Tissue factor complex

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. 

B51. Broze, G. J., Warren, L. A., Novotny, W. F., Higuchi, D. A., Girard, J. J., and Miletich, J. P The lipoprotein-associated coagulation inhibitor which inhibits the factor Vll-tissue factor complex also inhibits factor Xa Insight into its possible mechanism of action. Blood 71,335-343 (1988). 

The activity of factor Vila is enhanced astronomically (10 millionfold) upon binding to tissue factor. The VII or VHa-tissue factor complex activates factors IX and X and autoactivates factor VII. Although the activity of the tissue factor-factor VII complex is expressed without the presence of the negatively charged phosphatidylserine, the activity can be enhanced by its presence (9). 

Factor VII exhibits a weak procoagulant activity on its own, typically accounting for about I -2% of the total factor Vll/Vlla activity (17), Upon binding to tissue factor, a 10,000,000-fold increase in factor Vila enzymatic activity is observed (18). Both factor VII and factor Vila bind to tissue factor with equal affinity (19), How factor VII is initially activated is not known, though it is hypothesized that factor Xa can activate factor VII in a back-activation reaction. The factor VIla—tissue factor complex can then activate factor X leading to the generation of thrombin and ultimately to the formation of fibrin strands. 

D. W. Banner The factor Vlla/tissue factor complex. Thrombosis and Haemostasis 78, 512(1997). 

Tissue factor is a membrane protein found in organs and surrounding the vasculature. Tissue factor is exposed to blood as a consequence of vessel wall damage or inflammatory cytokine release from vascular cells or monocytes. Coagulation is initiated when factor Vila binds to exposed or expressed tissue factor (see Fig. 100-2). The factor Vlla-tissue factor complex activates factors IX and X. Activated platelets form complexes with factor IXa-factor Vnia (tenase) and factor... 

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. 

Extrinsic Pathway. Coagulation is initiated when tissue extracts with Hpid—protein properties are released from the membranes of endothehal cells following injury or insult. These substances, collectively designated tissue thromboplastin, complex with circulating Factor VII and in the presence of calcium ions subsequentiy activate Factor X (Fig. 1). In vitro evidence suggests that Factor X can be activated less rapidly through the interaction of kaUikrein [9001-01-8] with Factor VII. 

FXa complexes bind to and neutralize tissue factor/ FVIIa complexes, the key starting point of the extrinsic clotting cascade (see earlier) (Fig. 7). Heparin is able to enhance this reaction by direct binding to the complex and by releasing TFPI from the unaltered vessel wall, which then can access the TF-exposing surface. 

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

Activated on surface of activated platelets by tenase complex (Ca, factors Villa and IXa) and by factor Vila in presence of tissue factor and Ca. ... 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

Once injured or activated by a toxic substance (e.g., bacterial toxins, placenta chemicals, snake venom, etc.), endothelial cells and monocytes respond by generating tissue factor on the cell surface. This, in turn, leads to the generation of tissue factor-factor Villa complexes, followed by unregulated and excessive generation of thrombin, fibrin, systemic microthrombi and consumption of coagulation factors,... 

The fluidity of blood is a result of the inhibition of a complex series of enzymic reactions in the coagulation cascade (see Fig. 10). When triggered either intrinsically (by contact with foreign surfaces ), or extrinsically (by tissue factors from damaged cells), inactive proenzymes (factors XII, XI, IX, and X) are transformed into activated pro-teinases (XHa, XIa, IXa, and Xa, respectively). Each proteinase catalyzes the activation of the following proenzyme in the sequence, up to formation of thrombin (Factor Ha), another proteinase that catalyzes partial... 

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.

Some 5-25 per cent of individuals suffering from haemophilia A develop anti-factor VIII antibodies, and 3-6 per cent of haemophilia B sufferers develop anti-factor IX antibodies. This complicates treatment of these conditions and, as mentioned previously, one approach to their treatment is direct administration of factor Vila. The therapeutic rationale is that factor Vila could directly activate the final common steps of the coagulation cascade, independently of either factor VIII or IX (Figure 12.1). Factor Vila forms a complex with tissue factor that, in the presence of phospholipids and Ca2+, activates factor X. 

Figure 9.4. Schematic representation of the mechanism of action of the coaguligand approach. Cross linking of truncated Tissue Factor to tumour endothelial cells leads to local blood coagulation via the tTF/fVIIa complex. tTF, truncated Tissue Factor fVIIa, factor Vila fX (A), factor X (A).

---