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. Author manuscript; available in PMC: 2015 Dec 1.
Published in final edited form as: Sleep Breath. 2014 Feb 9;18(4):761–766. doi: 10.1007/s11325-014-0938-4

Severity of Obstructive Sleep Apnea is Associated with Elevated Plasma Fibrinogen in Otherwise Healthy Patients

Abu Shamsuzzaman 1,2, Raouf S Amin 1, Andrew D Calvin 2, Diane Davison 2, Virend K Somers 2
PMCID: PMC4384427  NIHMSID: NIHMS669200  PMID: 24510497

Abstract

Purpose

Obstructive sleep apnea (OSA) has been implicated in both cardiovascular and cerebrovascular diseases. Systemic inflammation and coagulation may be related to cardiovascular pathophysiology in patients with OSA. Fibrinogen is a major coagulation protein associated with inflammation, and long-term elevated plasma fibrinogen is associated with an increased risk of major cardiovascular diseases. We assessed whether severity of OSA is associated with levels of fibrinogen in newly diagnosed, untreated, and otherwise healthy OSA patients.

Methods

We studied 36 men with OSA and 18 male control subjects [apnea-hypopnea index (AHI) <5 events/hour]. OSA patients were divided into mild (AHI ≥5<15 events/hour) and severe (AHI ≥15 events/hour) OSA groups. Morning fibrinogen levels in OSA patients were compared to those in control subjects of similar age, body mass index, blood pressure, smoking habits, and alcohol consumption.

Results

Fibrinogen levels were significantly elevated in patients with severe OSA compared to both control (P=0.003) and mild OSA (P=0.02) subjects after adjustment for covariates. However, there were no significant differences in fibrinogen levels between mild OSA and control subjects. Fibrinogen levels were directly related to AHI and arousal index and inversely related to mean and lowest oxygen saturation during sleep.

Conclusions

Severity of OSA was associated with increased fibrinogen level independent of other factors, suggesting that apneic events and oxygen desaturation during sleep are mechanisms for increased fibrinogen levels in patients with OSA.

Keywords: Sleep apnea, coagulation, inflammation, cardiovascular disease, risk factors

Introduction

Obstructive sleep apnea (OSA) has been increasingly implicated in cardiovascular and cerebrovascular diseases [1-5]. Mechanisms such as increased sympathetic activity [6], hypertension [7], endothelial dysfunction [8], chronic inflammation [9], and coagulation [10] are potential mediators of increased risk of cardiovascular diseases.

Fibrinogen, an important contributor to the coagulation system, also has been identified as a major independent risk factor for cardiovascular and cerebrovascular diseases [11-20]. A recent meta-analysis by the Fibrinogen Studies Collaboration (FSC) reported a strong association between plasma fibrinogen level and risks of coronary heart disease, stroke, and other vascular and nonvascular mortality in healthy, middle-aged adults [21]. According to the FSC, a long-term increase of 100 mg/dL in fibrinogen level is associated with an approximate doubling in risk of major cardiovascular diseases [21]. A recently published systemic review has confirmed the significance of elevated fibrinogen for prediction of future cardiovascular risk even in the healthy, middle-aged population [22].

OSA results in repetitive and severe nocturnal hypoxemia and sleep disturbances [23]. Hypoxemia at high altitude causes increased synthesis of both fibrinogen [24] and cytokines [25]. Sleep deprivation also induces an increase in cytokines [26,27]. Thus, both chronic nighttime hypoxemia and sleep disturbances in OSA patients may lead to elevated proinflammatory cytokines, markers of inflammation, and plasma fibrinogen levels. Previous studies in patients with OSA determined that elevated fibrinogen levels were related to obesity [28] and the presence of comorbidities such as hypertension [29] and stroke [30] and were improved after nasal continuous positive airway pressure (CPAP) treatment [31,32]. However, a recent randomized and placebo-controlled crossover trial of OSA treatment with CPAP did not determine any significant treatment effects on elevated plasma fibrinogen levels [33]. Limited data are available on the effects of severity of OSA on plasma fibrinogen in otherwise healthy OSA patients. One recent study did not find any significant correlation between severity of OSA and elevated plasma fibrinogen levels in children with OSA [34]. Sleep fragmentation and hypoxemia, two important mechanisms of increased fibrinogen in OSA patients, are less evident in childhood OSA compared to adults with OSA. Therefore, we sought to determine whether severity of OSA is associated with elevated levels of plasma fibrinogen in adult OSA patients who were newly diagnosed, untreated, and otherwise healthy.

Methods

Subjects were recruited prospectively before the sleep study from the Sleep Laboratory at the Mayo Clinic in Rochester, MN. The presence and severity of OSA were determined by standard overnight polysomnography, including electroencephalography, electrooculography, electromyography, oximetry, thermistor measurements of airflow, measurements of rib cage, and abdominal movements of breathing. An apnea was defined as complete cessation of airflow for at least 10 seconds. Hypopnea was defined as 30% or greater reduction of respiratory signals for at least 10 seconds associated with oxygen desaturation of ≥4%. The apnea-hypopnea index (AHI) was calculated as the total number of respiratory events per hour of sleep.

Subjects were divided into two groups, those with and those without OSA, according to the AHI. OSA was diagnosed as the presence of AHI ≥5 events/hour. Newly diagnosed patients with OSA were divided into mild OSA (AHI ≥5<15 events/hour) and moderate-to-severe OSA (AHI ≥15 events/hour) groups. Control subjects were those with AHI <5 events/hour. Additional control subjects were recruited for sleep studies from Rochester and the surrounding area through local advertisement. Those with occult OSA by overnight polysomnography (AHI ≥5 events/hour) were excluded from the study. All recruited OSA patients were free of other diseases and had never been treated for OSA. The control group was free of any acute or chronic cardiovascular, inflammatory, or sleep disorders and on no medications.

Baseline demographic data, heart rate, and blood pressure (SpaceLabs® blood pressure monitor 90207, Issaquah, Washington, USA) were measured in each subject. Venous blood was collected in the early morning, between 6:00 AM and 7:00 AM, after full overnight polysomnography. The quantitative determination of fibrinogen was performed by the clotting method of Clauss on the STA Compact (Parsippany, NJ, USA) with fibrinogen reagents (Diagnostica Stago, Parsippany, NJ, USA) using plasma stored at -80°C. Intra-assay coefficients of variation were 5.3% at 110 mg/dL and 2.4% at 282 mg/dL. Inter-assay coefficients of variation were 3.5% at 111mg/dL and 2.5% at 286 mg/dL. Informed written consent was obtained from all subjects. The study was approved by the Institutional Human Subjects Review Committee of the Mayo Clinic, Rochester, MN.

Statistical Analysis

Statistical analyses were performed using JMP 7.0.1 (SAS Institute, Inc., Cary, NC, USA). Study groups were mild OSA, moderate-to-severe OSA, and control. Means and standard error of the means (SEM) were calculated for continuous variables. Differences between groups were calculated using the Wilcoxon rank-sum test for continuous variables. Categorical variables were described as proportion and calculated using the Chi-square test. To compare groups, an analysis of covariance (ANCOVA) model was used with covariates including age, body mass index (BMI), smoking habits and alcohol consumption, mean blood pressure, and heart rate. Bivariate associations between plasma fibrinogen and severity of OSA [log transformed AHI, arousal index (AI), mean oxygen desaturation, lowest oxygen desaturation, and percent sleep time with >90% oxygen saturation (SpO2)] were analyzed with Spearman correlation. A value of P<0.05 was considered statistically significant.

Results

Baseline characteristics of the study population are described in Table 1. Both the moderate-to-severe and mild OSA patients and the control subjects were similar with regard to demographics (age and BMI), personal habits (smoking and alcohol), and hemodynamics (blood pressure and heart rate). AHI in moderate-to-severe OSA patients was higher than in both control subjects (49.7±4.4 vs. 1.6±5 events/hour, P<0.01) and patients with mild OSA (49.7±4.4 vs. 10.4±7.1 events/hour, P<0.01). Mean SpO2 during sleep was lower in moderate-to-severe OSA patients than in both control subjects (92.5±0.5 vs. 95.7±0.6 %, P<0.01) and patients with mild OSA (92.5±0.5 vs. 93.4±0.8 %, P<0.01). The moderate-to-severe OSA patients spent more sleep time at <90% SpO2 than did both control subjects (14.7±2.9 vs. 0.2±3.5 %, P<0.01) and patients with mild OSA (14.7±2.9 vs. 4.2±4.7 %, P<0.01). Patients with mild OSA had higher AHI (10.4±7.1 vs. 1.6±5.3 events/hour, P<0.01), lower mean SpO2 (93.4±0.8 vs. 95.7±0.6 %, P<0.01), and spent more sleep time at <90% SpO2 (4.2±4.7 vs. 0.2±3.5 %, P<0.01) than control subjects.

Table1. Baseline demographics, personal habits, hemodynamics, and sleep profiles for men with obstructive sleep apnea (OSA) and control subjects.

Control
(N=18)		 Mild OSA
(N=10)		 Severe OSA
(N=26)
Mean age, yrs 44±3 50±4 47±2
Age range, yrs 25 – 66 34 – 69 38 – 67
BMI, kg/m2 30±1 32±2 35±1
Nonsmoker: smoker 17:1 5:5 20:6
Alcohol, drinks/wk 2.89±1.07 3.70±1.43 2.42±0.89
Systolic BP, mmHg 130±3 129±4 137±2
Diastolic BP, mmHg 74±3 76±3 77±2
Mean BP, mmHg 92±2 93±3 96±2
HR, bpm 70±3 71±3 75±2
AHI, events/h 1.6±5.3 10.4±7.1* 49.7±4.4*†
AI, events/h 8.5±5.2 18.6±6.9 56.1±4.3*†
Mean SpO2, % 95.7±0.6 93.4±0.8 92.5±0.5*†
Lowest SpO2, % 90.7±2.0 79.5±2.7* 77.3±1.7*†
SpO2 <90%, % sleep time 0.2±3.5 4.2±4.7 14.7±2.9*†
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Values are means ± SEM. BMI, body mass index; BP, blood pressure; HR, heart rate; AHI, apnea hypopnea index; AI, arousal index; SpO2, oxygen saturation.

*

P<0.01 vs. Control

†

P<0.01 vs. Mild OSA

Plasma fibrinogen levels were significantly elevated in patients with moderate-to-severe OSA than in both control subjects (398±18 vs. 331±25 mg/dL, P=0.003) and patients with mild OSA (398±18 vs. 334±25 mg/dL, P=0.02) after adjustment for covariates in the ANCOVA model including age, BMI, blood pressure, heart rate, smoking habits, and alcohol consumption (Figure 1). However, plasma fibrinogen levels were not significantly different in patients with mild OSA and control subjects (Figure 1). Plasma fibrinogen levels were directly related to AHI and AI, and inversely related to mean SPO2, and lowest SPO2 (Figure 2).

Figure 1.

Figure 1

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Plasma fibrinogen in control subjects and patients with mild and moderate-to-severe OSA. Values are expressed as least square means ±SEM after adjustment for covariates (age, BMI, blood pressure (BP), heart rate (HR), smoking habits, and alcohol consumption) using the ANCOVA model. Patients with moderate-to-severe OSA have significantly elevated fibrinogen levels compared to controls and patients with mild OSA. Note that fibrinogen level is not significantly different in patients with mild OSA and control subjects.

Figure 2.

Figure 2

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Correlation between plasma fibrinogen and severity of OSA expressed as (A) AHI, (B) AI, (C) mean oxygen saturation (SPO2), and (D) lowest SPO2 during sleep. AHI and AI are directly related to the level of plasma fibrinogen (A and B). Levels of mean and lowest SPO2 during sleep are inversely related to the level of plasma fibrinogen (C and D).

Discussion

A novel finding of our study is that the severity of sleep apnea as evidenced by the number of apneic events and by oxygen desaturation during sleep was associated with increased plasma fibrinogen level independent of age, BMI, blood pressure, heart rate, smoking habits, and alcohol consumption, suggesting sleep apnea as a potential mechanism for increased fibrinogen levels in patients with moderate-to-severe OSA. Plasma fibrinogen in this group was significantly higher, compared not only to control subjects without OSA, but also compared to patients with mild OSA (Figure 1). The current prospective case-control study recruited only those OSA patients who were newly diagnosed, untreated for OSA, and without any chronic and acute illness. Therefore, elevated levels of plasma fibrinogen in moderate-to-severe OSA patients reported in the current study were not caused by the presence of comorbidities associated with OSA.

Increased plasma cytokines such as IL-6 [25,24] and increased synthesis of fibrinogen [24] have been described during hypoxic conditions at high altitude. Increased daytime plasma levels of IL-6 also have been noted following sleep deprivation and in patients with excessive daytime sleepiness [26,27], and sleep deprivation also induces an increase in cytokines [26,27,35]. Fibrinogen is an acute-phase protein synthesized from the liver in response to infection and inflammation, and inflammatory cytokines modulate fibrinogen biosynthesis [36]. Therefore, OSA-related effects including hypoxic conditions and sleep disturbance during repeated apneic events with consequent sleep deprivation and daytime somnolence may be factors contributing to elevated levels of plasma fibrinogen in OSA patients.

Plasma fibrinogen is emerging as an important biomarker for cardiovascular risk [14-16,11]. Hyperfibrinogenemia has been reported as an independent risk factor for subsequent stroke, heart attack, and cardiovascular death in stroke survivors [15,37]. Systemic inflammation, thought to itself contribute to cardiovascular risk, also increases synthesis of fibrinogen by the liver [38]. Fibrinogen enhances thrombosis and atherosclerosis via its effects on platelet aggregation, blood rheology, and endothelial-cell injury [39]. Thrombosis superimposed on atherosclerosis contributes importantly to cardiovascular events [40,41,15]. Fibrinogen and its degradation products may further damage blood vessels by stimulating smooth muscle proliferation and migration [42,43].

A morning rise of plasma fibrinogen levels, attenuated after one night of nasal CPAP treatment, has been reported in OSA patients [44]. However, consistently elevated fibrinogen levels, which is a marker of cardiovascular risk, have been associated with stroke in patients with OSA [30]. Elevated levels of fibrin D-dimer are observed in OSA patients with hypertension [29]. However, a recent study in children with OSA did not find any significant association between severity of OSA and elevated plasma fibrinogen [34]. Obesity is commonly associated with OSA which affects levels of plasma fibrinogen [28]. In addition, several classic risk factors of cardiovascular diseases including age, gender, smoking habits, and alcohol consumption affect levels of plasma fibrinogen [45,46].

Our results indicate that the level of plasma fibrinogen in patients with OSA was directly related to AHI and AI and inversely related to oxygen saturation during sleep (Figure 2). Additionally, patients with severe OSA had elevated fibrinogen compared not only to control subjects, but also to patients with mild OSA (Figure 1). However, there was no significant difference in fibrinogen levels between patients with mild OSA and control subjects. Arousal index, mean SpO2 and percent sleep time spent with <90% SpO2 in mild OSA patients were not significantly different from the levels of these in control subjects, which may explain our result of an insignificant difference in plasma fibrinogen levels between patients with mild OSA and control subjects. Partial sleep loss due to repeated arousals and the level of hypoxia during sleep may be important mechanisms of elevated plasma fibrinogen levels in patients in OSA.

The results of our study have important clinical significance in that CPAP treatment in OSA patients only reduced the level of AHI and did not completely eliminate apneic events during sleep. Thus a moderate reduction of AHI to a level similar to that in mild OSA significantly reduced levels of plasma fibrinogen, thereby potentially decreasing the risk of cardiovascular morbidity and mortality. Indeed, a significant reduction of plasma fibrinogen levels in OSA patients after a brief period of nasal CPAP treatment has been previously reported [44].

One limitation of the current study was that all of the subjects were men, and the results in men cannot be extrapolated to women with OSA since women generally have increased plasma fibrinogen levels compared to men with similar age and BMI [45]. Therefore, OSA in women may be associated with further increases in fibrinogen levels and thus increase the risk of coagulopathy. Future study will determine whether OSA also affects plasma fibrinogen levels in women. An additional limitation of the study was regarding the methods, where nasal airflow was determined using a thermistor instead of the current standard procedure using nasal pressure sensors. Considering that patients with moderate-to-severe OSA had an average AHI of 50±4 events/h, we anticipate that the difference in nasal-flow measurement by nasal pressure sensor instead of thermistor would not have had a significant effect on the results.

In this study, we found that newly diagnosed OSA patients who were untreated and without any comorbid conditions, including hypertension or stroke, had elevated levels of plasma fibrinogen compared to control subjects. We also found that the severity of sleep apnea, as evidenced by the number of apneic events and by oxygen desaturation during sleep, was associated with increased fibrinogen level independent of age, BMI, blood pressure, heart rate, smoking habits, and alcohol consumption, suggesting sleep apnea as a potential mechanism for increased fibrinogen levels. Therefore, elevated plasma fibrinogen may be an important risk factor linking OSA to cardiovascular and cerebrovascular pathology.

Acknowledgments

The authors are grateful to J. Denise Wetzel, CCHMC Medical Writer, for critical review of the manuscript.

Sources of Support: These studies were supported by an American Heart Association Scientist Development Grant (0730129N, AS) and the National Institutes of Health (NIH) grants HL-70302, HL-65176, TW05463, TW05469, and 1 UL1 RR024150. This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Dr. Somers has served as a consultant for Respicardia, NeuPro, Apnex and ResMed and is an investigator on studies funded with a gift to Mayo Foundation from from the Philips-Respironics Foundation.

Footnotes

Conflict of Interest: The other authors declare that they have no conflict of interest.

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