Coagulation Collusion? The Overlapping Roles of OSA and Metabolic Syndrome in Prothrombotic States
Obstructive sleep apnea syndrome (OSAS) is well known to be a highly prevalent sleep disorder. It is characterized by repeated disruptions of breathing during sleep leading to excessive daytime sleepiness, neurocognitive deterioration, endocrinologic and metabolic effects, and overall decreased quality of life.1 Metabolic syndrome constitutes a collection of interrelated risk factors of metabolic origin that increase the chances of developing heart disease, stroke, and diabetes. According to the National Cholesterol Education Program (NCEP) guidelines, a diagnosis of metabolic syndrome requires three or more of the following risk factors: waist circumference 102 cm, triglycerides 1.7 mmol/L, high-density lipoprotein cholesterol (HDL-C) < 1.04 mmol/L, blood pressure 130/85 mm Hg, and fasting glucose 6.1 mmol/L.2
Multiple epidemiological studies have found links between OSAS and metabolic syndrome. Vgontzas et al. reported that fasting glucose and insulin levels were significantly higher in OSAS patients compared to weight matched controls. They also found that OSAS led to systemic inflammation and metabolic syndrome.3 Gruber et al. prospectively studied 38 subjects with OSAS and 41 controls. After adjusting for age, body mass index (BMI), and smoking, OSAS patients were found to be nearly six times more likely to have metabolic syndrome than controls.4 Lam et al. reported a similar likelihood in a study of 255 subjects.5
Recently, a number of observational and case control studies have shown associations between OSAS, metabolic syndrome and procoagualant states. While causality is yet to be firmly established, there appears to be evidence indicating an intricate interplay between sleep cycles, arousal mechanisms, and acute thrombosis.6 An elegant review by Liak et al. summarized the findings of all original peer-reviewed articles, meta-analyses and systematic reviews regarding coagulability in OSAS between 1990 and 2011. This showed that hematocrit, blood viscosity, certain clotting factors, tissue factor, platelet activity, and whole blood coagulability were increased, while fibrinolysis was impaired in patients with OSA.7 There was an association between OSA and increased levels of factors XIIa, VIIa, thrombin, PAI-1, fibrinogen, and tissue factor. Although von Willebrand factor levels were also increased, the association with OSA was unclear.7
A case-control study was recently published by Peng et al. in Thrombosis Research (6/2014). The incidence of venous thromboembolism (VTE) and pulmonary embolism (PE) were used as concrete clinical endpoints. This retrospective cohort study used data from the Longitudinal Health Insurance Database (LHID), a subset of the NHIRD established by the Bureau of National Health Insurance (NHI) in Taiwan from 1996 to 2011. 3,511 patients with OSA and 35 110 sex and age matched comparison individuals were included in this study. The incidence of deep vein thrombosis (DVT) was higher in the OSA cohort than in the comparison cohort (8.62 vs. 1.96 per 10,000 person-y), and the risk was 3.50 (95% CI = 1.83–6.69) after controlling for age, sex, hypertension, diabetes, hyperlipidemia, heart failure, malignancy, and atrial fibrillation. After a 12-year follow-up, the cumulative incidence in the OSA cohort was approximately 0.8% higher than the comparison cohort (log-rank P <0.0001). Regardless of the presence or absence of comorbidity, the OSA patients exhibited a higher risk than did the individuals in the comparison group. Furthermore, in an analysis stratified according to the follow-up duration, the risk was 4.94- and 3.05-fold higher in the OSA cohort than in the comparison cohort during the first two years and subsequent 10 years, respectively (95% CI = 1.44–17.0 and 1.42–6.52, respectively).8
As with OSA, a number of case control studies have been published exploring the potential association between the metabolic syndrome and VTE. Ageno et al. compared the incidence of metabolic syndrome in a group of 93 patients with a first episode of unprovoked DVT and in 107 controls.9 They found metabolic syndrome to be significantly more prevalent in patients with unprovoked DVT than in controls, with an adjusted odds ratio of 2.16 [95% confidence interval (CI) 1.19– 3.90]. This observation was confirmed subsequently by the results of three other case control studies with odds ratio of 1.71, 2.2, and 2.38.10-12
Contrary to the above findings, in a post hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, the presence of metabolic syndrome was not found to be associated with an increased risk of VTE.13 However, this conclusion has been criticized since the authors measured only four of the five features of the metabolic syndrome, and the cut-offs used for defining hypertension, dyslipidemia, and insulin resistance were different from those commonly proposed for diagnosis of this entity.
Two other longitudinal studies have shown associations between metabolic syndrome and VTE. 6,170 individuals enrolled in the Tromso Study were assessed for the presence of metabolic syndrome and followed up for a median of 12.3 years. In these Caucasian patients, the baseline prevalence of metabolic syndrome was 21.9%. During follow-up, the overall incidence of VTE was 2.92 per 1,000 person-years (194 validated events). Metabolic syndrome was independently associated with an increased risk of VTE, with an adjusted hazard ratio of 1.65 (95% CI 1.22–2.23). The risk of VTE increased linearly with an increasing number of the features of the metabolic syndrome, but this association remained significant only if abdominal obesity was included. Abdominal obesity was also the only component of metabolic syndrome to be independently associated with VTE.14
The second study, carried out in the population of the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, evaluated 20,374 individuals with a mean follow-up of 12.5 years. Mean age and gender were similar to the Tromso study; however, in the LITE study, 23% of the enrolled subjects were African Americans. The incidence of the metabolic syndrome in the LITE study was 34% in women and 30% in men, and the number of adjudicated VTE events was 358. A significant association between the metabolic syndrome and VTE was found only in men, with a hazard ratio of 1.84 (95% CI 1.30–2.59). Abdominal obesity was again independently associated with an increased risk of VTE, in both men and women, whereas the clustering of at least three other features of the metabolic syndrome in the absence of abdominal obesity was not.15
In summary, there is a growing body of evidence demonstrating a relationship between OSA and metabolic syndrome. Both clinical entities have independently been shown to be associated with hypercoaguable states, and specific pathologic factors have been identified. Epidemiologic studies to investigate their combined roles in the pathogenesis of VTE and PE need further exploration.
- Hoffstein V. Blood pressure, snoring, obesity, and nocturnal hypoxaemia. Lancet 1994;344:643-5.
- Grundy SM, Brewer Jr. HB, Cleeman JI, Smith Jr. SC, and Lenfant C. Definition of metabolic syndrome: report of the national heart, lung, and blood institute/American heart association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004;24:e13–e18.
- Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005;2005:9: 211–24.
- Gruber A, Horwood F, Sithole J, Ali NJ, Idris I. Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc Diabetol 2006;5:22.
- Lam JC, Lam B, Lametal C. Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir Med 2006;100:980–7.
- Kiely JL, McNicholas WT. Cardiovascular risk factors in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000;16:128-33.
- Liak C, Fitzpatrick M. Coagulability in obstructive sleep apnea. Can Respir J 2011;18:338-48.
- Peng YH, Liao WC, Chung WS, et al. Association between obstructive sleep apnea and deep vein thrombosis / pulmonary embolism: a population-based retrospective cohort study. Thromb Res 2014;34:340-5.
- Ageno W, Prandoni P, Romualdi E, et al. The metabolic syndrome and the risk of venous thrombosis. A case control study. J Thromb Haemost 2006;4:1914-18.
- Ambrosetti M, Ageno W, Salerno M, Pedretti RF, Salerno-Uriarte JA. Metabolic syndrome as a risk factor for deep vein thrombosis after acute cardiac conditions. Thromb Res 2007;120:815-18.
- Ay C, Tengler T, Vormittag R, et al. Venous thromboembolism – a manifestation of the metabolic syndrome. Haematologica 2007;92:373–9.
- Jang MJ, Choi W, Bang SM, et al. Metabolic syndrome is associated with venous thromboembolism in the Korean population. Arterioscler Thromb Vasc Biol 2009;29:311–5.
- Ray JG, Lonn E, Yi Q, Rathe A, et al. Venous thromboembolism in association with features of the metabolic syndrome. Q J Med 2007;100:679–84.
- Borch KH, Braekken SK, Mathiesen EB, et al. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: The Tromsø Study. J Thromb Haemost 2009;7:739–45.
- Steffen LM, Cushman M, Peacock JM, et al. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). J Thromb Haemost 2009;7:746–51.
Keywords: Arousal, Atrial Fibrillation, Blood Platelets, Blood Pressure, Blood Viscosity, Body Mass Index, Cholesterol, HDL, Diabetes Mellitus, Factor XIIa, Fibrinogen, Fibrinolysis, Glucose, Heart Failure, Hematocrit, Hyperlipidemias, Hypertension, Inflammation, Insulin Resistance, Metabolic Syndrome, National Health Programs, Obesity, Abdominal, Plasminogen Activator Inhibitor 1, Pulmonary Embolism, Quality of Life, Risk Factors, Sleep Apnea, Obstructive, Smoking, Stroke, Thrombin, Thromboplastin, Triglycerides, Venous Thromboembolism, Venous Thrombosis, von Willebrand Factor, Waist Circumference
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