(Circulation. 1999;99:3050-3055.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance
From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich (Y.Z., W.P.F.), and the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium (P.C.)
Correspondence to William P. Fay, MD, University of Michigan Medical Center, 7301 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail wfay{at}umich.edu
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.
Key Words: thrombosis • thrombolysis • platelets • plasminogen activators
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