Tissue factor pathway

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). 

Nemerson Y. The tissue factor pathway of blood coagulation. Semin Hematol 1992 29, 170-6. 

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. 

Factor IX (Christmas factor) is next in the intrinsic mechanism cascade. It can be activated either by XIa or by Vila of the tissue factor pathway. The absence of a functional factor IX leads to the inherited X-linked bleeding disorder hemophilia B which affects 1 in 30,000 males. The condition can be mild or very serious551552 and may be caused by a variety of mutations or by incorrect splicing of the messenger RNA for the 416-residue factor IX. The level of factor IX in blood increases with age, almost doubling by old age.552a... 

Factor IXa causes a rapid activation of factor X only if Ca2+, phospholipid,553 554 and the accessory factor Villa555 are present. The IXa Villa complex acts on X about 2 x 105 times faster than does IXa alone. This complex cleaves the same bonds in X as does the VIIa Va complex formed in the tissue factor pathway.514 The 2332-residue factor VIII and factor V have similar structures that include three repeats of a domain homologous to the blue copper-containing plasma protein ceruloplasmin (Chapter 16).556-559 Tyrosine 1680 of VIII apparently must be converted to a sulfate ester for full activity.560... 

Why do we have the intrinsic pathway when the tissue factor pathway provides rapid clot formation The answer seems to be that the tissue factor pathway is needed immediately after injury but that it is turned off quickly by the anticoagulation systems of the body. As a result the protease plasmin begins to dissolve (lyse) the clot within a few hours. The intrinsic pathway is apparently needed to maintain the clot for a longer period.514... 

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. 

McVey JH. Tissue factor pathway. Bailliere s Clin Haemat 1994 7(3) 469-484. 

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. 

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