A kinetic model of the circulatory regulation of tissue plasminogen activator.
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.
Chandler
W L
WL
Department of Laboratory Medicine, University of Washington, Seattle 98195.
D000328:Adult; D000368:Aged; D000941:Antigens / Q000032:analysis; D001775:Blood Circulation / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D003198:Computer Simulation; D004730:Endothelium, Vascular / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D008954:Models, Biological; D015849:Plasminogen Inactivators / Q000276:immunology / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000502:physiology*
D000941:Antigens; D015849:Plasminogen Inactivators; D010959:Tissue Plasminogen Activator