Plasma Factor VII Coagulant Activity Research Articles

The genetic variation rs6903956 in the novel androgen-dependent tissue factor pathway inhibitor regulating protein (ADTRP) gene is not associated with levels of plasma coagulation factors in the Singaporean Chinese

BackgroundGenome-wide association study (GWAS) has reported that rs6903956 within the first intron of androgen-dependent tissue factor pathway inhibitor (TFPI) regulating protein (ADTRP) gene is associated with coronary artery disease (CAD) risk in the Chinese population. Although ADTRP is believed to be involved in the upregulation of TFPI, the underlying mechanism involved is largely unknown. This study investigated the association of rs6903956 with plasma Factor VII coagulant activity (FVIIc) and fibrinogen levels, which are regulated by TFPI and are independent risk predictors for CAD.MethodsWe conducted the analysis in both Chinese adult (N = 309) and neonatal cohorts (N = 447). The genotypes of the rs6903956 single nucleotide polymorphism (SNP) were determined by the polymerase chain reaction restriction fragment length polymorphism method (PCR–RFLP). FVIIc and fibrinogen level were measured from citrated plasma. The association between rs6903956 and coagulation factors was tested by linear regression with adjustment for possible confounders. Analysis was carried out in adults and neonates separately.ResultsNo significant association was observed between rs6903956 and plasma FVIIc nor fibrinogen levels with adjustment for age, gender, body mass index (BMI) and cigarette smoking in adults (P for FVIIc = 0.464; P for fibrinogen = 0.349). The SNP was also not associated with these two coagulation factors in the neonates (P for FVIIc = 0.579; P for fibrinogen = 0.359) after adjusting for gestational age, gender and birth weight.ConclusionsSNP rs6903956 on ADTRP gene was not associated with plasma FVIIc nor fibrinogen levels.

Tissue Factor, Tissue Factor Pathway Inhibitor and Factor VII Activity in Cardiovascular Complicated Type 2 Diabetes Mellitus

Tissue factor (TF) is the main initiator of the extrinsic coagulation pathway through factor VII (FVII) activation, which is physiologically inhibited by tissue factor pathway inhibitor (TFPI). Alteration of this pathway has been described in Type 2 diabetes mellitus (T2DM). The aim of this study is to assess TF and TFPI plasma levels and FVII coagulant activity (FVIIa) in T2DM in relation to cardiothrombotic disease and their correlation to metabolic and clinical behavior of the patients. The study was conducted on 80 T2DM patients divided to accordingly; groupI: 40 patients without a history or clinically detected heart disease, and groupII: 40 patients with a history of myocardial infarction compared to 30 controls. The patients were recruited from Ain Shams University diabetes clinic from September 2007 to February 2009 after informed consent was obtained. Peripheral blood samples were taken for measurement of plasma TF and TFPI levels using ELISA technique and quantitative FVIIa using FVII deficient plasma. Plasma levels of TF, TFPI and FVIIa were significantly higher in T2DM patients compared to the controls (p<0.001). TF (236.50±79.23)and TFPI (242.33±85.84)were significantly higher in group II, compared to group I (150.33±81.16), (152.8± 82.46), (p<0.001). TF and TFPI were significantly correlated to body mass index and glycemic control. Also, TF and TFPI were significantly higher in hypertensives (p=0.001) and dyslipidemics (p=0.006) but not in smokers (p=0.64), (p=0.11) respectively. There was a correlation between high TF, TFPI plasma levels, FVIIa activity and cardiothrombotic complications in T2DM especially in the presence of high risk factors such as poor glycemic control, dyslipidemia and obesity. Future target therapy against TF may be beneficial for T2DM patients.

Genotype-phenotype relationship of F7 R353Q polymorphism and plasma factor VII coagulant activity in Asian Indian families predisposed to coronary artery disease

Elevated factor VII (FVII) level is a risk factor for coronary artery disease (CAD). We investigated the role of R353Q polymorphism in the F7 gene in 139 Indian families with CAD, comprising of 222 affected subjects, 105 unaffected subjects and 126 affected sibling pairs. Plasma per cent FVIIc activity (FVII.c activity) differed ignificantly across R353Q genotype (P < 0.0001). Frequency of subjects with RR and QQ genotypes were higher in 4th quartile and 1st quartile of FVII.c activity, respectively (P < 0.0001). F7 R353Q SNP was able to explain up to 7% of variation in FVII.c activity by regression analysis and an additive genetic component of variance of 28.04% by heritability analysis. Quantitative trait loci analysis showed suggestive linkage evidence of F7 SNP with per cent FVII.c activity (LOD score -1.82; P = 0.002). Individuals with RR and RQ genotypes carried an OR of 2.071 (95% c.i. = 1.506-2.850) and 2.472 (95% c.i. = 1.679-3.641), espectively, towards CAD risk. There was significant correlation of FVII.c activity with lipid markers, particularly among those with RR and RQ genotype after covariate adjustment. In conclusion, the F7 R353Q SNP appears to moderately influence plasma FVII.c activity and risk of CAD in Indians.

Factor VII, blood lipids and fat intake: gene–nutrient interaction and risk of coronary heart disease with the factor VII R353Q polymorphism

The relation between dietary fat, blood lipids, plasma factor VII coagulant activity (FVIIc) and risk of coronary heart disease (CHD) according to the R353Q polymorphism in the factor VII gene was assessed. Cross-sectional study of 15,073 individuals participating in the European Prospective Investigation of Cancer (EPIC) Norfolk, 7433 of which had FVIIc available. Nested case-control study of 985 CHD cases and 2009 matched controls. FVIIc was significantly associated with total fat intake in females, especially in the RR homozygotes (standardized beta=0.24; 95% confidence interval (95% CI) 0.08-0.40; P<0.01), but there were no associations with intakes of saturated, monounsaturated or polyunsaturated fatty acids according to genotype and no associations in males. FVIIc was significantly positively associated with total cholesterol (P<0.01) and with triacylglycerol (P<0.001) in both genders, with an interaction according to genotype for triacylglycerol in males: beta Q allele carriers 0.26 (95% CI 0.18-0.34), beta RR homozygotes 0.16 (95% CI 0.12-0.20) (Z interaction=-2.24; P<0.05). There was no effect of genotype on the odds ratio (OR) for incident CHD: OR 0.89 for Q allele carriers compared with RR homozygotes (95% CI 0.77-1.02) in 985 cases and 2009 matched controls. These results show a strong association between dietary fat intake and FVIIc in women, and between serum triacylglycerol and cholesterol and FVIIc levels in both genders. The R353Q genotype only marginally affected modulation of FVIIc by dietary fat. The association between triacylglycerol and FVIIc was significantly stronger in males carrying the Q allele than in those with the RR genotype.

Coagulation factors, activation markers and risk of coronary heart disease: the Northwick Park Heart Studies.

Coagulation factors, activation markers and risk of coronary heart disease: the Northwick Park Heart Studies.

Influence of stearic acid on hemostatic risk factors in humans

Stearic acid has been claimed to be prothrombotic. Elevated plasma factor VII coagulant activity (FVIIc) may raise the risk of coronary thrombosis in the event of plaque rupture. Fibrinogen, an acute-phase protein, is necessary for normal blood clotting; however, elevated levels of fibrinogen increase the risk of coronary heart disease (CHD). Here I report the results of three controlled, human dietary intervention studies, which used a randomized crossover design to investigate the hemostatic effects of stearic acid-rich test diets in healthy young men. A diet high in stearic acid (shea butter) resulted in a 13% lower fasting plasma FVIIc than a high palmitic acid diet, and was 18% lower than a diet high in myristic and lauric acids (P = 0.001) after 3 wk of intervention. The stearic acid-rich test fat increased plasma fibrinogen concentrations slightly compared with the myristic-lauric acid diet (P < 0.01). When investigating the acute effects of fatty meals, those high in stearic acid (synthesized test fat) resulted in a smaller postprandial increase in FVII than those high in trans and oleic FA, indicating a smaller increase in activated FVII after ingesting stearic acid compared with fats high in monounsaturated FA, probably caused by lower postprandial lipemia. Thus, the present investigations did not find dietary stearic acid to be more thrombogenic, in either fasting effects compared with other long-chain FA, or in acute effects compared with dietary unsaturated FA, including trans monounsaturated FA. The slightly increased effect on fasting plasma fibrinogen may be biologically insignificant, but it should be investigated further.

Prevalence in a Tunisian Arabic population of factor VII DNA variants and relation to factor VII plasma levels

Background A raised plasma factor VII (FVII) level is a risk factor for coronary heart disease. DNA variants have been described to be associated with alteration in FVII levels. The prevalence of FVII polymorphisms is unknown in the Tunisian Arab population. Methods In a group of 240 healthy Tunisians, we examined the relationship between levels of FVII coagulant activity (FVIIc) and two polymorphisms in the FVII gene. One polymorphism alters arginine at position 353 to glutamine (R/Q) and the other is a 10 base pair insertion (0/10 bp). Results The FVII distribution was in accordance with the Hardy-Weinberg equilibrium. The allele frequencies of Q and 10 bp were 0.212 and 0.235, respectively. There were significant differences in these allelic frequencies between Tunisian and other populations ( p<0.001). We observed lower FVIIc levels among subjects with the Q allele compared to RR subjects (RR: 98.17%, RQ/QQ: 57.41%, p<0.0001). For the 0/10 polymorphism, no statistically difference was observed. Conclusion The prevalence of the Q allele which was found to be associated with lower plasma FVIIc levels is high in Tunisian population. Further analyses should yield information on the protective role of carrying the Q allele for coronary heart disease.

Effects of prior moderate exercise on exogenous and endogenous lipid metabolism and plasma factor VII activity

Moderate exercise reduces postprandial triacylglycerol concentrations, which are a risk marker for coronary heart disease. The present study sought to determine the qualitative nature of exercise-induced changes in lipid metabolism and their association (if any) with changes in factor VII activation. Eleven normotriglyceridaemic men, aged 51.7+/-6.1 years (mean+/-S.D.), participated in two oral fat tolerance tests after different pre-conditions: control (no exercise), and exercise (90 min of brisk walking the day before). Venous blood samples were obtained in the fasted state and for 8 h after ingestion of a high-fat meal (1.32 g of fat, 1.36 g of carbohydrate, 0.30 g of protein and 10 mg of [1,1,1-(13)C] tripalmitin x kg(-1) body mass). Prior exercise reduced postprandial plasma triacylglycerol concentrations by 25+/-3% (mean+/-S.E.M.), with lower concentrations in the Svedberg flotation rate (Sf) 20--400 (very-low-density lipoprotein) fraction accounting for 79+/-10% of this reduction. There was no effect on plasma factor VII coagulant activity or on the concentration of the active form of factor VIIa. Prior exercise increased postprandial serum 3-hydroxybutyrate and plasma fatty acid concentrations, decreased serum postprandial insulin concentrations and increased exogenous (8 h (13)C breath excretion of 15.1+/-0.9% of ingested dose compared with 11.9+/-0.8%; P=0.00001) and endogenous postprandial fat oxidation. These data raise the possibility that reduced hepatic secretion of very-low-density lipoprotein plays a role in the attenuation of plasma triacylglycerol concentrations seen after exercise, although it is possible that increased triacylglycerol clearance also contributes to this effect.

The effects of structurally defined triglycerides of differing fatty acid composition on postprandial haemostasis in young, healthy men

The aim of this study was to investigate whether a number of key haemostatic factors were altered when healthy young individuals were challenged with a fat load of physiological size contained within a meal composed of normal ingredients and whether this response was modified when the fatty acid composition of the meal was altered radically. Eight healthy male volunteers each randomly consumed four meals which were identical in terms of gross nutritional content (41% of energy provided as fat, 17% as protein and 42% as carbohydrate) but which differed in fatty acid composition. To reduce the possible influence of fatty acid position within the triglyceride molecule on lipid absorption and subsequent metabolic effects, the structural integrity of 91% of fat (test triglycerides such as 1,3 distearoyl-2-oleoyl glycerol (S-O-S), trioleine (O-O-O), and 1,3 dilinoleoyl-2-oleoyl glycerol, (L-O-L)) in the meals was controlled so that the principal fatty acid in the sn-2 position was oleic acid (18:1n-9). Meals rich in either a test triglyceride or a control oil provided 44±6 g of fat. No significant alterations from fasted values of elevated plasma factor VII coagulant activity (FVII c) or F 1+2 were observed. FVII a varied significantly over the postprandial time course; however, when expressed as a percentage of the fasting value, the FVII a responses to O-O-O and L-O-L differed significantly but this was not evident when the absolute values were analysed. Similarly, no difference in plasma fibrinopeptide A (FPA) concentrations were evident. After all four meals, chylomicron contained proportionately more palmitic acid and generally less oleic acid than the ingested lipids. This study clearly demonstrates that postprandial haemostatic responses of young healthy individuals to a physiological fat load are minimal, (irrespective of triglyceride structure).

Weight-Loss Induced Changes in Plasma Factor VII Coagulant Activity and Relation to the Factor VII Arg/Gln353 Polymorphism in Moderately Obese Adults

Elevated plasma factor VII coagulant activity (factor VIIc) may be an independent risk factor for coronary heart disease. Several cross-sectional studies suggest that a polymorphism of the factor VII gene (Arg-Gln353) interacts with plasma triglyceride level in determining factor VIIc, but prospective data are lacking. Factor VII genotype, factor VIIc, and triglyceride level were measured in moderately obese adults aged 25 to 45 who underwent a six-month clinical trial to evaluate strategies for weight loss. A total of 48 men and 50 women who experienced substantial weight loss (mean: 10 kg) provided samples for genetic analysis. Overall, 78% of participants were homozygous for the Arg353 allele, while the remaining 22% were heterozygous (Arg/Gln353). At the baseline examination, heterozygotes had lower mean factor VIIc than Arg353 homozygotes (92% vs. 112%; p<0.001), and genotype explained 18% of the variance of factor VIIc. Average six-month weight loss was similar in both genotypes; mean reductions in factor VIIc following weight loss were greatest among Arg353 homozygotes with high initial values (> 120%). Cross-sectional and longitudinal associations between plasma factor VIIc and triglyceride level were not dependent on genotype. These data confirm that the Gln353 allele is associated with lower factor VII coagulant activity in moderately obese adults, but they do not support the hypothesis that the Arg-Gln353 polymorphism interacts with plasma triglyceride level in determining factor VIIc.

Factor VII Polymorphisms in Populations With Different Risks of Cardiovascular Disease

Increased plasma factor VII coagulant activity (FVII:C) has been associated with the risk of ischemic heart disease (IHD). Differences in plasma FVII:C among individuals are associated with three common polymorphisms in the FVII gene. Therefore, we investigated FVII polymorphisms in four populations that differ in their risk of developing cardiovascular disease, namely, Europeans, Greenland Inuit, Gujarati Indians, and Afrocaribbeans. We studied (1) the promoter polymorphism, which is the result of a decanucleotide insertion in the FVII promoter at position -323 from the start of translation; (2) the hypervariable region 4 polymorphism (HVR4), which is the result of a variable number of tandem repeats in intron 7; and (3) the RQ353 polymorphism, a guanine-to-adenine substitution in the position of the codon for amino acid 353 resulting in an amino acid replacement of arginine (R) by glutamine (Q) in the FVII protein. The frequencies of these three polymorphisms and their linkage disequilibrium were different in the four populations studied. The frequencies of the alleles associated with higher plasma FVII:C were lower in the Europeans than in the Inuit, a population with a lower incidence of IHD. There was an association between both the promoter polymorphism and the RQ353 polymorphism and the plasma FVII:C in the Europeans, the Inuit, and the Gujarati Indians, and an association only between the RQ353 polymorphism and plasma FVII:C in the Afrocaribbeans. Only in the Inuit was the HVR4 polymorphism associated with plasma FVII:C. In multiple regression analysis, the additional information provided by the promoter polymorphism when the other polymorphisms were already included in the model was the most pronounced, suggesting that the promoter polymorphism may be the functional mutation having the greatest effect on determining plasma FVII:C.

Diet, gender, and plasma thrombomodulin

We reported earlier about the lowering of serum total cholesterol, systolic blood pressure, and plasma factor VII coagulant activity (FVIIc), and the increase in plasma tissue-plasminogen activator (t-PA) activity in young volunteers consuming a strictly controlled low-fat/high-fiber diet for a period of 8 months (9, 10). These observations suggest that the experimental diet had anti-atherogenic and anti-thrombogenic properties. The reduced FVIIc and raised t-PA activity might reflect a dietary mediated reduction in the extent of endothelial cell damage. Such an effect would namely be expected to be associated with less intimal tissue factor expression (and thus to less subsequent FVII activation), and to less endothelial plasminogen activator inhibitor (PAI) secretion (and thus higher t-PA actvity). We were unable to detect any changes in plasma PA1 concentrations in the actual study, however (10). This might be due to the very large intraindividual variance of PA1 (11). TM may be a more sensitive and specific marker of endothelial cell damage. To further elucidate whether the experimental diet affected the extent of endothelial cell damage, we made a post-hoc estimation of plasma TM concentrations in participants of the study. In addition, we describe observations of TM in relation to gender and other hemostatic variables.

Effects of balloon injury on systemic plasma factor VII coagulant activity and intimal hyperplasia in the rabbit

Effects of balloon injury on systemic plasma factor VII coagulant activity and intimal hyperplasia in the rabbit

Effects of Balloon Injury on Systemic Plasma Factor Vii Coagulant Activity and Intimal Hyperplasia in the Rabbit

Effects of Balloon Injury on Systemic Plasma Factor Vii Coagulant Activity and Intimal Hyperplasia in the Rabbit

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.

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.

A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals.

We have identified a genetic polymorphism of factor VII that is strongly associated with plasma factor VII coagulant activity (factor VIIc) in healthy individuals from the United Kingdom. This polymorphism was detected after Msp I digestion of polymerase chain reaction-amplified genomic DNA. In a sample of 284 men, the frequency of the M2 allele (loss of cutting site) is 0.1, and individuals with the M1M2 genotype have factor VIIc levels 22% below the sample mean (p less than 0.0001). Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. The base change that gives rise to the Msp I polymorphism is a G-to-A substitution in the codon for amino acid 353, leading to replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele (designated Gln 353). Three individuals homozygous for the M2 allele have both low factor VIIc and low factor VII protein concentrations. The conformation of the Gln 353 molecule may be different from that of the Arg 353 protein, affecting its intracellular processing, secretion, turnover in plasma, or activity. In view of its association with lower factor VIIc levels, possession of the M2 allele may confer protection against thrombosis and myocardial infarction.

Atherosclerosis and coronary bypass surgery in hereditary factor VII deficiency

A 66-year-old man with homozygous deficiency of factor VII (less activity than 4 percent of normal) had a minimal hemorrhagic tendency and severe coronary atherosclerosis, and underwent aortocoronary saphenous vein bypass surgery. Although plasma factor VII coagulant activity and cross-reacting material were markedly reduced, comparable amounts of factor VII antigen were detected in peripheral blood mononuclear cells of both the patient and of a normal subject by Western blotting techniques. Accelerated coagulation was observed following brief exposure of the patient's phytohemagglutinin-stimulated peripheral blood mononuclear cells to low concentrations of ambient factor VII in vitro. Evidence indicates that factor VII plays a role in vivo in both hemostasis and atherogenesis and it might be assumed that factor VII deficiency would both predispose to excessive bleeding and forestall atherosclerosis. However, these observations suggest that factor VII-mediated thrombin generation may proceed by partitioning of small amounts of factor VII on tissue factor-expressing cells and that factor VII contained within monocytes may facilitate tissue factor-induced coagulation by these cells. These features may provide efficient coagulation activation despite a deficiency of the plasma coagulant protein. The current results may explain, at least in part, the minimal bleeding tendency, and also the occurrence of thrombosis and atherosclerosis in certain persons with factor VII deficiency.

Association between dietary fat intake and plasma factor VII coagulant activity — A predictor of cardiovascular mortality

Repeated measurements were made in 8 adults factor VII coagulant activity (VII c) and fibrinogen concentration (two haemostatic variables associated with cardiovascular mortality), together with factor VII concentration, factor X, prothrombin, and serum cholesterol and triglyceride concentrations, while the usual diet was recorded by precise weighing over 12–14 days. In 6 subjects measurements were continued while low-fat and high-fat diets were taken for a further 2 and 3 weeks respectively. Plasma VII c was related positively and independently to fat and protein intake, whereas factor VII concentration was associated only with protein consumption. In a second study, consumption of 50% extra energy for one day increased VII c significantly when taken mainly as fat but not when taken mostly as carbohydrate. The character of the VII c response to fat intake suggested an association with post-prandial lipaemia. A high d fat intake may lead not only to coronary atheroma but also to fibrin deposition and thrombus formation through direct activation of the coagulation system.