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-1 inhibits thrombolysis mediated by pharmacological concentrations of tPA.


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.
Zhu
Y
Y
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Carmeliet
P
P
Fay
W P
WP
D000818:Animals; D001792:Blood Platelets; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology*; D016893:Carotid Stenosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D002712:Chlorides; D005290:Ferric Compounds; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010958:Plasminogen / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D002712:Chlorides; D005290:Ferric Compounds; D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; C024555:ferric chloride