© 1996 American Heart Association, Inc.
Articles |
Population Correlates of Coagulation Factor VII
Importance of Age, Sex, and Menopausal Status as Determinants of Activated Factor VII
INSERM, Cardiovascular Epidemiology Unit U258, Hopital Broussais, Paris (P.-Y.S., R.A.), Laboratoire Serbio, Gennevilliers, (A.-M.V., P.B., J.A.), and Centre d'Investigations Preventives et Cliniques, Paris (J.-M.K., L.G.), France.
Correspondence to Dr Pierre-Yves Scarabin, INSERM–Cardiovascular Epidemiology Unit U258, Hopital Broussais, 96, rue Didot, 75674 Paris Cedex 14, France.
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Abstract |
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Factor VII coagulant activity (FVIIc) has been found to be related to cardiovascular risk factors and may be an independent predictor of coronary heart disease (CHD). Whether these associations are due to changes in FVII activation rather than FVII concentration remain unclear. Therefore, we investigated the relationships between activated factor VII (FVIIa) and CHD risk factors in healthy subjects (336 men and 348 women) aged 25 to 64 years. In addition to direct quantitation of FVIIa by use of a recombinant, truncated tissue factor, FVIIc and factor VII antigen (FVII:Ag) levels were measured by standard procedures. There were highly significant correlations between the three techniques of FVII assay (r>+.55). Plasma FVIIc and FVIIa levels increased with age in both sexes, but the rate of rise was significantly greater in women than men. At younger ages, mean values of FVIIc and FVIIa were significantly lower in women than men, whereas at older ages the reverse was observed. After adjustment for age, postmenopausal women had significantly higher mean levels of FVIIc and FVIIa than did premenopausal women. Hormone replacement therapy significantly reversed the rise in FVIIc in postmenopausal women, and a similar trend in FVIIa was also observed. Age-, sex-, and menopause-related changes in FVIIc were partly explained by a higher proportion of fully active FVII molecules, as indicated by significant differences in the FVIIa-to-FVII:Ag ratio. Oral contraceptive use was associated with high FVIIc levels, and this effect was mainly due to an increase in FVII:Ag. Levels of FVIIa were positively correlated with serum cholesterol concentrations in both sexes. There were no strong associations between FVIIa levels and other CHD risk factors, including smoking habits, alcohol consumption, blood pressure, obesity, glucose, triglycerides, and serum lipoprotein(a) concentrations. Multiple regression analysis showed independent effects of age and cholesterol levels on FVIIa in men, whereas age and menopausal status were the main predictors of FVIIa in women. Our results show that FVII activation is associated with CHD risk factors. These findings are consistent with a possible role for FVII in the pathogenesis of CHD. Furthermore, our data suggest that the dramatic rise in CHD incidence in postmenopausal women as well as the cardioprotective effect of estrogen may be mediated through FVII and blood coagulation.
Key Words: activated factor VII • factor VII coagulant activity • factor VII antigen • menopause • hormone replacement therapy
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Introduction |
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FVII is a vitamin K–dependent protein that plays an important role in the initiation of TF-induced coagulation. Most FVII circulates in the plasma as a zymogen of the serine protease FVIIa. In the presence of TF, native FVII is converted to its activated two-chain form, FVIIa. This reaction can be catalyzed by several coagulation proteases, including FXa, FIXa, FXIIa, thrombin, and FVIIa. The TF-FVIIa complexes rapidly cleave FIX and FX in their active forms and may cause thrombin generation and fibrin clots. Therefore, when cell-surface TF is exposed to plasma, low levels of FVIIa may serve a "priming" function for "triggering" the clotting cascade.1
Clinical and epidemiological data suggest that FVII may be involved in the pathogenesis of CHD. An elevated FVIIc level has been shown to be related to increased risk for myocardial infarction in a prospective cohort study,2 and recent longitudinal data suggest that the association is confined to the occurrence of fatal CHD cases.3 4 Population-based studies have reported consistent associations between FVIIc and CHD risk factors. Levels of FVIIc increase with age in both men and women,5 6 7 8 9 and postmenopausal women have higher mean values of FVIIc than do premenopausal women of the same age.6 8 10 11 12 OC use is associated with higher FVIIc levels,13 14 15 and serum cholesterol and TG concentrations are also positively correlated with FVIIc levels.8 16 17 18 19 20 Finally, experimental studies have shown a positive relation between the day-to-day variation in dietary fat intake and FVIIc.21 However, whether these associations are due to a higher proportion of FVIIa rather than an increase in the concentration of native FVII protein is not well documented. The FVIIc assay measures the sum of both zymogen FVII and FVIIa. FVII assays have been alleged to be able to measure FVII activation, and a number of indicators have been used so far.22 23 24 25 A clot-based FVII assay that directly measures FVIIa is now available.26 Therefore, we investigated the relationships between FVIIa levels and CHD risk factors in healthy subjects. In addition to quantifying FVIIa, FVIIc and FVII:Ag were measured by standard procedures.
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Methods |
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Study Population
Healthy white subjects aged 25 to 64 years were recruited from a health checkup center in Paris (Centre d'Investigations Preventives et Cliniques). A random sample stratified by age (10-year intervals) and sex (336 men and 348 women) was selected between September 1993 and August 1994. All participants gave their informed consent before further investigations were performed. The response rate was
95%. The subjects completed a set of standardized, self-administered questionnaires on personal history (including CHD, hypertension, diabetes, and cancer), drug intake, smoking habits, alcohol consumption, menopausal status, and sex hormone use. The participants had to be free of cardiovascular disease, diabetes, and cancer. Subjects taking antihypertensive medication, cholesterol-lowering drugs, and/or antithrombotic treatment were not eligible. Subjects were classified as smokers if they smoked at least one cigarette per day and as nonsmokers if they had never smoked or had stopped smoking at the time of the examination. The number of cigarettes smoked per day was recorded for the current smokers. No attempt was made to estimate daily alcohol intake, and subjects were categorized only as current drinkers or nondrinkers. Women were classified as postmenopausal if they had not had normal menstrual periods for at least 6 months. The postmenopausal women were further classified according to the type of menopause (natural or surgically induced). Women who had undergone hysterectomy with or without unilateral oophorectomy and who were >50 years old were classified as having undergone natural menopause. The type of HRT (preparations, combination with progestins, and route of estrogen administration) and the formulation of OCs were systematically recorded. BP was measured with a sphygmomanometer with the subject in the supine position after a 10-minute rest. BMI was computed as weight in kilograms divided by height squared (meters squared).
Blood Sampling and Assay Procedures
After an overnight fast, venous blood (9 volumes) was collected between 9 and 10 AM into siliconized tubes (Vacutainer, Becton Dickinson) containing 1 volume of 3.2% trisodium citrate. The first 5 mL of blood was discarded. Platelet-poor plasma was obtained by centrifugation at 4000g and 20°C for 30 minutes. Without delay, aliquots of plasma were transferred to plastic tubes and stored in liquid N2 until assayed within 6 months following blood collection. At the time of assay, plasma samples were transferred to a 37°C water bath for 15 minutes and then handled at room temperature to avoid cold activation.
FVIIa was determined with a clot-based assay using a soluble, recombinant, truncated TF as described.26 Coagulation times were converted to FVIIa concentrations (nanograms per milliliter) by comparison with a standard curve drawn from various concentrations of purified recombinant FVIIa. FVIIc was assayed in a regular one-stage system using rabbit thromboplastin as previously described.7 A commercially available FVII-deficient substrate plasma was used in both FVIIa and FVIIc assays (Diagnostica Stago). The reagent consisted of freeze-dried, citrated human plasma from which FVII had been removed by selective immunoadsorption. FVII:Ag was determined with an enzyme-linked immunosorbent assay kit (Diagnostica Stago) as described.27 Results were expressed as a percentage of normal pooled plasma standard. The FVIIa-to-FVII:Ag ratio was calculated as an indicator of conversion of FVII to FVIIa. The intra-assay coefficients of variation in our laboratory were 4% for FVIIc, 3% for FVII:Ag, and 5% for FVIIa.
Serum total cholesterol and TG levels were measured by enzymatic methods. Serum glucose was determined with a commercial enzyme assay kit (GOD-PAP, Boehringer Mannhein). Serum lipoprotein(a) was measured by an enzyme-linked immunosorbent assay (IMMUNOZYM-Lp(a), IMMUNO).
Statistical Analysis
The procedures used were available in the SAS software package (Statistical Analysis System Institute Inc). The distributions of FVIIc, FVII:Ag, and FVIIa-to-FVII:Ag ratios were approximately normal (ie, gaussian). The distributions of FVIIa, TGs, and lipoprotein(a) were positively skewed and therefore, these variables were logarithmically transformed. However, all mean values in the Tables are given as arithmetic means. FVII levels were first examined by age and sex. The population was divided into subjects <45 or 
45 years of age, 45 being the median of the age distribution. A two-way ANOVA was used to simultaneously test for age and sex effects. Interaction terms between the two factors (ie, agexsex) were included in the models. An ANCOVA was used to assess the effects of OC, menopausal status, and HRT on FVII after controlling for age and BMI. Pearson's correlation coefficients were used to detect any associations between FVII levels and other cardiovascular risk factors in men and women separately. Finally, stepwise multiple linear regressions were used for men and women separately to assess the independence of associations between CHD risk factors and FVII levels. A forward-stepping procedure was used with only those CHD risk factors that had been found to be significantly related to FVII levels in the univariate analysis. Because of the heterogeneity of hormone users and small subsample size, OC status and HRT were not entered into the multivariate models. Two-tailed values of P<.05 were considered statistically significant.
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Results |
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Table 1
shows the general characteristics of the study population according to sex. Mean values of BMI, systolic and diastolic BP, and serum TG and glucose concentrations were significantly higher in men than women. The percentage of drinkers was higher in men than women, whereas no significant difference in the number of current smokers was observed according to sex. However, daily cigarette use was higher in men than women (5.5 versus 3.3 cigarettes per day, respectively, P<.05).
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Table 2 shows the correlation coefficients between techniques of the FVII assay in men and women separately. FVIIc was closely related to FVII:Ag. FVIIa was correlated with both FVIIc and FVII:Ag. The associations of FVIIc with FVIIa and with the FVIIa-to-FVII:Ag ratio were stronger in women than men, although these differences were not significant. There was a weak but still significant correlation between the FVIIc-to-FVII:Ag ratio (an indicator of FVII activity state that has been previously used) and FVIIa concentration in both sexes.
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Age- and sex-specific mean values of FVII are shown in Table 3. In both men and women plasma levels of FVIIa and FVIIc increased with age, and this rate of increase was significantly greater in women than men. Univariate regression coefficients showed that FVIIa increased by 0.069 ng/mL and 0.023 ng/mL per year in women and men, respectively. The rates of increase in FVIIc per year were 1.16% in women and 0.44% in men. Before 45 years of age, the mean values of FVIIa and FVIIc were significantly lower in women than men (by 0.6 ng/mL and 8%, respectively). Conversely, the mean levels of FVIIa and FVIIc were significantly higher in women than men after 45 years of age (by 0.7 ng/mL and 7%, respectively). Similar sex-related differences in FVII:Ag levels and FVIIa-to-FVII:Ag ratios were found.
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Table 4 shows the mean values of FVII by OC use status. All the women but one who were taking OCs used formulations that contained <50 µg ethinyl estradiol in combination with a large variety of progestins. Data for premenopausal women who were using progestins alone were excluded (n=16). After adjustment for age and BMI, OC users had FVIIc levels that were significantly higher than those of nonusers. There was a substantial increase in the FVII:Ag concentration in OC users (+20%, P<.001). Although the mean FVIIa level was higher and the FVIIa-to-FVII:Ag ratio lower in OC users, neither difference was statistically significant.
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Among the 348 women included in the study, 211 were premenopausal and 137 postmenopausal. Menopause was natural in 109 women and had been surgically induced in 28 (12 with bilateral oophorectomy and 16 with hysterectomy, with or without unilateral oophorectomy). Fifty-three postmenopausal women were receiving HRT and three were taking progestin alone. All HRT users were given estrogen in combination with progestin. The route of estrogen administration was percutaneous in 43 women and oral in 10. Table 5 shows mean levels of FVII by menopausal status and HRT use after allowance for age and BMI. Fifty-seven premenopausal women who were taking sex hormones were excluded from this analysis. Postmenopausal women who were not receiving HRT had higher mean levels of FVIIa and FVIIc than did premenopausal women, with significant differences of 1.1 ng/mL and 15%, respectively. There were also significant menopause-related changes in FVII:Ag levels (+10%). However, the FVIIa-to-FVII:Ag ratio was significantly higher in postmenopausal women who were not receiving HRT than in premenopausal women. There were no striking differences in FVII levels according to type of menopause (results not shown). Postmenopausal women who were receiving HRT had FVIIc levels close to those observed in premenopausal women (115% versus 111%, respectively). There was a similar trend toward lower FVIIa concentrations (4.6 ng/mL versus 3.9 ng/mL, respectively). Percutaneous estrogen use significantly reversed the rise in FVIIc, FVIIa, and the FVIIa-to-FVII:Ag ratio in postmenopausal women. There was no significant difference between routes of estrogen administration. However, the number of oral estrogen users was small.
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Table 6 shows sex-specific correlation coefficients between FVII and other cardiovascular risk factors. In both men and women, FVIIc and FVII:Ag were significantly correlated with BMI, diastolic BP, and serum total cholesterol concentration. In women FVIIa concentration significantly increased with BMI, BP, serum cholesterol, TGs, and glucose levels. In men FVIIa concentration was significantly associated only with diastolic BP and serum cholesterol levels. There was a highly significant positive correlation between the FVIIa-to-FVII:Ag ratio and serum cholesterol levels in women.
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Tables 7 through 10 show independent associations between FVII levels and cardiovascular risk factors in men and women. With regard to FVIIc and FVII:Ag (Table
s 7 and 8), a similar pattern of relationships was observed. In addition to menopausal status in women, BMI, serum cholesterol, and TGs levels were consistent predictors of FVII in both sexes. These CHD risk factors accounted for 36% and 17% of the total variation of FVIIc in women and men, respectively. By contrast (Table 9), the percentage of explained variance was lower when FVIIa was taken as a dependent variable (19% and 3%, respectively). In women, age and menopausal status were independently and significantly related to FVIIa concentration. In men, serum cholesterol levels and age made independent contributions to the variation in FVIIa. Menopausal status was the main determinant of the FVIIa-to-FVII:Ag ratio, but no strong association for this ratio was observed in men (Table 10).
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Discussion |
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There is increasing evidence of an important role for TF and FVIIa in the initiation of blood coagulation via the so-called extrinsic coagulation pathway.1 Population-based studies provide evidence that elevated FVIIc levels may be involved in the pathogenesis of CHD. However, the relevance of increased FVIIc to thrombogenesis remains unclear, and the clinical significance of elevated FVIIc has given rise to controversy because of the many forms of FVII that exist in plasma and the different methods currently in use for measuring FVIIc.1 28 High FVIIc levels may be due to elevated total FVII mass (ie, FVII:Ag), elevated FVIIa, or both. In addition, a phospholipase-sensitive form of FVII has also been described.29 The source of thromboplastin and the nature of FVII-deficient plasma may play an important role in the techniques of FVIIc measurement. There is evidence that FVIIc assays using bovine thromboplastin are more sensitive to FVIIa than are those that employ rabbit or human thromboplastin.24 25 More recently, an international study30 showed that the Northwick Park FVIIc assay,2 which utilized a FVII-deficient plasma depleted of protein C, exhibited increased responsiveness to FVIIa when compared with other FVIIc assays, such as the PROCAM4 or ARIC8 assays, which used substrate plasma depleted of FVII only (as in the present work). If elevated FVIIa concentration is the actual risk factor for thrombotic disease, then some discrepancies between results of different cardiovascular surveys may be partially due to the ability of each type of FVIIc assay to detect FVIIa. Therefore, the availability of a reliable FVII assay that measures FVIIa directly may contribute to a better understanding of the changes in FVIIc in relation to thrombotic risk as well as to CHD risk factors.
Our data confirm that trace levels of FVIIa may circulate in the blood of healthy subjects.26 31 Individual values ranged from 0.4 to 14.3 ng/mL (mean, 4.1). The strong correlation between FVIIa and FVII:Ag is consistent with an equilibrium between FVII zymogen and its active form (1% of total FVII:Ag). High plasma levels of FVIIa could result from both elevated zymogen FVII and increased conversion of native FVII to FVIIa. However, correlation does not imply causation, and it is also conceivable that the FVIIa concentration would regulate FVII synthesis. The weak but significant relations between the FVIIc-to-FVII:Ag ratio and both FVIIa and the FVIIa-to-FVII:Ag ratio were not found in a recent Japanese study.31 Differences in the sensitivity of FVIIc assays may partly account for this discrepancy. We used rabbit thromboplastin for the FVIIc assay, and our results suggest that the FVIIc-to-FVII:Ag ratio, previously used as an indirect indicator of FVIIa, may provide valid information on the degree of FVII activation. However, the FVIIc-to-FVII:Ag ratio remains a poor index of the activity state of FVII when compared with actual, direct FVIIa measurement.
Our data show an increase in FVIIa levels with age in both men and women, as recently described.26 31 Furthermore, the FVIIa-to-FVII:Ag ratio was positively correlated with advancing age in both sexes. These results are consistent with previous work that used an indirect approach to assess the degree of FVII activation in healthy women.7 This finding may be relevant to the increased risk of CHD in the elderly. Two recent reports failed to detect any difference in FVIIa levels between men and women,26 31 but sample sizes were smaller than in the present study and age was not taken into account. Our results show a striking interaction between the effects of age and sex on FVIIa levels. The rate of increase in both FVIIa and the FVIIa-to-FVII:Ag ratio as a function of age was threefold greater in women than men. Multivariate analysis suggests that a substantial part of the relation between age and FVIIa concentrations in women is mediated by changes during menopause. Similar age- and sex-related differences in FVIIc have been reported elsewhere.5 Interestingly, young women, who are at low risk for CHD, also have low FVIIa levels compared with those for men of the same age. In the elderly, the reverse is observed. This finding somewhat parallels the age- and sex-related differences in blood cholesterol, especially in the LDL fraction, that is a major determinant of CHD risk.32
Population-based studies have shown that postmenopausal women have higher FVIIc levels than do premenopausal women of similar age.6 8 10 11 12 We previously reported that menopause-related changes in FVIIc could be only partially explained by total FVII concentrations.11 Our results provide evidence for an association between menopause and high FVIIa levels. Furthermore, this relation may be due to a higher proportion of FVIIa, as indicated by the change in the FVIIa-to-FVII:Ag ratio. These differences are substantial and remain significant after adjustment for the main CHD risk factors. Our findings suggest that the higher CHD risk in postmenopausal than in premenopausal women may be partly mediated through changes in FVII activation. On the other hand, HRT reversed the high FVIIc levels in postmenopausal women, and a similar effect on FVIIa concentrations was also found, especially in postmenopausal women who were taking percutaneous estrogen. These differences are consistent with our previous findings33 and may help to explain the association between HRT and the reduction of CHD risk in postmenopausal women.34 Alternatively, it has recently been reported that the possible cardioprotective effect of HRT may be mediated through an increased fibrinolytic potential.35 Further data on the influence of the route of estrogen administration on hemostatic variables are required, and randomized, clinical trials are needed to clarify the effect of HRT on blood coagulation.
Women who use OCs have higher FVIIc and FVII:Ag levels than do nonusers, and these effects are related to the dose of ethinyl estradiol.13 14 15 36 While our data confirm these associations, we failed to detect a significant difference in FVIIa levels between OC users and nonusers. These results are in agreement with two recent reports.15 26 Therefore, it is doubtful that elevated FVIIc is the mechanism underlying the increased thrombotic risk in OC users.37 However, the number of OC users in our study may not have been large enough to detect a difference in FVIIa concentrations. In addition, the women in our study were using formulations that contained low doses of estrogen.
The positive associations between FVIIc and both serum cholesterol and TG concentrations are well documented, but the underlying mechanisms are unclear.16 17 18 19 20 38 A weak and nonsignificant association between raised FVIIa levels and high serum cholesterol concentrations has been recently reported in small populations.31 39 Our results show a positive correlation between FVIIa concentration and cholesterol level in a healthy population, as previously suggested.17 18 This association was stronger in women than men, and the relation remained significant in men even after allowance for the main CHD risk factors. In contrast, the rise in FVIIc with serum TG concentration appeared to result from high concentrations of zymogen FVII rather than from an increase in FVIIa levels. A short-term effect of TG-rich lipoproteins on FVII reactivity in men has been reported.40 41 42 43 Our data suggest that a long-term increase in blood cholesterol levels may also result in minor FVII activation, perhaps through dietary fat intake. This finding has yet to be confirmed in hyperlipidemic patients as well as in dietary studies with adequate number of subjects.
There is evidence for an association between raised FVIIc and an increase in the subsequent risk of fatal CHD. However, the biologic significance of this relation remains controversial. Several case-control studies of CHD recently reported conflicting results with respect to FVIIa concentration.31 39 44 Surprisingly, increased thrombin generation without any change in FVIIa concentration has been found in the acute phase of myocardial infarction.44 Longitudinal data are needed to investigate the relevance of FVIIa to the prediction of CHD risk.
In conclusion, our cross-sectional study shows that FVII activation is associated with some major cardiovascular risk factors. These findings are consistent with a possible role for FVII in the pathogenesis of CHD. Furthermore, our data suggest that the dramatic rise in CHD incidence in postmenopausal women, as well as the cardioprotective effect of estrogen, may be mediated through FVII and blood coagulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant from the French Research and Technology Ministry (Eureka Programme Thrombocheck EU 827).
Received October 2, 1995;
revision received February 26, 1996;
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