Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome

Abstract

Objective:

To investigate whether leukocyte count, fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 activity (PAI-1) are increased in subjects with the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the World Health Organisation (WHO).

Design:

Cross-sectional study.

Subjects:

A total of 520 overweight and obese subjects: 379 women and 141 men, visiting the weight management clinic of a University Hospital.

Subjects and measurements:

Waist circumference, triglycerides, HDL cholesterol, blood pressure and fasting glucose were determined, and the presence or absence of the metabolic syndrome according to the NCEP-ATPIII criteria was assessed. In 349 subjects, data on the waist-to-hip ratio (WHR) and albumin excretion rate were available and the WHO criteria were applied. Insulin resistance was defined using the HOMA-IR index.

Results:

Subjects with the metabolic syndrome according to the NCEP-ATPIII criteria had significantly higher levels of leukocyte count (P<0.001) and PAI-1 (P<0.001), while no significant differences were found for fibrinogen or vWF (P>0.05). Using the WHO criteria, similar results were found except for vWF, where higher levels were found in subjects with the metabolic syndrome. When subjects were classified according to the number of components of the metabolic syndrome, levels of leukocyte count, vWF and PAI-1 activity were significantly different (P<0.05). In logistic regression analysis PAI-1, gender and leukocyte count were independent determinants of the metabolic syndrome (P<0.001).

Conclusion:

Evidence for being a true component of the metabolic syndrome is strong for PAI-1, less for leukocyte count and weak for vWF and fibrinogen.

Introduction

Obesity has been shown to be associated with an increased risk for cardiovascular disease, in part through its association with the classic cardiovascular risk factors.1 Reaven2 was the first to describe a cluster of metabolic abnormalities as ‘Syndrome X’ featured by insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension.2 Syndrome X was later referred to as either the ‘Insulin Resistance Syndrome’ or the ‘Metabolic Syndrome’. Recently, diagnostic criteria for the metabolic syndrome were suggested by the World Health Organisation (WHO)3 and the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP-ATPIII).4

In recent years, new insights into the pathogenesis of cardiovascular disease have been gathered and now atherosclerosis is generally viewed as a state of chronic low-grade inflammation, reflected by increased levels of leukocyte count, fibrinogen or c-reactive protein (CRP).5 An upregulation of proinflammatory cytokines leads to disturbances in the normal function of the vascular endothelium, reflected by impaired endothelium-dependent vascular relaxation and increased secretion of endothelial-derived products such as von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1).6 In addition, inflammatory mechanisms may upregulate procoagulant factors, downregulate natural anticoagulants and inhibit fibrinolytic activity.7 Recent reports have suggested an association between the different components of the metabolic syndrome and inflammatory markers,8 endothelial dysfunction9 and some markers of hemostasis and fibrinolysis.10

The present study aims to investigate whether nontraditional cardiovascular risk factors such as leukocyte count, fibrinogen, vWF and PAI-1, as markers of inflammation, coagulation, endothelial cell activation and fibrinolysis, are elevated in subjects with the metabolic syndrome, as defined by the NCEP-ATP III4 and WHO3 guidelines.

Materials and methods

Subject characteristics

Subject characteristics are shown in Table 1. Five hundred and twenty patients, 379 women (308 pre- and 71 post-menopausal) and 141 men, were included. Subjects were 104 overweight (BMI25–29.9 kg/m2) and 416 obese (BMI30 kg/m2) men and women visiting the weight management clinic of the University Hospital Antwerp. Subjects had to be 18 years or older and medication influencing coagulation such as oral anticonceptives, hormonal replacement therapy, anticoagulants, platelet inhibitors, acetyl-salicyl-acid derivatives, non-steroidal anti-inflammatory drugs or recent antibiotic use were not allowed. Patients taking lipid or blood pressure lowering medication were also not included. Other exclusion criteria were Cushing's disease, hypo- or hyperthyroidism (TSH>4 or <0.1 μU/ml, respectively), manifest hypertriglyceridemia (>400 mg/dl) and diabetes. All patients were clinically examined by a physician and shown to be, in general, good health. The study was approved by the ethical committee of the University Hospital Antwerp and all patients gave their informed consent.

Table 1 Subject characteristics

In 27 patients (5.2%), type 2 diabetes was diagnosed, 78 (15.0%) had impaired glucose tolerance and 414 (79.6%) showed a normal glucose tolerance status. Subjects were asked if they were currently smoking cigarettes and were classified as non-smokers (n=301), former smokers (n=93) or current smokers (n=126), and non-smokers were compared with current smokers. Higher levels of leukocyte count (7.7±2.1 vs 6.4±1.5 × 109/l; P<0.001) and fibrinogen (379±90 vs 350±72 mg/dl; P=0.001) were found among smokers, while no significant differences were found in Von Willebrand factor antigen (vWF:Ag) levels (158±64 vs 160±59%; P=0.529) or PAI-1 activity (19.2±9.5 vs 18.6±10.3 AU/ml; P=0.336).

Anthropometric measurements

All measurements were performed in the morning, with patients in fasting conditions and undressed. Height was measured to the nearest 0.5 cm and body weight was measured with a digital scale to the nearest 0.1 kg. Body mass index (BMI) was calculated as weight in kg over height in m2. Waist circumference was measured at the mid-level between the lower rib margin and the iliac crest. Hip circumference was measured at the level of the trochanter major and the waist-to-hip ratio (WHR) was calculated. Body composition was determined by bio-impedance analysis as described by Lukaski et al.11 and fat mass percentage was calculated, using the formula of Deurenberg et al.12 Systolic and diastolic blood pressures were determined on the right arm of the patient, after at least 5 min resting, using a mercury sphygmomanometer.

Laboratory analyses

A fasting blood sample was taken from an antecubital vein between 0800 and 1000 hours to determine fasting levels of triglycerides and HDL cholesterol. For assay of leukocyte count, fibrinogen, vWF:Ag and PAI-1 activity, blood was collected without stasis. A minimal oral glucose tolerance test was performed with 75 g of glucose, with blood samples taken to determine glucose and insulin in the fasted state and 2 h after the glucose load. Glucose tolerance status was determined according to the WHO criteria.3 Insulin resistance was estimated using the homeostasis model assessment (HOMA) as described by Matthews et al.13 and was calculated as (insulin (mU/l) × glucose (mmol/l))/22.5, with 1 as a reference value for normal insulin sensitivity.

Plasma glucose, total cholesterol and triglycerides were measured on Vitros 750 XRC (Ortho Clinical Diagnostics, Johnson & Johnson, UK). HDL cholesterol was measured on Hitachi 912 (Roche Diagnostics, Germany). Insulin levels were measured with the Medgenix two-site IRMA assay (BioSource, Belgium). Oestradiol was measured with a RIA assay (DiaSorin, Italy). FSH and TSH were measured using Vitros Immunodiagnostic Products (Ortho-Clinical Diagnostics, Johnson & Johnson, UK). Urine was collected during 24 h. Urinary albumin content was measured by immunonephelometry (Dade-Behring Nephelometer; Marburg GmbH; Germany) and the albumin excretion rate (AER) was calculated.14

Leukocyte count was measured on ADVIA 120 (Bayer, US; normal range: 4.3–10.0 × 109/l), fibrinogen was assayed with a Clauss–Vermylen-based thrombin-clotting assay with the STA-Fibrinogen reagents on an STA-analyzer (Stago, France; normal range: 200–400 mg/dl). vWF:Ag was measured with an ELISA technique (Asserachrom, Stago, France; normal range: 60–160%). PAI-1 activity (expressed as AU/ml) was measured using a chromogen substrate method (Coatest, Chromogenix, Sweden; normal range: 5–15 AU/ml).

Identification of the metabolic syndrome

The metabolic syndrome was evaluated according to the NCEP-ATPIII criteria, with patients having the metabolic syndrome if they meet three or more of the following criteria: (1) abdominal obesity (waist circumference >102 cm in men and >88 cm in women), (2) hypertriglyceridemia (150 mg/dl), (3) low HDL cholesterol (<40 mg/dl in men and <50 mg/dl in women), (4) high blood pressure (130/85 mmHg), (5) high fasting glucose (110 mg/dl).

In 349 patients, presence of the metabolic syndrome according to the WHO criteria3 could be evaluated based on the following criteria: type 2 diabetes, impaired glucose tolerance, impaired fasting glucose and/or insulin resistance plus two or more of the following criteria: (1) high blood pressure (140/90 mmHg), (2) hyperlipidemia (triglycerides 150 mg/dl and/or HDL cholesterol <35 mg/dl in men and <39 mg/dl in women), (3) central obesity (WHR >0.90 in men and >0.85 in women and/or BMI >30 kg/m2), (4) microalbuminuria (urinary albumin excretion rate 20 μg/min). As suggested previously,15 we defined insulin resistance as the upper quartile (4.26) of the distribution of the calculated HOMA-IR index in patients with normal glucose tolerance. It has been shown that the HOMA-IR index was able to rank individuals according to insulin resistance in a similar way as the euglycemic hyperinsulinemic clamp.16

Statistical analyses

Statistical calculations were performed using the statistical package SPSS version 11.0.1. (SPSS, Chicago, IL, USA). Normality of distribution was verified with a Kolmogorov–Smirnov test. Values are expressed as mean±s.d. for normally distributed variables or as median (range) for skewed variables. Since most of the variables were not normally distributed, and were not normalized after log transformation, the Spearman Rank correlations were calculated. Partial correlations were calculated to control for influencing factors. Linear regression with studentized residuals was used to test whether differences were independent of influencing factors. Differences in continuous variables were tested with a Mann–Whitney U-test or Kruskal–Wallis test, as appropriate. Differences in prevalences were determined with the χ2-test. In order to evaluate the most important metabolic determinants of the different hemostatic and fibrinolytic factors, a stepwise multiple regression analysis was performed. Multiple logistic regression, stepwise forward, was used to determine whether hemostatic or fibrinolytic factors were independent determinants of the presence of the metabolic syndrome. Results were considered significant if P<0.05.

Results

Metabolic syndrome

According to the NCEP-ATPIII criteria, 249 of the 520 (47.9%) patients included in the study were diagnosed as having the metabolic syndrome. The prevalence of the metabolic syndrome was significantly higher in men (65.2%) compared to women (41.4%) (P<0.001). The prevalence of the metabolic syndrome increased with decreasing glucose tolerance (41.4% in normal glucose tolerant patients; 72.6% in patients with impaired glucose tolerance and 81.5% in newly diagnosed diabetic patients; P<0.001) and with increasing body weight (20.2% in overweight subjects and 54.8% in obese subjects; P<0.001). In the whole group, smoking prevalence was significantly higher in subjects with the metabolic syndrome compared to subjects without the metabolic syndrome (34.7 vs 25.0%; P=0.033). However, this was not true when women and men were analyzed separately (P>0.05; Table 2). In a subgroup of 349 patients, WHO criteria were applied and 124 (35.4%) patients were defined as having the metabolic syndrome, with higher percentages in men compared to women (49.0 vs 30.1%; P=0.001). With WHO criteria, no differences were found in smoking prevalence (Table 2).

Table 2 Inflammatory, hemostatic and fibrinolytic factors and metabolic syndrome according to NCEP-ATPIII and WHO criteria

Inflammatory, hemostatic and fibrinolytic factors and the metabolic syndrome

Using the NCEP-ATPIII criteria, leukocyte count and PAI-1 activity were consistently higher in subjects with the metabolic syndrome compared to subjects without the metabolic syndrome (Table 2; P<0.05). Differences in leukocyte count persisted after adjustment for age, fat mass % or BMI. Differences in PAI-1 remained significant after correction for age or fat mass %. After correction for BMI, the differences were still significant in the whole group and in the female group, but were no longer significant in the male subgroup (P=0.104). Fibrinogen and vWF:Ag levels were not significantly higher in subjects with the metabolic syndrome (Table 2). Subjects were classified according to their total number of components of the metabolic syndrome (Figure 1). Leukocyte count, vWF:Ag and PAI-1 activity were significantly different between the subgroups (P<0.05).

Figure 1
figure1

Leukocyte count, fibrinogen, von Willebrand factor and plasminogen activator inhibitor-1 (PAI-1) activity in subjects classified according to the number of components of the metabolic syndrome (NCEP-ATPIII criteria).

Comparing subjects with and without the metabolic syndrome according to the WHO criteria yielded similar results. However, using the WHO criteria we did find higher levels of vWF:Ag in the whole group (P=0.008) and in the female subgroup (P=0.021; Table 2). Differences in leukocyte count remained significant after correction for age or fat mass %. After correction for BMI, the difference in the female subgroup became borderline significant (P=0.081). Differences in PAI-1 remained significant after correction for age, fat mass % or BMI (P0.001). The higher levels of vWF:Ag found in the whole group and the female subgroup remained significant after correction for age. After correction for fat mass %, the difference was significant in the whole group (P=0.018) and became borderline significant in the female subgroup. After adjustment for BMI, no significant differences could be found.

Regression analyses

The contribution of the different components of the metabolic syndrome in the determination of the inflammatory, hemostatic and fibrinolytic factors was assessed with multiple stepwise regression analysis (Table 3).

Table 3 Stepwise multiple regression analysis with leukocyte count, fibrinogen, vWF and PAI-1 as dependent variables, and age, gender (women=0; men=1), BMI, waist, triglycerides, HDL cholesterol, fasting glucose and systolic and diastolic blood pressure as independent variables

Logistic regression with the presence or absence of the metabolic syndrome as dependent variable and age, gender, leukocyte count, fibrinogen, vWF:Ag and PAI-1 activity as independent variables showed gender, leukocytes and PAI-1 activity as independent determinants (P<0.001) (Table 4). Adding smoking status to the model did not influence the outcome.

Table 4 Logistic regression with the presence or absence of the metabolic syndrome as dependent variable, and age, gender (0=female; 1=male), leukocyte count, fibrinogen, vWF:Ag and PAI-1 activity as independent variables

Discussion

In this study, we compared levels of leukocyte count, fibrinogen, vWF:Ag and PAI-1 as inflammatory, hemostatic and fibrinolytic markers in mainly obese subjects with and without the metabolic syndrome as defined by the NCEP-ATPIII4 and WHO3 criteria. In this group of patients attending a weight management clinic, 46.0% was diagnosed as having the metabolic syndrome according to NCEP-ATPIII criteria and 35.5% according to WHO criteria (P<0.001). This is higher compared to the ≈25% found in the general population,17 but lower as the 68% found in a group of subjects enrolled in a structured weight loss program.18 The exclusion of patients taking medication influencing coagulation, blood lipids or blood pressure probably lowered the percentage of patients diagnosed with the metabolic syndrome in our study.

It has been shown that individuals with the metabolic syndrome are at increased risk for cardiovascular morbidity and mortality.19 The traditional risk factors associated with the metabolic syndrome do not sufficiently explain all the excess vascular risk attributed to the syndrome. Therefore, precise definition of additional disturbances associated with the metabolic syndrome may be an important step in the identification of the obese patient at risk. Increases in inflammatory, hemostatic and/or fibrinolytic factors may explain in part this higher cardiovascular risk. The results found in this study were fairly consistent when using WHO or NCEP-ATPIII criteria.

Based on the results of this study, fibrinogen should not be considered as a component of the metabolic syndrome. We did not find significantly higher levels of fibrinogen in subjects with the metabolic syndrome as defined by the NCEP-ATPIII or WHO criteria. Studies using the NCEP-ATPIII criteria17, 20, 21, 22 did find higher levels of fibrinogen in subjects with the metabolic syndrome, whereas most,22, 23 but not all,21 studies using the WHO criteria did not find an increase in fibrinogen. However, these studies were population based while we selected patients from a weight management clinic resulting in a higher mean BMI. As BMI was the most important determinant of fibrinogen levels, this probably resulted in higher levels of fibrinogen in our subjects.

The evidence for vWF:Ag being a true component of the metabolic syndrome is weak. While we did not find higher levels of vWF:Ag in subjects with the metabolic syndrome defined with the NCEP-ATPIII criteria, we did find significantly higher levels of vWF:Ag in patients with the metabolic syndrome using the WHO criteria in the whole group and the female subgroup. Results from other studies are rather conflicting: while two other studies using WHO criteria23, 24 also did not find higher levels of vWF:Ag in subjects with the metabolic syndrome, a recent study in older hypertensive patients25 did find higher levels of vWF:Ag using both NCEP-ATPIII and WHO criteria. However, in the latter study,25 baseline vWF levels did not predict the development of the metabolic syndrome regardless of the criteria used. Since modified NCEP-ATPIII criteria – BMI >28.8 kg/m2 instead of waist circumference – were used and all patients were hypertensive, the results cannot be compared to results found in the present study.

Leukocyte count, as a marker of inflammation, may be considered as a component of the metabolic syndrome. The increase in leukocyte count associated with the metabolic syndrome was also found in other studies using NCEP-ATPIII17, 21, 22 or WHO criteria,23 confirming the link between inflammation and the metabolic syndrome. Ridker et al.26 recently stated that, given the consistency of data on hsCRP in large epidemiological studies, the time has come to add hsCRP as a clinical criterion for the metabolic syndrome.

Levels of PAI-1 were markedly higher in subjects with the metabolic syndrome, confirming results found in other studies using NCEP-ATPIII20 and WHO criteria.24 In multiple regression analyses, the different components of the metabolic syndrome accounted for up to 22% of the variability of plasma PAI-1 activity and for 9–14% of the variability of fibrinogen, vWF:Ag and leukocyte count.

For that reason, we support again the 10-year-old suggestion by Juhan-Vague et al.27 to definitely accept increased PAI-1 levels as a true component of the metabolic syndrome. The two recent working definitions of the metabolic syndrome3, 4 did not include increased levels of PAI-1 as a criterion for the definition of the metabolic syndrome since they did not find it necessary for the recognition of the condition3 or because it cannot be identified by routine clinical evaluation.4 However, prospective studies have shown that PAI-1 is a predictor for future cardiovascular events28 and the onset of type 2 diabetes.29 In contrast to hsCRP, the measurement of PAI-1 antigen or activity in routine clinical practice is limited by practical considerations such as the cost and standardization of blood sampling and assays,26 making it difficult to define a cut point for abnormal PAI-1 values as a clinical criterion for the metabolic syndrome. However, the measurement of PAI-1 could provide additional information on the risk of the individual patient for future cardiovascular events and to decide who will benefit most from intensive lifestyle treatment.

In conclusion, this study shows that leukocyte count, vWF and PAI-1 are increased in subjects with the metabolic syndrome, although evidence for being a true component of the syndrome is strongest for PAI-1, less for leukocyte count and weakest for vWF:Ag and fibrinogen.

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Mertens, I., Verrijken, A., Michiels, J. et al. Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome. Int J Obes 30, 1308–1314 (2006). https://doi.org/10.1038/sj.ijo.0803189

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Keywords

  • coagulation
  • fibrinolysis
  • inflammation
  • metabolic syndrome

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