Effects of recombinant plasminogen activator inhibitor type 1 on fibrinolysis in vitro and in vivo.

A biologically active recombinant PAI-1 (rPAI-1) was evaluated for its effects on clot lysis in vitro and in vivo. At concentrations of 0.5 to 10 micrograms/ml, the rPAI-1 significantly prolonged the time to lysis of rabbit euglobulin clots both in the presence and absence of exogenous tissue plasminogen activator. To examine the effects of PAI in vivo, we infused rPAI-1 into conscious rabbits after i.v. injection of homogenized fibrin clots, and assessed fibrinolysis by measuring the appearance of d-dimer fibrin degradation products (FDP). Plasma fibrinolytic activity, PAI activity and antigen were also measured in plasma samples taken during and after infusion of rPAI-1. In control rabbits, endogenous fibrinolytic activity resulted in a significant and continual generation of FDP, reaching 32.6 +/- 13.6 ng/ml 90 minutes after fibrin injection. Infusion of 1, 2, or 5 micrograms/kg/min rPAI-1 led to dose dependent increases in PAI activity and antigen, while FDP levels at 90 minutes were only 8.8 +/- 2.9, 5.7 +/- 2.4, and 0.3 +/- 0.3 ng/ml, respectively. Complete inhibition of fibrinolysis was observed with 10 micrograms/kg/min rPAI-1. These studies directly demonstrate that increases in PAI-1 impair the fibrinolytic system, and support indirect observations of an association between elevated levels of this protein and thromboembolic diseases.