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At least 19 recordsLinked to original sources
PubMed1980

Activation of 125I-factor IX and 125I-factor X: effect of tissue factor and factor VII, factor Xa and thrombin.

Activation of Factor IX and Factor X was studied by adding 125I-Factor IX or 125I-Factor X to reaction mixtures and quantitating cleavage products by reduced sodium dodecylsulfate gel electrophoresis. Thrombin failed to activate Factors IX or X; Factor Xa produced insignificant amounts of cleavage products of both factors. In contrast, the reaction product of tissue factor and Factor VII cleaved large amounts of both Factor IX and Factor X in purified systems and in plasma. In incubation mixtures of plasma containing added 125I-Factor IX or 125I-Factor X, tissue factor and Ca2+ ions, the percentage of total radioactivity in the heavy chain peak of 125I-IXa and the heavy chain peak of 125I-Xa increased at a similar rate. When the tissue factor was diluted, similar curves were obtained for percent cleavage of 125I-Factor IX and percent cleavage of 125I-Factor X plotted against tissue factor concentration. These findings support the hypothesis that activation of Factor IX by the tissue factor-Factor VII reaction produce represents a physiologically significant step in normal haemostasis.

Blood Coagulation↗
PubMed1985

Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population--II. Baseline data on the relation to blood pressure, blood glucose, uric acid, and lipid fractions.

In a preceding paper the baseline data in the Münster Arteriosclerosis Study (PROCAM study) of the levels of fibrinogen, factor VIIc and factor VIIIc were described, and their correlation of age, body weight, smoking, alcohol, pill-using and menopause discussed. In this part the relationship of these coagulation factors to blood pressure, blood glucose, uric acid and lipid parameters, which were examined in 4186 apparently healthy individuals, is presented. The correlations are described using two different statistical models, first the Pearson correlation coefficients after allowing each clotting factor for the effects of age, cigarette and alcohol consumption, body weight, menopausal state, pill using and the other clotting factors, and secondly by a multiple regression analysis. The data suggest that there are multiple interrelationships between hemostatic factors and the variables under consideration. The most striking positive correlations were found for factor VIIc to blood glucose and triglycerides in men and women and to HDL-cholesterol in women.

Age Factors↗
PubMed1985

Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause.

The Münster Arteriosclerosis Study (MAS) is a prospective, longitudinal epidemiological study on an industrial population in Westfalia aimed to establishing clinical and laboratory data with possible relationship to cardiovascular events. The data presented here describe the baseline measurements of fibrinogen, factor VIIc and factor VIIIc from the recruitment of 2880 male and 1306 female persons and their relationship to age, gender, bodyweight, smoking, alcohol, pill-using and menopause. The correlations were made by means of a multiple regression analysis. We found an increase of those coagulation factors with age, a correlation of F VII and fibrinogen with body-weight index and of fibrinogen with cigarette smoking. No correlation was found for alcohol consumption. F VIII and F VII were significantly higher after onset of menopause and F VII and fibrinogen in women using the pill.

Adolescent↗
PubMed1983

How to measure factor VII and factor VII activation.

This communication describes the different techniques that can be used to evaluate the activity state of factor VII in plasma samples. At the present time direct methods for quantitation of activated factor VII (factor alpha-VIIa) are not available. Combined methods are therefore used to measure the degree of factor VII activation. These methods can be summarized in the following way: a regular factor VII clotting assay measuring factor VII coagulant activity (factor VIIc) is carried out simultaneously with: (1) a factor VII antigen assay (factor VIIag): (2) a coupled amidolytic factor VII assay (factor VIIam), or (3) a factor VII clotting assay utilizing bovine tissue thromboplastin (VIIbt). The activity state of factor VII can then be calculated from either of the following ratios: f.VIIc/f.VIIag; f.VIIc/f.VIIam, or f.VIIbt/f.VIIc. A study of the potency of a 30-fold activated factor VII to activate factor X in the presence of phospholipids is also included. This experiment demonstrates that even a low factor VII concentration (0.01 U/ml in the coupled amidolytic assay and 0.30 U/ml in the factor VII clotting assay) causes a significant activation of factor X when incubated together in the presence of lipids and calcium ions. Activated factor VII may therefore possess potential thrombotic properties even in the absence of exposed tissue thromboplastin in the blood circulation.

Animals↗
PubMed1993

Levels of plasma factor VII and factor VII activated forms as a function of plasma triglyceride levels.

It has been shown that triglyceride levels are one of the determinants of factor VII levels. In this study we have simultaneously evaluated, in a group of 102 healthy individuals, the different forms of factor VII, namely factor VII mass, factor VII coagulant activity, activated factor VII double-chain form and factor VII-phospholipid complex, in relation to triglyceridaemia. The data showed a highly significant correlation of factor VII mass, factor VII coagulant activity and factor VII-phospholipid complex with triglycerides. No correlation was observed between the activated factor VII double-chain form and triglycerides. These data, together with analysis of the linear and orthogonal regression slopes, suggest that increase of plasma factor VII coagulant activity as a function of plasma triglyceride levels is attributable to an increase in both mass and activity of factor VII and that the increase in activity is dependent on an increase of factor VII-phospholipid complex rather than activated factor VII double-chain form. The ratio between the slopes of the regression straight line of factor VII mass and factor VII-phospholipid complex in relation to triglycerides was 2.23 (95% confidence limits 1.74-2.50), thus indicating that the contribution of factor VII mass is prevalent over that of the factor VII-phospholipid complex.

Adult↗
PubMed1977

Combined factor VII and factor VIII deficiency due to a casual association of heterozygosis for factor VII deficiency and hemophilia A.

A patient with combined factor VII and factor VIII deficiency is discussed. The propositus is a 21-year-old male who presented a mild bleeding tendency. The patient appears to be a hemophilia and at the same time heterozygote for factor VII deficiency. This conclusion is based on the fact that heterozygosis for factor VII deficiency was present in the father and in other relatives of the paternal side. On the contrary, no factor VII deficiency was present in the maternal side of the family. However, the maternal grandfather was known to have been a bleeder and the propositus' mother, his sister and his aunt had low-normal factor VIII levels and were probably hemophilia A carriers. This type of combined factor VII and factor VIII deficiency appears to be due to the casual association of two independently segregating defects.

Adult↗
PubMed2001

Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding.

We examined recombinant activated factor VII (rVIIa) administered by continuous infusion to eight patients with inhibitors to factor VIII, undergoing elective surgery. rVIIa was infused at a fixed rate of 16.5 microg/kg/h for a median of 13.5 days (range 1-26). There was effective haemostasis at this infusion rate in only one of two minor procedures and two of six major operations. Three patients experienced excessive bleeding despite plasma factor VII activity around 10 IU/ml. Serious bleeding occurred in two other patients caused by procedural errors unrelated to rVIIa and required re-operation. The median rVIIa clearance on day 1 was 57 ml/h/kg (range 18-100) and on day 3 was 100 ml/h/kg (range 61-200). Clearance on the final infusion day was not significantly different from day 3. The infusion did not induce pathological activation of the coagulation mechanism. The only thrombotic adverse events were two episodes of superficial thrombophlebitis of the infused vein in one subject. In conclusion, the 16.5 microg/kg/h infusion rate reliably achieves plasma factor VII activity levels of 10 IU/ml, but this level does not provide reliable haemostasis.

Adult↗
PubMed1975

Activation and control of factor VII by activated factor X and thrombin. Isolation and characterization of a single chain form of factor VII.

Factor VII purified as previously described, was found to consist of two polypeptide chains joined by disulfide bridges. We now report the isolation and 200,000-fold purification of a single chain form of Factor VII. This was accomplished by protecting the molecule against proteolysis by including benzamidine during the entire purification. The purification was essentially as previously reported except that barium cirtate was substituted for barium sulfate as an absorbant for Factor VII as it resulted in a 4-fold increase in yield. Single chain Factor VII is rapidly hydrolyzed by Factor Xa in the presence of calcium ions and phospholipids, and by thrombin, to a two-chain form which possesses at least 85 times the Factor VII clotting activity of the single chain species. The two-chain form of the enzyme requires tissue factor in order to activate Factor X. From the observed rates of activation of Factor VII by Xa in the presence of calcium ions and phospholipids, it was calculated that at approximately physiological concentration, Factor VII activity would increase at an initial rate of 20-fold per min; this reaction is sufficiently rapid to constitute a feedback control mechanism. The action of thrombin is approximately 40-fold slower under these conditions. Diisopropylphosphorofluoridate inactivates the single chain and two-chain forms of Factor VII at approximately equal rates. After inhibition, the single chain species could be cleaved but not activated by proteolysis.

Animals↗
PubMed1981

Isolation and characterization of human factor VII. Activation of factor VII by factor Xa.

A procedure has been developed for the isolation of human Factor VII to apparent homogeneity as judged by the analytical disc electrophoretic system of Davis (pH 8.9) and by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The isolated procedure involves adsorption of Factor VII onto barium citrate, ammonium sulfate fractionation, DEAE-Sephadex chromatography, and preparative polyacrylamide gel electrophoresis. The overall yield of Factor VII is 15 to 20% of starting plasma and the purified protein has a specific activity of 1800 to 2200 units/mg in a clotting assay. Factor VII protein obtained by this method has only 1.3 to 1.5 times more activity in a one-stage clotting assay than in a coupled amidolytic assay (Seligsohn, U., Osterud, B., and Rapaport, S. I. (1978) Blood 52, 978-988), which is taken to mean than it contains less than 5% of activated Factor VII. Human Factor VII is a single chain glycoprotein with an apparent molecular weight of 50,000 +/- 2,000 as determined by SDS-polyacrylamide gel electrophoresis. It has alanine as an NH2-terminal amino acid residue and contains 8.8 gama-carboxyglutamic acid residues/mol of protein. Incubation of purified Factor VII with Factor Xa in the presence of Ca(II) and phospholipid results in a rapid up to 25-fold increase in its clotting activity. Factor VII activity in the coupled amidolytic assay remains unchanged throughout the incubation. Activation of Factor VII by Factor Xa is associated with cleavage of the Mr = 50,000 native protein to a protein consisting of two chains of Mr = about 26,000 and 22,000 as determined by SDS-polyacrylamide gel electrophoresis in the presence of 2-mercaptoethanol. Other properties of human Factor VII, including its amino acid composition and its reactions with an anti-Factor VII antibody, are described.

Amino Acids↗
PubMed1998

Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII.

High levels of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) have been found to be effective in providing haemostasis in haemophiliacs and in normal individuals with acquired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided over whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. Our group originally favoured a TF-dependent mechanism; however, we have recently found that, at levels comparable with those attained therapeutically, FVIIa activates enough FX on activated platelets to restore platelet surface thrombin generation. These data now lead us to favour a primarily (although not necessarily exclusively) TF-independent mechanism for the haemostatic effect of high-dose FVIIa. We believe that a platelet surface localization of FVIIa activity explains both its safety and efficacy, as well as its haemostatic effect in patients with thrombocytopenia and platelet function defects. Localization on activated platelets would tend to restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in haemophiliacs would provide FXa in a favourable location to escape inhibition by plasma protease inhibitors and be incorporated into platelet prothrombinase complexes. Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug.

Dose-Response Relationship, Drug↗
PubMed1984

Immunoaffinity purification of bovine factor VII.

Factor VII has been purified to homogeneity from bovine plasma by a procedure that includes affinity purification on an immunoadsorbent column. Recovery was determined by both coagulant assay and liquid scintillation counting, using 3H-factor VII as an internal standard. The purification factor calculated by both methods was approximately 120,000-fold, with a final yield of approximately 18%. Homogeneity was assessed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. The material migrated as a single polypeptide chain of 53,000 daltons, and following activation by factor Xa, the one-chain zymogen was quantitatively converted to two-chain factor VIIa. Conversion of affinity-purified factor VII to factor VIIa resulted in up to a 119-fold activation of the coagulant activity, which is 2.7-4 times greater than the activatability reported for factor VII prepared by other methods. Zur et al. calculated that pure factor VII, uncontaminated by traces of factor VIIa, would be activated 123-fold upon conversion to factor VIIa. The close agreement between observed activatability of affinity-purified factor VII and the theoretical prediction suggests that we have isolated factor VII essentially free of factor VIIa. The purification data from three lots of bovine plasma yield an estimate for the plasma concentration of factor VII from 10.1 nM to 18.5 nM.

Animals↗
PubMed1986

Characterization of a cDNA coding for human factor VII.

Factor VII is a precursor to a serine protease that is present in mammalian plasma. In its activated form, it participates in blood coagulation by activating factor X and/or factor IX in the presence of tissue factor and calcium. Clones coding for factor VII were obtained from two cDNA libraries prepared from poly(A) RNA from human liver and Hep G2 cells. The amino acid sequence deduced from the cDNAs indicates that factor VII is synthesized with a prepro-leader sequence of 60 or 38 amino acids. The mature protein that circulates in plasma is a single-chain polypeptide composed of 406 amino acids. The amino acid sequence analysis of the protein and the amino acid sequence deduced from the cDNAs indicate that factor VII is converted to factor VIIa by the cleavage of a single internal bond between arginine and isoleucine. This results in the formation of a light chain (152 amino acids) and a heavy chain (254 amino acids) that are held together by a disulfide bond. The light chain contains a gamma-carboxyglutamic acid (Gla) domain and two potential epidermal growth factor domains, while the heavy chain contains the serine protease portion of the molecule. Factor VII shows a high degree of amino acid sequence homology with the other vitamin K-dependent plasma proteins.

Amino Acid Sequence↗
PubMed1995

Effect of treatment with low-dose warfarin-aspirin on activated factor VII.

Factor VII is an independent risk factor for ischemic heart disease. We performed a prospective study to evaluate the effect of combined low-dose warfarin-aspirin on activated factor VII (factor VIIa) and to determine if abruptly stopping this treatment is associated with a rebound in the level of factor VIIa. Thirty-three patients with clinically stable coronary artery disease were treated with combined 3 mg warfarin and 80 mg aspirin daily for 8 weeks. The factor VIIa level was measured before treatment, weekly during treatment, and 2 weeks after stopping treatment. The mean percent of pretreatment levels of factor VIIa for weeks 1 through 8 of treatment were 60%, 60%, 72%, 70%, 71%, 70%, 74%, and 87%, respectively (P < .05 compared with pretreatment for weeks 1 through 7 inclusive); 2 weeks after stopping treatment, the level was 122% (95% confidence interval [CI]; 111% to 133%; P < .001 compared with pretreatment). The mean percent level of factor VIIa on-treatment was 74% (P < .001). Factor VIIa is reduced by 26% on average during treatment. This finding provides further rationale for the antithrombotic effect of low-dose warfarin. The results suggest a rebound in the factor VIIa level may occur after treatment is stopped. The potential rebound and its clinical importance should be evaluated by further studies.

Aged↗
PubMed1990

Increased activity of factor VII and factor VII-phospholipid complex measured using a Normotest system in subjects with hyperlipidemia.

Coagulation factor VII and factor VII-phospholipid complex (factor VIIpl), an activated form of factor VII, were measured using a Normotest system in 128 patients with various types of hyperlipoproteinemias and in 45 control subjects. A positive correlation was found between both factors VII (p less than 0.001) and VIIpl (p less than 0.0001) and serum triglycerides. Similar correlations were established with very low density lipoproteins. A positive correlation was also observed between factor VIIpl and total cholesterol, whereas inverse correlations were found with high-density lipoproteins for both factors VII and VIIpl. No positive correlation could be found between low-density lipoproteins and factors VII and VIIpl. This study has shown that patients with hyperlipoproteinemias associated with high serum triglyceride levels, with or without high cholesterol levels, have increased activity of factors VII and VIIpl, both previously associated with an increased risk of coronary heart disease.

Adult↗
PubMed1989

Activation of human factor VII by factors IXa and Xa on human bladder carcinoma cells.

Single chain factor VII is converted by limited proteolysis to its activated form, factor VIIa, by a number of blood coagulation proteases including factor IXa and factor Xa. We have determined the relative rate of human factor VII activation by human factors IXa and Xa in two different systems: one containing Ca++ and human bladder carcinoma (J82) cells, and the other containing Ca++ and mixed brain phospholipids. The rate of factor VII activation was determined by a one stage coagulation assay, and proteolytic cleavage of factor VII was assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting techniques. On a molar basis, factor Xa was sixfold more efficient than factor IXa beta in activating factor VII when the activation reaction occurs on J82 cell surfaces. In contrast, when incubation takes place in a suspension of mixed phospholipids, factor Xa was 18-fold more efficient in activating factor VII than factor IXa beta. In addition, factor IXa alpha activated factor VII at a rate approximately one-half that observed using factor IXa beta. In the absence of cells or phospholipids, no activation of factor VII by either factors IXa or Xa was observed. The addition of stoichiometric amounts of either recombinant human factor VIII (des B-domain) or plasma-derived factor VIIIa failed to augment the rate of factor VII activation by either factors IXa alpha or IXa beta. Likewise, purified human factor Va failed to influence the rate of factor VII activation by factor Xa in either system. Collectively, our studies reveal that J82 cells possess procoagulant phospholipid capable of readily supporting the activation of factor VII by either factors IXa beta or Xa. Our data also demonstrate that the relative ability of factor IXa beta and Xa to activate factor VII is significantly different when these reactions occur on tumor cell surfaces as compared with suspensions of mixed phospholipids.

Blood Coagulation Tests↗