Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance

Background-Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA), Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a. murine carotid injury model to test the hypothesis that PAI-I inhibits thrombolysis mediated by pharmacological concentrations of tPA., Methods and Results-Platelet-rich thrombi were induced in wild-type mice (PAI-1 +/+; n=11) and PAI-l-deficient mice (PAI-I -/-; n=11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between PAI-1 +/+ and PAI-1 -/- mice. Clot lysis was induced by infusion of heparin (200 U/kg bolus, 70 U.kg(-1).h(-1) drip), human plasminogen (50 mg/kg) and tPA at 20 (n=10) or 100 (n=12,) mu g.kg(-1).min(-1). Mean plasma tPA antigens were 2.7 mu g/mL (tPA infusion, 20 mu g.kg(-1).min(-1)) and 5.5 mu g/mL (tPA infusion, 100 mu g.kg(-1).min(-1)), with no significant differences between PAI-1 +/+ mice and PAI-1 -/- mice, Reperfusion after tPA 20 mu g.kg(-1).min(-1) occurred in 1 of 5 PAI-1 +/+ mice versus 5 of 5 PAI-1 -/- mice (P=0.0006). Reperfusion occurred in all mice that received tPA 100 mu g.kg(-1).min(-1), but reperfusion times were significantly shorter in PAI-1 -/- mice (17.8+/-2.6 minutes, n=6) than in PAI-1 +/+ mice (35.7+/-5.1 minute, n=6; P=0.01), Histological analyses confirmed that carotid thrombi were platelet rich and that PAI-1 was distributed uniformly throughout thrombi from PAI-1 +/+ mice. Lysates of PAI-1 +/+ platelets inhibited human tPA, whereas PAI-I -/- platelet lysates did not. Conclusions-PAI-1 is a major determinant of the resistance of platelet-rich arterial thrombi to lysis by pharmacological concentrations of tPA. Strategies to inhibit or resist PAI-1 may enhance thrombolysis.