutic inactivation of a2AP markedly reduced these injurious effects and saved lives after ischemic stroke.
Author Disclosures: G. Reed: Employment; Significant; NIH funded Translational Sciences. Research Grant; Significant; NIH STTR. Ownership Interest; Significant; Translational Sciences. A. Houng: None. D. Wang: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate – Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico, Tennessee, U.S. Virgin Islands.
- © 2015 by American Heart Association, Inc.