Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:485-492

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wamala, S. P.
Right arrow Articles by Orth-Gomér, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wamala, S. P.
Right arrow Articles by Orth-Gomér, K.
Related Collections
Right arrow Pathophysiology
Right arrow Risk Factors
Right arrow Anticoagulant mechanisms
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:485-492.)
© 1999 American Heart Association, Inc.


Original Contributions

Socioeconomic Status and Determinants of Hemostatic Function in Healthy Women

Sarah P. Wamala; Mittleman A. Murray; Myriam Horsten; Margita Eriksson; Karin Schenck-Gustafsson; Anders Hamsten; Angela Silveira; Kristina Orth-Gomér

From the Department of Public Health Sciences, Division of Preventive Medicine, Karolinska Institute, Stockholm, Sweden (S.P.W., M.H., K.O.-G.); the Department of Epidemiology, Harvard School of Public Health, Boston, Mass (M.A.M.); and the Department of Cardiology (M.E., K.S.-G.), and the Atherosclerosis Research Unit, King Gustaf V Research Institute (A.H., A.S.), Karolinska Hospital, Stockholm, Sweden.

Correspondence to Sarah P. Wamala, MSc, Karolinska Institutet, Department of Public Health Sciences, Division of Preventive Medicine, Novum Plan 7, Post fack 30, S-141 57 Huddinge, Sweden. E-mail Sarah.Wamala{at}phs.ki.se


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Abstract—Hemostatic factors are reported to be associated with coronary heart disease (CHD). Socioeconomic status (SES) is 1 of the determinants of the hemostatic profile, but the factors underlying this association are not well known. Our aim was to examine determinants of the socioeconomic differences in hemostatic profile. Between 1991 and 1994, we studied 300 healthy women, aged 30 to 65 years, who were representative of women living in the greater Stockholm area. Fibrinogen, factor VII mass concentration (FVII:Ag), activated factor VII (FVIIa), von Willebrand factor (vWF), and plasminogen activator inhibitor-1 (PAI-1) were measured. Educational attainment was used as a measure of SES. Low educational level and an unfavorable hemostatic profile were both associated with older age, unhealthful life style, psychosocial stress, atherogenic biochemical factors, and hypertension. Levels of hemostatic factors increased with lower educational attainment. Independently of age, the differences between the lowest (mandatory) and highest (college/university) education in FVII:Ag levels were 41 µg/L (95% confidence interval [CI], 15 to 66 µg/L, P=0.001), 0.26 g/L (95% CI, 0.10 to 0.42 g/L, P=0.001) in fibrinogen levels, and 0.11 U/mL (95% CI, 0.09 to 0.12 U/mL, P=0.03) in levels of vWF. The corresponding differences in FVIIa and PAI-1 were not statistically significant. With further adjustment for menopausal status, family history of CHD, marital status, psychosocial stress, lifestyle patterns, biochemical factors, and hypertension, statistically significant differences between mandatory and college/university education were observed in FVII:Ag (difference=34 µg/L; 95% CI, 2 to 65 µg/L, P=0.05) but not in fibrinogen (difference=0.03 g/L; 95% CI, -0.13 to 0.19 g/L, P=0.92) or in vWF (difference=0.06 U/mL; 95% CI, -0.10 to 0.22 U/mL, P=0.45). An educational gradient was most consistent and statistically significant for FVII:Ag, fibrinogen, and vWF. Age, psychosocial stress, unhealthful life style, atherogenic biochemical factors, and hypertension mediated the association of low educational level with elevated levels of fibrinogen and vWF. Psychosocial stress and unhealthful life style were the most important contributing factors. There was an independent association between education and FVII:Ag, which could not be explained by any of these factors.


Key Words: hemostatic function • life style • psychosocial stress • socioeconomic status • women


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Hemostatic factors have been reported to be associated with coronary heart disease (CHD) morbidity1 2 3 4 5 6 7 8 9 10 and mortality11 12 in both men and women. Fibrinogen, factor VII, and von Willebrand (vWF) are coagulation factors that may increase the likelihood of atherothrombotic diseases, whereas plasminogen activator inhibitor-1 (PAI-1) is the rapid inhibitor of the endogenous fibrinolytic enzyme system. Fibrinogen may contribute to CHD by influencing the progression of coronary atherosclerosis2 13 14 as well as by precipitating the formation of occlusive thrombus.15 16 vWF and PAI-1 have been suggested to be associated with carotid atherothrombotic diseases17 and to be related to recurrent myocardial infarction (MI).7 In particular, vWF has been related to both recurrent MI and death in patients who survived a first MI.8 9 11 Activated factor VII (FVIIa) has been reported to be a useful index of thrombin production during coagulation.18

A social gradient in CHD has been found in both men and women, the risk of heart attack being higher in low socioeconomic strata. Educational attainment is the most consistent and reliable socioeconomic status (SES) measure that is associated with CHD.19 Among the hemostatic factors, fibrinogen has received greatest attention, particularly in men. Inverse relations with education have been reported.5 20 21 22 In the Atherosclerosis Risk in Communities (ARIC) Study, a univariate association between low education and elevated levels of coagulant factor FVII (FVII:C) was observed in both men and women.23 In contrast, an educational gradient in vWF, FVIIa, and PAI-1 has not been well documented. Although levels of hemostatic factors have been reported to be more elevated in women than in men,1 5 6 21 23 24 factors contributing to their SES differentials among women are not well known. Understanding the determinants of hemostatic profile in relation to SES may be useful in designing preventive strategies geared to reducing socioeconomic differences in atherosclerosis and thrombosis or premature CHD.

Some studies have reported strong associations of hemostatic factors with major cardiovascular risk factors, such as genetic factors,25 26 27 smoking,3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 19 23 24 28 29 a sedentary life style,23 30 obesity,4 5 17 23 30 31 low alcohol consumption,23 24 31 poor lipid profile,1 3 4 5 20 23 30 hypertension,3 4 23 30 social isolation,29 and psychosocial job stress.32 33 34 The main objective of this study was to investigate the association between SES and hemostatic profile and to assess the contribution of other cardiovascular risk factors to this association. Educational attainment was used as a measure of SES. Our hypothesis was that low education is associated with psychosocial stress, which may lead to an unhealthful life style, thereby resulting in an unfavorable hemostatic profile. Cardiovascular risk factors included background factors (age, family history of CHD, menopausal status, and marital status), psychosocial factors (social isolation and work stress), lifestyle patterns (smoking, physical activity, alcohol consumption, dietary habits, and obesity), biochemical factors (glucose, C-reactive protein [CRP], triglycerides, total cholesterol, HDL, and LDL), and hypertension. To the best of our knowledge, this is the first study to examine the association between SES and hemostatic profile in relation to a wide range of cardiovascular risk factors in women.


*    Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The study group comprised 300 healthy women aged 30 to 65 years. They constitute the control subjects of the Stockholm Female Coronary Risk Study, which is a population-based case-control study.35 The study was approved by the Karolinska Hospital Ethics Committee (No. 91;119), Stockholm, Sweden, and the study subjects gave informed consent to participate. The healthy women were chosen from the population register of the greater Stockholm area, which includes each person's identification numbers (based on birth date and sex). "Healthy" was defined as being free from symptoms of heart disease and without hospitalization for any illness during the prior 5-year period. The healthy women were compared with a random sample of 2500 women of the same age range from the general population of Stockholm,36 and no differences were found in the distribution of educational attainment or lifestyle patterns (smoking and body mass index). Seventeen percent of the healthy women declined to participate, mainly due to difficulties in arranging time off from work. There were no significant differences in the mean age between participants and nonparticipants. More detailed information about recruitment of study subjects has been given elsewhere.35

Data Collection
A questionnaire on lifestyle and psychosocial factors was mailed to the subjects before their visit to the research clinic. Questionnaires were completed at home and brought to the research clinic, where the research nurse reviewed them together with the subject to complete missing answers. Internal nonresponse rate was <10%. Anthropometric measures, gynecological interview, blood pressure, and fasting blood samples were all collected and assessed at the research clinic.

Blood Samples
Venous blood samples were drawn from the right arm of each subject in the resting position by antecubital vein puncture with a 1.4-mm Wasserman needle. The blood sampling was performed between 8 and 9 AM after 12 hours of fasting. After drawing the first 2 mL, blood was allowed to run freely into the tubes. Samples for the hemostatic factors were drawn first.

For the analyses of hemostatic factors, venous blood was drawn into 10-mL plastic tubes containing 0.13 mol/L trisodium citrate, 9 parts of blood to 1 part of citrate solution. The blood samples were immediately mixed and centrifuged at 2000g for 15 minutes at room temperature. The supernatant plasma was snap-frozen and stored at -70°C.

For the analyses of lipids and lipoproteins, venous blood was drawn into a 10-mL, precooled, sterile tube containing 0.12 mL of 0.34 mol/L tripotassium EDTA and kept on ice until they were centrifuged at 3000g. Plasma (4 mL) was obtained, immediately frozen to -70°C, and sent in batches to the processing laboratory once per month for further analyses.

Hemostatic Factors (Main Outcome)
Fibrinogen determination was performed with a polymerization rate method.37 vWF was determined immunochemically by means of ELISA (Asserachrom vWF, STAGO).38

Plasma levels of FVIIa were determined by a clotting assay using soluble, recombinant, truncated tissue factor (a kind gift from Prof James H. Morrissey, Oklahoma Medical Research Foundation, Oklahoma City),39 40 as previously described.41 Coagulation times were converted to FVIIa concentration (µg/L) by comparison with a standard curve constructed from varying concentrations of purified recombinant FVIIa (a kind gift from Dr Mirella Ezban, Novo Nordisk A/S, Gentofte, Denmark). Data were collected on a Compaq Presario 425 microcomputer (Compaq Computer Corp) and analyzed using Windows Research Software supplied with the ACL-300 coagulometer (Instrumentation Laboratories), as described.41 Intra-assay and interassay coefficients of variation were 3.9% and 9.1%, respectively. FVII mass concentration was determined as FVII antigen (FVII:Ag) by using an enzyme immunoassay kit (Novoclone FVII EIA kit, Dako A/S; a kind gift from Dr Mirella Ezban). PAI-1 was determined by a functional spectrophotometric method (Biopool AB).42

Measure of SES
The highest education attained was reported by subjects in a self-administered questionnaire, which was later examined by a research nurse. Educational attainment was categorized into 3 levels, as previously done in studies of hemostatic profile23 : (1) low education (mandatory or less than high school), corresponding to 9 years of schooling or less; (2) medium (high school), corresponding to 10 to 13 years of schooling; and (3) high (college or university), corresponding to 14 years of schooling or more.

Background Factors
Age at examination was obtained from the date of birth given in the census register. Family history of CHD was defined as having a first-degree relative with a history of CHD at any age. Menopausal status was categorized as premenopausal or postmenopausal (having had no menses for at least 6 months before the examination) with or without hormone replacement therapy (HRT). Women >50 years of age who were started on HRT before menopause or who had undergone bilateral oophorectomy were classified as postmenopausal. Marital status was categorized as single, widowed, divorced, or cohabiting (married or living with a male companion).

Psychosocial Stress
Social isolation was derived as an index of 3 instruments: social support,43 leisure social activities (such as going with others to the movies, concerts, theaters, museums, church, restaurants, or clubs, or inviting guests into one's home), and household size (total number of people living in one's household). Women were defined as socially isolated when their total scores were >=75th percentile. Psychosocial work stress was described as lacking control or having low decision latitude at work, based on the Swedish version of the Karasek demand/control questionnaire.44 Work stress was considered present when the total scores were <=25th percentile.

Lifestyle-Related Factors
Cigarette smoking and physical activity were assessed according to the World Health Organization criteria. Diet was assessed using an 88–food item frequency questionnaire with relative portion sizes.45 Dietary variables included total energy intake, total fat, carbohydrate, total fiber, protein intake, and alcohol consumption. Nutrient calculation of dietary factors has been documented elsewhere.46 The total average amount of alcohol (100% ethanol) consumed was calculated in grams per day, after taking into account the frequency, amount, and alcohol content in specific beverages.47 Low alcohol consumption was defined as not drinking or consumption <=25th percentile. Obesity was defined as body mass index >29 kg/m2 or a waist-to-hip circumference ratio >0.85.

Biochemical Factors
Total cholesterol was determined with CHOD-PAP and triglycerides with GPD-PAP enzymatic methods with reagents from Boehringer Mannheim. HDLs were determined on the basis of the isolation of LDL and VLDL from serum by precipitation. The cholesterol content of the supernatant was measured enzymatically.48 CRP was analyzed by immunoturbidimetric determination (Orion Diagnostica).49 Fasting serum glucose was analyzed by the GOD-PAP method.50 All measurements were carried out in the same laboratory (CALAB), with an automated multichannel analyzer.51 Cutoff points of biochemical factors were adapted from the treatment guidelines of the European Atherosclerosis Society.52

Hypertension
Hypertension was defined as systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or a history of hypertension (according to the physician's diagnosis). Systolic and diastolic blood pressures were measured with subjects in the supine position after a 5-minute rest; phases I and V of the Korotkoff sound were used.

Statistical Methods
To attain normality, hemostatic factors were logarithmically transformed in all analyses. Geometric means are presented. The SEs of geometric means were calculated using the delta method. To retain power, PAI-1 levels at zero were assigned a value of 0.001 before logarithmic transformation. ANOVA and ANCOVA (using the standard least-squares method) were performed for univariate and multivariate analyses, respectively. In the multivariate analyses, 6 models were generated. Risk factors were grouped into sets as follows: lifestyle patterns (smoking, physical activity, obesity, and alcohol consumption); psychosocial stress (social isolation and work stress); biochemical factors (glucose, CRP, triglycerides, and LDL and HDL cholesterol); and hypertension. Least-squares means of hemostatic factors were estimated for each level of education. The linear trend for the effect of education was assessed by computing P values for trend. JMP Statistics and Stata for Macintosh were used to run the analyses.


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
The distribution of hemostatic and other cardiovascular risk factor characteristics are shown in Table 1Down.


View this table:
[in this window]
[in a new window]
 
Table 1. Distribution of Hemostatic Factors and Other Cardiovascular Risk Factors

Univariate/Bivariate Analyses
Cardiovascular Risk Factors and Hemostatic Profile
Elevated levels of fibrinogen were observed among women who were divorced (mean=3.42 g/L), widowed (mean=3.31 g/L), and single (mean=3.22 g/L) compared with women who were married (mean=3.11 g/L, P=0.01). The association with marital status was not statistically significant for other hemostatic variables. Elevated levels of FVII:Ag (r=0.12, P=0.05) and of PAI-1 (r=0.14, P=0.02) were associated with high total fat intake and also with a high total energy intake (r=0.15, P=0.02 for FVII:Ag and r=0.13, P=0.03 for PAI-1). The associations of carbohydrate, protein, and total fiber intake with hemostatic profile were not statistically significant. An unfavorable hemostatic profile was associated with smoking, a sedentary life style, obesity, psychosocial stress, atherogenic biochemical factors, and hypertension, as shown in Table 2Down.


View this table:
[in this window]
[in a new window]
 
Table 2. Concentrations of Hemostatic Factors in Relation to Other Cardiovascular Risk Factors, Means and (SEM)

Educational Attainment and Cardiovascular Risk Factors
Comparing women with mandatory with those with a college/university education revealed that a larger proportion were older (mean=58 versus 55 years, P=0.001), were hypertensive (26% versus 11%, P=0.02), were obese (34% versus 16%, P=0.01), were smokers (38% versus 20%, P=0.01), were socially isolated (34% versus 11%, P=0.0003), and reported work stress (56% versus 22%, P<0.0001). Compared with college/university, mandatory education was also associated with lower levels of HDL cholesterol (mean=1.7 versus 1.9 mmol/L, P=0.05) and elevated levels of total cholesterol (mean=6.2 versus 5.8 mmol/L, P=0.004), LDL cholesterol (mean=4.0 versus 3.6 mmol/L, P=0.006), and triglycerides (mean=1.1 versus 0.9 mmol/L, P=0.02). Although there was a tendency for women with low education to have unhealthful dietary habits, this association did not show statistical significance.

Educational Attainment and Hemostatic Profile
Women with the lowest (mandatory) education had elevated levels of hemostatic factors compared with women with the highest (college/university). After comparing women of mandatory with those of a college/university education level, statistically significant differences were found in fibrinogen(difference=0.32 g/L; 95% CI, 0.16 to 0.48 g/L), vWF (difference=0.15 U/mL; 95% CI, 0.05 to 0.25 U/mL), and FVII:Ag (difference=46 µg/L; 95% CI, 21 to 73 µg/L). The corresponding figures for FVIIa (difference=0.3µg/L; 95% CI, -0.1 to 0.7 µg/L) and PAI-1 (difference=1.8 IU/mL; 95% CI, -4.0 to 7.6 IU/mL) did not reach statistical significance (Table 3Down).


View this table:
[in this window]
[in a new window]
 
Table 3. Mean Values of Hemostatic Factors by Educational Attainment

After adjustment for age, statistically significant differences between the lowest and highest education were observed for levels of fibrinogen (0.26 g/L; 95% CI, 0.10 to 0.42 g/L), vWF (0.11 U/mL; 95% CI, 0.10 to 0.12 U/mL), and FVII:Ag (41 µg/L; 95% CI, 15 to 66 µg/L; Table 3Up).

Multivariate Analyses
We further examined the contribution of life style, psychosocial stress, biochemical factors, and hypertension to the association of education with fibrinogen, vWF, and FVII:Ag (Table 4Down).


View this table:
[in this window]
[in a new window]
 
Table 4. Association of Educational Attainment With Fibrinogen, vWF, and FVII:Ag in Relation to Other Cardiovascular Risk Factors

Fibrinogen and vWF
For both fibrinogen and vWF, statistically significant associations with education persisted after adjustment for biochemical factors and hypertension in models 4 and 5 (P<0.05). These associations, however, weakened after adjustment for psychosocial stress and lifestyle patterns (P>0.05, Table 4Up).

After simultaneous adjustment for all risk factors in model 6, there was no statistically significant difference in fibrinogen concentration between the 2 extreme levels of education (difference=0.03 g/L; 95% CI, -0.13 to 0.19 g/L, P=0.92). Independently of other risk factors, elevated levels of fibrinogen were observed in women who were hypertensive (3.39 versus 3.06 g/L, P=0.002), smokers (3.19 versus 2.97 g/L, P=0.004), and obese (3.29 versus 3.10 g/L, P=0.03) and in those who had elevated levels of CRP (ß=1.12, P=0.04). After adjustment for family history of CHD, marital status and menopausal status did not alter these results (Table 4Up).

After adjustment for all risk factors, the difference in levels of vWF when women of mandatory education were compared with those with a college/university education was 0.06 U/mL (95% CI, -0.10 to 0.22 U/mL), and this difference was not statistically significant (P=0.45, Table 4Up). None of the other risk factors had a statistically significant independent effect on vWF.

Factor VII Antigen
A statistically significant difference in the concentration of FVII:Ag between mandatory and college/university education persisted after individual adjustment for psychosocial stress, lifestyle patterns, biochemical factors, and hypertension in models 2 through 5 (difference >30 µg/L; P=0.01, Table 4Up). This difference persisted after simultaneous adjustment for all risk factors in model 6 (difference=34 µg/L; 95% CI, 2 to 65 µg/L, P=0.05). Another independent association of FVII:Ag was observed with triglycerides (ß=1.5, P=0.03). Further adjustment for total fat and total energy intake did not substantially alter these results. The associations of FVII:Ag with total fat intake and total energy were at borderline statistical significance (P=0.09). Further adjustment for family history of CHD, marital status, and menopausal status did not alter the associations observed above.


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Low education and unfavorable hemostatic profile were both associated with older age, unhealthful life style, psychosocial stress, atherogenic biochemical factors, and hypertension. Levels of hemostatic factors increased with lower educational attainment, and this association was strongest and most consistent for FVII:Ag, fibrinogen, and vWF. The associations of education with FVIIa and PAI-1 were not statistically significant. Further adjustment for age, lifestyle patterns, psychosocial stress, biochemical factors, and hypertension explained a substantial part of the educational gradient in fibrinogen and vWF, but the gradient for FVII:Ag could not be fully explained by these factors. In the multivariate analyses, statistically significant independent effects on fibrinogen were found with smoking, obesity, CRP, and hypertension, whereas independent effects on FVII:Ag were found only with triglycerides.

Adjustment for psychosocial stress and lifestyle factors substantially weakened the associations of education with fibrinogen and vWF, whereas adjustment for biochemical factors and hypertension had a much smaller impact on these associations. This observation provides some support for the hypothesis that low education is associated with psychosocial stress, which may lead to an unhealthful lifestyle and result in an unfavorable hemostatic profile.

To the best of our knowledge, this is the first study to show the strong associations of low education with elevated levels of vWF and also an independent association between low education and elevated levels of FVII:Ag, after adjustment for a wide range of cardiovascular risk factors. The observed associations of low education with elevated levels of fibrinogen are consistent with earlier studies.5 20 21 22 In Finnish men and women (45 to 64 years old), the association between education and FVII:Ag was absent (P>0.80),22 whereas in the ARIC Study, low education was strongly associated with elevated levels of FVII:C.23 The absence of an association between educational attainment and PAI-1 has been previously reported.29 The univariate associations of hemostatic factors with major cardiovascular risk factors in the present study are consistent with results from other studies.1 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 23 24 25 29 30 31

Although the biological pathways between psychosocial stress and hemostatic profile are not well known, it is suggested that a combination of low SES, social isolation, and work stress may gradually increase the susceptibility to stress. Stressful situations may influence endocrine responses, including circulating cortisol levels,53 which may in turn increase insulin resistance, resulting in increased circulating fatty acids, raising triglycerides and lowering HDL levels. For example, plasma triglyceride has been shown by the present study and others23 to be an independent determinant of FVII. In addition, work stress has previously been associated with low HDL levels, after adjustment for age and other cardiovascular risk factors.54 Furthermore, work stress has previously been associated with obesity and was reported to contribute to some of the socioeconomic gradient in obesity among women.46 These studies44 54 suggest possible mechanisms by which psychosocial stress may influence biological risk factors known to disturb the hemostatic profile.5 23 31

Hemostatic Function and CHD
How hemostatic proteins may damage the circulatory system is not fully known. Hemostatic risk factors have been suggested to play a causative role in the development of atherosclerosis.5 6 23 24 55 56 57 58 59 In addition, they may be markers of inflammation and endothelial dysfunction.60 High plasma concentrations of fibrinogen, vWF, and FVII may also precipitate coronary events by enhancing procoagulant activity and reducing fibrinolytic defenses in the presence of a disrupted intracoronary plaque.61

Limitations and Strengths of the Study
The design of this study does not account for time trends of risk factor levels (eg, quitting smoking or exercising more) that may influence the strength of the association between SES and the hemostatic profile. In addition, measurement of some hemostatic factors, such as FVII, is biochemically difficult, because 2 forms of FVII molecules are present in plasma. The major proportion of FVII circulates in the zymogen single-chain form. However, low levels of the activated double-chain form ({approx}1% of the FVII mass) are also present and appear to serve a priming function for triggering the clotting cascade. It is difficult to compare results obtained in different studies because of large variations in laboratory techniques and analyses. Of note, we had the opportunity to assess the association of educational attainment and other cardiovascular risk factors with both FVII mass and FVIIa, free of FVII zymogen, by using sensitive and specific methods. Furthermore, the measured levels of hemostatic factors are influenced by gene polymorphisms27 and gene-environment interactions that were not investigated in this study. It should also be emphasized that the study sample is community based and representative of Swedish women living in a metropolitan area. The response rate was extremely high (83%). Importantly, the report is based on healthy women whose hemostatic levels were not influenced by MI or any other acute-phase reactions, as has been earlier reported.62

Conclusions
The educational differentials in hemostatic profile are suggested to be strongly mediated by lifestyle patterns and psychosocial stress and in part by biochemical factors and hypertension. Unfavorable cardiovascular risk factor profiles in persons with low educational attainment appear to be associated with an increased risk of atherosclerosis and thrombosis, which is reflected in the hemostatic profile. Smoking, a sedentary life style, obesity, hypertension, hyperlipidemia, and psychosocial stress are modifiable risk factors that should be considered in preventive strategies aimed at reducing both atherosclerosis and thrombosis, particularly among persons with low SES.


*    Acknowledgments
 
This work was supported by grant No. HL45785 from the National Institutes of Health, Bethesda, Md (to K.O.-G., K.S.G.); grants No. B93-19X-10407 and K98-19X-8691 from the Swedish Medical Research Council (to K.O.-G.); a grant from the Swedish Heart-Lung Foundation (to K.O.-G.); and a grant from the Swedish Labor Market Insurance Company (to K.O.-G.).

Received December 29, 1997; accepted July 21, 1998.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
1. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Hemostatic function in ischemic heart disease: principal results of the Northwick Park Study. Lancet. 1986;2:533–537.[Medline] [Order article via Infotrieve]

2. Stone MC, Thorp JM. Plasma fibrinogen: a major coronary risk factor. J R Coll Gen Pract. 1985;35:565–569.[Medline] [Order article via Infotrieve]

3. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA. 1987;258:1183–1186.[Abstract/Free Full Text]

4. Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–505.[Abstract]

5. Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol. 1990;43:933–939.

6. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997;96:1102–1108.[Abstract/Free Full Text]

7. Hamsten A, de Faire U, Waldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3–9.[Medline] [Order article via Infotrieve]

8. Haines AP, Howarth D, North WR, Goldenberg E, Stirling Y, Meade TW. Hemostatic variables and the outcome of myocardial infarction. Thromb Haemost. 1983;50:800–803.[Medline] [Order article via Infotrieve]

9. Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991;66:351–355.[Abstract/Free Full Text]

10. Yarnell JWG, Sweetnam PM, Elwood PC, Eastham R, Gilmor RA, O'Brien JR. Hemostatic factors and ischemic heart disease: The Caerphilly study. Br Heart J. 1985;53:483–487.[Abstract/Free Full Text]

11. Cortellaro M, Broschetti C, Cofrancesco E, Zanusi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, della Volpe A, Polli E, and the PLAT Study Group. The PLAT study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients: principal results. Arterioscler Thromb. 1992;12:1063–1070.[Abstract/Free Full Text]

12. Thompson SG, Kienast J, Pyke S, Haverkate F, van de Loo J. Hemostatic factors and the risk for myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.[Abstract/Free Full Text]

13. Lowe GDO, Drummond MM, Lorimer AR, Hutton I, Forbes CD, Prentice CR, Barbanel JC. Relation between extent of coronary artery disease and blood viscosity. BMJ. 1980;1:673–674.

14. Handa K, Kono S, Saku K, Sasaki J, Kawano T, Hiroki T, Arkawa K. Plasma fibrinogen levels as an independent indicator of severity of coronary atherosclerosis. Atherosclerosis.. 1989;77:209–213.[Medline] [Order article via Infotrieve]

15. Smith EB, Staples EM. Hemostatic factors in human aortic intima. Lancet. 1981;1:1171–1174.[Medline] [Order article via Infotrieve]

16. Grotta JC, Yatsu FM, Pettigrew LC, Rhoades H, Bratina P, Vital D, Alam R, Earls R, Picone C. Prediction of carotid stenosis progression by lipid and hematologic measurements. Neurology. 1989;39:1325–1331.[Abstract/Free Full Text]

17. Wu KK, Folsom AR, Heiss G, Davis CE, Conlan MG, Barnes R. Association of coagulation and inhibitors with carotid artery atherosclerosis: early results of the ARIC study. Ann Epidemiol. 1992;2:471–480.[Medline] [Order article via Infotrieve]

18. Miller GJ. Environmental influences on hemostasis and thrombosis: diet and smoking. Ann Epidemiol. 1992;2:387–391.[Medline] [Order article via Infotrieve]

19. Winkleby MA, Jatulis DE, Frank E, Fortmann SP. Socioeconomic status and health: how education, income and occupation contribute to risk factors for cardiovascular disease. Am J Public Health. 1992;82:816–820.[Abstract/Free Full Text]

20. Wilson T, Kaplan GA, Kauhanen J, Cohen R, Wu M, Salonen R, Salonen JT. Association between plasma fibrinogen concentration and five socioeconomic indices in Kuopio Ischemic Heart Disease Risk Factor Study. Am J Epidemiol. 1993;137:292–300.[Abstract/Free Full Text]

21. Moller L, Kristensen TS, Plasma fibrinogen and ischemic heart disease risk factors. Arterioscler Thromb. 1991;11:344–350.[Abstract/Free Full Text]

22. Myllykangas M, Pekkanen J, Rasi V, Haukkala A, Vantera E, Salomaa V. Hemostatic and other cardiovascular factors and socioeconomic status among middle aged Finnish men and women. Int J Epidemiol. 1995;24:1110–1116.[Abstract/Free Full Text]

23. Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo M. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis. 1991;91:191–205.[Medline] [Order article via Infotrieve]

24. Folsom AR, Conlan MG, Davis CE, Wu KK. Relations between hemostasis variables and cardiovascular risk factors in middle aged adults. Ann Epidemiol. 1992;2:481–494.[Medline] [Order article via Infotrieve]

25. Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb. 1994;14:193–198.[Abstract/Free Full Text]

26. Lane A, Cruickshank JK, Mitchell J, Henderson A, Humphries S, Green F. Genetic and environmental determinants of factor VII coagulant activity in ethnic groups at differing risk of coronary heart disease. Atherosclerosis. 1992;94:43–50.[Medline] [Order article via Infotrieve]

27. Hamsten A, Eriksson P, Karpe F, Silveira A. Relationship of thrombosis and fibrinolysis to atherosclerosis. Curr Opin Lipidol. 1994;5:382–389.[Medline] [Order article via Infotrieve]

28. Kannel WB, D`Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking and risk of cardiovascular disease: insights from the Framingham study. Am Heart J. 1987;113:1006–1010[Medline] [Order article via Infotrieve]

29. Rosengren A, Wilhelmsen L, Welin L, Tsipogiami A, Teger-Nilsson AC, Wedel H. Social influences and cardiovascular risk factors as determinants of plasma fibrinogen concentration in a general population sample of middle aged men. BMJ. 1990;300:634–638.

30. Balleisen L, Assmann G, Bailey J, Epping PH, Schule H, Van de Loo J. Epidemiological study on factor VII, VIII and fibrinogen in an industrial population, II: baseline data on the relation to blood pressure, blood glucose, uric acid and lipid fractions. Thromb Haemost. 1985;54:721–723.[Medline] [Order article via Infotrieve]

31. Cushman M, Yanez D, Psaty BM, Fried LP, Heiss G, Lee M, Polak JF, Savage PJ, Tracy RP. Association of fibrinogen and coagulation factors VII and VII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Am J Epidemiol. 1996;143:665–676.[Abstract/Free Full Text]

32. Brunner E, Smith GD, Marmot MG, Canner R, Beksinska M, O'Brien J. Childhood social circumstances and psychological and behavioral factors as determinants of plasma fibrinogen. Lancet. 1996;347:1008–1013.[Medline] [Order article via Infotrieve]

33. Davis MC, Mathews KA, Meilahn EN, Kiss JE. Are job characteristics related to fibrinogen levels in middle-aged women? Health Psychol. 1993;4:310–318.

34. Mattiasson I, Lindgarde F. The effect of psychosocial stress and risk factors for ischemic heart disease on the plasma fibrinogen concentration. J Intern Med. 1993;234:45–51.[Medline] [Order article via Infotrieve]

35. Orth-Gomér K, Mittleman M, Schenck-Gustafsson K, Wamala SP, Eriksson M, Belkic K, Kirkeeide R, Svane B, Rydén L. Lipoprotein(a) as determinant of coronary heart disease in young women. Circulation. 1997;95:329–334.[Abstract/Free Full Text]

36. Romelsjö A, Hasin D, Hilton M, Boström G, Diderichsen F, Haglund B, Hallqvist J, Karlsson G, Svanström L. The relationship between stressful working conditions and high alcohol consumption and severe alcohol problems in an urban general population. Br J Addict. 1992;87:1173–1183.[Medline] [Order article via Infotrieve]

37. Vermylen C, de Vreker RA, Verstraete M. A rapid enzymatic method for assay fibrinogen: fibrin polymerization time (FPT test). Clin Chim Acta. 1963;8:418–424.[Medline] [Order article via Infotrieve]

38. Amiral J, Adalbert B, Adam M. Application enzyme immunoassay to coagulation testing. Clin Chem. 1984;30:1512–1516.[Abstract/Free Full Text]

39. Wildgoose P, Nemerson Y, Hansen LL, Nielsen FE, Glazer S, Hedner U. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood. 1992;80:25–28.[Abstract/Free Full Text]

40. Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantification of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood. 1993;81:734–744.[Abstract/Free Full Text]

41. Silveira A, Green F, Karper F, Blombäck M, Humphries S, Hamsten A. Elevated levels of factor VII activity in the postprandial state: effect of the factor VII Arg-Gln polymorphism. Thromb Haemost. 1994;72:734–739.[Medline] [Order article via Infotrieve]

42. Wiman B, Chmielewska J, Ranby M. Inactivation of tissue plasminogen activator in plasma: demonstration of a complex with a new rapid inhibitor. J Biol Chem. 1984;259:3644–3657.[Abstract/Free Full Text]

43. Undén A-L, Orth-Gomér K. Development of a social support instrument for use in population surveys. Soc Sci Med. 1989;29:1387–1392.

44. Karasek R, Baker D, Marxer F, Ahlbom A, Theorell T. Job decision latitude, job demands, and cardiovascular disease: a prospective study of Swedish men. Am J Public Health. 1981;71:694–705.[Abstract/Free Full Text]

45. Willet WC, Sampson L, Stampfer J, Rosner B, Bain C, Witschi J, Hennekens CH, Speizer FE. Reproducibility and validity of semiquantitative food frequency questionnaire. Am J Epidemiol. 1995;122:51–65.[Abstract/Free Full Text]

46. Wamala SP, Wolk A, Orth-Gomér K. Determinants of obesity in relation to socioeconomic status in middle aged Swedish women. Prev Med. 1997;26:734–744.[Medline] [Order article via Infotrieve]

47. Myrhed M. Alcohol consumption in relation to factors associated with ischemic heart disease: a cotwin control study. Acta Med Scand. 1974;suppl:567.

48. Riepponen P, Marniemi J, Rautaoja T. Immunoturbidimetric determination of apolipoprotein A-1 and B in serum. Scand J Clin Lab Invest. 1987;47:739–744.[Medline] [Order article via Infotrieve]

49. Harju L, Munter M. A quantitative immunonephelometric determination of C-reactive protein in serum. Kuopio, Finland: XXI Nordic Congress in Clinical Chemistry. 1988.

50. Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem. 1969;6:24–27.

51. Jungner I, Walldius G, Holme I, Steiner E. Apolipoprotein B and A-1 in relation to serum cholesterol and triglycerides in 43 000 Swedish males and females. Int J Clin Lab Res. 1992;21:247–255.[Medline] [Order article via Infotrieve]

52. Study Group of the European Atherosclerotic Society. Strategies for the prevention of coronary heart disease: a policy statement of the European Atherosclerotic Society. Eur Heart J. 1987;8:77–78.[Abstract/Free Full Text]

53. Brindley DN, McCann BS, Niaura R, Stooney CM, Suarez EC. Stress and lipoprotein metabolism: modulators and mechanisms. Metabolism 1993;42(suppl 1):3–15.

54. Wamala SP, Wolk A, Schenck-Gustafsson K, Orth-Gomér K. Socioeconomic status and lipid profile in healthy middle-aged women in Sweden. J Epidemiol Community Health. 1997;51:400–407.[Abstract/Free Full Text]

55. Brozovic M. Physiology mechanisms in coagulation and fibrinolysis. Br Med Bull. 1977;33:23123–23128.

56. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993;118:956–963.[Abstract/Free Full Text]

57. Cook NS, Ubben D. Fibrinogen as a major risk factor in cardiovascular disease. Trends Pharmacol Sci. 1990;11:444–451.

58. Wolinsky HA. A proposal linking clearance of circulating lipoproteins to tissue metabolic activity as a basis for understanding atherogenesis. Circ Res. 1980;47:301–311.[Free Full Text]

59. Suzuki T, Yamauchi K, Matsushita T, Furumichi T, Furui H, Tsuzuki J, Saito H. Elevation of factor VII activity and mass in coronary artery disease of varying severity. Clin Cardiol. 1991;14:731–736.[Medline] [Order article via Infotrieve]

60. Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med. 1995;332:677–679.[Free Full Text]

61. Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]

62. Dormandy J, Ernst E, Matrai A, Flute PT. Hemorheological changes following acute MI. Am Heart J. 1982;104:1364–1367.[Medline] [Order article via Infotrieve]




This article has been cited by other articles:


Home page
CirculationHome page
M. A. Albert, R. J. Glynn, J. Buring, and P. M Ridker
Impact of Traditional and Novel Risk Factors on the Relationship Between Socioeconomic Status and Incident Cardiovascular Events
Circulation, December 12, 2006; 114(24): 2619 - 2626.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
E. B. Loucks, L. F. Berkman, T. L. Gruenewald, and T. E. Seeman
Social Integration Is Associated With Fibrinogen Concentration in Elderly Men
Psychosom Med, May 1, 2005; 67(3): 353 - 358.
[Abstract] [Full Text] [PDF]


Home page
AJPHHome page
K. Steenland, S. Hu, and J. Walker
All-Cause and Cause-Specific Mortality by Socioeconomic Status Among Employed Persons in 27 US States, 1984-1997
Am J Public Health, June 1, 2004; 94(6): 1037 - 1042.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
I. A. Ghiu, R. E. Ferrell, O. Kulaputana, D. A. Phares, and J. M. Hagberg
Selected genetic polymorphisms and plasma coagulation factor VII changes with exercise training
J Appl Physiol, March 1, 2004; 96(3): 985 - 990.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
A. Steptoe and M. Marmot
Burden of Psychosocial Adversity and Vulnerability in Middle Age: Associations With Biobehavioral Risk Factors and Quality of Life
Psychosom Med, November 1, 2003; 65(6): 1029 - 1037.
[Abstract] [Full Text] [PDF]


Home page
Arch Intern MedHome page
K. W. Lee and G. Y. H. Lip
Effects of Lifestyle on Hemostasis, Fibrinolysis, and Platelet Reactivity: A Systematic Review
Arch Intern Med, October 27, 2003; 163(19): 2368 - 2392.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
A. Steptoe, S. Kunz-Ebrecht, N. Owen, P. J. Feldman, G. Willemsen, C. Kirschbaum, and M. Marmot
Socioeconomic Status and Stress-Related Biological Responses Over the Working Day
Psychosom Med, May 1, 2003; 65(3): 461 - 470.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
A. Steptoe, S. Kunz-Ebrecht, N. Owen, P. J. Feldman, A. Rumley, G. D. O. Lowe, and M. Marmot
Influence of Socioeconomic Status and Job Control on Plasma Fibrinogen Responses to Acute Mental Stress
Psychosom Med, January 1, 2003; 65(1): 137 - 144.
[Abstract] [Full Text] [PDF]


Home page
Psychosom. Med.Home page
R. von Kanel, P. J. Mills, C. Fainman, and J. E. Dimsdale
Effects of Psychological Stress and Psychiatric Disorders on Blood Coagulation and Fibrinolysis: A Biobehavioral Pathway to Coronary Artery Disease?
Psychosom Med, July 1, 2001; 63(4): 531 - 544.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
M Horsten, M.A Mittleman, S.P Wamala, K Schenck-Gustafsson, and K Orth-Gomer
Depressive symptoms and lack of social integration in relation to prognosis of CHD in middle-aged women. The Stockholm Female Coronary Risk Study
Eur. Heart J., July 1, 2000; 21(13): 1072 - 1080.
[Abstract] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Kumari, M. Marmot, and E. Brunner
Social Determinants of von Willebrand Factor : The Whitehall II Study
Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1842 - 1847.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wamala, S. P.
Right arrow Articles by Orth-Gomér, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wamala, S. P.
Right arrow Articles by Orth-Gomér, K.
Related Collections
Right arrow Pathophysiology
Right arrow Risk Factors
Right arrow Anticoagulant mechanisms