June 15, 1999Circulation184 citations
View Full PaperPlasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance
Key Result
PAI-1 deficiency significantly increased reperfusion rates after tPA infusion compared to wild-type mice (100% vs 20%, P=0.0006), demonstrating PAI-1 is a major determinant of thrombolysis resistance.
Structured PICO
Does PAI-1 deficiency improve tPA-mediated arterial thrombolysis in a murine carotid injury model?
P
Population
22 mice (11 wild-type and 11 PAI-1-deficient) with ferric chloride-induced platelet-rich thrombi.
E
Exposure
PAI-1 deficiency (PAI-1 -/- mice) treated with tPA (20 or 100 microg/kg/min), heparin (200 U/kg bolus, 70 U/kg/h drip), and human plasminogen (50 mg/kg)
C
Comparator
Wild-type mice (PAI-1 +/+) treated with the same tPA, heparin, and human plasminogen regimen
O
Outcome
Reperfusion rate and reperfusion timesurrogate
PAI-1 is a major determinant of resistance to tPA-mediated lysis in platelet-rich arterial thrombi, suggesting that strategies to inhibit PAI-1 may enhance thrombolysis.
Main Result
Absolute Event Rate: 100% vs 20%
p-value: p=0.0006
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) microg. kg-1. min-1. Mean plasma tPA antigens were 2.7 microg/mL (tPA infusion, 20 microg. kg-1. min-1) and 5.5 microg/mL (tPA infusion, 100 microg. kg-1. min-1), with no significant differences between PAI-1 +/+ mice and PAI-1 -/- mice. Reperfusion after tPA 20 microg. 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 microg. 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.
Cite This Study
Zhu et al. (Tue,) conducted a other in Platelet-rich arterial thrombi (n=22). PAI-1 deficiency vs. Wild-type mice (PAI-1 +/+) was evaluated on Reperfusion after tPA 20 microg/kg/min (p=0.0006). PAI-1 deficiency significantly increased reperfusion rates after tPA infusion compared to wild-type mice (100% vs 20%, P=0.0006), demonstrating PAI-1 is a major determinant of thrombolysis resistance.