PLASMINOGEN-ACTIVATOR INHIBITOR-1 SUPPRESSES ENDOGENOUS FIBRINOLYSIS IN A CANINE MODEL OF PULMONARY-EMBOLISM

Background. Plasminogen activator inhibitor-1 (PAI-1), the specific, fast-acting inhibitor of tissue-type plasminogen activator (t-PA), binds to fibrin and has been found in high concentrations within arterial thrombi. These findings suggest that the localization of PAI-1 to a thrombus protects that same thrombus from fibrinolysis. In this study, clot-bound PAI-1 was assessed for its ability to suppress clot lysis in vivo. Methods and Results. Autologous, canine whole blood clots were formed in the presence of increasing amounts of activated PAI-1 (0-30-mu-g/ml). Approximately 6-8% of the PAI-1 bound to the clots under the experimental conditions. Control and PAI-1-enriched clots containing iodine-125-labeled fibrin(ogen) were homogenized, washed to remove nonbound elements, and delivered to the lungs of anesthetized dogs where the homogenates subsequently underwent lysis by the endogenous fibrinolytic system. I-125-labeled fibrin degradation products appeared in the blood of control animals within 10 minutes and were maximal by 90 minutes. PAI-1 reduced fibrin degradation product release in a dose-responsive manner at all times between 30 minutes and 5 hours (greater-than-or-equal-to 76% inhibition at 30 minutes, PAI-1 greater-than-or-equal-to 6-mu-g/ml). PAI-1 also suppressed D-dimer release from clots containing small amounts of human fibrin(ogen). t-PA administration attenuated the effects of PAI-1, whereas latent PAI-1 (20-mu-g/ml) had no effect on clot lysis. Blood levels of PA and PAI activity remained unaltered during these experiments. Conclusions. The results indicate that PAI-1 markedly inhibits endogenous fibrinolysis in vivo and, moreover, suggest that the localization of PAI-1 to a forming thrombus is an important physiological mechanism for subsequent thrombus stabilization.