(Circulation. 1996;94:2171-2176.)
© 1996 American Heart Association, Inc.
Articles |
Circulating Levels of Factor VII, Fibrinogen, and von Willebrand Factor and Features of Insulin Resistance in First-Degree Relatives of Patients With NIDDM
the Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, UK.
Correspondence to Dr Michael W. Mansfield, Unit of Molecular Vascular Medicine, G-Floor, Martin Wing, The General Infirmary, Leeds, LS1 3EX, UK. E-mail michaelm@pathology.leeds.ac.uk.
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Abstract |
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Background First-degree relatives of patients with non–insulin-dependent diabetes mellitus (NIDDM) have an increased risk of coronary artery disease partly attributable to clustering of risk factors in association with insulin resistance. Circulating levels of some hemostatic factors predict coronary events, and there is growing evidence that insulin resistance is also associated with abnormalities of coagulation and fibrinolysis. This study examined the hypotheses that elevated levels of factor VII coagulant activity (FVII:C), fibrinogen, and von Willebrand factor (vWF) occur (1) in first-degree relatives of NIDDM patients and (2) in association with recognized features of insulin resistance.
Methods and Results Fasting blood samples were taken from 132 first-degree relatives of NIDDM patients and 151 age-matched control subjects for measurement of FVII:C, fibrinogen, vWF, insulin, total and HDL cholesterol, triglyceride, glucose, and HbA1C. Levels of FVII:C (130% versus 122%, P<.02) and fibrinogen (3.0 versus 2.7 g/L, P=.002) were higher in relatives than in control subjects, and there was no significant difference in levels of vWF (0.98 versus 0.95 IU/mL). There was a graded association with features of insulin resistance, which was strongest for FVII:C, weaker for fibrinogen, and weakest for vWF.
Conclusions FVII:C and fibrinogen levels are increased in relatives of patients with NIDDM. Levels of FVII:C and, to a lesser extent, fibrinogen and vWF cluster with other risk factors associated with insulin resistance. Abnormalities of circulating hemostatic factors, possibly in relation to insulin resistance, may contribute to cardiovascular risk in relatives of patients with NIDDM.
Key Words: coagulation • diabetes mellitus • genetics • insulin • risk factors
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Introduction |
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Insulin resistance, with its attendant clustering of cardiovascular risk factors (obesity, increased waist-to-hip ratio, hypertension, hyperinsulinemia, glucose intolerance, hypertriglyceridemia, and low HDL cholesterol), is recognized as a major determinant of coronary artery disease both in the general population and in conditions associated with insulin resistance.1 2 It has become clear that the syndrome of insulin resistance also involves abnormalities of hemostasis, particularly suppression of fibrinolysis through elevated levels of PAI-1.3 4 5 6 Inspection of data from cross-sectional studies indicates that levels of the coagulant factors FVII, vWF, and fibrinogen also correlate to various degrees with some features of insulin resistance,7 8 9 and these factors are all elevated in NIDDM.10 11 12 13 14 In large prospective studies, including the Northwick Park Heart Study, Framingham, PROCAM, PLAT, and ECAT studies, circulating levels of fibrinogen,15 16 17 18 19 20 FVII activity,16 17 and vWF19 21 have been related to the development or progression of coronary artery disease.
Relatives of subjects with NIDDM show an increased prevalence of cardiovascular risk factors that predict progression to diabetes and suggest a link between underlying insulin resistance and increased vascular risk in such subjects.22 23 24 25 26 It is possible that elevated levels of coagulant factors in relatives of NIDDM patients may contribute to this increased vascular risk either in association with insulin resistance or independently.
In this study, we compared circulating levels of FVII activity, fibrinogen, and vWF in the relatives of NIDDM patients with those in control subjects and examined their relationship to other recognized features of insulin resistance in both groups. In view of the strong genetic influence on circulating levels of FVII, we also determined genotype at a common coding Arg-Gln polymorphism in exon 827 and a common decanucleotide insertion polymorphism in the promoter of the FVII gene.28
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Methods |
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We recruited 132 first-degree relatives of NIDDM patients through the diabetes center at the General Infirmary in Leeds. All but 2 of the relatives came from different families. We recruited 151 unrelated control subjects without a personal or close family history of diabetes from large employers in Leeds. All subjects were Caucasian, and each subject gave informed consent according to a protocol approved by the United Leeds Teaching Hospitals (NHS) Trust Research Ethics Committee.
After an overnight fast of at least 10 hours and then a 20-minute rest, fasting blood samples were drawn from an antecubital vein with a 19-gauge needle without venous stasis. Blood was taken into 0.9% citrate (pH 8.8) on ice at a ratio of 9 parts blood to 1 part citrate for assay of fibrinogen and PAI-1 levels and into lithium heparin on ice for analysis of insulin levels. These samples were centrifuged at 2560g at 4°C for 30 minutes. Blood was taken into 0.9% citrate at room temperature for assay of FVII activity (FVII:C) and vWF and was centrifuged at 2560g at room temperature for 20 minutes. Aliquots of plasma from the spun samples were snap-frozen in liquid nitrogen and stored at -40°C until assay. Blood was collected into lithium fluoride for plasma glucose estimation, into lithium heparin for plasma lipid analysis, and into EDTA for glycosylated hemoglobin (HbA1C) estimation and DNA extraction.
Blood pressure was measured to the nearest 2 mm Hg with subjects in a sitting position. Systolic and diastolic blood pressures were calculated from the mean of three readings. Subjects receiving blood pressure–lowering therapy were excluded from analysis of blood pressure levels. BMI was calculated from weight in kilograms divided by the square of height in meters. Current smoking habit was recorded as current smoker or nonsmoker and pack-year history (the number of cigarettes smoked per day multiplied by the duration of smoking in years and divided by 20).
FVII:C levels were measured by an ACL 3000 plus (Instrumentation Laboratory) with FVII-deficient plasma and rabbit thromboplastin (Instrumentation Laboratory) as reagents. FVII:C was expressed as a percentage of activity given by calibration plasma. Thirteen subjects were excluded from analysis of FVII levels: 1 subject (NIDDM relative) who was receiving warfarin therapy and 10 relatives and 2 control subjects recruited early in the study from whom room-temperature citrated plasma samples were not processed. Fibrinogen was measured by the Clauss method,10 vWF by ELISA (Dako), PAI-1 activity by chromogenic assay (Spectrolyse, Biopool), and plasma insulin levels by radioimmunoassay (Pharmacia). Measurements of plasma glucose (by a glucose oxidase method), cholesterol, and triglyceride were made with a Hitachi 747 autoanalyzer (Boehringer Mannheim). HDL cholesterol was measured by a Hitachi 717 autoanalyzer (Boehringer Mannheim) after removal of chylomicrons, LDL, and VLDL by precipitation with phosphotungstic acid and magnesium chloride. HbA1C was measured by Glycomat autoanalyzer (Ciba Corning) with a reference range of 4.5% to 6.5%. Interassay and intra-assay coefficients of variation were 4.3% and 3.2%, respectively, for FVII:C, 3.5% and 2.0% for fibrinogen, 4.7% and 2.8% for vWF, 8.0% and 5.0% for PAI-1 activity, and 15% and 4.4% at 8 mU/L and 3.8% and 2.5% at 30 mU/L for the insulin assay.
Values for relative insulin resistance were estimated by use of the HOMA, which assumes that normal-weight, healthy subjects <35 years old have 100% ß-cell function and an insulin resistance of unity.29
Genotype at the FVII Arg-Gln and promoter decanucleotide polymorphisms was determined as described previously.30 At the Arg-Gln polymorphism, the alleles are denoted by the appropriate amino acid abbreviation, Arg or Gln. At the promoter polymorphism, the more frequent allele, absence of the insertion, was denoted as "A" and the less frequent allele, presence of the insertion, as "a." Full genotype data were absent from 3 relatives and 5 control subjects, genomic DNA was unavailable from 6 individuals, and PCR amplification failed repeatedly at each polymorphism in 1 different individual.
Values for age and HDL cholesterol did not conform to a normal distribution and are presented as medians with 25th and 75th percentiles. Differences in these measurements between groups were assessed by the Mann-Whitney test. Values for BMI, insulin, relative insulin resistance, triglyceride, fibrinogen, vWF, and PAI-1 activity were loge transformed because their distributions then conformed to normality. For these variables, data are presented as geometric mean and antilog 95% CI. Differences in continuous and parametric data between the two groups were assessed by Student's t test. Differences in categorical data between the two groups were assessed with the 
2 test. At the FVII gene polymorphisms, subjects homozygous for the infrequent alleles Gln or a were grouped with those heterozygous at that polymorphism. Spearman bivariate correlation was used to assess the relationship of levels of FVII:C, fibrinogen, and vWF levels with other continuous variables. Factorial ANOVA was used to compare levels of hemostatic factors between relatives and control subjects, allowing for differences in (nonhemostatic) variates found to correlate with that factor on Spearman analysis, with sex as a forced variable in each case and genotype as a covariate for FVII:C levels. Multiple linear regression analysis with the same covariates was then performed for relatives and control subjects separately. Statistical significance was taken as P<.05. All statistical analyses were performed with SPSS for Windows version 6.1.
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Results |
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The clinical characteristics of the relative and control groups are shown in Table 1
. There was no significant difference between the median ages of the two groups. There was a preponderance of women in both groups, more marked in the NIDDM relatives, who also showed a greater prevalence of current cigarette smoking. The relatives had greater BMI than the control subjects; this was attributable to differences in weight and mean height levels being very similar: relatives, 168 cm and control subjects, 169 cm. Use of antihypertensive agents was similar in the two groups, and when such subjects were excluded from analysis, levels of both systolic and diastolic blood pressures were comparable in the two groups. The NIDDM relatives showed higher fasting levels of insulin and triglycerides and lower levels of HDL cholesterol, but there was no difference in fasting levels of glucose or of HbA1C (Table 1). The HOMA estimation of insulin resistance was greater in the relatives than in the control subjects. Levels of PAI-1 were higher in relatives than in control subjects and were significantly correlated with the features of insulin resistance: BMI, fasting insulin, and triglyceride (r>.30, P<.0005) and HDL cholesterol (r<-.22, P<.05) in both relative and control groups.
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Factor VII:C
Levels of FVII:C were significantly higher in relatives than control subjects, with a mean difference of 8% (P<.02) (Table 1
), and tended to be higher in women than in men in both groups, although these differences did not reach standard levels of significance, even when the groups were combined (Table 2). Levels of FVII:C were not different between smokers and nonsmokers.
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In both relatives and control subjects, FVII:C levels correlated with BMI, insulin, triglyceride, total cholesterol levels, PAI-1 activity, HbA1C, and age. In the relatives, FVII:C also correlated with systolic and diastolic blood pressures and in the control subjects, with fasting glucose (Table 3).
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Variation at the FVII gene did not explain the increased FVII:C levels in relatives, because at both polymorphisms, the genotype frequencies were no different between the two groups: exon 8 Arg-Gln polymorphism: relatives, Arg/Arg 110, Arg/Gln 18, and Gln/Gln 1; control subjects, Arg/Arg 118, Arg/Gln 27, and Gln/Gln 1; promoter decanucleotide polymorphism: relatives, A/A 114, A/a 12, a/a 3; and control subjects, A/A 121, A/a 25. These frequencies were in Hardy-Weinberg equilibrium at each polymorphism. In relatives and control subjects, levels of FVII:C were lower in carriers of the Gln allele than Arg/Arg homozygotes (relatives, 110% versus 134%, P<.0005; control subjects, 108% versus 127%, P<.001) or the a allele compared with A/A homozygotes (relatives, 103% versus 134%, P<.0005; control subjects, 108% versus 126%, P=.002). When genotypes at both loci were entered into stepwise regression models for FVII:C levels in the combined group of relatives and control subjects, the Arg-Gln genotype was invariably retained in the model and the promoter decanucleotide insertion rejected, suggesting a closer association of Arg-Gln genotype with circulating levels.
In a factorial ANOVA model allowing for the effect of other covariates, FVII:C remained associated with the Arg-Gln genotype (coefficient [B]=21, P<.0005), loge insulin (B=15, P<.0005), total cholesterol (B=5.4, P<.0005), and age (B=.29, P<.01) but was not independently associated with having a first-degree relative with NIDDM. The other insignificant covariates were HbA1C, sex, HDL cholesterol, and triglyceride, and the R2 value was .40. To examine for interaction between Arg-Gln genotype and triglyceride levels, as has been reported previously,27 a genotype-triglyceride interaction term was added to the model, but this term did not contribute significantly to the determination of FVII:C levels. In separate linear regression models, FVII:C levels remained independently and significantly related to Arg-Gln genotype, insulin levels, and age in the relatives and Arg-Gln genotype, insulin, cholesterol, and triglyceride in the control subjects.
Fibrinogen
Levels of fibrinogen were significantly higher in relatives than in control subjects, with a mean difference of 0.24 g/L (P<.002) (Table 1), and were higher in women than men in both relative and control groups (Table 2). Fibrinogen levels were higher in smokers (3.2 g/L) than nonsmokers (2.8 g/L) (P<.0005), although when analyzed by group, this difference reached significance only in the relatives (3.3 versus 2.9 g/L, P<.005), with a low frequency of smoking in the control subjects. This effect of smoking on fibrinogen levels did not fully account for the higher fibrinogen levels in the relatives when smoking habit, history of ever having smoked, and/or pack-year history were entered with sex in a factorial ANOVA model.
In relatives and control subjects, levels of fibrinogen correlated with age, HbA1C, and BMI, and in the control subjects only, with fasting levels of insulin, total cholesterol, and triglyceride (Table 3).
In an ANOVA model examining fibrinogen levels in all subjects, current smoking (B=.092, P<.01), sex, with higher levels in women (B=.080, P<.005), loge BMI (B=.35, P<.0005), age (B=.004, P<.0005), and HbA1C (B=.06, P<.0005) remained independently related to (loge) fibrinogen levels. Having a first-degree relative with NIDDM was not an independent predictor of fibrinogen levels. The other covariates were total cholesterol, insulin, and triglyceride, and the R2 value was .26. In the separate regression models, fibrinogen levels remained independently related to smoking habit, age, and BMI in the relatives and sex, age, triglyceride, HbA1C, and BMI in the control subjects.
von Willebrand Factor
Levels of vWF were similar in relative and control groups (Table 1), with higher levels in female subjects of both groups (Table 2) but no difference between smokers and nonsmokers.
On factorial ANOVA, loge levels of vWF were independently related to sex (B=.12, P<.005), age (B=.008, P<.0005), and loge insulin levels (B=.17, P<.005), with no difference in vWF levels between relatives and control subjects. This model had an R2 value of only .17. In separate regression models, vWF levels remained independently related to age and insulin levels in relatives and control subjects, and the association with sex just failed to reach significance in the relatives (P=.06) and control subjects (P=.07).
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Discussion |
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In this study, we found increased levels of both FVII:C and fibrinogen but not vWF in the first-degree relatives of NIDDM patients. The relatives also showed evidence of increased expression of insulin resistance, with increased levels of its metabolic features as described by others23 26 ; higher levels of PAI-1, which have not been described previously; and increased insulin resistance as estimated by the HOMA model. The statistical models indicate that the differences in levels of FVII:C and fibrinogen were related to the higher BMI, fasting levels of insulin and triglyceride, and prevalence of smoking (for fibrinogen only) in the relatives, although causal associations cannot be inferred from such models.
Factor VII:C
Elevated levels of FVII:C may contribute to increased coronary risk in relatives of NIDDM patients. The difference in FVII:C levels of 8% between relatives and control subjects is small in the context of the findings of the Northwick Park Heart Study, in which a 25% increase in FVII:C was associated with a 62% increase in risk of a major coronary event in 5 years.17 However, in contrast to the FVII:C assay we used, the assay used in the Northwick Park Heart Study also detects activated FVII, and this may increase its power to predict coronary disease.31
Levels of FVII:C were correlated with most (insulin, triglyceride, PAI-1 activity, and BMI) but not all (HDL cholesterol) of the features of insulin resistance examined in the study. An association with blood pressure was evident in the relatives but not control subjects; however, the exclusion of those few subjects receiving antihypertensive therapy who would probably have shown the highest pressures may have blunted these associations. The association of FVII levels with metabolic features of insulin resistance, particularly BMI and dyslipidemia, has been well documented.7 8 9 30 In addition, the ARIC study reported a positive association between levels of insulin and FVII:C.7 Our data take these findings further by demonstrating that FVII:C levels also correlate with plasma PAI-1 activity, lending weight to the association of FVII levels with features of insulin resistance that we found both within our two study groups and as a trend across the two groups.
The tendency to higher FVII:C levels in women in this study is in keeping with similar findings in both healthy and diabetic populations.7 8 32
It is clear that differences in FVII genotype frequencies did not account for the higher levels of FVII in the relatives of NIDDM patients. The finding that genotype at the promoter decanucleotide polymorphism is a less powerful predictor of FVII levels than the Arg-Gln polymorphism, with which it is in linkage disequilibrium, is in keeping with similar data from patients with NIDDM30 and supports the evidence suggesting that the Arg-Gln polymorphism is functional.33
Fibrinogen
Cigarette smoking was strongly related to fibrinogen level but did not account for the difference between relatives and control subjects. The different frequencies of cigarette smoking between the two groups probably reflect some bias toward recruiting health-conscious control subjects. It is reassuring in this respect that mean height was no different between the two groups, suggesting no important difference in socioeconomic background.
In comparison with FVII, the bivariate associations of circulating fibrinogen concentrations with the features of insulin resistance were less striking; indeed, in the relatives there was no significant association of fibrinogen with either fasting insulin or triglyceride levels. The absence of fasting insulin level as an independent predictor of fibrinogen levels in the regression models is a further indication that an underlying association with insulin resistance, if present, is weaker than is the case for FVII in the subjects we studied.
An association between fibrinogen levels and BMI, LDL cholesterol, and triglyceride has been reported in many studies,34 and the ARIC study also found rising fibrinogen levels across rising quartiles of fasting insulin concentration.7 In contrast to this, the association between fibrinogen levels and insulin resistance measured by glycemic clamping methods has yielded varying results, with no association found in obese women4 and cigarette smokers35 but a strong correlation found in hypertensive men.3
von Willebrand Factor
In contrast to our findings for FVII:C and fibrinogen, we found no difference in levels of vWF between relatives and control subjects. Furthermore, there was no consistent or strong association of vWF levels with the features of insulin resistance in either group or in the groups combined.
In conclusion, first-degree relatives of patients with NIDDM show alterations in hemostasis in addition to the clustering of vascular risk factors associated with insulin resistance. These abnormalities may theoretically contribute to the increased vascular risk of such subjects, although prospective studies would be required to determine the extent of this effect.
Our data suggest that levels of FVII:C may be a further hemostatic marker of underlying insulin resistance, explaining the higher levels in NIDDM relatives and possibly accounting for the predictive power of FVII:C levels with respect to coronary artery disease.17 An association of fibrinogen with the features of insulin resistance is less clear in our data, and other factors, including smoking habit, may have also contributed to the higher levels in the relatives. Although NIDDM relatives are at increased risk of premature atherosclerosis, there was no difference between relatives and control subjects in levels of vWF, a marker of endothelial damage,21 suggesting that subclinical vascular disease did not account for the difference in fibrinogen levels.
If the association of these abnormalities of hemostasis with insulin resistance is confirmed, it will offer a mechanism through which insulin resistance can contribute to thrombosis in addition to atherogenesis. This may open further avenues for tackling the increased burden of coronary disease in relatives of NIDDM patients and other subjects with insulin resistance.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the British Heart Foundation, the Northern and Yorkshire Regional Health Authority, and the United Leeds Teaching Hospitals Special Trustees.
Received March 5, 1996; revision received May 23, 1996; accepted June 1, 1996.
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 J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
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J. D Mills and P. J Grant Insulin resistance, haemostatic factors and cardiovascular risk The British Journal of Diabetes & Vascular Disease, January 1, 2002; 2(1): 19 - 26. [Abstract] [PDF]
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 P. A. Sakkinen, P. Wahl, M. Cushman, M. R. Lewis, and R. P. Tracy Clustering of Procoagulation, Inflammation, and Fibrinolysis Variables with Metabolic Factors in Insulin Resistance Syndrome Am. J. Epidemiol., November 15, 2000; 152(10): 897 - 907. [Abstract] [Full Text] [PDF]
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 H. P. Kohler and P. J. Grant Plasminogen-Activator Inhibitor Type 1 and Coronary Artery Disease N. Engl. J. Med., June 15, 2000; 342(24): 1792 - 1801. [Full Text] [PDF]
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 D. A. Lane and P. J. Grant Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease Blood, March 1, 2000; 95(5): 1517 - 1532. [Full Text] [PDF]
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 J. B. Meigs, M. A. Mittleman, D. M. Nathan, G. H. Tofler, D. E. Singer, P. M. Murphy-Sheehy, I. Lipinska, R. B. D'Agostino, and P. W. F. Wilson Hyperinsulinemia, Hyperglycemia, and Impaired Hemostasis: The Framingham Offspring Study JAMA, January 12, 2000; 283(2): 221 - 228. [Abstract] [Full Text] [PDF]
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 A. Fu and K. S. Nair Age effect on fibrinogen and albumin synthesis in humans Am J Physiol Endocrinol Metab, December 1, 1998; 275(6): E1023 - E1030. [Abstract] [Full Text] [PDF]
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J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
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