Background—The role of plasminogen system components in focal cerebral ischemic infarction (FCI) was studied in mice deficient in plasminogen (Plg^−/−), in tissue or urokinase plasminogen activator (tPA^−/− or uPA^−/−), or in plasminogen activator inhibitor-1 or α₂-antiplasmin (PAI-1^−/− or α₂-AP^−/−).

Methods and Results—FCI was produced by ligation of the left middle cerebral artery and measured after 24 hours by planimetry of stained brain slices. In control (wild-type) mice, infarct size was 7.6±1.1 mm³ (mean±SEM), uPA^−/− mice had similar infarcts (7.8±1.0 mm³, P=NS), tPA^−/− mice smaller (2.6±0.80 mm³, P<0.0001), PAI-1^−/− mice larger (16±0.52 mm³, P<0.0001), and Plg^−/− mice larger (12±1.2 mm³, P=0.037) infarcts. α₂-AP^−/− mice had smaller infarcts (2.2±1.1 mm³, P<0.0001 versus wild-type), which increased to 13±2.5 mm³ (P<0.005 versus α₂-AP^−/−) after intravenous injection of human α₂-AP. Injection into α₂-AP^−/− mice of Fab fragments of affinospecific rabbit IgG against human α₂-AP, after injection of 200 μg human α₂-AP, reduced FCI from 11±1.5 to 5.1±1.1 mm³ (P=0.004).

Conclusions—Plg system components affect FCI at 2 different levels: (1) reduction of tPA activity (tPA gene inactivation) reduces whereas its augmentation (PAI-1 gene inactivation) increases infarct size, and (2) reduction of Plg activity (Plg gene inactivation or α₂-AP injection) increases whereas its augmentation (α₂-AP gene inactivation or α₂-AP neutralization) reduces infarct size. Inhibition of α₂-AP may constitute a potential avenue to treatment of FCI.