Activation of factor VII

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). 

Small doses of heparin are used for the prophylaxis of infusion-related thrombophlebitis (23). Low molecular weight heparin is added to recombinant factor Vila to prevent a 50% loss of activity of factor VII within 4 hours of storage (9). In one case, however, there was co-preci-pitation of reconstituted factor Vila and low molecular weight heparin in syringes (24). The authors therefore suggested that a parallel saline infusion be used instead of heparin to prevent thrombophlebitis. 

Excessive clotting due to over-activation of factor VII or failed coagulation inhibition path interactions (Mutations of Va and Villa or protein S)... 

Also see color figure.) Tissue factor-factor Vila complex. The three-dimensional structure of the complex of factor Vila and tissue factor (minus the transmembrane polypeptide domain of the tissue factor) in the absence of membrane surface. It is approximately 115 A in length and has a diameter of 40-50 A. Factor Vila shows its four distinct domains the Gla domain, two EGF-like domains, and the proteinase domain. Tissue factor contacts factor VHa via the interface between the two fibronectin type Ill-like domains. All four domains of factor Vila appear to be involved in the interaction between tissue factor and factor Vila. The Gla domain of factor Vila is folded very similarly to the Gla domain of prothrombin (Gla domain of prothrombin fragment 1). Activation of factor VII can be catalyzed by thrombin, factor Xa, factor Vila, and factor Xlla—all by cleavage at Arg -Ile . Secondary structures are shown in the center diagram two views of the close interactions between TF and factor Vila are shown in the two diagrams at each side. 

In general, the Factor VII activity estimated by a substrate assay correlated well with Factor VII activity determined by a clot-endpoint assay (P4, S13). However, some differences have been seen. Activation of Factor VII by kaolin or by exposure to cold temperatures (2-8°C) increased the level of clotting Factor VII by 4-7 times but bad no effect on the amount detected by the substrate assay (S9, TIO). It has been postulated that the partially carbox-ylated molecules of Factor VII present in patients plasma during anticoagulant therapy are detected by a substrate assay but not in a clot-endpoint test (P4). These differences between the two assay systems have been used to screen for hereditary Factor VII deficients and to detect the presence of Factor Vila in thrombotic disorders and in components for transfusion therapy (S13). 

Alternatively, damage to blood vessels leads to release of tissue factor and activation of factor VII (start of the extrinsic pathway). 

How important these steps are in the initiation of the coagulation cascade is unknown. Individuals lacking HMWK, prekallikrein, or Factor XII do not suffer from bleeding disorders. Under usual conditions, activation of Factor VII with subsequent activation of Factors IX and X is thought to be sufficient to activate the coagulation pathway. 

Our study relied on regression analysis to examine the relative effects of two related dietary factors (TG and oxidized TG). Obviously, it would be better if we could have compared the effects of fresh and aged walnut oil on factor Vila. Furthermore, we need to identify the active component. However, it is of interest that plasma linoleic acid had been identified as the factor that activated factor VII in Swedish men (52). In that study, oxidation products of linoleic acid were not measured. Could it be that linoleic acid reflected the absorption of linoleic acid oxidation products in the Swedish study Perhaps the oxidized linoleic acid and not the cfr.cw-linoleic acid itself was the activator of factor VII. 

It should not be assumed that hydroxy fatty acids are biologically inactive. Hydroxy fatty acids are chemotactic and vasoactive. Such fatty acids could perturb phospholipids in membranes. For instance, cardiolipin containing hydroxy-linoleic acid does not support the electron transport coupled to ATP production of the mitochondrion. 5-Hydroxy de-canoic acid is a well-known inhibitor of the K -ATP channel. Isoprostanes, trihydroxy oxidation products of arachi-donic acid, are vasoconstrictors (76). 13-Hydroxy linoleic acid (13-HODE) is a lipoxygenase-derived metabolite that influences the thromboresistant properties of endothelial cells in culture (77). However, there is some doubt about the tme nature of these hydroxy-fatty acids generated by the cells, as there are several GSH- and NADPH-dependent pathways that can immediately reduce hydroperoxy- to hydroxy-fatty acids. Furthermore, the reduction step of the analytical method would have converted the hydroperoxy- to a hydroxy-group. Nevertheless, much work remains to be done to determine the relative contribution of hydroperoxy- and hydroxy- to the biological effects of fried fat, and in particular their role in endothelial dysfunction and activation of factor VII. There have been earlier suggestions that a diet rich in lipid peroxidation products may lead to atherosclerosis and CHD (34,78). 

Factor VII. This is a vitamin K-dependent serine protease that functions in the extrinsic coagulation pathway and catalyzes the activation of Factors IX and X. Factor VII is present constitutively in the surface membrane of pericytes and fibroblasts in the adventitia of blood vessels, vascular endothehum, and monocytes. It is a single-chain glycoprotein of approximately 50,000 daltons. 

Vitamin K is a fat-soluble vitamin cofactor for the activation of factors II, VII, IX, and X in the liver. Almost all neonates are vitamin K-deficient at as a result of (1) insignificant transplacental vitamin K crossover, (2) lack of colonization of the colon by vitamin K-producing bacteria, and (3) inadequate dietary vitamin K intake (especially in breast-fed infants because human milk contains less vitamin K than infant formula or cow s milk). Vitamin K-deficiency bleeding (VKDB) refers to bleeding attributable to vitamin K deficiency within first 6 months of life. It occurs in three general time frames early (0-24 hours), classic (1-7 days), and late (2-12 weeks). Early onset occurs rarely and usually is associated with maternal ingestion of anticonvulsants, rifampin, isoniazid, and warfarin. Classic vitamin K-dependent bleeding usually results from the lack of prophylactic vitamin K administration in... 

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). 

Factors II, VII, and X are stable in plasma maintained under refrigeration for up to 6 hours. Plasma refrigerated for 6 hours and subsequently frozen at — 20°C and at -70°C showed no deterioration in the levels of these factors for up to 14 days. Factor V was stable for 6 hours when plasma was stored at 4°C. However, 20% of the activity of factor V was lost in plasma stored frozen at -20°C for over 7 days (104). Even in samples stored frozen at - 70°C, 10% of the activity of factor V was lost after 7 days (104). 

Additionally, attention has been focused on some factors that, operating in the hemostatic balance, have been attributed the role of risk markers of clinical events. Thus, increased plasma concentration of factor VII, fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), and the already mentioned Lp(a) have been associated with the occurrence of CHD. Much work has been done on the modulation of these factors by HT (for a review see Cano and Van Baal 2001), and both similarities and differences have been found in the sparse literature on SERM action. Raloxifene and droloxifene decrease fibrinogen more actively than does HT (Walsh et al. 1998 Herrington et al. 2000). In contrast, the effective reduction demonstrated for PAI-1 with oral HT was not confirmed for raloxifene or droloxifene (Walsh et al. 1998 de Valk-de Roo et al. 1999 Herrington et al. 2000). 

An overview of the coagulation cascade and sites of action for coumarins and heparin is shown in A. There are two ways to initiate the cascade (B) 1) conversion of factor XII into its active form (Xlla, intrinsic system) at intravascular sites denuded of endothelium 2) conversion of factor VII into Vila (extrinsic system) under the influence of a tissue-derived lipoprotein (tissue thromboplastin). Both mechanisms converge via factor X into a common final pathway. 

Warfarin acts as a vitamin K antagonist and suppresses the hepatic formation of prothrombin and of factors VII, IX, and X, causing a markedly reduced prothrombin activity of the blood.Warfarin also causes dilatation and engorgement of blood vessels and an increase in capillary fragility. The two effects can combine to produce hematomas, severe blood... 

The effect of continuously administered low-dose 17-beta-estradiol (E2) + norethisterone acetate (NETA) on coagulation and fibrinolytic factors has been studied in 120 menopausal women, using two dosage variations (1 mg of E2 with 0.25 mg or 0.5 mg of NETA) compared with placebo over a year (53). In either dose, the combination significantly lowered plasma concentrations of factor VII, fibrinogen, antithrombin, and plasminogen activator inhibitor-1 (PAI-1) compared with placebo. These changes appear favorable, since they may lead to increased fibrinolytic activity and could reduce the risk of coronary heart disease. However, antithrombin activity was also reduced, which may increase the risk of venous thromboembolism. 

A model of blood coagulation. With tissue factor (TF), factor VII forms an activated complex (VIIa-TF) that catalyzes the activation of factor IX to factor IXa. Activated factor XIa also... 

Freeze-dried concentrates of plasma containing prothrombin, factors IX and X, and varied amounts of factor VII (Proplex, etc) are commercially available for treating deficiencies of these factors (Table 34-3). Each unit of factor IX per kilogram of body weight raises its activity in plasma 1.5%. Heparin is often added to inhibit coagulation factors activated by the manufacturing process. However, addition of heparin does not eliminate all thromboembolic events. 

Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977 74 5260-5264. 

Recombinant activated human factor VII, increasingly popular in the treatment of major bleeding. 

The cascade is not a simple linear one. The concerted action of activated Factors Vlll and fX is required in the intrinsic pathway for the activation of Factor X. The rate of prothrombin activation by activated Factor X alone is inadequate to meet physiological needs an additional protein, proaccelerin or Factory, is also required. In addition to prothrombin. Factors VII, IX, and X contain y-carboxyglutamate and hence are vitamin K-dependent, as are three... 

Figure 10.37. Blood-Clotting Cascade. A fibrin clot is formed by the interplay of the intrinsic, extrinsic, and final common pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) by contact with abnormal surfaces produced by injury. The extrinsic pathway is triggered by trauma, which activates factor VII and releases a lipoprotein, called tissue factor, from blood vessels. Inactive forms of clotting factors are shown in red their activated counterparts (indicated by the subscript "a") are in yellow. Stimulatory proteins that are not themselves enzymes are shovm in blue. A striking feature of this process is that the activated form of one clotting factor catalyzes the activation of the next factor.

Factor VII is the most sensitive of the vitamin K-dependent clotting factors. The mode of action is tissue factor-dependent activation of factors Xa and IXa on the surfaces of activated platelets (1). Factor Xa leads to thrombin generation and hemostasis, by converting fibrinogen to fibrin. This process is limited to the site of injury, since exposure of tissue factor from the subendothelial matrix has a role in the action of recombinant factor Vila, thereby reducing the risk of thromboembohc events (2). 

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