FULL-LENGTH HUMAN TISSUE FACTOR PATHWAY INHIBITOR INHIBITS HUMAN ACTIVATED PROTEIN-C IN THE PRESENCE OF HEPARIN

Previous studies have demonstrated that tissue factor pathway inhibito r (TFPI) purified from a hepatoma cell line failed to inhibit human ac tivated protein C (APC) or human thrombin. In the present study, we ha ve examined the ability of full-length TFPI and a truncated form of TF PI lacking the third Kunitz-type domain and C-terminal tail (TFPI1-161 ) to inhibit the amidolytic activity of human APC in the presence and absence of heparin. TFPI readily inhibited APC amidolytic activity onl y in the presence of heparin, whereas TFPI1-161 failed to inhibit APC amidolytic activity in the presence or absence of heparin. Optimal inh ibition of APC by TFPI was observed at 1 U/ml heparin. The results of competition studies between factor Xa and APC for inhibition by TFPI i n the presence of heparin suggested that the second Kunitz-type domain in TFPI was responsible for the inhibition of APC.