Summary
Tissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation
of the extrinsic pathway of coagulation. In humans, injection of heparin results in
a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important
for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant
two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding.
Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with
and without this C-terminus.
FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with
and without simultaneous intravenous injections of low molecular weight heparin (450
anti-XaU/kg).
Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor
10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin
was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found
in the group receiving the two compounds simultaneously, suggesting that the releasable
pool of FL-TFPI is removed very slowly in the absence of circulating heparin.
