Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor.

摘要

The tissue factor (TF) pathway of blood coagulation is initiated when factor VIIa binds to TF and proteolytically activates FIX and FX. The key regulator of this pathway is TF pathway inhibitor (TFPI), a multivalent Kunitz-type proteinase inhibitor that directly inhibits FXa and produces FXa-dependent feedback inhibition of the FVIIa-TF complex. In the final quaternary inhibitory complex containing FXa, TFPI, FVIIa and TF, the Kunitz-2 domain of TFPI interacts with FXa and the Kunitz-1 domain interacts with FVIIa. The formation of this complex is frequently described as a two-step process in which TFPI binds to FXa, and the FXa-TFPI complex subsequently binds to FVIIa-TF. Kinetic studies, however, strongly suggest that TFPI interacts with the tertiary FVIIa-TF-FXa complex before FXa is released from the FVIIa-TF complex after the cleavage of FX [1].