Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: Relationship to elevated TPA antigen in patients with high PAI-1 activity levels

Background: To evaluate the effect of plasminogen activator inhibitor type 1 (PAI-1) levels on the clearance of total tissue plasminogen activator (TPA) antigen, we studied the clearance of active TPA and TPA/PAI-1 complex in subjects with low (181±109 pmol/L; n=7) and high (1166±322 pmol/L; n=4) baseline active PAI-1. Methods and Results: A 5-μg/kg bolus of TPA was infused over a 15-second period followed by measurement of TPA activity, TPA antigen, TPA/PAI-1, TPA/C1 inhibitor, PAI-1 activity, and PAI-1 antigen over a 4-hour period. α-Phase clearance of total TPA antigen was faster in subjects with low PAI-1 (t( 1/4 ) of 3.5±0.7 minutes) versus high PAI-1 (t( 1/4 ) of 5.3±0.9 minutes) (P=.006). Clearance of all factors was best fit by a two-compartment pharmacokinetic model based on a computer-simulated human circulatory system. The average hepatic clearance fraction in the two- compartment model was greater for active TPA (89±10%, t( 1/4 ) of 2.4±0.3 minutes) than for TPA/PAI-1 complex (48±17%, t( 1/4 ) of 5.0±1.8 minutes) (P=.0006). Conclusions: Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.