Tissue factor pathway inhibitor TFPI

Primarily, tissue factor pathway inhibitor (TFPI) binds to and inactivates FXa. In a second step TFPI/... 

Tissue factor pathway inhibitor (TFPI) is a major physiologic inhibitor of coagulation. It is a protein that circulates in the blood associated with lipoproteins. TFPI directly inhibits factor Xa by binding to the enzyme near its active site. This factor Xa-TFPI complex then inhibits the factor Vlla-tissue factor complex. 

Tissue factor pathway inhibitor (TFPI), a 42-kDa protein with three Kunitz domains, is a potent inhibitor of coagulation. It inhibits tissue factor-factor Vila complex upon binding to the active site of Kunitz domain one. Factor Xa is inhibited upon binding to the active site of the second Kunitz domain of TFPI (27). 

Fig. 6. Mechanism of inhibition of tissue factor pathway inhibitor (TFPI). Kunitz domain 1 (Dl) inhibits TF-VIIa complex. Domain 2 (D2) inhibits Xa.

A specific immunoassay for measuring two-chain factor VIIa levels in plasma has been developed to identify activation of factor VII in patients with acute coronary syndromes suchs as myocardial infarction and unstable angina (12). Because regulation of factor VIIa is believed to be mediated by tissue factor pathway inhibitor (TFPI), its measurement is also useful in assessing thombotic and cardio-vasular disorders. Because TFPI is released by heparin, its measurement is also useful in assessing the efficacy of heparin and endothelial cell function (93). 

Predicted secondary structure of tissue factor pathway inhibitor (TFPI) showing the Factor Xa and Factor Vila inhibitory domains. The arrows point to the PI sites. 

Hamamoto T Yamamoto M, Nordfang O, Petersen JGL, Foster DC, Kisiel W. Inhibitory properties of full-length and truncated tissue factor pathway inhibitor (TFPI). J Biol Chem 1993 268( 12) 8704-8710. 

Kristensen HI, Ostergaard R Nordfang O, Abilolgaard U, Effect of tissue factor pathway inhibitor (TFPI) in the HEPTEST assay and in an amidolytic anti factor Xa assay for LMW heparin, Thromb Haemost I 992 68(3)3 10-3 14. 

UFH acts directly on platelets to promote platelet aggregation and releases platelet factor 4 (PF4) from the endothelium. PF4 binds UFH and neutralizes its anticoagulant action (5). Furthermore, UFH induces the release of tissue factor pathway inhibitor (TFPI) from platelets and endothelial cells into the circulation, One of the major effects of UFH is the release of free-type TFPI, which strongly inhibits FVIIa tissue factor, Therefore, the anticoagulant actions of UFH vary depending on the individual patient and are influenced by the level of PF4, antithrombin, and histidine-rich GP... 

TFPI2 Tissue factor pathway inhibitor (TFPI) 2... 

Moatti D, Seknadji P Galand C, et al, Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects impact of the V264M substitution on plasma levels of TFPI. Arterioscler Thromb Vase Biol 1999 19 862-869. 

Kleesiek K, Schmidt M, Gotting C, et al. The 536C—>T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosi. Thromb Haemost I 999 82 1-5,... 

Several other approaches to antithrombotic dmg development are in both pre-clinical and clinical investigations with only limited data available at this time. Tliese include ctor Xa and fector VII inhibitors, thrombomodulin, activated protein C, tissue factor pathway inhibitor (TFPI), PAI inhibitors and protease annexin. 

Z. Y. Ye, R. Takano, K. Hayashi, T. V. Ta, et al., Structural requirements of human tissue factor pathway inhibitor (TFPI) and heparin for TFPI-heparin interaction, Throm. Res. 89 263 (1998). 

Tissue factor pathway inhibitor (TFPI) is a Kunitz type inhibitor composed of three Kunitz domains. The N-terminal Kunitz domain binds to and inhibits the VHa-TF complex that activates factor X (Fig. 11.6a), whereas the downstream Kunitz domain binds directly to factor Xa and inhibits it strongly and permanently. No function has yet been demonstrated for the third Kunitz domain. The C-terminal region of TFPI is basic and remains attached to endothelial cell surfaces where it inhibits inadvertent factor Xa activation. Studies in mice indicate that knocking out the gene for TFPI stops fetal development. Indeed, clotting diseases such as a stroke and heart attacks are associated with mutations of AITH, HCII and ZPI, but not of TFPI. Like TF (Sect. 11.3.1), diminished TFPI activity may be incompatible with life. 

Specific inhibitors of clotting factors are also critical in the termination of clotting. For instance, tissue factor pathway inhibitor (TFPI) inhibits the complex ori F-VII —Xg. Separate domains in 1 FPl inhibit VII3 and X,j. Another key inhibitor is antithrombin Ilf a plasma protein that inactivates thrombin by forming an irreversible complex with it. Antithrombin III resembles... 

Francischati IM, Valenzuela JG, Andersen JF et aL Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis identification of factor X and faaor Xa as scaffolds for the inhibition of faaor Vlla/tissue factor complex. Blood 2002 99 3602-3612. 

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