Abstract 504: Circulating Alpha-2-Antiplasmin Affects Microvascular Thrombosis, Ischemic Neurodegeneration and Mortality in Mice Following Cerebral Thromboembolism

Abstract

Introduction: For unknown reasons, clinical studies suggest that high circulating levels of human alpha2-antiplasmin may increase the risk of thrombotic vascular diseases such as stroke and contribute to the failure of tissue plasminogen activator therapy. Hypothesis: We tested the hypothesis that circulating alpha2-antiplasmin affects thrombosis, tissue injury and fibrinolysis in a translational model of middle cerebral artery thromboembolism. Methods and Results: Elevated alpha2-antiplasmin levels significantly decreased thrombus dissolution (p<0.001), enhanced matrix metalloproteinase-9 (MMP-9) expression (p<0.001) and worsened brain injury (p<0.001) and swelling (p<0.001). Conversely, genetic deficiency of circulating alpha2-antiplasmin, enhanced dissolution of thromboemboli (p<0.001) and reduced brain injury (p<0.001). Circulating alpha2-antiplasmin had dynamic effects on stroke outcomes because specific alpha2-antiplasmin inactivation after thromboembolism saved lives (p<0.001), prevented disability, decreased brain infarction (p<0.001), reduced hemorrhage (p<0.05) and brain swelling (p<0.001). Inactivation of alpha2-antiplasmin led to reductions in MMP-9 (p<0.001), microvascular thrombosis (p<0.001), blood brain barrier breakdown and apoptosis (p<0.01). Conclusions: These data suggest that alpha2-antiplasmin has deleterious effects in experimental stroke, which are mediated through the fibrinolytic pathway to alter culprit thrombus dissolution, as well as through other mechanisms that contribute to downstream microvascular thrombosis, hemorrhage, MMP-9 expression, apoptosis and blood brain barrier leakage.