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.


RESULTS
A 5-microg/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. alpha-Phase clearance of total TPA antigen was faster in subjects with low PAI-1 (t(1/2) of 3.5+/-0.7 minutes) versus high PAI-1 (t(1/2) 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(1/2) of 2.4+/-0.3 minutes) than for TPA/PAI-1 complex (48+/-17%, t(1/2) 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.
Chandler
W L
WL
Department of Laboratory Medicine, University of Washington, Seattle 98195-7110, USA. chandler@mail.labmed.washington.edu
Alessi
M C
MC
Aillaud
M F
MF
Henderson
P
P
Vague
P
P
Juhan-Vague
I
I
D000328:Adult; D000941:Antigens / Q000032:analysis; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism / Q000493:pharmacokinetics*; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*
D000941:Antigens; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator