VII Coagulant Activity Research Articles

Genetic Determinants of Plasma Factor VII Activity in the Japanese

We investigated the frequency of the factor VII Gln353 (FVII Gln353) allele in Japan, where coronary artery disease is much less common and factor VII coagulant activity (FVIIc) is lower than in Western countries. Japanese males (n = 144) aged 40-59 years living in 2 different districts were studied, and the FVIIc and activated factor VII (FVIIa) levels were measured with human (FVIIa Hum) and bovine soluble tissue factor (FVIIa Bov). The frequency of the FVII Gln353 allele in the 2 districts was 0.026 and 0.052 (combined: 0.034), which was about one third of that in a European population. Thus, the lower FVIIc level in Japanese is not due to the effect of FVII Gln353 allele. Ten individuals with the Gln353 allele showed a 39% decrease of FVIIa Hum levels and a 29% decrease of the FVIIa Bov level compared with 134 individuals homozygous for the FVII Arg353 allele. These decreases of FVIIa were greater than the decrease of FVIIc (17%), suggesting that FVII Gln353 may be difficult to activate in vivo. The marked decrease of FVIIa levels in individuals with the FVII Gln353 allele suggests that they are genetically protected against cardiovascular disease irrespective of ethnic background, by virtue of their decreased FVIIa level.

Effect on blood lipids, coagulation, and fibrinolysis of a fat high in myristic acid and a fat high in palmitic acid

The hypothesis that myristic acid (C14:0) has a stronger cholesterol-increasing potential than does palmitic acid is based on very few experimental observations. A randomized, strictly controlled dietary study was therefore designed to investigate the effect of a synthetic fat that was high in myristic acid, and palm oil, which is high in palmitic acid, on lipoproteins and hemostatic variables. Twelve men were served two diets (40% of energy as fat) with 41% of fat as myristic (diet M) or palmitic acid (diet P) for 3 wk with 1 mo between the two dietary schedules. Plasma HDL cholesterol was 8% higher with diet M than with diet P: 1.10 +/- 0.06 (mean +/- SEM) vs 1.01 +/- 0.05 mmol/L (P < 0.006). Diet M raised factor VII coagulant (F VIIc) activity to 98% (77-117%) vs 96% (71-109%) (medians and ranges) after diet P (P = 0.02). Total and LDL-cholesterol concentrations did not differ between the diets. In conclusion, the myristic acid test fat was not more cholesterolemic than was palm oil, but it did induce a minor rise in F VIIc activity.

Plasma phospholipid fatty acid composition and factor VII coagulant activity

Plasma phospholipid fatty acid composition reflects, to a moderate degree, the fatty acid composition of the diet. To determine whether plasma phospholipid fatty acid composition might influence factor VII coagulant activity (factor VII c, we examined 2207 middle-aged adults free of diabetes and cardiovascular disease. Factor VII c was associated positively with the percentage of fatty acids that was saturated, and it was associated negatively with the linoleic acid percentage and the phospholipid polyunsaturated/ saturated fatty acid ratio. For example, a 1.9% greater saturated fatty acid level was associated with approximately a 5% higher factor VII c. These results suggest a role for dietary fat composition, or related dietary patterns, in determining levels of factor VII c.

Associations between habitual diet, platelet function, fibrinogen and factor VII coagulant activity in young Finns

Associations between habitual diet, platelet function, fibrinogen and factor VII coagulant activity in young Finns

XbaI polymorphism of apolipoprotein B and factor VII coagulant activity: a dietary intervention study

XbaI polymorphism of apolipoprotein B and factor VII coagulant activity: a dietary intervention study

Factor VII coagulant activity and cholesterol changes in premenopausal women consuming a long-term cholesterol-lowering diet.

We periodically obtained blood samples from mildly hypercholesterolemic, but otherwise healthy, premenopausal women who were recruited to participate in a study of a long-term, cholesterol-lowering diet. All meals were prepared and most meals were consumed in the study center dining facility. Tests performed on blood samples included fibrinogen, cholesterol, factor VII coagulant activity (VIIc), and other measures of factor VII. We found that when women switched from a typical American diet (37% fat, polyunsaturated fatty acid to saturated fatty acid [P/S] ratio 0.5, 300 mg cholesterol/d) to a diet lower in fat and cholesterol (American Heart Association phase 2 diet: 30% fat, P/S ratio of 1, 150 to 200 mg cholesterol/d) and maintained that diet for 20 weeks, their plasma cholesterol levels decreased by approximately 6% after 4 weeks and remained at that level until study termination. Likewise, VIIc decreased by approximately 11% while factor VII antigen, total factor VII activity, and fibrinogen concentration did not change appreciably from baseline values. Our results show that premenopausal women benefit from a diet lower in total and saturated fat by a reduction in blood cholesterol and VIIc. Extrapolation from data on men in the Northwick Park Heart Study indicates that the 11% decrease in VIIc activity would correspond to an approximately 30% decrease in risk of mortality from coronary heart disease.

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus

We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. Twenty-five women with uncomplicated insulin-dependent diabetes mellitus, allocated to treatment with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene (treatment group, n = 12) or with nonhormonal contraception (control group, n = 13), were prospectively followed up for 12 months. Nonparametric methods were used for statistical evaluation. No statistical differences in the biochemical risk markers were noted between the two groups at the start of the study. In the treatment group serum levels of low-density lipoprotein cholesterol decreased, whereas the concentrations of total cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides were unchanged. Within the coagulation system factor VII coagulant activity increased, while fibrinogen levels were unchanged. In the fibrinolytic system we found unchanged activities but decreased antigen concentrations of tissue plasminogen activator and plasminogen activator inhibitor. The concentration of von Willebrand factor increased, but no change in albumin excretion rates were found. In the control group no changes in any of the variables were observed. Intake of modern oral contraceptives does not deteriorate the cardiovascular risk profile in women with insulin-dependent diabetes mellitus, but our study indicates a risk of disturbances of the endothelial integrity, which needs further investigation.

Low-fat, high-fiber diet favorably affects several independent risk markers of ischemic heart disease: observations on blood lipids, coagulation, and fibrinolysis from a trial of middle-aged Danes

We served a low-fat (28% of energy), high-fiber (3.3 g/MJ) diet according to Nordic nutrition recommendations (Rec diet), and a high-fat diet (39% of energy) corresponding to the average Danish diet (Dane diet) for periods of 2 wk in a randomized crossover study of 21 healthy middle-aged individuals. The Rec diet resulted in lower serum concentrations of low-density-lipoprotein (LDL) cholesterol (medians: 2.77 vs 3.04 mmol/L, P < 0.001) and high-density-lipoprotein (HDL) cholesterol (1.08 vs 1.24 mmol/L, P < 0.001), and higher fasting triglycerides (1.11 vs 0.86 mmol/L, P = 0.04) than did the Dane diet. Furthermore, the Rec diet lowered plasma factor VII coagulant activity (FVIIc) (88% vs 96%, P = 0.002) and raised plasma fibrinolytic activity. Our observations indicate that a low-fat, high-fiber diet may not only reduce the atherogenic but also the thrombogenic tendency of an individual compared with a diet corresponding to the average Danish diet.

Fat high in stearic acid favorably affects blood lipids and factor VII coagulant activity in comparison with fats high in palmitic acid or high in myristic and lauric acids

The effect of fats high in individual, prevalent saturated dietary fatty acids on lipoproteins and hemostatic variables in young healthy subjects was evaluated in a randomized strictly controlled metabolic feeding study. Three experimental diets: shea butter (S; 42% stearic acid), palm oil (P; 43% palmitic palmitic acid), and palm-kernel oil with high-oleic sunflower oil (ML; 10% myristic acid, 30% lauric acid) were served to 15 men for 3 wk each, separated by washout periods. Diet S compared with diet P resulted in significant reduction in plasma cholesterol (22%) LDL cholesterol (26%), apolipoprotein B (18%), HDL cholesterol (12%), apolipoprotein A-I (13%), and a 13% lower factor VII coagulant activity (P = 0.001). Similar differences were observed between diets S and ML. In conclusion, intake of shea butter high in stearic acid favorably affects blood lipids and factor VII coagulant activity in young men, compared with fats high in saturated fatty acids with 12-16 carbons.

Factor VII-Deficient Substrate Plasmas Depleted of Protein C Raise the Sensitivity of the Factor VII Bio-Assay to Activated Factor VII: an International Study

Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.

Non-Fasting Factor VII Coagulant Activity (FVII:C) Increased by High-Fat Diet

Preliminary observations have suggested that non-fasting factor VII coagulant activity (FVII:C) may be related to the dietary fat content. To confirm this, we performed a randomised cross-over study. Seventeen young volunteers were served 2 controlled isoenergetic diets differing in fat content (20% or 50% of energy). The 2 diets were served on 2 consecutive days. Blood samples were collected at 8.00 h, 16.30 h and 19.30 h, and analysed for triglycerides, FVII coagulant activity using human (FVII:C) or bovine thromboplastin (FVII:Bt), and FVII amidolytic activity (FVII:Am). The ratio FVII:Bt/FVII:Am (a measure of FVII activation) increased from fasting levels on both diets, but most markedly on the high-fat diet. In contrast, FVII:Am (a measure of FVII protein) tended to decrease from fasting levels on both diets. FVII:C rose from fasting levels on the high-fat diet, but not on the low-fat diet. The findings suggest that high-fat diets increase non-fasting FVII:C, and consequently may be associated with increased risk of thrombosis.

Elevated Levels of Factor VII Activity in the Postprandial State: Effect of the Factor VII Arg-GIn Polymorphism

A genetic polymorphism (Arg/Gln353) of coagulation factor VII was recently identified and shown to be associated with differences in basal factor VII coagulant activity. Postprandial lipaemia seems to exert an acute but evanescent effect on the activity of factor VII, and the influence of the Arg/Gln353 polymorphism on factor VII activation during postprandial lipaemia was therefore studied in male post-infarction patients [age 48.8 +/- 3.3 years (mean +/- SD)] with Arg/Arg (n = 23) and Arg/Gln (n = 8) genotypes. Factor VII antigen (VIIag) and activity along with plasma lipoproteins were determined before and after intake of a mixed meal-type of oral fat load. Patients with the Arg/Gln genotype had basal VIIag and activated factor VII (VIIa) levels 75% and 48%, respectively, of those of patients homozygous for the Arg allele. In absolute terms, VIIa increased more in homozygotes for the Arg allele (delta 0-6 h VIIa 1.76 +/- 1.48 ng/ml) than in heterozygotes (0.60 +/- 0.27 ng/ml) in response to fat intake, but the percentage increase in VIIa molecules did not differ significantly between subjects with Arg/Arg and Arg/Gln genotypes (37 +/- 32% versus 27 +/- 15%). This suggests that the influence of the Arg/Gln polymorphism on factor VII activity is mainly accounted for by differences in the basal factor VII protein level between genotypes. Since most of our lives are spent in the postprandial state, possession of the factor VII-Gln353 allele is likely to confer protection against coronary heart disease by reducing the amount of VIIa produced in response to fat intake.

The activation of factor VII in citrated plasma by charged long-chain saturated fatty acids at the interface of large triglyceride-rich lipoproteins

The prolonged incubation of dilute plasma on ice in the presence of added sulphatide vesicles or the long-chain saturated fatty acids (FA) stearic acid (C18:0) or behenic acid (C22:0) induced a concentration-dependent increase in factor VII coagulant activity (VIIc). The addition of FA at various ratios to human serum albumin showed the micellar non-bound pool to be responsible for this effect, FA bound to the high-affinity or low-affinity binding sites of albumin having no influence on VIIc. Plasma VIIc also increased following addition of behenate-enriched lipoprotein particles produced by incubation of the d < 1.006 g/ml lipoprotein fraction with this FA, or addition of lipoprotein remnants produced by pre-incubation of the d < 1.006 g/ml fraction with lipoprotein lipase. Long-chain saturated fatty acids in the interface of lipoprotein remnants, produced by the interaction of triglyceride-rich lipoprotein particles with lipoprotein lipase, appear to provide a surface that activates the contact system of coagulation and subsequently factor VII.

Nicotine effects on eicosanoid formation and hemostatic function: Comparison of transdermal nicotine and cigarette smoking

Objectives. The purpose of this study was to examine the possible role of nicotine in enhancing coagulation and to assess the potential cardiovascular toxicity of transdermal nicotine therapy for smoking cessation.Background. Cigarette smoking increases the risks of acute coronary events. A likely contributing mechanism is activation of coagulation. The role of nicotine in enhancing coagulability has not been resolved.Methods. We compared in a crossover study the effects of cigarette smoking, transdermal nicotine and placebo transdermal nicotine, each for 5 days, in 12 healthy smokers.Results. Cigarette smoking increased the urinary excretion of 11-dehydro-thromboxane B2(reflecting thromboxane A2generation) and increased plasma concentration of the platelet alphagranule constituents, platelet factor 4 and beta-thromboglobulin, compared with placebo treatment, indicating in vivo platelet activation. Cigarette smoking was also associated with higher levels of fibrinogen in plasma. Transdermal nicotine produced plasma levels of nicotine in the same range as those during smoking but had no effect on thromboxane A2metabolite excretion, platelet alpha-granule release or plasma fibrinogen, compared with placebo. Excretion of 2,3-dinor-6-keto-PGF1α(reflecting prostacyclin generation) was not significantly influenced by any treatment. These results suggest that nicotine as such is not responsible for the platelet activation or elevation of plasma fibrinogen seen in smokers. However, we cannot exclude the possibility that intermittent bolus-like dosing of nicotine from cigarettes could have different effects from those produced by continually released transdermal nicotine. Other findings were that cigarette smoking and transdermal nicotine treatment were both associated with a higher white blood cell count compared with the placebo patch condition, suggesting a direct effect of nicotine to increase circulating white cells. Factor VII coagulant activity (VIIc) was significantly lower during cigarette smoking, than during either nicotine or placebo patch conditions.Conclusions. Transdermal nicotine has less effect on platelet activation and catecholamine release than does cigarette smoking, and its use in smoking cessation treatment of patients with coronary heart disease is likely to be safer than cigarette smoking.

Low‐dose warfarin decreases coagulability without affecting prothrombin complex activity

To assess the efficacy of a fixed, low dose of warfarin in lowering factor VII coagulant activity (FVII:C) and to investigate the effects on the plasma coagulation cascade. An open pilot study with two dose levels of warfarin: 1.25 and 2.5 mg day-1 during two consecutive 4-week periods. All subjects received aspirin 75 mg day-1. Prothrombin fragment 1 + 2 (F(1 + 2)), protein C, protein S, FVII:C, factor X and P-prothrombin complex activity (P-PT) were measured at baseline, at 2-week intervals and 4 weeks after end of treatment. Coagulation activation peptide F(1 + 2) was used as a marker of thrombin formation. Twelve male patients with a history of myocardial infarction. Inclusion was made through a written questionnaire. Warfarin 1.25 mg day-1 lowered FVII:C from 113 U dl-1 to 107 U dl-1 (P = 0.025) and F(1 + 2) from 1.60 nmol l-1 to 1.27 nmol l-1 (P = 0.013) but had no effect on protein C or P-PT. A dose of 2.5 mg day-1 induced further lowering of FVII:C (91 U dl-1, P = 0.0042), and also of protein C from 116% to 99% (P = 0.034) and P-PT from 107% to 81% (P = 0.0096) mean values. Warfarin 1.25 mg day-1 seems to exert an anticoagulant effect without reduction in PT or the natural anticoagulant protein C and is suggested, in combination with aspirin, to be a safe and simple therapy against arterial thrombotic disease, making regular PT controls unnecessary.

Factor VII activation and oral contraceptives

The relation between oral contraceptive (OC) use and changes in factor VII activation using standard factor VII clotting test and enzyme-linked immunosorbent assay (ELISA) for the quantification of antigen factor VII (factor YIIag) in view of the increased risk of thromboembolism in OC users was studied. 30 healthy women using OC and 30 women matched for age and smoking status were recruited from a health check-up center in Paris. The combined OC contained 50 mcg of ethinyl estradiol with any progestogen. Controls had not taken any hormonal therapy for the 2 previous months. The mean duration of OC use was 50 months with a range of 6-204 months. Fasting venous blood (9 volumes) was collected during the menstrual cycle into siliconized vacutainer tubes containing 3.2% trisodium citrate (1 volume). Factor VIIc was assayed using a human factor VII-deficient plasma. Factor VIIag was measured by ELISA using a commercial kit (Diagnostic Stago, France). The activity of factor VII was assessed by calculating the ratio of factor VIIc to factor VIIag. Serum cholesterol and triglyceride concentrations were determined by enzymatic methods using automated procedure and reagents from Boehringer Mannheim. There was a significant difference between the 2 groups only in serum triglyceride concentrations. There was a positive correlation between factor VIIc and factor VIIag in both controls and OC users (r = 0.71 and 0.87, respectively; p 0.0001). Both factor VIIc and factor VIIag levels were positively associated with serum triglyceride concentrations (correlation coefficients ranged from 0.26 (p 0.10) to 0.46 (p 0.05) with the 2 groups). Mean levels of factor VIIc and factor VIIag were significantly higher in OC users than in controls (about 17% and 21%, respectively). The ratio of factor VIIc and factor VIIag was not significantly higher in OC users than in controls. The raised factor VII coagulant activity in OC users failed to provide evidence of an enhanced activation of factor VII relative to OCs.

The relationship between factor VII coagulant activity and factor XII activation induced in plasma by endogenous or exogenously added contact surface

The contribution of various enzymes in the activation of factor VII, determined from the increase in factor VII coagulant activity (VIIc), was investigated following the exposure of citrated plasma to low temperature. The contact system of coagulation was initiated either by the contact surface present in certain plasmas (i.e. plasma from women in late pregnancy) or by micellar stearate added to plasma diluted with an equal volume of buffer (plasma from normal healthy subjects or from women in late pregnancy). With either of the contact surfaces, increase of VIIc and the concentration of enzymes derived from factor XII (XIIa) depended on the potency of the contact surface. The stearate-induced VIIc in diluted plasmas from women in late pregnancy or from normal subjects was inhibited by 60-70% in the presence of anti-factor IX monoclonal antibody. VIIc was not increased in XII-deficient plasma following the addition of stearate. The addition of purified human factor XII to this plasma restored the increase in VIIc and the activation of factor XII. In factor IX-deficient plasma, the stearate-induced increase in VIIc was only 38% of that seen in normal plasma and was restored by the addition of purified factor IX. Similarly in factor XI-deficient plasma, the stearate-induced increase in VIIc and the factor XII activation were 48% and 69% of that found in normal plasma. The addition of EDTA (2 mM) did not alter the extent of factor XII activation induced by contact surface, but it did inhibit the rise in VIIc. It is concluded that in the presence of contact surface the activation of factor XII and the sequential activation of factor XI and of factor IX results in the activation of factor VII. Activated factor IX is responsible for the major part of the factor VII activation whereas the rest may be through the direct activation by XIIa.

Favorable long-term effect of a low-fat/high-fiber diet on human blood coagulation and fibrinolysis.

In an 8-month strictly controlled dietary study of 16 healthy young men, the long-term effect of a low-fat (26% of energy) high-fiber (4.5 g/MJ) diet on cardiovascular risk markers of the hemostatic system was assessed. Fasting blood sampling was performed during a 4-week baseline period and then monthly during the intervention. A matched control group of 16 men on habitual diets was also monitored. Median fibrinolytic activity of tissue-type plasminogen activator (t-PA) in plasma was significantly elevated (twofold to fourfold) by the experimental diet. A significant increase in the systemic fibrinolytic activity of the euglobulin fraction of plasma was also observed. Median plasma factor VII coagulant activity (F VIIc) was depressed by 5-10% during the first 2 months and the last month of the study period. The dietary change did not significantly affect plasma levels of fibrinogen, t-PA antigen, or plasminogen activator inhibitor type I antigen. In conclusion, young men who were switched from a typical Danish diet high in saturated fat to a low-fat/high-fiber diet showed a permanent increase in plasma fibrinolytic activity and a biphasic decrease in F VIIc. The dietary change thus had a favorable effect on cardiovascular risk markers of the hemostatic system.

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.

Positive Association Between Self-Reported Fatty Food Consumption and Factor VII Coagulant Activity, a Risk Factor for Coronary Heart Disease, in 4246 Middle-Aged Men

Raised levels of factor VII coagulant activity (VIIc) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIc. We explored this further in 4,246 men aged 45-69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month. In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIc was 7.8% of standard (95% CI 5.1-10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIc, serum cholesterol and BMI. Thus, the VIIc difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level. This study adds to the evidence that dietary fat intake influences VIIc and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.