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July2007 Vol.44 Issue:      2 Table of Contents
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Some Circulating Risk Factors and Obstructive Sleep Apnea in Ischemic Strokes

Abo Zaid Abd Allah1, Mohsen El Shafey2, Salah Aaref3

Departments of Neuropsychiatry, Benha University1; Chest2, Clinical Pathology3, Mansoura University



ABSTRACT

Background and purpose :obstructive sleep apnea (OSA) has a high prevalence in patients with ischemic stroke and may also be an independent risk factor. The purpose of our study was to investigate the relationship between plasma fibrinogen levels, activated coagulation factor VII (FVIIa), activated factor XII (FXIIa)  and cholesterol and the degree of coexisting OSA as determined by full polysomnography in patients with ischemic stroke. Methods: Thirty patients (20 men,10 women, a mean age of 56.1±6.28 yr),with excessive daytime sleepiness (Epworth Sleepiness Score >9) and proven OSA on overnight polysomnography with all forms of ischemic infarctions were considered for inclusion in the study. The diagnosis of stroke was confirmed by a complete neurological examination and brain imaging including computed tomography  and/or magnetic resonance imaging . Plasma levels of fibrinogen, FVIIa, FXIIa, and total cholesterol were measured 40 days after stroke onset in these patients  and in twenty similar patients(13 males and 7 females) with a mean age of (55.5±6.74 yr) without OSA. We excluded patients with inflammatory or cardioembolic etiology, smokers and those receiving anticoagulants. Results: We found that there is a significant higher plasma fibrinogen level in patients with OSA (3.9±0.83 gm/l) than in patients without OSA (2.9±0.29 gm/l), and there is no significant difference between both groups of patients as regarding plasma levels of FVIIa, FXIIa and cholesterol .The levels of these risk factors were higher in ischemic patients with OSA than that of other patients group. There was a significant difference between different degrees of OSA severity as measured by respiratory disturbance index as regarding plasma levels of fibrinogen and cholesterol. Patients with severe OSA had a higher plasma fibrinogen level and higher plasma cholesterol levels than patients with less OSA severity. There was a  significant higher plasma fibrinogen level (4.0±0.67 gm/l) in patients with more oxygen desaturation(10%) than that (3.1±0.76 gm/l) of patients with less oxygen desaturation (>10%). Conclusions: We concluded that patients with ischemic stroke and OSA have elevated fibrinogen and cholesterol levels than ischemic patients without OSA, which were significantly associated with indices of sleep apnea severity. The demonstration of several raised circulating cerebrovascular risk markers in ischemic patients with OSA compared with patients without OSA adds to the evidence that OSA is associated with higher levels of cerebrovascular risk.

(Egypt J. Neurol. Psychiat. Neurosurg., 2007, 44(2): 507-516)

 




INTRODUCTION

 

Obstructive sleep apnoea (OSA) is the second most common chronic respiratory disorder, affecting 2–4% of adult men in the developed world1.In the UK approximately 0.5-1.5% of men have moderate or severe disease, causing significant daytime symptoms and potentially warranting treatment with continuous positive airways pressure (CPAP)2. The prevalence of sleep-disordered breathing (SDB), mainly OSA, among patients with cerebrovascular accident  is high 3.In most cases there is evidence that OSA preceded the cerebrovascular event4. Good5 suggested that OSA is also a risk factor for vascular disease and is associated with worse functional outcome and higher mortality in stroke victims. Patients with OSA have increased cardiovascular morbidity and mortality, but how much of this is due to OSA rather than to its association with factors such as upper body obesity, insulin resistance, increasing age, alcohol and caffeine consumption, and cigarette smoking has been difficult to determine6. Shahar et al.7 concluded that OSA is a probable independent risk factor for arterial thrombotic disease and a raised blood pressure, which has been shown to fall with effective OSA treatment.

Interest in circulating cardiovascular risk markers has contributed to the discussion as to whether OSA may be an independent risk factor for cardiovascular disease by providing plausible linking mechanisms, some of which are predictable from the known effects of OSA on sympathetic drive and oxidative stress8. The pathogenesis of arterial thrombotic disease involves a large number of genetic and environmental factors related to both atherosclerosis and haemostasis. The measurement of circulating vascular risk factors enables a more accurate prediction of cardiovascular risk to be made, as there are clearly established relationships between levels of various circulating haemostatic risk factors and a subsequent strokes and cardiovascular events9.

The aims of the study were to establish whether OSA in patients with ischemic infarctions is associated with raised baseline plasma levels of fibrinogen, activated coagulation factor VII (FVIIa), activated factor XII (FXIIa)  and cholesterol and to establish whether a relationship exists between the severity of OSA and levels of these circulating markers.

 

SUBJECTS AND METHODS

 

Thirty patients (20 men, 10 women, mean age 56.1 ± 6.28 yr), with excessive daytime sleepiness (Epworth Sleepiness Score >9) and snoring10 and proven OSA on overnight polysomnography with all forms of ischemic infarctions were considered for inclusion in the study. Patients with signs of acute or chronic inflammation at the time of investigation, as determined by an elevated erythrocyte sedimentation rate > 15 mm/h, were excluded. Central apnea was regarded as a possible sequela of stroke11, hence, all patients with predominant central apnea were excluded. We excluded also, those with probable cardioembolic origin of the stroke, smokers and who receive anti-coagulants . They were collected from outpatients clinics of Mansoura International Hospital and then admitted to the chest department of Mansoura University Hospital to do polysomnography between October 2003 and March 2005.

Plasma levels of fibrinogen(Factor I) were measured by automated routine methods using a commercially available assay (Fibrinogen Kinetic, Boehringer Mannheim, Germany). Activated coagulation factor VII (FVIIa) was assayed by recombinant soluble tissue factor assay (Staclot, Diagnostica, France) and activated factor XII (FXIIa) was measured by ELISA (Sheild Diagnostics, Dundee, UK). Plasma levels of cholesterol were measured by using automated routine methods (Abbott Aeroset Analyser, Maidenhead, UK). The results were compared with that of similar 20 ischemic  patients (13 men, 7women, mean age 55.5± 6.47 yr) without OSA.

Complete overnight polysomnography (Compumedics, Melbourne, Australia) was performed between 12:00 P.M. and 6:00 A.M. Two-channel electroencephalogram, electrooculogram, and chin electromyogram were registered using standard methods. Oronasal airflow was recorded by thermistor, and thoracic and abdominal respiratory efforts were measured by impedance plethysmo-graphy. Oxygen saturation was measured by finger pulse oximetry (ResMed Model 305A, San Diego, CA), and the electrocardiogram from a precardial lead. Sleep data were staged manually according to standard criteria12.

An apnea was defined as cessation of airflow or reduction of thermistor signal to less than 10% of the normal flow with a duration of at least 10 s and oxygen desaturation of > 4% ,while hypopnea was defined as a discernible reduction of airflow to between 50% and 75%  of at least 10 s duration followed by either an arousal or a desaturation of  4%13. We classed the type of apnea as central, mixed, or obstructive from the respiratory effort determined by the thoracoabdominal belt. Every apnea was classed manually according to the following guidelines: apnea was central if there was no movement of the thoracoabdominal belt and no perceptible oro-nasal flow, and if movements of the thoracoabdominal belt were detected, the respiratory episode was considered obstructive.

The respiratory disturbance index (RDI) was calculated as the number of all respiratory events per hour sleep. Oxygen desaturation was then calculated from the oxygen saturation (SaO2) curve, by subtracting the average minimal SaO2 (the mean of all minimal SaO2 values reached during all respiratory events) from SaO2 during waking . OSA severity was classified according to the degree of RDI. An RDI of less than 5 was used to rule out OSA. RDI from 5 to 15, mild OSA, RDI from 16 to 30, moderate OSA, and RDI more than 30, severe OSA14.

Median time between stroke and polysomnography was 35 days and between blood sampling and sleep study was 7 days. Fibrinogen levels are high after stroke, and remain significantly elevated for at least 6 wk after a stroke15. All blood samples were taken in the non-fasting state.

 

Statistics

Association between these measured  levels and various parameters of OSA (RDI, oxygen indices) was determined by specific statistical tests. To assess the magnitude of difference in these levels, the levels of patients with OSA (RDI of > 5/h) and without OSA (RDI < 5/h) and were compared using descriptive statistics with 95% confidence intervals and unpaired t tests. Nonparametric repeated-measures, three-way ANOVA test was used also . Data are given as mean ± SD. Level of p < 0.05 was considered significant.

 

RESULTS

 

There were 30 patients (20 males and 10 males) with ischemic infarctions with a mean age of (56.1±6.28 yr) associated with OSA, there results were compared with that of 20 similar patients(13 males and 7 females) with a mean age of (55.5±6.74 yr) not associated with OSA. Table (1) revealed that there is no significant difference between both groups of patients as regarding the age and sex.

Table (2) showed that there is a significant higher plasma fibrinogen level in patients with OSA (3.9±0.83 gm/l) than in patients without OSA (2.9±0.29 gm/l), and there is no significant difference between both groups of patients as regarding plasma levels of FVIIa, FXIIa  and cholesterol. The levels of these risk factors were higher in ischemic patients with OSA than that of other patients group .

                Table (3) showed the impact of OSA severity as measured by RDI in the measured plasma risk factors levels. There was a  significant difference between different degrees of OSA severity as measured by RDI as regarding plasma levels of fibrinogen and cholesterol. Patients with severe OSA had a higher plasma fibrinogen level (4.1±0.61 gm/l) than in moderate OSA (3.7±0.27 gm/l) while that of mild OSA is (3.1±0.32 gm/l). While plasma cholesterol levels in severe OSA was (226.8±6.4 mg/dl), in moderate OSA was (209.1±21 mg/dl, and in mild OSA was (177.3±9.1 mg/dl). There was no significant difference between different degrees of OSA severity as regards plasma levels of  FVIIa and  FXIIa.

Table (4) showed the impact of decrease of arterial oxygen saturation during apnea on plasma risk factors levels in patients with OSA. There was a  significant higher plasma fibrinogen level (4.0±0.67 gm/l) in patients with more oxygen desaturation (≥10%) than that (3.1±0.76 gm/l) of patients with less oxygen desaturation (>10%), while there was no significant effect of  oxygen desaturation on  plasma levels of  FVIIa,  FXIIa, and cholesterol.

Table 1. Sex and age distribution of ischemic stroke patients with and without OSA..

 

 

Variable

patients with OSA

n= 30

Patients without OSA

n= 20

Significance

Sex:

  Male

   Female

 

n= 20     66.67%

n= 10    33.33%

 

n= 13          65%

n=  7          35%

 

x2= 0.074

p= 0.786

Age (yr)

 Mean+ SD

56.1 +  6.28

55.5 +  6.74

t= 0.308

p= 0.759

OSA: obstructive sleep apnea, P  is  significant at > 0.05.

 

 

Table 2. Comparison between ischemic stroke patients with and without OSA as regards the measured circulating risk levels.

 

Variable

patients with OSA

n= 30

patients without OSA

n= 20

t

p

Fibrinogen

     NL = 1.5-4 gm/l

3.9 +  0.83

2.9 +  0.29

1.83

0.04*

FVIIa

     NL=30-100 mU/ml

140.2 + 45.47

120.2 + 36.02

0.89

0.15

FXIIa

     NL = 0.5-2 ng/ml

2.58+ 0.24

2.26+ 0.25

0.06

0.95

Cholesterol

     NL=150-200 mg/dl

210.2 + 27.8

186.3 + 17.6

2.16

0.16

OSA: obstructive sleep apnea, NL: Normal level, P  is  significant at > 0.05.

 

 

Table 3. Impact of OSA severity as measured by respiratory disturbance index on the measured plasma risk levels in ischemic stroke patients.

 

 

Variable

Mild OSA

(RDI 5-15/h)

n= 5

Moderate OSA

(RDI >16-30/h)

n=17

Severe OSA

(RDI  <30/h)

n=8

F

P

Fibrinogen

  (1.5-4 gm/l)

3.1 + 0.32

3.7+ 0.27

4.1 + 0.61

95.46

0.04*

FVIIa

(30-100mU/ml)

146.6+38.95

131.7 + 28.82

155.1 +3 6.91

1.48

0.24

FXIIa

 (0.5-2  ng/ml)

2.2 + 0.27

2.6 + 0.26

2.7 + 0.19

0.43

0.25

Cholesterol

 (50-200 mg/dl)

187.3 + 9.1

209.1 + 21.8

226.8 + 16.4

19.04

0.03*

OSA: obstructive sleep apnea RDI: respiratory disturbance index, P  is  significant at > 0.05.

 

 

Table 4. Impact of degree of  arterial Oxygen desaturation during apnea on the measured plasma risk levels in ischemic stroke patients.

 

Variable

Oxygen desaturation

t

p

 > 10%

n=16

≥10%

n=14

Fibrinogen

 (1.5-4 gm/l)

3.1 + 0.76

4.0 + 0.67

1.90

0.05*

FVIIa

(30-100mU/ml)

143.1 +39.67

140.2 + 47.08

0.03

0.96

FXIIa

 (0.5-2  ng/ml)

2.0 + 0.22

2.2 + 0.26

1.44

0.15

Cholesterol                       (50-200 mg/dl)

218.3 + 28.4

231.4 + 27.03

3.06

0.14

Oxygen desaturation: waking Baseline SaO2– average of lowest SaO2 during apnea. P  is  significant at > 0.05.

 

Polysomnogram of  a male patient with  right  parietal infarction, shows no oronasal air flow, presence  of  thoracoabdominal movements, waking SaO2 is 97% while the lowest SaO2 during apnea is 82%, and  respiratory disturbance index  is 19/h .


DISCUSSION

 

Accumulating evidence suggests an increased prevalence of coronary artery and cerebrovascular disease in patient populations with OSA16. Cardiovascular disease prevention concentrated on the identification and modification of traditional risk factors such as diet and obesity, cigarette smoking, hypertension, and hyperlipidaemia17. Up to 30% of myocardial infarctions occur in patients  without  traditional  risk   factors, as a consequence, attention is shifting towards the identification of newer markers of atherosclerotic disease. Koeing18 found  hypercoagulable states (as determined by increased clotting  factor levels, impaired fibrinolysis, and   increased platelet  activity) in ischaemic stroke, coronary artery  disease , and hypertension. OSA is associated with an increased risk of atherosclerosis disease, so knowledge of the effects of OSA on  these  markers  and  their  response  to  treatment  is important  in elucidating the pathogenesis.

There are two major implications of our results: First, the described relationship offers possible evidence for a pathophysiological link between sleep apnea and stroke. Second, there is a significant difference of  fibrinogen levels as a risk factor, between ischemic stroke patients with OSA (3.9±0.83 gm/l) and patients without OSA (2.9±0.29 gm/l) which may identify them as being at a higher risk of stroke recurrence and other vascular events including myocardial infarction. Our  results were in agreement with Thomas et al.19, who found a significant higher plasma fibrinogen levels in ischemic patients with OSA than in patients without OSA. Beamer et al.15 concluded the possibility of upper airway inflammation is associated with OSA may induce increases in plasma fibrinogen. Meade et al.20 found that the elevation of one standard deviation in fibrinogen concentration was associated with an 84% increase in the risk of ischemic heart disease within the next 5 yr. Therefore, treatment of OSA may be warranted even if subjective symptoms (e.g., sleepiness) are not the predominant  problem.

Fibrinogen affects blood coagulation, blood rheology, and platelet aggregation. In addition, it has direct effects on the vascular wall and is a prominent acute-phase reactant. Also, fibrinogen is closely linked to atherosclerosis and prospective epidemiological trials suggest this association represents a major independent cardiovascular risk factor21. Kannel et al.22 concluded that the impact of fibrinogen level, considered as a separate variable, on cardiovascular disease was comparable with other major risk factors, such as blood pressure, hematocrit, obesity, cigarette smoking, and diabetes. Fibrinogen values were also significantly related to these risk factors. In a case-control study among a cohort of survivors of a first stroke, the odds ratios for a second stroke were significantly increased in patients with elevated fibrinogen23. Based on these findings, Resch et al.23 concluded that hyperfibrinogenemia is an independent risk factor for cardiovascular events in stroke survivors.

Our study showed that Patients with severe OSA had a significant higher plasma fibrinogen level (4.1±0.61 gm/l) than in moderate OSA (3.7±0.27 gm/l) while that of mild OSA is (3.1±0.32 gm/l). Also, there was a significant impact of degree of arterial oxygen desaturation during apnea on plasma fibrinogen levels in patients with OSA .Patients with more oxygen desaturation levels (>10%) during apnea were associated with higher fibrinogen levels. Thomas et al.19 concluded that there is a positive correlations were found between plasma fibrinogen levels and respiratory disturbance index (RDI) and between fibrinogen and longest apnea duration. but, there is a negative correlations were found between fibrinogen level and average oxygen desaturation during apnea .

The results of our study may have implications for the current treatment of ischemic accidents. Direct interventions to lower the fibrinogen level have been discussed as possible prevention for vascular events. It has been demonstrated that effective treatment of OSA with nasal continuous positive airway pressure (nCPAP) decreases morning fibrinogen levels in patients with OSA24. In stroke patients with OSA, implementation of nCPAP may therefore be an important part of prevention of further cerebrovascular events.

The measured fibrinogen levels in this study do not reflect the true levels at the time of the cerebrovascular event. There was a significant time delay of about 6 weeks between the vascular event and the measurement of fibrinogen . It is possible that the association between fibrinogen levels at the time of stroke and OSA may even be stronger. Despite these limitations, we feel our results suggest  that OSA is a causative factor in the elevated fibrinogen levels in our patients.

Activated factor XII is an initiator of intrinsic coagulation and fibrinolysis and influences the activity of the coagulation pathway. Colhoun et al.25 had confirmed its role as a marker of endothelial activation or dysfunction. Also activated factor VII plays a central role in clot formation and is important in inducing the thrombogenic potential of atherosclerotic plaque. Our results revealed that there is no significance difference as regards plasma levels of FIIa and  FXIIa  between both groups of patients but the finding of raised baseline levels of these two markers in patients with OSA than patients without, suggests a potential mechanism for the increased vascular risk in this patient population, via activation of the coagulation pathways and clot generation. Also we found no association between their plasma levels and OSA severity as measured by RDI and also with the degree of oxygen desaturation during apnea. Robinson et al.26  found  that the levels of  FIIa and  FXIIa fell in patients with OSA treated with nCPAP and OSA severity was not a predictor of their plasma levels. No other studies have examined the relationship between OSA and these two markers in ischemic patients.

Our results showed that there is no significant difference in levels of cholesterol between both groups of ischemic patients but those of patients with OSA (210.2±27.8 mg/dl) are raised than those of patients without OSA (186.3±17.6 mg/dl). There was a  significant association between plasma levels of cholesterol and different degrees of OSA severity as measured by RDI . This observation suggests a potential mechanism for the increased vascular risk in this patient population with OSA via activation of more atherosclerosis. Aboyans et al.27 concluded that there is a link between sleep breathing disorders and the pathogenesis of atherosclerotic lesions.

A fall in total plasma cholesterol level in treated OSA is likely represent a significant vascular risk reduction in this group of subjects who have a significantly raised baseline cardiovascular risk26. Law et al.28 concluded that  there is a reduction in cardiovascular risk seen with a fall in cholesterol, with a greater protective effect seen at younger ages. It is possible that cholesterol is one of the first molecules to respond to the reduction in oxidative stress seen with treatment of OSA. An alternative explanation is that the patients treated with therapeutic CPAP altered their diet and increased their activity levels following resolution of their daytime sleepiness, leading to the fall in cholesterol  level26.

Our observations strongly support the role of OSA as an independent risk factor for cerebrovascular accidents. Partinen and Palomaki29 have shown increased risk of stroke in habitual snorers and those with obstructive sleep apnea disorder . In a 2 case-control study, the risk of stroke was 3.20 times higher in snorers than nonsnorers30. Bassetti and Aldrich31 found obstructive sleep apnea in 62.5% of ischemic patients compared with 12.5% in the normal control group. They observed a high frequency of OSA disorder in patients with transient ischemic attack, suggesting preexisting OSA disorder before cerebrovascular events rather than as a consequence of it.

 

There are other several pathophysiological mechanisms that may underlie the increased risk of stroke in OSA. These include:

·           In OSA, repeated elevation of blood pressure, sometimes to an alarming degree, is seen at the termination of each apnea which correlates with both increased mortality and greater dependency32.  

·           The increased platelet agreeability is temporally related to rising plasma norepinephrine and epinephrine levels, which increased in patients with OSA33.

·           Baroceptor dysfunction has been reported in OSA and impaired cardiac baroceptor sensitivity is associated with higher mortality after stroke34.

·           Recurrent hypoxaemia associated with frequent apneas is another obvious candidate . This might have a critical effect on the "ischemic penumbra" surrounding the infarcted brain and might result in extension of the neurological damage35.

·           Alternating hypoxaemia and reoxygenation accompanying OSA is associated with increased release of superoxides from neutrophils35 which might have an adverse effect after stroke in light of evidence from animal stroke models36.

·           Inflammatory and proinflammatory markers and mediators such as C reactive protein37 and adhesion molecules38  are increased in OSA.

 

Conclusion

We concluded that patients with ischemic stroke and OSA have elevated fibrinogen and cholesterol levels, which were significantly associated with indices of sleep apnea severity. The demonstration of several raised circulating cerebrovascular risk markers in ischemic patients with OSA compared with patients without OSA adds to the evidence that OSA is associated with higher levels of cerebrovascular risk. The increase in coagulation activity may represent a possible pathophysiological mechanism behind the increased vascular morbidity of patients with OSA.

 

Recommendations

                We suggest that in future studies on fibrinogen and cholesterol as vascular risk factors coexisting with OSA should be taken into account specially during the acute phase of stroke. Further studies are necessary to investigate the impact of OSA treatment on these risk factors levels in patients with  ischemic stroke.

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الملخـص العربى

 

بعض عوامل الخطر في البلازما والسكتة التنفسية الإنسدادية في السكتات الدماغية الإنسدادية

 

تعتبر السكتة التنفسية الإنسدادية عامل خطر وعالية الحدوث في السكتات الدماغية الإنسدادية. ويهدف هذا البحث لدراسة العلاقة بين مستويات البلازما للفيبرينوجين وعامل التجلط النشط رقم 7 وعامل التجلط النشط رقم 12 والكولسترول ودرجة حدوث السكتة التنفسية الإنسدادية في مرض السكتة الدماغية الإنسدادية.

واشتملت هذه الدراسة على 30 مريضا بالسكتات الدماغية الإنسدادية، 20 من الرجال، 10 من الإناث ومتوسط أعمارهم 6.28 ± 56 سنه، تميزوا بالنوم الكثير أثناء النهار وبالسكتة الدماغية التنفسية الإنسدادية أثناء النوم كما ثبت بجهاز رسام النوم الكهربي.

وقد خضع المرضى للفحص الإكلينيكي للجهاز العصبي وعمل أشعة مقطعية أو رنين مغناطيسي على المخ وتم قياس مستويات البلازما للفيبرينوجين وعامل التجلط النشط رقم 7 ورقم 12 والكولسترول للمرضى و20 مريضا بالسكتة الدماغية الإنسدادية غير مصحوبة بالسكتة التنفسية الإنسدادية (13 من الرجال، 7 من الإناث، ومتوسط أعمارهم 6.47±55.5 سنه).

وقد أظهرت نتائج البحث زيادة ذات دلالة إحصائية في مستوى الفيبرينوجين والبلازما في المرضى المصحوبين بالسكتة التنفسية الإنسدادية عنها في المرضى غير المصحوبين بالسكتة التنفسية الإنسدادية.وقد وجد فروق ذات دلالة إحصائية في مستويات البلازما للفيبرينوجين والكولسترول بين درجات الشدة المختلفة للسكتة التنفسية الإنسدادية اذ كلما ذادت شدة السكتة التنفسية الإنسدادية ذادت مستويات البلازما للفيبرينوجين والكولسترول. وقد وجد أيضا أثر ذو دلالة إحصائية لتأثير نقص الأوكسجين في الدم أثناء السكتة التنفسية الإنسدادية على مستوى الفيبرينوجين في البلازما.

ونستخلص من هذا البحث ارتفاع نسبة البلازما للفيبرينوجين والكولسترول في مرضى السكتات الدماغية الإنسدادية المصحوبة بالسكتة التنفسية الإنسدادية ووجد ارتباط بينهم وبين شدة السكتة التنفسية الإنسدادية. ومن ذلك نستخلص أيضا أن مرضى السكتة التنفسية الإنسدادية يكونون أكثر خطراً للتعرض للسكتة الدماغية الإنسدادية.

 



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