Elsevier

Sleep Medicine

Volume 14, Issue 1, January 2013, Pages 58-65
Sleep Medicine

Original Article
Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea

https://doi.org/10.1016/j.sleep.2012.07.009Get rights and content

Abstract

Objective

Obstructive sleep apnea (OSA) has been associated with an increased risk of atherothrombotic events. A prothrombotic state might partially explain this link. This study investigated OSA patients’ day/night rhythm of several prothrombotic markers and their potential changes with therapeutic continuous positive airway pressure (CPAP).

Methods

The study included 51 OSA patients [apnea hypopnea index (AHI) ⩾10] and 24 non-OSA controls (AHI < 10). Of the 51 OSA patients, 25 were randomized to CPAP and 26 to placebo-CPAP. Twelve blood samples were collected over a 24 h period to measure prothrombotic markers. For the apneic patients these samples were collected before treatment and after 3 weeks of treatment with either CPAP or placebo-CPAP. Day/night variation in prothrombotic markers was examined using a cosinor analysis.

Results

Compared with controls, OSA patients showed lower mesor (mean) and amplitude (difference between maximum and minimum activity) of D-dimer. In unadjusted (but not in adjusted) analysis, patients showed higher mesor of plasminogen activator inhibitor-1 (p < 0.05 in all cases). No significant group differences were seen in mesor and amplitude for either soluble tissue factor or von Willebrand factor, or the acrophase (time of the peak) and periodic pattern for any prothrombotic markers. There were no significant differences in changes of periodic pattern and in day/night rhythm parameters of prothrombotic markers pre- to post-treatment between the CPAP and placebo condition.

Conclusions

There may be altered day/night rhythm of some prothrombotic markers in OSA patients compared with controls. CPAP treatment for 3 weeks did not affect day/night rhythm of prothrombotic markers in OSA patients differently from placebo-CPAP.

Introduction

Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by transient and repetitive upper airway collapse during sleep. There is increasing evidence both from epidemiologic and mechanistic studies for a link between OSA and cardiovascular disease (CVD) that seems independent of sociodemographic and established cardiovascular risk factors [1]. Prospective studies have found that OSA increases the risk of incident atherothrombotic events such as myocardial infarction (MI) and stroke [2], [3], [4], [5]. There is also evidence that OSA is associated with an increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism [6], [7].

Several mechanisms may contribute to the initiation and progression of atherosclerosis in OSA [1]. One of these is a prothrombotic state due to a hemostatic imbalance between the coagulation and fibrinolysis systems [8], [9]. Continuous narrowing of sclerotic arteries through fibrin deposits in the vessel wall develops over decades; at the time of atherosclerotic plaque rupture, enhanced clotting may accelerate thrombus growth, thereby inducing critical myocardial or cerebral ischemia [10]. A vulnerable plaque may rupture when exposed to high shear forces during apnea-triggered blood pressure (BP) peaks. The risk of MI in OSA patients is elevated between midnight and 6:00 AM [11], possibly suggesting a triggering role of OSA physiology for MI onset.

Following up on this day/night variation in MI onset in patients with OSA and a day/night rhythm in hemostatic activity [12], [13], we recently reported the first and only data on chronobiological variation in prothrombotic markers in OSA from a sample of 38 OSA patients and 22 non-OSA controls (who are also part of the present study) [14]. We found that compared with controls, OSA patients had greater circulating levels of plasminogen activator inhibitor (PAI)-1, a major endogenous inhibitor of fibrinolysis [15], over a 24 h period; however, adjustment for systolic blood pressure (BP), body mass index (BMI), and smoking made this group difference non-significant. Relatively lower levels of the fibrin degradation product D-dimer in OSA patients relative to controls further supported the notion of a decreased fibrinolytic capacity in OSA over a 24 h period. The first aim of this study was to confirm these previous findings for PAI-1 and D-dimer using a larger sample size of OSA patients and to additionally investigate the day/night variation of two other prothrombotic markers – soluble tissue factor (sTF) and von Willebrand factor (vWF) – between OSA patients and controls. Soluble TF plays a major role in atherothrombosis by virtue of exerting procoagulant activity and thrombus propagation after plaque rupture [16]. The VWF exerts procoagulant function through stabilizing clotting factor VIII and the firm attachment of platelets to the site of the atherosclerotic lesion, where exposure of subendothelial structures occurs during MI [17].

Continuous positive airway pressure (CPAP) may reduce prothrombotic activity in OSA patients, including levels of PAI-1 [18], fibrinogen [19], and platelet aggregability [20], but findings are mixed [21]. Previous studies assessed prothrombotic markers at only one or two time points. Therefore, a natural question is whether CPAP treatment might normalize alterations in the 24 h day/night rhythm of prothrombotic activity in OSA. The second aim of this study was to investigate the effect of 3 weeks of treatment with either CPAP or placebo-CPAP on the day/night rhythm of PAI-1, D-dimer, sTF, and VWF in OSA patients. We hypothesized that, compared with placebo-CPAP, CPAP would favorably affect prothrombotic changes in OSA patients. We adjusted our analysis for important confounders of the apnea–hemostasis relationship, namely age, BMI, and BP [8].

Section snippets

Study participants

All participants provided a written informed consent to the study protocol, which was approved by The University of California San Diego (UCSD) Human Research Protection Program. We recruited patients with untreated OSA and healthy non-OSA controls from the community by advertisement, word-of-mouth, or referral from local medical practitioners. Participants with a history of major medical illnesses other than OSA and hypertension, current psychiatric diagnoses, and intake of psychotropic

Subject characteristics

The demographic and medical characteristics of the 75 study participants per OSA status and treatment allocation are presented in Table 2. The proportion of men was greater (p  0.013) and MAP was higher (p  0.032) in both groups of OSA patients compared with controls; no significant differences across the three groups were seen in terms of age, BMI, smoking status, and sleepiness. Comparison on treatment allocation revealed similar gender distribution and BP, but higher AHI (p = 0.006) in patients

Discussion

Consistent with previous studies on day/night variation in prothrombotic markers [12], [30], there was a significant day/night variation over the 24 h period in D-dimer and PAI-1 for study participants as a whole. VWF did not show day/night variation over the 24 h period, a finding that is consistent with a previous smaller study [31], but not with a large population-based study [30], suggesting that large samples might be required to detect VWF variability across the 24 h cycle. Soluble TF also

Conflicts of Interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2012.07.009.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

Acknowledgments

This work was financially supported by Grants HL44915, HL073355, AG08415, M01 RR00827 and CA23100 from the National Institutes of Health.

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