(Circulation. 1997;96:761-768.)
© 1997 American Heart Association, Inc.
Articles |
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
From the Department of Laboratory Medicine (W.L.C., P.H.), University of Washington, Seattle; the Laboratory of Hematology (M.C.A., M.F.A., I.J.-V.), CJF INSERM, Marseille, France; and the Department of Diabetology and Nutrition CHU Timone (P.V.), Marseille, France.
Correspondence to Wayne L. Chandler, MD, Department of Laboratory Medicine, Box 357110, University of Washington, Seattle, WA 98195-7110. E-mail chandler{at}mail.labmed.washington.edu
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. 
-Phase clearance of total TPA
antigen was faster in subjects with low PAI-1 (t1/2 of
3.5±0.7 minutes) versus high PAI-1 (t1/2 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%,
t1/2 of 2.4±0.3 minutes) than for TPA/PAI-1 complex
(48±17%, t1/2 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.
Key Words: plasminogen activators • hepatic clearance • plasma
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