Humans clear active t-pa faster than t-pa/pai-1 complex

To determine whether active t-PA was cleared faster from the plasma than t-PA/PAI-1 complex we studied the clearance of infused t-PA in 11 healthy human volunteers with low and high levels of plasma PAI-1 activity. 5ug/kg of t-PA was infused over 15 seconds. Blood samples were obtained over the next 4 hours for measurement of t-PA activity, total t-PA antigen, t-PA/PAI-1 complex, t-PA/C1-inhibitor complex, PAI-1 activity and total PAI-1 antigen. Clearance was evaluated in two ways : by determining the alpha-phase half-life of total t-PA from 2 to 12 minutes after infusion and using a kinetic model of the human circulatory system to model formation and clearance of each factor. In 7 subjects with low PAI-1 activity (mean 8+5 lU/mL), the alphaphase half-life was 3.5±0.7 min. In the 4 subjects with high PAI-1 activity (mean 52+14 lU/mL) the alpha-phase half-life was 5.3+0.9 min (p=0.006). This indicated that total t-PA was cleared slower in the presence of high PAI-1 activity. Using the kinetic circulatory model we adjusted the hepatic clearance fractions for active t-PA and t-PA/PAI-1 complex to produce the best weighted leastsquare fit with measured levels of these factors during clearance. The average hepatic clearance fractions were 86+11 % for active t-PA and 47+10% for t-PA/PAI-1 complex (n=7, p=0.00001). These extraction fractions were equivalent to a half-lives of 2.3+0.4 min for active t-PA and 4.7+1.3 min for t-PA/PAI-1 complex. We conclude that active t-PA is cleared faster from the blood than t-PA/PAI-1 complex. This may explain in part higher levels of total t-PA seen in patients with high levels of PAI-1 activity.