Tissue factor pathway inhibitor

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. 

Broze GJ Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 1995 46 103. 

LMWHs are formed by various methods of fractionation or depolymerization of polymeric heparin (Table 7.1). Although they are enzymatically derived from UFH, they have a different site of achon and can be administered subcutaneously. LMWHs exert their anhcoagulant effect by inhibiting factor Xa and augmenting tissue-factor-pathway inhibitor, but minimally affect thrombin or factor Ila (Figs. 7.1 and 7.2)." Thus, the PTT, a measure of antithrombin (anh-factor Ila) achvity, is not used to measure the achvity of LMWHs. 

FIGURE 7-4. Coagulation cascade. AT, antithrombin HCII, heparin cofactor II TFPI, tissue factor pathway inhibitor. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In ... 

HCII heparin co-factor II TFPI tissue factor pathway inhibitor... 

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). 

Broze G. J., Jr. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol 1992 29, 159-69. 

Zoldhelyi P, Chen ZQ, Shelat HS, et al. Local gene transfer of tissue factor pathway inhibitor regulates inti-mal hyperplasia in atherosclerotic arteries. Proc Natl Acad Sci USA. Mar 27 2001 98(7) 4078 083. 

Another serine protease inhibitor of the al-antitrypsin family (serpin) is heparin cofactor II (HCII), which also forms a 1 1 complex with thrombin, but does not react with factor Xa [4,10]. The rate of inhibition of thrombin is not only increased by heparinoids but also by the related glycosaminoglycan dermatan sulfate. The identification of an inhibitor variant and site-directed mutagenesis studies on HC II cDNA led to the understanding that the binding sites for heparin and dermatan sulfate may be overlapping but not identical. Further proteinase inhibitors interacting with heparinoids are tissue factor pathway inhibitor and protease nexin-1. 

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. 

See color plate.) The primar/ hemostatic response. Following loss of vascular integrity platelets adhere to subendothelial wall matrix, which triggers their activation. Abbreviations HT, hydroxy tryptamine TFPI, tissue factor pathway inhibitor. 

See color plate.) The coagulation cascade. The formation of fibrin strands is the result of a sequential activation of a number of enzymes. The hemostatic balance is maintained by endogenous inhibitors such as AT, HC-II, and TFPI. Abbreviations AT, antithrombin TFPI, tissue factor pathway inhibitor. 

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. 

Huang ZFs Wun TC, Broze GJ, Kinetics of factor Xa inhibition by tissue factor pathway inhibitor, J Biol Chem 1993 268(3 6) 26,950—26,955. 

Enjyoji K, Miyaya X Kamikubo Y Kato H, Effect of heparin on the inhibition of factor Xa by tissue factor pathway inhibitor a segment, Gly 212-Phe 243, of the third Kunitz domain is a heparin binding site. Biochemistry 1995 34 5725-5735,... 

Lindahl AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coag Fibrinol 1992 3 439-449. 

Alban S, Gastpar R, Plasma levels of total and free tissue factor pathway inhibitor as individual pharmacological parameters of various heparins, Thromb Haemost 2001 85(5) 824-829. 

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. 

I I I Warn-Cramer BJ, Rapaport SI. Studies of factor Xa/phospho-lipid induced intravascular coagulation on rabbits. Effects of immunodepletion of tissue factor pathway inhibitor. Arteriosclerosis Thrombosis 1993 13(1 I) 1551-1557. 

I 12 CreaseyAA, ChangACK, Feigen L, Wun TC, Taylor FB, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993 91 2850-2860. 

I 13 Khouri RK, Koudsi D, Fu K, Omberg RL, Wun TC. Prevention of thrombosis by topical application of tissue factor pathway inhibitor in a rabbit model of vascular trauma. Ann Plast Surg 1993 30(5)398-404. 

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... 

Formation of thrombus at the site of endothelial damage. Von Willebrand factor exposed at sites of endothelial damage acts to bind platelets to the vessel wall. Tissue factor, expressed on subendothelial tissue and cytokine-primed macrophages, acts to generate thrombin, which activates platelets and produces fibrin. TFPI, normally present on the endothelial surface, can be released by heparins and can inhibit tissue factor-induced thrombin generation. Abbreviations ADP adenosine disphosphate TFP1, tissue factor pathway inhibitor. 

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