Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI)? and TFPI?.

ABSTRACT: Tissue factor pathway inhibitor (TFPI) is an alternatively spliced protein with two isoforms, TFPI? and TFPI?, which differ in their C-terminal structure and cellular localization. Detailed characterization of their inhibitory activity is needed to define potentially unique inhibitory roles in tissue factor (TF)-mediated thrombotic and inflammatory disease, and to understand how pharmaceuticals targeted to different structural regions of the TFPI isoforms alter hemostasis in hemophilia patients.The TF inhibitory activity of TFPI? localized to the surface of CHO cells was compared with that of soluble TFPI? by the use of in vitro and in vivo assays.In TF-factor VIIa-mediated FXa generation assays, TFPI? was a slightly better inhibitor than TFPI?, which was approximately three-fold better than TFPI-160, a soluble, altered form of TFPI similar to TFPI?. In direct FXa inhibitory assays, TFPI? had an IC50 2.5-fold lower than that of TFPI? and 56-fold lower than that of TFPI-160. TFPI? inhibited TF-mediated CHO cell migration though Matrigel, whereas TFPI? and TFPI-160 were poor inhibitors, demonstrating that TFPI? effectively blocks TF-initiated signaling events during cellular migration through matrices that are not permeable to soluble forms of TFPI. Furthermore, TFPI? inhibited TF-dependent CHO cell infiltration into lung tissue following tail vein injection into SCID mice, and blocked the development of consumptive coagulopathy.TFPI? is a slightly better inhibitor of TF procoagulant activity than TFPI?. As a surface-associated protein, TFPI? is a much better inhibitor of TF-mediated cellular migration than soluble TFPI?, and may specifically act in the inhibition of TF-mediated signaling events on inflamed endothelium and/or monocytes.

SUBMITTER: Maroney SA 

PROVIDER: S-EPMC3656975 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature