Factor VIIc Research Articles

Association of factor VII genotype with plasma factor VII activity and antigen levels in healthy Indian adults and interaction with triglycerides.

Plasma factor VII activity (factor VIIc) is one of the independent risk factors for coronary artery disease and is controlled by both genetic and environmental factors. Several studies in healthy Caucasian subjects have revealed an association of a common genetic polymorphism at residue 353 (Arg-->Gln) of the factor VII gene with plasma factor VIIc. We have investigated the influence of this polymorphism (factor VII Arg/Gln353) on fasting plasma factor VIIc and antigen (factor VIIag) levels and its interaction with triglyceride levels in 185 healthy Dravidian Indians of both sexes (128 men, 57 women). The frequency of Gln353 has been found to be significantly higher in Dravidian Indians (0.29; confidence interval, 0.27 to 0.30) than in Caucasians (0.10). The distribution of factor VII Arg/Gln353 genotypes was at Hardy-Weinberg equilibrium. The carriers of the Gln353 allele had significantly lower plasma factor VIIc and factor VIIag in men (P < .05). The factor VII Arg/Gln353 polymorphism explained 13% and 11% of the total variance of plasma factor VIIc and factor VIIag, respectively, in men (P < .001) and 6% and 9% in women (P > .1). The genotype-specific correlation of factor VIIc and factor VIIag with triglyceride levels was stronger in carriers of the Gln353 allele (r = .38 and .41; P < .001) than in Arg353 homozygotes (r = .09 and .27; P = .19 and .005, respectively).

African-American factor VII-deficient variants in Georgia (FVII variants).

We studied African-American Factor (FVII)-deficient variants and carriers in Georgia by measuring their levels of FVII antigen (FVIIAG) and FVII procoagulant (FVIIC). Factor VIIAG was determined using enzyme-linked immunoassay (ELISA), whereas FVIIC was measured in two ways: 1) by fibrin clotting methods that employed human recombinant (HRFVIIC), human placental (HPFVIIC), rabbit brain (RBFVIIC), and bovine brain (BBFVIIC) thromboplastins; and 2) by an amidolytic method (AMFVIIC). Prothrombin time tests (PT) were also performed by standard methods. These 4 FVII-deficient patients and 3 carriers demonstrated the following results: PT: 18.2 +/- 6.5 sec; FVIIAG: 73.0 +/- 14.9%; HRFVIIC: 30.6 +/- 20.3%; HPFVIIC: 30.5 +/- 21.4%; RBFVIIC: 25.3 +/- 21.4%; BBFVIIC: 30.6 +/- 17.5%; AMFVIIC: 44.1 +/- 18.3%. We conclude that a group of clinically mild African-American FVII-deficient variants exists in Georgia. This group is characterized by the presence of FVIIAG and decreased FVIIC, using a variety of thromboplastins; and excellent correlation was noted for both human thromboplastins.

Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study.

Cerebral white matter lesions are a common finding on MRI in elderly persons. We studied the prevalence of white matter lesions and their relation with classic cardiovascular risk factors, thrombogenic factors, and cognitive function in an age- and gender-stratified random sample from the general population that consisted of 111 subjects 65 to 84 years of age. Overall, 27% of subjects had white matter lesions. The prevalence and severity of lesions increased with age. A history of stroke or myocardial infarction, factor VIIc activity, and fibrinogen level were each significantly and independently associated with the presence of white matter lesions. Significant relations with blood pressure level, hypertension, and plasma cholesterol were present only for subjects aged 65 to 74 years. White matter lesions tended to be associated with lower scores on tests of cognitive function and were significantly associated with subjective mental decline. This study suggests that classic cardiovascular risk factors, as well as thrombogenic factors, are associated with white matter lesions in subjects over 65 years of age in the general population, and that these lesions may be related to cognitive function.

Factor VII coagulant activity is related to blood lipids in the elderly. The Rotterdam study

Objective: To study the distribution of factor VII coagulant activity and its association to serum lipids in the elderly. Methods: The Rotterdam study is a single centre population based prospective cohort study among 7,983 subjects aged 55 years and over. Baseline measurements include assessment of factor VII activity, serum total and high density lipoprotein (HDL) cholesterol. Results: The results are based on the first 1,805 consecutive participants in which factor VIIc, and serum lipids were measured. We excluded 89 persons that were using anticoagulant drugs, leaving 604 men (mean age 70.5 years (SD 8.3) and 1,112 women (mean age 71.9 years (9.2)). Mean levels of cholesterol were 6.3 mmol/l (SD 1.2) and 6.8 mmol/l (1.2) and of HDL cholesterol were 1.2 mmol/l (0.3) and 1.4 mmol/l (0.3) in men and women, respectively. Factor VIIc was normally distributed with a mean of 101 % (20) in men and 111 % (20) in women. Factor VIIc was not associated with age. Linear regression analysis demonstrated that factor VIIc was positively and significantly associated with serum total cholesterol. An increase in total cholesterol of 1 mmol/1 was associated with an increase in factor VIII of 5% (SE 0.5). This association did not materially change after adjustment for age, smoking habit, and body mass index. A comparison of the relatively older age groups with the younger ones revealed similar associations. The magnitude of the association was the same in men and women. HDL cholesterol was not independently associated with factor VIII. Conclusion: Factor VIIc increases with increasing cholesterol with the same strength in the elderly.

Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men.

Coronary thrombosis is regarded as the final occlusive event in the progress of coronary heart disease (CHD). Disturbances of the hemostatic system may favor this process and thus may indicate increased risk of myocardial infarction. Coagulation and lipid factors were measured in 2116 healthy male participants of the Prospective Cardiovascular Münster (PROCAM) study. After 6 years of follow-up, 82 coronary events (9 sudden cardiac deaths and 14 fatal and 59 nonfatal myocardial infarctions) were observed. The mean plasma fibrinogen levels of the event and nonevent groups differed by 0.25 g/L (2.88 [SD, 0.68] versus 2.63 [SD, 0.63] g/L, respectively; P = .001). The incidence of coronary events in the upper tertile of the plasma fibrinogen distribution was 2.4-fold higher than in the lower tertile. By multiple logistic function analysis, plasma fibrinogen was found to be an independent risk indicator for CHD (P < .05). Individuals in the high serum low-density lipoprotein (LDL) cholesterol tertile who also showed high plasma fibrinogen concentrations had a 6.1-fold increase in coronary risk. Unexpectedly, individuals with low plasma fibrinogen had a low incidence of coronary events even when serum LDL cholesterol was high. The mean factor VIIc activities in the event and nonevent groups did not differ significantly (112.3% [SD, 19.9] versus 108.4% [SD, 21.6]; P = .09). There was, however, a trend toward higher factor VIIc values when only fatal events were taken into account. Thus, higher levels of plasma fibrinogen markedly increased the predictive power of high serum LDL cholesterol. Low plasma fibrinogen is associated with low coronary risk even when LDL is raised.

Curvilinear Relations between Age and Hemostatic Parameters in Chinese

The role of hemostatic factors in the pathogenesis of cardiovascular disease has gained much attention recently. Information about hemostatic factors, and their age patterns is sparse for orientals. With the data collected in the Cardiovascular Disease Risk Factor Two-township Study in Taiwan, this study shows that, in general, the older the age, the stronger the tendency toward thrombosis. With advancing age, prothrombin time, activated partial thromboplastin time, and antithrombin-III level decreased steadily; but mean values of fibrinogen, factor VIIc, and factor VIIIc increased. Gender differences in the age patterns of the above factors are carefully described. Curvilinear relations between hemostatic factors and age were demonstrated for adults aged 18 and above for all hemostatic factors studied. This curvilinearity should be taken into consideration when adjusting for the effect of age in data analysis to avoid residual confounding, particularly when the age range of the study subjects is wide.

Both Fish Oil and Olive Oil Lowered Plasma Fibrinogen in Women with High Baseline Fibrinogen Levels

This double-blind, cross-over study with olive oil as placebo, examined the effect of a daily dosage of 6 g fish oil on cardiovascular risk markers of 20 healthy young volunteers (10 men, 10 women). Serum lipids and lipoproteins, and plasma coagulation and fibrinolytic enzymes, including fibrinogen concentrations and plasminogen activator inhibitor-1 (PAI-1) activity were measured at baseline and after 6-week supplementation of either fish or olive oil. The results showed that fish oil had an independent lowering effect on triglycerides and coagulation factors Vc and VIIc. Both fish and olive oil significantly raised PAI-1 levels and lowered plasma factor Xc and fibrinogen levels in the women, who had higher initial levels than the men. Mean fibrinogen levels of the women were lowered from 3.23 +/- 0.98 to 2.64 +/- 0.55 g/l and from 3.19 +/- 0.72 to 2.66 +/- 0.49 g/l by fish and olive oil respectively. This study raises the question whether a particular fatty acid or group of fatty acids, or another constituent of the oil such as vitamin E may be responsible for the fibrinogen lowering effect.

Glycometabolic control, lipids, and coagulation parameters in patients with non-insulin-dependent diabetes mellitus.

Diabetes mellitus and hyperlipidemia are associated with coronary heart disease and with hypercoagulability, another independent risk factor for coronary heart disease. In 65 non-insulin-dependent diabetes mellitus patients [41 females, 24 males, median age 66 years (range 43-81 years)] treated with antidiabetic agents glycometabolic control (HbA1c), lipids (Quetelet index and blood lipids), and several coagulation parameters were studied in comparison with a reference group. Serum triglycerides were elevated [median (interquartile range) 2.3 (1.3) mmol/l vs. 1.6 (0.7) mmol/l in the controls (P < 0.001)], whereas the median lipoprotein(a) concentration was 65 (157) mg/l in the diabetic patients versus 44 (114) mg/l in the control group (not significantly different). Median high-density lipoprotein-cholesterol concentrations were slightly decreased in the diabetic patients: 1.2 (0.3) mmol/l compared with 1.3 (0.4) mmol/l in the control group (P < 0.02). Elevated levels of fibrinogen, fibrin monomers, thrombin-antithrombin III complex, and factor VIIIc were found in the diabetic patients and factor VII in male diabetic patients. These elevated coagulation parameters are indicators of an activated coagulation system in this patient group. By Spearman's rank test, only HbA1c values correlated with anti-thrombin III (r = 0.27, P < 0.03) and showed a tendency towards a correlation with lipoprotein(a) (r = 0.23, P < 0.07). Triglycerides correlated with the Quetelet index (r = 0.27, P < 0.03), high-density lipoprotein-cholesterol (r = -0.41, P < 0.001), and factor VII (r = 0.35, P < 0.01), whereas serum cholesterol concentrations correlated with factor VII (r = 0.27, P < 0.04) and with fibrin monomers (r = 0.29, P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of coronary heart disease and associated risk factors among elderly Finnish men in the Seven Countries Study

The prevalence of coronary heart disease (CHD), cardiovascular disease (CVD) and associated risk factors was studied in 413 men aged 70–89, the survivors of the Finnish cohorts of the Seven Countries Study. Men were divided into five categories according to manifestations of prevalent CVD: I, history or ECG evidence of previous myocardial infarction (MI; 48 men, 12%); II, typical angina pectoris (AP; 56 men, 14%); III, other ischaemic electrocardiographic (ECG) changes (82 men, 20%); IV, stroke, transient ischaemic attack, intermittent claudication or minor ECG changes (other CVD; 78 men, 19%); V, free of CVD (149 men, 36%). Both systolic and diastolic blood pressures were lowest in men with previous MI and in men free of CVD, and highest in men with other ischaemic ECG changes ( P = 0.017). Low HDL-cholesterol (< 0.9 mmol/l) was more prevalent and the total/HDL-cholesterol ratio and triglyceride levels were higher in men with prevalent CHD ( P < 0.05). Total and LDL-cholesterol, smoking, body mass index, fibrinogen, coagulation factor VIIc, apolipoprotein A-I, apolipoprotein B and lipoprotein(a) were not associated with prevalent CVD. The results show that manifestations of CHD and CVD are common among elderly Finnish men. Low HDL-cholesterol, total/HDL ratio, triglycerides and hypertension were associated with manifest CVD cross-sectionally.

The inter‐relationship of factor VII and its activity state with plasma lipids in healthy male adults

A close inter-relationship between raised factor VII clotting activity and elevated blood lipids, particularly serum triglycerides, is well established. A study of factor VII, its activation state and of plasma lipids has been undertaken in two groups of healthy middle-aged males to elucidate this mechanism. A control group with normal factor VII levels were closely matched for age and body-mass index with a second group with elevated levels. Factor VII assays, using rabbit and bovine thromboplastin and a factor VII Ag method, were employed. Triglycerides correlated with the rabbit factor VII thromboplastin assay and factor VII Ag (P < 0.05) but not with the bovine thromboplastin method. Higher HDL-cholesterol and apolipoprotein A-I levels were found in subjects with increased factor VII (P < 0.001) and appeared to be due to differences in alcohol consumption. Cholesterol levels were significantly higher with elevated factor VII. Differential testing suggests that higher factor VII is predominantly mediated through a rise in total VII, rather than an increase in its activity state.

Hemostatic factors and blood lipids in young Buddhist vegetarians and omnivores

A comparison was made between the hemostatic and lipid profiles of 55 young Chinese Buddhist vegetarians (23 men, 32 women) and 59 Chinese medical students (20 men, 39 women) aged 20-30 y. The modern Buddhist vegetarian diet is high in carbohydrate (63% of energy in men, 58% in women) and has a high polyunsaturated-saturated fatty acid ratio, with moderate fat content (25% for men, 30% for women). Rice and soybean proteins are the major protein sources. This study demonstrated that the major beneficial effects of a modern Buddhist vegetarian diet are on blood concentrations of cholesterol, the ratio of apolipoprotein A-I to apolipoprotein B, glucose, and uric acid, but not on most hemostatic factors studied, which included fibrinogen, factor VIIc, factor VIIIc, and plasminogen. Vegetarian men had significantly higher concentrations of antithrombin III than nonvegetarian men.

G6PD haplotypes spanning Xq28 from F8C to red/green color vision.

The most telomeric region of the human X chromosome within band Xq28 consists of a gene-rich region of about 3 Mb which contains the genes for coagulation factor VIIIc, glucose-6-phosphate dehydrogenase (G6PD), and red/green color vision. We have studied five polymorphic sites from this region, in a sample of normal people from the Cosenza province of Southern Italy. These sites, which span a distance of some 350 kb, are in strong linkage disequilibrium. Of the 32 possible haplotypes only 10 were found, and 4 of these account for 80% of all X chromosomes analyzed. In addition, we found that all G6PD-deficient people with the G6PD Mediterranean mutation belong to only two haplotypes. One of these (Med 1) is found only within a small subregion of the area investigated, west of the Appennine mountain range. Most remarkably, all Med 1 G6PD-deficient individuals also had red/green color blindness. The more frequent haplotype (Med 2) is the same in Calabria and in Sardinia, where it accounts for about 90% of the G6PD Mediterranean mutations, despite the fact that gene flow between the populations of Sardinia and Southern Italy must have been limited. These data do not enable us to determine whether the two types of G6PD Mediterranean have arisen through two separate identical mutational events or through a single mutational event followed by recombination. However, the data indicate relatively little recombination over an extended region of the X chromosome and they suggest that the G6PD Mediterranean mutation is recent by comparison to the other polymorphisms investigated.

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.

Prothrombotic and Antithrombotic Factors are Elevated in Patients with Type 1 Diabetes Complicated by Microalbuminuria

Increased urinary albumin loss in patients with Type 1 diabetes is associated with accelerated atherosclerosis. Prothrombotic factors known to be associated with cerebrovascular and coronary artery disease in the general population, antithrombotic factors, were studied in 52 patients with Type 1 diabetes and varying urinary albumin loss and 24 non-diabetic control subjects. Fibrinogen increased from 2.5 g l-1 (95% confidence interval 2.3-2.8) in control subjects and 2.8 g l-1 (2.6-3.0) in diabetic patients without microalbuminuria to 3.1 g l-1 (2.7-3.5) with microalbuminuria (p < 0.005 vs control; p < 0.001 vs without microalbuminuria). Factor VIIc increased from 81% (75-86% in non-diabetic control subjects and 84% (78-90%) in diabetic patients without microalbuminuria to 103% (89-117%) with microalbuminuria (p < 0.005 vs control; p < 0.05 vs without microalbuminuria) and 118% (86-150%) with albuminuria (p < 0.005 vs control and p < 0.001 vs without microalbuminuria). Levels of the antithrombotic factors protein C, protein S, and antithrombin III also rose in the diabetic patients with evidence of renal damage. Elevation of prothrombotic factors has been associated with increased risk of microvascular disease, whereas elevation of antithrombotic factors has no known protective effect. Therefore, this pattern of alteration of haemostatic factors in diabetic renal disease may contribute to the increased risk of vascular disease associated with both microalbuminuria and albuminuria.

Hemostatic changes in heart transplant recipients and their relationship to accelerated coronary sclerosis.

Hemostasis was assessed in 115 steady-state heart transplant recipients (HTRs) and compared with that of 23 age-matched healthy controls and 21 age-matched patients with ischemic heart disease (IHD). Compared with the controls, the HTRs had increased levels of fibrinogen (mean and 95% confidence limits of 4.50 [4.32-4.68] g/L versus 3.47 [3.07-3.87] g/L, P < 0.001), factor VIIC (1.16 [0.98-1.21] IU/ml versus 0.99 [0.89-1.10] IU/ml, P < 0.001), and von Willebrand factor antigen (1.72 [1.58-1.88] IU/ml versus 1.00 [0.80-1.26] IU/ml, P < 0.001). HTRs had increased antithrombin III activity (P = 0.002) and protein C activity (P = 0.002), with a decrease in total protein S levels (P < 0.001) but no change in free protein S levels. Stepwise discriminant analysis of hemostatic variables showed that fibrinogen was the best discriminator of the three groups, classifying 55.6% of HTR, 40% of IHD, and 66.7% of the controls. More marked prothrombotic changes were found in HTRs transplanted for IHD than for other causes; this reached significance for prothrombin (P = 0.048), factor IX (P = 0.003), and poor fibrinolytic activity as measured by euglobulin clot lysis time (P = 0.008). The HTRs with accelerated coronary sclerosis (ACS) tended to have the most prothrombotic changes; this reached significance with factor IX (P = 0.03). In conclusion, HTRs have perturbed hemostasis; the net effects of these changes are prothrombotic. The relationship between prothrombotic changes and ACS merits further studies.

Effects of hydroxymethylglutaryl-coenzyme a reductase inhibitors on some blood coagulation parameters

Ninety-two patients affected by polygenic hypercholesterolemia with and without atherosclerotic cardiovascular disease were treated with simvastatin or pravastatin for 6 months. The effect of the drugs on lipid profiles, fibrinogen plasma behavior, and factor VIIc plasma activity was evaluated. A significant reduction in serum levels of total and low-density lipoprotein cholesterol and an increase in the high-density lipoprotein cholesterol/total cholesterol ratio were observed. Factor VIIc plasma activity significantly decreased in all patients. Fibrinogen concentration showed no significant increase during the follow-up period. No significant correlation was observed between clotting factors and lipidemic parameters, whereas fibrinogen plasma behavior was inversely correlated with factor VIIc plasma activity. Our data suggest that hydroxymethylglutaryl-coenzyme A reductase inhibitors, such as simvastatin and pravastatin, can reduce the hypercoagulability state associated with hypercholesterolemia.

Metabolic clearance of vasopressin and an analogue resistant to vasopressinase in human pregnancy.

The metabolic clearance rate (MCR) of arginine vasopressin (AVP) increases fourfold during human pregnancy. To explore whether circulating vasopressinase may play a role in this change, six women underwent a three-tier infusion clearance study, twice, in random order, to determine the MCRs of either AVP or 1-deamino-8-D-AVP (dDAVP, an analogue resistant to degradation by vasopressinase). Volunteers were tested in late pregnancy (LP), 24-48 h postdelivery (PD), and 5-6 (PP1) and 10-12 (PP2) wk postpartum, thus examining MCRs when vasopressinase levels were high, before and after removal of the placenta (LP and PD), and when plasma enzyme activity was becoming (PP1) and became (PP2) undetectable. Manipulation of infusate permitted comparison of MCRs at three plasma levels whose range was similar at each test period. PAVP and PdDAVP (2.2 and 10 pg/ml, respectively, during the initial infusion) increased to 8 and 31 pg/ml, stepwise increments that had no influence on respective MCRs (AVP: 3.4, 2.2, 0.77, and 0.67 l/min during LP, PD, PP1, and PP2 compared with 0.18, 0.21, 0.17, and 0.15 l/min for dDAVP). Comparison of similar and submaximal urinary osmolality revealed PdDAVP values three- to fourfold greater than PAVP. Von Willebrand factor (VWF) and factor VIIIc levels increased almost fourfold in response to dDAVP during pregnancy, but only doubled in the nonpregnant state; these differences did not reach significance. We conclude that although AVP disposal rates increase fourfold in pregnancy, those of dDAVP change little, suggesting a role of vasopressinase in the increased MCR of AVP in gestation (as well as in the genesis of certain polyuric disorders of pregnancy).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and change of cardiovascular risk factors among men born 1900-19: the Finnish cohorts of the Seven Countries Study.

In a 30-year follow-up survey of the Finnish cohorts of the Seven Countries Study in 1989, 470 men aged 70-89 years were examined in two rural areas of Finland, in the East and in the West. Life-style-related coronary heart disease risk factors were at high levels in both groups, but the difference between areas found in the same cohort in middle age had mostly disappeared or partially reversed. Mean levels of systolic/diastolic blood pressure, body mass index, fasting blood glucose, blood glucose after 2-hour oral glucose tolerance test, and plasma fibrinogen were higher in the West than in the East (p < or = 0.05), but serum thiocyanate which reflects smoking habits was higher in the East (p < 0.001). No significant differences between areas were found in mean levels of serum total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, lipoprotein (a), plasma coagulation factor VIIc, and prevalence of current smoking.

Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women

The purpose of this study was to examine key variables in the regulation of coagulation and fibrinolysis during intake of low-dose oral contraceptives containing newly developed progestogens. Thirty-four healthy young women were allocated to 12 consecutive cycles of treatment with monophasic combinations of 20 micrograms ethinyl estradiol and 150 micrograms desogestrel (n = 15) or 30 micrograms ethinyl estradiol and 75 micrograms gestodene (n = 19). Nonparametric analysis of variance was used for statistical evaluation. In both groups plasma levels of fibrinogen and Factor VIIc increased, and the capacity of coagulation inhibition was affected by increased protein C and decreased protein S levels. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and by reduced activity and concentration of plasminogen activator inhibitor. Thrombin-antithrombin III complexes and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the degree of activation of the coagulation system or the efficacy of fibrinolysis. The overall dynamic balance between generation and resolution of fibrin was maintained during treatment with both hormonal compounds. Our findings suggest that the risk of thrombosis in normal women should not be increased.

Genetic factors determining thrombosis and fibrinolysis.

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the 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%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)