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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 68  |  Issue : 4  |  Page : 552-559

Is obstructive sleep apnea a risk factor for development of venous thromboembolism?


Department of Chest, Zagazig University, Zagazig, Egypt

Date of Submission20-Feb-2019
Date of Acceptance15-Jul-2019
Date of Web Publication8-Nov-2019

Correspondence Address:
MD Amal Abd El-Azem
Assistant Professor, Chest Diseases Department, Faculty of Medicine, Zagazig University, Zipcode 00003, Zagazig, Sharkia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejcdt.ejcdt_46_19

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  Abstract 


Background Obstructive sleep apnea (OSA) is associated with hypercoagulable state that could lead to venous thromboembolism (VTE) occurrence and recurrence.
Aim To study the relationship between OSA and the development of VTE.
Patients and methods This prospective study was conducted from September 2013 to March 2017 in the sleep laboratory clinic of Zain Hospital in Kuwait. A total of 72 previously diagnosed patients with OSA and 35 controls were included in the study. The patients were presented in the emergency department with acute clinical manifestations of pulmonary embolism or deep vein thrombosis or both. They were subjected to full history, general and local examination, urgent computed tomography pulmonary angiography, or ventilation/perfusion lung scan to confirm the diagnosis of pulmonary embolism. If deep venous thrombosis was also suspected, color Doppler ultrasound was also performed. After clinical stability, full night polysomnography was performed. Laboratory investigations for inherited thrombophilia were also done.
Result During the follow-up period, of our 72 patients with OSA, 18 patients developed VTE, which recurred in four patients. Among the 18 patients with OSA who developed VTE, 12 (67%) patients had severe OSA, with apnea–hypopnea index (AHI) more than or equal to 30/h, and six (33%) patients had AHI of 10–29/h. Baseline oxygen saturation (SaO2) was 90±3. Mean nocturnal SaO2 was 79±4. Low nocturnal SaO2 was 73±5. Percentage of total sleep time with SaO2 less than 90% (CT90) was 32±4. Oxygen desaturation index was 29.6±4.2. Among the patients with OSA with VTE, 12 patients were obese (BMI≥30) with a higher incidence of comorbidities. Their Epworth sleepiness score was 17.9±2.5. Overall, 83% of them had severe OSA (AHI ≥30/h), with a significant lower mean nocturnal SaO2, and low nocturnal SaO2 with a higher CT90 and oxygen desaturation index. VTE recurrent patients also showed a higher incidence of comorbidities and worse polysomnographic parameters than patients with one attack of VTE.
Conclusion Patients with OSA are likely to be at increased risk for occurrence and recurrence of VTE. This increased risk was attributed to the pathophysiological effects of OSA rather than the effect of obesity alone. OSA and obesity acted additively or synergistically to intensify the risk of VTE. This risk was higher among the patients who were not compliant with continuous positive airway pressure (CPAP) device, suggesting an increased risk with increasing severity of OSA.

Keywords: intermittent hypoxia, obstructive sleep apnea, recurrent pulmonary embolism, venous thromboembolism


How to cite this article:
Abd El-Azem A. Is obstructive sleep apnea a risk factor for development of venous thromboembolism?. Egypt J Chest Dis Tuberc 2019;68:552-9

How to cite this URL:
Abd El-Azem A. Is obstructive sleep apnea a risk factor for development of venous thromboembolism?. Egypt J Chest Dis Tuberc [serial online] 2019 [cited 2021 Jun 13];68:552-9. Available from: http://www.ejcdt.eg.net/text.asp?2019/68/4/552/270546




  Introduction Top


Obstructive sleep apnea (OSA) is characterized by recurrent episodes of either partial or complete obstruction of the upper airways during sleep, resulting in intermittent oxygen deprivation and sleep fragmentation [1]. Now OSA has been considered to play a role in the pathogenesis of many cardiovascular diseases, including congestive heart failure, systemic hypertension, arrhythmia, and stroke. Moreover, there is evidence that OSA is associated with a hypercoagulable state that predisposes to occurrence and recurrence of venous thromboembolism (VTE) [2]. Theoretically, OSA can affect the three pathways of Virchow’s risk triad. The intermittent hypoxia releases inflammatory mediators and increases oxidative stress that causes endothelial dysfunction, increases platelet activity, and reduces fibrinolytic capacity, which induces a hypercoagulable state [3].


  Aim of the work Top


The aim was to determine the effect of OSA as a risk factor for the occurrence and recurrence of VTE [pulmonary embolism (PE) and/or deep vein thrombosis (DVT)].


  Patients and study design Top


We prospectively evaluated the occurrence of PE and/or DVT among patients with OSA who were regularly followed up in our sleep laboratory clinic of Zain Hospital, Kuwait, from September 2013 to March 2017. The study was approved by the institutional ethics committee at the hospitals, and all participants gave their written informed consent. We performed this prospective observational study on 90 patients who were newly diagnosed as having OSA. The diagnosis was done according to the standard method of American Academy of Sleep Medicine, using Somnoscreen plus (SOMNO medics GmBH, Randersacker, Germany) [4]. Continuous positive airway pressure (CPAP) treatment was advised according to the guidelines [5]. They were educated to notice any warning signs of VTE and to seek rapid medical advice at our emergency department to confirm the occurrence of PE and/or DVT. The date of OSA diagnosis was defined as the index date. All patients were followed up from the index date to the end of the study (March 2017). History was taken on admission about previous attacks of VTE. If they had a known standard risk factor, they were excluded from the study, but if no risk factors, it was considered as the first attack, and if documented again during the period of study, it was considered as recurrent VTE. Four patients were excluded from the study because PE occurred as a complication after orthopedic surgery. Another two patients were excluded owing to inherited deficiency of protein S. Seven patients refused to be included in the study and five patients were not compliant for follow-up, so we continued with 72 patients. Written consent was taken from all studied patients.

Method of study and workup

The written statement mean that the first starting point for selection of our cases was to receive our OSA patients in acute clinical situation suggestive of VTE.

All participants were subjected to the following:
  1. Complete history taking including smoking, alcohol consumption, and any risk factor for VTE [prolonged immobilization, trauma, major surgery, cancer, atrial fibrillation (AF), or oral contraceptive pills]. Previous attacks of DVT or PE. Other comorbidities such as chronic obstructive pulmonary disease, restrictive lung disease, hypertension, dyslipidemia, congestive heart failure, ischemic heart disease, diabetes mellitus, and AF.
  2. Local chest and lower limb examinations.
  3. D-dimer, complete blood count, ECG, and ECHO.
  4. Doppler ultrasound on the suspected lower limb to diagnose DVT.
  5. Computed tomography pulmonary angiography, and if contraindicated, ventilation/perfusion lung scanning (V/Q). Once PE and/or DVT were confirmed, the patients were admitted to start anticoagulation and to continue investigations.
  6. Full overnight sleep study was done for all patients after clinical stability.
  7. Laboratory investigations for inherited thrombophilia screening tests were done including protein C and S, antithrombin III, factor V Leiden mutation, prothrombin gene mutation, and lupus anticoagulant.


The control group

Overall, 35 individuals were selected from those who were referred to the sleep clinic for suspicious of OSA owing to obesity or snoring. They were BMI matched to the patients to detect whether the increased incidence of VTE was attributable to the effect of OSA or to obesity per se. Epworth sleepiness score (ESS) was applied and was within normal range [6]. Overnight sleep study was done for all controls, and they were normal. They had no risk factors for VTE or past history of thrombotic attacks.

Polysomnography

The study included monitoring of the electroencephalogram, ECG, electrooculogram, electromyogram, thoracic and abdominal movements, oro-nasal airflow, snoring, body position, and pulse oximetry. Obstructive apnea was defined as complete cessation of oro-nasal airflow, lasting at least 10 s with persistent respiratory effort. Apnea was defined as more than 90% decrease in oro-nasal airflow relative to baseline level, lasting 10 s or longer. Hypopnea was defined as more than 30% decrease in oro-nasal airflow, lasting 10 s or more, associated with more than 4% decrease in arterial oxygen saturation (SaO2) below the baseline level or an arousal. Apnea–hypopnea index (AHI) was defined as the average number of apnea and/or hypopnea events per hour of sleep. The baseline SaO2 was defined as the mean saturation during the first 15 min after falling asleep. Mean nocturnal SaO2 was defined as the average SaO2 during sleep. Minimum SaO2 was defined as the lowest SaO2 value recorded during sleep. CT90 was defined as the percentage of time spent asleep with SaO2 less than 90%. Oxygen desaturation index (ODI) was defined as the average number of desaturation episodes per hour of sleep. ODI was calculated by dividing the total number of oxygen desaturations by the total hours of sleep. Desaturation was defined as more than or equal to 4% reduction in SaO2 from baseline lasting more than or equal to 10 s [4].

Inclusion criteria

  1. Newly diagnosed patients with OSA were included.


Exclusion criteria

The following were the exclusion criteria:
  1. Less than 18 years of age.
  2. Patients with history of other sleep disordered breathing.
  3. Patients diagnosed as having central sleep apnea.
  4. Previous attacks of PE and or/DVT.
  5. PE owing to infective endocarditis or connective tissue disease.
  6. Patients receiving anticoagulants.
  7. Pregnant women or those receiving hormone replacement therapy.
  8. Severe comorbidities with suspected survival less than 12 months.
  9. Patients with obstructive or restrictive lung disease.
  10. Patients with hematological disorders that predispose to hypercoagulable state.
  11. Patients with any risk factor for VTE such as malignancy, prolonged immobilization, and AF.


Statistical analysis

All statistical analyses were carried out using SPSS software version 16.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were described as mean with SD, whereas dichotomous variables were described as numbers and percentages. For comparisons between groups at each time point, unpaired t test was used for normally distributed variables and Mann–Whitney U test for nonnormally distributed variables. Frequencies were generated for categorical variables and compared with the χ2 test. P value of less than or equal to 0.05 was considered statistically significant.


  Results Top


The study was conducted on 72 patients with OSA and 35 BMI-matched controls. The general baseline characteristics of the studied participants are presented in ([Table 1]). There was no significant difference between patients with OSA and control group regarding age, sex, and BMI. Ex-smoking and alcohol consumption were significantly higher in patients with OSA. Regarding comorbidities, OSA had a significant higher prevalence of diabetes mellitus, dyslipidemia, and cerebrovascular disease. D-dimer, ESS, and daytime sleepiness were significantly higher in patients with OSA. Overall, 76% of our patients with OSA were mild to moderate (AHI 10–29/h) and 24% were severe (AHI≥30/ h). Other polysomnographic parameters showed a significant lower baseline SaO2%, mean nocturnal SaO2%, low nocturnal SaO2, with higher CT90% and ODI in patients with OSA. ([Table 2]), showed a comparison between the studied groups regarding occurrence of VTE. Of the 72 patients with OSA, 18 developed VTE. Five patients in the control group developed VTE. In both groups, those with VTE showed significant higher prevalence of smoking, alcohol consumption, and medical comorbidities and higher D-dimer level. All patients with OSA either with or without VTE presented with daytime sleepiness. Regarding OSA severity, of the 18 patients with OSA with VTE, 12 (67%) patients had severe OSA (AHI≥30/h). Other polysomnographic parameters showed significant worse parameters among patients with OSA with VTE than those without VTE. [Table 3] showed a comparison between three groups. Group 1 represents obese patients with OSA with VTE. Group 2 represents nonobese patients with OSA with VTE. Group 3 represents obese control with VTE. Among the 18 patients with OSA who developed VTE, 12 (66%) patients were obese and six (33%) patients were not obese. All the studied patients with VTE either obese or not obese had hypertension and diabetes (100%), and also all patients of group 3 had hypertension, diabetes, and dyslipidemia. Other comorbidities were significantly prevalent in obese than in nonobese patients with OSA. All patients with OSA with VTE either obese or not obese were presented with daytime sleepiness. Regarding OSA severity, 83% in group 1 and 33% in group 2 were severe. Other polysomnographic parameters showed significant worse parameters among obese than nonobese patients with OSA with VTE. Interestingly, the mean values of these parameters were normal in group 3 in spite of being obese. We can study the effect of OSA as an independent risk factor for developing VTE versus the effect of obesity alone through the comparison between groups 2 and 3. Group 2 had significantly higher ESS and daytime sleepiness scores and worse polysomnographic parameters than group 3. [Table 4] shows the comparison between patients with OSA with recurrent and nonrecurrent VTE. Among the 18 patients with OSA with VTE, four patients developed a second attack of VTE during the period of follow-up, whereas 14 patients did not show recurrence. VTE recurrent patients were older with significant higher BMI. Those with one attack of VTE were more compliant with CPAP device. All patients with OSA (with or without recurrence) were hypertensive and diabetic (100%). Cerebrovascular disease was significantly higher among those with recurrence. Both groups showed high level of D-dimer. All patients with recurrent VTE had severe OSA (AHI≥30/h) and significant worse polysomnographic parameters than those without recurrence.
Table 1 General baseline characteristics of the studied participants

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Table 2 Comparison between the studied groups regarding the occurrence of venous thromboembolism (pulmonary embolism and or/deep vein thrombosis)

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Table 3 Comparison between obstructive sleep apnea patients and controls (who developed venous thromboembolism) regarding obesity

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Table 4 Comparison between recurrent and nonrecurrent venous thromboembolism among obstructive sleep apnea patients

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  Discussion Top


There is an increasing perception that there is an association between OSA and a hypercoagulable state through many mechanisms. The intermittent nocturnal hypoxemia produces ROS and increases the production of inflammatory cytokines that downregulate activated protein C and decrease fibrinolytic activity promoting thrombus formation [7]. [Table 1] shows higher prevalence of comorbidities among patients with OSA which was consistent with that found by Cohen et al. [8], as they reported higher incidence of hypertension, diabetes, and dyslipidemia among patients with OSA. Our results showed a significant higher D-dimer level in patients with OSA, suggesting a hypercoagulable state in those patients, as also reported by Feng et al. [9]. Other studies noticed that female sex seemed to be more subjected to develop VTE [10]. However, as shown in [Table 2], our cohort population showed fewer females who developed VTE because we excluded pregnant females and those receiving oral contraceptive pills. Our results showed that cigarette smoking and alcohol consumption had a significant effect on the development of VTE. This was consistent with that found by Enga et al. [11], as they concluded that heavy smoking seemed to be a risk factor for provoking VTE. Other studies reported that heavy alcohol consumers were subjected to an increased risk of VTE [12]. We found high prevalence of hypertension and diabetes among patients with VTE than those without VTE. Similar results were found by Ageno et al. [13], as they concluded that patients with hypertension were at higher risk for DVT than controls. We noticed elevated D-dimer in patients with OSA with VTE. This was consistent with that found by Torbicki et al. [14], as they reported an association between higher D-dimer level among patients with OSA and the development of VTE. In the current study, daytime sleepiness was detected in all patients with OSA either with or without VTE. This was matched with that found by Mokhber et al. [15], as they reported excessive daytime sleepiness in OSA. Regarding OSA severity, we found that severe OSA was detected in 67% of VTE-developed patients and in 9% of the non-VTE patients. These results suggest that the prevalence of VTE increases with increasing OSA severity. Similar results were documented by Arnulf and Merino-Andreu [16], as they concluded that, the higher AHI, the higher risk of VTE. We found significant worse polysomnographic parameters among patients with OSA with VTE. These findings were consistent with that found by Budhiraja et al. [17], as they concluded that there was an association between VTE and the nocturnal hypoxemic events. Obesity is a well-known cause for OSA but it is not the only cause, as OSA may occur in nonobese individuals owing to adeno-tonsillar hypertrophy, macroglossia, mandibular deficiency, and upper airway narrowing. Obesity was associated with limited physical activity, venous stasis, impaired fibrinolysis, and high concentrations of clotting factors, which led to a procoagulant state [18]. Our results found that the risk of developing VTE increased with increasing BMI. Borch et al. [19] found that abdominal obesity and excessive visceral adiposity were an important risk factors for VTE. In ([Table 3]), we divided our cohort population into three groups to detect whether the risk of VTE was attributable to the effect of OSA or to obesity per se. We found that all polysomnographic parameters were normal in group 3 in spite of being obese. We could explain the occurrence of VTE in those patients to the effect of obesity as a risk factor. Against this conception, we had other obese patients (not OSA) but without developing VTE. So we can conclude that, although there was an association between obesity and VTE, the effect of obesity as an independent risk factor for developing VTE seemed to be weak. Similar results were found by many authors, as they concluded that the effect of obesity for developing VTE depended on the interaction between obesity and other risk factors (as genetic factors or hormonal therapy) rather than the effect of obesity alone [20]. This finding was evident in our study as we found VTE in nonobese OSA patients (group 2). Our study noticed worse polysomnographic parameters in obese patients with OSA with VTE than nonobese patients. These findings were consistent with that found by Von Känel et al. [7], as they mentioned that the intermittent hypoxemic events promote VTE in patients with OSA. [Table 4] showed comparison between recurrent and nonrecurrent VTE among patients with OSA. Four patients were presented with recurrent VTE whereas 14 patients had one attack of VTE. Our study showed that VTE recurrent patients were significantly older. This finding was consistent with that found by Duran et al. [21], as they documented that old age was a risk factors for VTE recurrence. Our study noticed higher BMI in patients with OSA with recurrent VTE than those without recurrence. Similar results were found by Nightingale et al. [22], as they documented that BMI was higher in patients with OSA with recurrent PE. Alonso-Fernández et al. [23] documented that obesity and OSA may synergistically or additively lead to upregulation of the procoagulant activity that may intensify the risk of recurrent PE. CPAP was prescribed for all patients, but their compliance was very poor. Our results showed lower CPAP compliance among those with recurrent VTE. Several studies concluded that CPAP therapy reduced the thromboembolic events in patients with OSA because it eliminated the nocturnal hypoxemia with reduction in ROS that lower the risk of PE occurrence and recurrence [24]. Our results showed higher D-dimer levels in patients with OSA with recurrent VTE. Similar results were found by Garcia Suquia et al. [25] who noticed significant elevation of D-dimer levels after stopping the anticoagulant therapy of the first attack of PE that predispose patients with OSA to recurrent PE. Other study done by Xie et al. [24] concluded that patients with OSA who developed PE required higher warfarin doses to achieve the target therapeutic level than patients without OSA and also needed to prolong the duration of anticoagulation. Other studies found a reverse relation between OSA and VTE as they concluded that OSA was commonly detected in patients diagnosed as having acute PE [26]. We found all patients with recurrent VTE had severe OSA. Arnulf and Merino-Andreu [16] also noticed that 63% of his patients with OSA with PE had severe OSA. Our study found that patients with recurrent VTE had significant lower polysomnographic parameters than those without recurrence. These findings were consistent with that found by Alberto Alonso, as they documented poor polysomnographic parameters as important risk factors for recurrent PE [24]. Another study documented that the risk of recurrent PE, which was previously attributed to obesity, is now of great concern that it might be related to the intermittent nocturnal hypoxemic events of OSA rather than owing to obesity per se [23]. Our study had some limitations like small sample size and short duration of the study, so we recommended for future studies to enlarge the sample size and to prolong the duration of study.


  Conclusion Top


Patients with OSA were likely to be at increased risk for occurrence and recurrence of VTE. This increased risk was attributed to the pathophysiological effects of OSA rather than the effect of obesity alone. OSA and obesity acted additively or synergistically to intensify the risk of VTE. This risk was higher among those not compliant to CPAP treatment. The risk was increased with increasing severity of OSA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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