Biological risk factors for deep vein trombosis

Hypercoagulable states due either to inherited or acquired thrombotic risk factors are only present in approximately half of cases of DVT, but the causes in the other half, remain unknown. The importance of biological risk factors such as hyperlipidemia, hypofibrinolysis and hemorheological alterations in the pathogenesis of DVT has not been well established. In order to ascertain whether the above mentioned biological factors are associated with DVT and could constitute independent risk factors, we carried out a case-control study in 109 first DVT patients in whom inherited or acquired thrombophilic risk factors had been ruled out and 121 healthy controls age (42+/-15 years) and sex matched. From all the biological variables analyzed (cholesterol, triglycerides, glucose, fibrinogen, erythrocyte aggregation, hematocrit, plasma viscosity and PAI-1) only fibrinogen concentration reached a statistically significant difference on the comparison of means (290+/-73 mg/dl in cases vs 268+/-58 mg/dl in controls, p<0.05). After this continuous variables were dichotomized according to our reference values, the percentage of cases with cholesterolemia >220 mg/dl, hematocrit >45% and fibrinogen >300 mg/dl was higher in cases than in controls: 38% vs 22%; p<0.01; 43% vs 27%; p<0.05; 36% vs 23%; p<0.05, respectively. The percentage of cases with PAI-1 values >30 ng/ml, 37% vs 25% was borderline significant; p=0.055. Multivariate logistic regression analysis showed that cholesterolemia >220 mg/dl and fibrinogen >300 mg/dl constitute independent predictors of venous thrombotic risk. The adjusted OR's were 2.03 (95% CI; 1.12-3.70) for cholesterolemia and 1.94 (95% CI; 1.07-3.55) for fibrinogen. When these two variables combined DVT risk rose about fourfold (3.96; p<0.05). Our results suggest that hypercholesterolemia and hyperfibrinogenemia should be added to the list of known DVT risk factors and we recommend adopting measures to decrease these variables in the population with a high risk of DVT.     

PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects

Impaired fibrinolysis as a result of increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma is a common finding in patients with deep vein thrombosis (DVT). A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to influence the levels of PAI-1. The 4G allele was found to be associated with higher plasma PAI-1 activity (act), but contradictory results on the incidence of the 4G allele in DVT patients have been reported. The aim of this study was to analyse whether the PAI-1 promoter 4G/5G genotype increases the risk of venous thrombosis in subjects with thrombophilic defects, and to determine the distribution of the PAI-1 4G/5G genotype and its relation to plasma PAI-1 levels in 190 unrelated patients with DVT in comparison with a control group of 152 healthy subjects. No differences between the 4G/5G allele distribution in the DVT group (0.43/0.57) and in the control group (0.42/0.58) were observed. However, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects. Significantly higher PAI-1 levels were observed in DVT patients than in the controls. Our results also showed significant differences in the plasma levels of PAI-1 antigen (ag) and PAI-1 act among the 4G/5G genotypes in DVT patients. A multivariate analysis revealed that, in the DVT group, PAI-1 ag levels were influenced by the 4G allele dosage, triglyceride levels and body mass index (BMI). The influence of the 4G allele dosage on PAI-1 levels was independent of the triglyceride levels and BMI. In the control group, no significant correlation between PAI-1 levels and 4G allele dosage was observed. In conclusion, the PAI-1 promoter polymorphism was found to have an influence on PAI-1 levels in DVT patients and on the risk of venous thrombosis in subjects with other genetic thrombophilic defects.     

High lipid levels and coronary disease in women in G?teborg--outcome and secular trends: a prospective 19 year follow-up in the BEDA*study.

AIMS: To provide contemporary data on the effect of high cholesterol and high triglycerides on the risk of coronary heart disease (CHD) and mortality in Swedish women and to describe secular trends with respect to serum lipids, body mass index (BMI) and smoking in the source population. METHODS: We followed 1372 women aged 39-64 years and without prior cardiovascular disease from 1980 to 1999 through record-linkage with the Swedish hospital discharge and cause-specific death registers. Risk factor measurements were done at baseline. Every fifth year between 1980 and 1995 coronary risk factors were assessed in independent samples of the source population. RESULTS: In multivariate analyses, a 1 mmol increase in cholesterol was associated with a 51% increased risk of myocardial infarction (MI) and/or revascularisation (MI; p<0.0001) and a 30% increased risk of being hospitalised for CHD (p<0.0004). Women with cholesterol, 7-7.9 mmol/l, had a threefold risk of MI (HR 3.44 (1.63-7.23)) and hazard ratios in the highest cholesterol category, > or =8 mmol/l, was 4.49 (1.92-10.50) as compared to women with cholesterol below 6 mmol/l. A 1 mmol increase in triglycerides was associated with a 49% increased risk of MI (p=0.002) and a 45% increased risk of being hospitalised for CHD (p=0.001) after adjustment for major coronary risk factors. A moderate increase in triglycerides, 1.0-1.5 mmol/l, conferred no significant increase in risk of coronary events as compared to below 1.0 mmol/l. Women with high triglycerides, 1.5-1.9 mmol/l, had a doubled risk of MI (HR 2.55 (1.20-5.42)) and hazard ratios in the highest triglyceride category, > or =2.0 mmol/l, was 3.35 (1.48-7.60). Both high cholesterol and high triglycerides predicted mortality but the magnitude was smaller than for coronary events. During the study period the proportion of women with low cholesterol profile, below 6.0 mmol/l, increased on average from 49 to 68% and the proportion of women with low triglyceride levels, below 1.0 mmol/l, decreased from 59 to 36% in the source population. A modest increase in BMI was noted. CONCLUSIONS: Both high fasting cholesterol and high fasting triglycerides strongly predicted coronary events in middle-aged Swedish women. The favourable decline in cholesterol levels and smoking rates during the study period was offset by a marked increase in triglyceride levels. The findings suggest that interventional strategies directed to correct abnormalities in the triglyceride metabolism may be specifically warranted in women.     

Raised plasminogen activator inhibitor-1 (PAI-1) is not an independent risk factor in the polycystic ovary syndrome (PCOS)

BACKGROUND: It has been postulated that an insulin-driven increase in plasminogen activator inhibitor-1 (PAI-1) levels may link insulin resistance to anovulatory infertility in women with PCOS and that it may place them at increased risk of thromboembolic disease. However, previous studies have been conflicting because many have failed to control for body mass index (BMI) which may affect PAI-1. The aim of this study was to investigate PAI-1 activity in women with PCOS and to compare it with unaffected controls of a similar BMI. DESIGN AND PATIENTS: 41 women with PCOS and 25 weight-matched controls participated in this cross-sectional study. Patients were evaluated clinically and by pelvic ultrasound and fasting blood samples were taken for haematological and biochemical tests. MEASUREMENTS: PAI-1 activity, insulin, glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, FSH, LH, PRL, testosterone, SHBG, 17-hydroxyprogesterone, plasminogen, fibrinogen (alpha2 antiplasmin, blood pressure and insulin sensitivity with a homeostasis model assessment (HOMA) computer programme. RESULTS: There was no significant difference in BMI or in (log) PAI-1 activity in women with PCOS compared with controls (BMI 29.5 +/- 5.6 vs. 28.4 +/- 6.3 kg/m2, P = 0.25 and PAI-1 2.56 (SD 0.85) vs. 2.14 (SD 0.98) au/ml, P = 0.07). The median fasting insulin level was significantly higher (17 (4.6-134.5) vs. 9.6 (3.7-41.5) mU/l, P < 0.01), and insulin sensitivity significantly lower in the PCOS group, ( 43.17% (5. 48-160) vs. 82.8% (21.8-193), P < 0.01). Women with PCOS also had a significantly higher free androgen index, LH/FSH ratio and a lower HDL/total cholesterol ratio. However blood pressure and all other lipid and haematological measurements were not significantly different between both groups. There were significant positive correlations between (log) PAI-1 activity and BMI (rho = 0.61), triglycerides (rho = 0.49) and fasting insulin (rho = 0.60) and a negative correlation with HDL cholesterol (rho = - 0.46). Triglyceride concentrations showed the most significant relationship with (log) PAI-1 activity on multiple regression. 29% of PCO women (12/41) gave a positive family history of thrombosis compared to 8% (2/25) in the control group. CONCLUSION: Plasminogen activator inhibitor-1 activity is not raised in women with PCOS independent of obesity and these results do not support the hypothesis that it may contribute to their anovulatory infertility, or increase their risk of thrombosis. The only significant metabolic features of the PCOS independent of obesity are insulin resistance, hyperinsulinaemia and lower HDL/total cholesterol ratio. The higher frequency of a positive family history of thrombosis in these women nevertheless requires further explanation.     

Triglyceride levels and the risk of coronary artery disease: a view from Australia.

A prospective study of cardiovascular disease in elderly Australians commenced in 1988 in Dubbo, New South Wales. The study population comprised 1,237 men and 1,568 women aged > or = 60 years. The prevalence rates of coronary artery disease (CAD) and putative risk factors were examined cross-sectionally in the baseline data. The age-standardized rate of CAD was 23.8/100 men and 18.1/100 women. In a univariate analysis, the major risk factors for CAD were hypertension, diabetes, family history, reduced high-density lipoprotein (HDL) cholesterol levels, and increased triglyceride levels. The prevalence rate of CAD was examined in those with low-density lipoprotein (LDL):HDL ratios < 5.0 or > 5.0. Most notably in women, the CAD rate was 16/100 with an LDL.HDL ratio < or = 5.0 and 28/100 with an LDL.HDL ratio > 5.0. In the latter group, the rate was 21/100 in those with triglycerides < or = 2.3 mmol/liter and 36/100 in those with triglycerides > 2.3 mmol/liter. In a multiple logistic model that controlled for many potential risk factors or confounding variables, CAD in men was significantly predicted by age, hypertension (odds ratio = 1.40), family history (odds ratio = 2.05), and low HDL cholesterol (odds ratio = 0.78). Significant predictors in women were age, years of education (odds ratio = 0.82), hypertension (odds ratio = 1.45), family history (odds ratio = 1.77), serum triglycerides (odds ratio = 1.30), and low HDL cholesterol (odds ratio = 0.73). An independent gradient of CAD risk with increasing triglyceride levels and a similar gradient with decreasing HDL cholesterol levels were found in women.(ABSTRACT TRUNCATED AT 250 WORDS)     

Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes

Type 2 diabetic patients have increased cancer risk. We developed and validated an all-site cancer risk score in a prospective cohort of 7374 Chinese type 2 diabetic patients free of known history of cancer at enrolment, using split-half validation. Spline Cox model was used to detect common risk factors of cancer and to guide linear transformation of non-linear risk factors. After a median follow-up period of 5.45 years, 365 patients (4.95%) developed cancer. Body mass index (BMI; <24.0 or > or =27.6 kg/m2), triglyceride (> or =0.81 to <1.41 mmol/l), high-density lipoprotein cholesterol (<0.9 or > or =1.8 mmol/l), total cholesterol (<4.3 mmol/l) and white blood cell (WBC) count (<5.8x10(9) count per litre) were associated with increased cancer risks and exhibited non-linear relationships. We further linear transformed these terms for selection using backward Cox regression (P<0.05 for stay) in the training dataset. In the test dataset, calibration was checked using Hosmer-Lemeshow test and discrimination checked using area under receiver operating characteristic curve. In addition to age and current smoking, only linear-transformed total cholesterol and WBC count were selected. The risk score was 0.0488xage (years)-0.5810xtotal cholesterol (mmol/l, coded to 4.3 if >4.3)-0.3596xWBC count (10(9) counts/l, 5.8 if >5.8)+0.6390xcurrent smoking status (1 if yes). The 5-year probability of cancer was 1-0.9590(EXP(0.9382x(RISK SCORE+1.5903))).The predicted cancer probability was not significantly different from the observed cancer probability during the 5-year follow-up. The adjusted area under receiver operating characteristic curve was 0.712. In conclusion, BMI, lipids and WBC count have predicting values for cancer.     

Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease

The increased risk of coronary heart disease (CHD) associated with depression is well documented. We hypothesized that impaired fibrinolysis is involved in this link. To explore the association of depressive mood and/or vital exhaustion with various measurements of fibrinolysis activity, 231 men (40 to 65 years old; 123 without CHD and taking no medication and 108 with documented CHD), completed the Center of Epidemiologic Studies Depression Scale and the Maastricht Questionnaire for vital exhaustion. Using classic cut-off points (Center of Epidemiologic Studies Depression Scale score >or=17, Maastricht Questionnaire score >or=8), 6.5% and 9.8% of subjects without CHD and 38% and 48.1% of those with CHD were classified as depressed and exhausted, respectively. Patients with CHD were older, had a higher body mass index, and higher levels of total cholesterol, glucose, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA) antigen, and fibrinogen; 47% were treated for hypertension. Depressed subjects had higher levels of PAI-1 activity (p = 0.006) and exhausted patients had higher levels of PAI-1 activity (p = 0.011) and fibrinogen (p = 0.009). After adjusting for clinical condition (with or without CHD), smoking, hypertension, triglyceride concentration, and body mass index, PAI-1 activity remained higher in depressed subjects (p = 0.03). This association persisted after further adjustment for vital exhaustion or for t-PA antigen and fibrinogen levels. t-PA antigen and fibrinogen levels were not associated with depressive mood in multivariate analyses. No fibrinolytic variable was associated with vital exhaustion in multivariate analyses. In conclusion, depressive mood, but not vital exhaustion, is associated with higher levels of PAI-1 activity, suggesting a possible impairment of fibrinolysis and indicating a potential additional mechanism by which depressive mood may act as a cardiovascular risk factor.     

Plasminogen activator inhibitor activity, 4G5G polymorphism of the plasminogen activator inhibitor 1 gene, and first-trimester miscarriage in women with polycystic ovary syndrome

We assessed whether hypofibrinolytic plasminogen activator inhibitor 1 (PAI-1 activity) showed an independent association with first-trimester miscarriage in the 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies (from a cohort of 967 women with PCOS). Prospectively, we hypothesized that Glucophage (Bristol-Myers Squibb, Princeton, NJ) promotes successful live births in women with PCOS by lowering PAI-1 activity before conception and maintaining further reductions of PAI-1 activity during the first trimester of pregnancy. We also assessed whether PAI-1 activity levels were independently related to PAI-1 genotype and to modifiable risk factors body mass index (BMI), insulin, and triglyceride. By stepwise logistic regression, with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208]; both > or =1 live birth and > or =1 first-trimester miscarriage [n = 111]; or first-trimester miscarriages only [n = 71]) and explanatory variables PAI-1 genotype, PAI-1 activity, insulin, homeostasis model assessment of insulin resistance, BMI, and triglyceride, PAI-1 activity was positively associated with first-trimester miscarriage (P = .004). For each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage category increased (odds ratio, 1.12; 95% confidence interval, 1.04-1.20). Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-1 activity fell 44%, but rose 19% in 23 women with first-trimester miscarriage (P = .03). In the 30 women with live birth pregnancies, median PAI-1 activity fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), whereas PAI-1 activity was either unchanged or rose in women with first-trimester miscarriage. Of the 921 women with PCOS who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87 (69%) of 126 normal female controls (chi(2) = 4.95, P = .026). The 4G allele frequency was 53% in women with PCOS vs 46% in controls (chi(2) = 4.3, P = .04). Of the 866 women with PCOS who had PAI-1 activity data, by stepwise regression, positive independent determinants of PAI-1 activity included BMI (partial R(2) = 10.6%, P < .0001), insulin (partial R(2) = 2.8%, P < .0001), triglyceride (partial R(2) = 1.1%, P = .0009), and the 4G4G-4G5G genotype (partial R(2) = 1%, P = .0011). The PAI-1 gene 4G polymorphism is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity. Preconception and first-trimester decrements in PAI-1 activity on Glucophage are associated with live births, whereas increments or no change in PAI-1 activity despite Glucophage appears to be associated with first-trimester miscarriage.     

Action levels for obesity treatment in 40 to 42-y-old men and women compared with action levels for prevention of coronary heart disease.

BACKGROUND: Guidelines for treating overweight and obesity have been suggested by the World Health Organization and other expert groups. We asked whether most men and women targeted in obesity guidelines would already be included in existing clinical recommendations for the prevention of coronary heart disease (CHD) or whether a new group of patients would be added to current workloads. SUBJECTS AND METHODS: In 1997 the Norwegian National Health Screening Service examined CHD risk factors in subjects aged 40-42 y living in three counties. We studied 6911 men and 7992 women who did not report treatment for diabetes, hypertension or the presence of cardiovascular disease. Estimated 10 y risk of CHD was calculated using the Framingham equation. RESULTS: The prevalence of single risk factors (systolic blood pressure > or =160 mmHg, diastolic blood pressure > or =95 mmHg, total cholesterol level > or =7.8 mmol/l and nonfasting glucose > or =11.1 mmol/l) ranged between 0 and 11% among subjects with body mass index > or =25 kg/m2. Adding low HDL cholesterol (<1.0 mmol/l for men, <1.1 mmol/l for women) and 10 y risk CHD risk to the classical risk factors increased prevalence to 16-50% (one or more risk factors or 10 y risk > or =10%). Sensitivities and specificities of using body mass index (BMI) or BMI and waist circumference as a screen for elevated CHD risk ranged between 22 and 91%. Screening for 10 y CHD risk of > or =10% or one or more risk factors among men and screening for one or more risk factors among women gave positive predictive values of 19-50%; however, the positive predictive value of screening for 10 y CHD risk of > or =10% was only 1-2% among women. Compared with men with BMI<30 kg/m2 or waist circumference <102 cm, those with measurements equal to or above these levels had statistically significantly higher adjusted odds ratios of elevated CHD risk (1.49, 95% CI 1.24-1.79 and 1.48, 95% CI 1.22-1.80, respectively); these associations were not observed among women. CONCLUSION: Using BMI and waist circumference to screen for CHD risk yields low positive prediction values, thus doubling the number of men and adding even more to the number of women seen by the practitioner for prevention of CHD.     

Impaired fibrinolysis and increased fibrinogen levels in South Asian subjects

The potential role of haemostatic risk markers is largely unexplored in South Asians, who have increased morbidity and mortality from cardiovascular disease and an increased prevalence of insulin resistance. To investigate differences in thrombotic risk markers between South Asian and White populations, 42 Asian and 50 White males and 96 Asian and 80 White females, clinically free from vascular disease, were recruited. Venous blood samples were taken for measures of haemostasis and determination of blood lipids. South Asian females showed lower fasting blood glucose than White females (4.6 vs. 4.8 mmol/l, P<0.008). In the South Asian population, total cholesterol was lower in females, with a similar trend in males (females 5.0 vs. 5.5 mmol/l, P<0.001; males 5.1 vs. WM 5.5 mmol/l, P=0.09), but no difference in triglyceride levels. South Asian subjects of both genders had markedly higher levels of fibrinogen (females 3.3 vs. 2.8 mg/dl, P<0.0005; males 3.0 vs. 2.5 mg/dl P<0.002) and PAI-1 activity (females 14.6 vs. 8.7 ng/ml, P<0.0005, males 21.3 vs. 12.2 ng/ml, ) P<0.0005). Factor VII:C was lower in both South Asian groups (females 110.9 vs. 122.4%, P<0.005; males 103.3 vs. 125%, P<0.0005). Factor XII was lower in South Asian females and there were no differences in Factor XII levels in male populations. These results suggest that elevated PAI-1 and fibrinogen in Asians of both genders may contribute to the increased vascular risk experienced in this population; however, the role of dyslipidaemia and Factor VII are not clear in these processes.