Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance

Abstract

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-1 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-1–deficient mice ( PAI-1 −/−; 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) μg · kg −1 · min −1 . Mean plasma tPA antigens were 2.7 μg/mL (tPA infusion, 20 μg · kg −1 · min −1 ) and 5.5 μg/mL (tPA infusion, 100 μg · kg −1 · min −1 ), with no significant differences between PAI-1 +/+ mice and PAI-1 −/− mice. Reperfusion after tPA 20 μg · 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 μg · 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-1 −/− 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.