D. M. Heywood

Circulating Levels of Factor VII, Fibrinogen, and von Willebrand Factor and Features of Insulin Resistance in First-Degree Relatives of Patients With NIDDM

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 HbAIC. 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.

Polymorphisms of the Factor VII Gene and Circulating FVII:C Levels in Relation to Acute Cerebrovascular Disease and Poststroke Mortality

BACKGROUND AND PURPOSE FVII:C has been shown to be an independent risk factor for myocardial infarction and is related to environmental and genetic factors. This study sought to investigate FVII:C levels and factor VII (FVII) gene polymorphisms in relation to stroke and disease outcome. METHODS To examine the association of FVII:C and the Msp I and promoter insertion polymorphisms of the FVII gene in acute stroke, 317 patients and 198 age-matched control subjects were studied. RESULTS FVII:C levels were significantly lower in patients at onset than 3 months later (119% versus 135%, respectively; P < .0005). Levels were significantly lower in patients at onset than in control subjects (124% [95% confidence interval, 120% to 129%] versus 141% [95% confidence interval, 135% to 148%], respectively; P < .0005) but were not significantly different at 3 months (135% [95% confidence interval, 128% to 141%] versus 141% [95% confidence interval, 135% to 148%], respectively). We found no difference in genotype distribution for either polymorphism between patients and control subjects, no difference in FVII:C level or genotype distribution between pathological types of stroke, and no relationship with poststroke mortality. Both polymorphisms were significantly associated with FVII:C levels in patients and control subjects. In a multiple regression model for patients, Msp I genotype, cholesterol, and smoking remained as independent predictors of FVII:C levels, accounting for 32% of interindividual variation. CONCLUSIONS These results suggest that neither FVII:C levels nor FVII gene polymorphisms are associated with cerebrovascular disease. There were no genotype-specific correlations of environmental factors with FVII:C, but there was evidence of an acute-phase or consumptive fall in FVII:C levels at the time of stroke, whereas levels increased to those similar for healthy age-matched control subjects by 3 months, when the acute phase had presumably subsided.

Sex Differences in Coagulation and Fibrinolysis in White Subjects With Non–Insulin-Dependent Diabetes Mellitus

The increase in cardiovascular risk associated with having non-insulin-dependent diabetes mellitus (NIDDM) is far greater in women than men. Conventional risk factors do not account for this excess, and attention has focused on the possible contribution of abnormalities of fibrinolysis and coagulation in NIDDM. In the general population a number of hemostatic factors have been shown to predict the occurrence or progression of coronary artery disease. To investigate sex differences in coagulation and fibrinolysis in NIDDM, we measured levels of fibrinogen, factor VII:C, von Willebrand factor, plasminogen activator inhibitor-1, and tissue plasminogen activator in 213 NIDDM subjects (124 men and 89 women) who were not receiving insulin therapy. The women had higher levels of factor VII:C (144% versus 120.5% in men, P < .0005) and plasminogen activator inhibitor-1 activity (25.6 versus 17.0 U/mL), and these differences remained significant when account was taken of the higher body mass index (29.6 versus 28.0 kg/m2, P = .02), glycosylated hemoglobin (7.2% versus 6.8%, P < .05), and cholesterol levels (6.3 versus 5.7 mmol/L, P < .0005) in women than men. In contrast, levels of fibrinogen (3.2 versus 3.1 g/L), tissue plasminogen activator antigen (10.6 versus 11.2 ng/mL), and von Willebrand factor (1.27 versus 1.23 IU/mL) were no different between women and men, respectively. These results suggest that elevated levels of plasminogen activator inhibitor-1 and factor VII:C may contribute to the increased cardiovascular risk of NIDDM that is particularly marked in women.

Levels of von Willebrand Factor, Insulin Resistance Syndrome, and a Common vWF Gene Polymorphism in Non‐insulin‐dependent (Type 2) Diabetes Mellitus

To examine the association between von Willebrand Factor (vWF) concentrations and features of the insulin resistance syndrome, 208 patients with Type 2 (non‐insulin‐dependent) diabetes (NIDDM) and 80 healthy controls were studied. A restriction fragment length polymorphism in exon 12 of the vWF gene, detected by Aat II endonuclease, was also examined. vWF concentrations were elevated in the patient group (patients 1.28 IU ml−1 vs controls 1.12 IU ml−1, p = 0.003). Genotype frequencies were in Hardy‐Weinberg equilibrium and genotype did not relate to vWF levels: means (95 % CI) were AA 1.29 (1.29–1.44) IU ml−1 n = 3; AG 1.28 (1.22–1.26) IU ml−1 n = 48; GG 1.29 (1.25–1.39) IU ml−1 n = 155. vWF correlated with age (r = 0.23 p < 0.0005), duration of diabetes (r = 0.23, p < 0.001), and fibrinogen (r = 0.22, p = 0.002) in the patient group, but was unrelated to blood lipids, HbA1C, body mass index, glucose, hypertension, and smoking. In a linear regression model, age and insulin remained as independent predictors of vWF levels, explaining 16 % of inter‐individual variance in the patient group. In conclusion, these findings show vWF concentrations are elevated in NIDDM and are weakly related to features of the insulin resistance syndrome. No relationship was demonstrated between the gene polymorphism studied and vWF concentrations in this group.