Summary
A computer simulation was developed to study the regulation of active tissue plasminogen
activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition
by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA,
PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The
model indicates that as the active PAI-1 concentration increases, the percent of t-PA
in the active form decreases exponentially. Further, the reaction between t-PA and
PAI-1 substantially reduces the half-lives of both active factors. By adjusting the
t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured
circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal
rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion
and not to variations in the t-PA secretion rate. In conclusion, the model predicts
that PAI-1 is an important regulator of the concentration, half-life and circadian
variation of active t-PA.
