The clearance of proteoglycan-associated human recombinant tissue factor pathway inhibitor (h-rTFPI) in rabbits: a complex formation of h-rTFPI with factor Xa promotes a clearance rate of h-rTFPI.

The very rapid clearance of human recombinant tissue factor pathway inhibitor (h-rTFPI) may result from its binding to vascular proteogly can and LDL receptor-related protein (LRP). To investigate the effect of factor Xa on the clearance of h-rTFPI, we developed a specific ELISA for h-rTFPI/factor Xa complex, and compared the pharmacokinetic parameters of h-rTFPI/factor Xa complex and the clearance rate of the cellular proteogly can-associated h-rTFPI/factor Xa complex with those of h-rTFPI by itself in rabbits. We found that the h-rTFPI/factor Xa complex disappeared from circulation at a rapid rate of clearance, having pharmacokinetic parameters similar to those of non-complexed h-rTFPI. After the rapid disappearance of the h-rTFPI complex from plasma, an intravenous injection of heparin resulted in a release of h-rTFPI/factor Xa complex into plasma. However, the recovery of heparin-releasable h-rTFPI/factor Xa decreased significantly in a time-dependent manner. Therefore, we examined the half-life of proteogly can-associated h-rTFPI/factor Xa and determined it to be 51 min, which was significantly shorter than that of h-rTFPI by itself (107 min). These results suggest that a complex formation of h-rTFPI with factor Xa promotes a clearance of proteogly can-associated h-rTFPI existing in the liver and kidney.