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Experimental Physiology 90.3 pp 411-416
DOI: 10.1113/expphysiol.2004.029306
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Chronic intermittent asphyxia increases platelet reactivity in rats

M. Dunleavy1, M. Dooley2, D. Cox2 and A. Bradford1

1 Department of Physiology2 Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 References
 
Sleep-disordered breathing is associated with chronic intermittent asphyxia and with a variety of cardiovascular abnormalities. Cardiovascular morbidity and mortality are linked to altered platelet function, and platelet function is affected in sleep-disordered breathing. As there is evidence that chronic continuous hypoxia may alter platelet number and function, the aim of the present study was to test the hypothesis that chronic intermittent asphyxia affects platelet count, activation and aggregation. Rats were treated with a hypercapnic hypoxic gas mixture (minimum of 6–8% O2, maximum of 10–14% CO2) for 15 s, twice per minute for 8 h per day for 3 weeks. Blood was analysed for platelet count, platelet activation (CD62p expression using flow cytometry), response to low dose ADP, haematocrit, red cell count and haemoglobin concentration. A platelet function analyser measured the closure time of an aperture, dependent on platelet aggregation. Compared to controls (n= 16), chronic intermittent asphyxia (n= 13) reduced body weight and increased right ventricular weight but had no significant effect on platelet count (control, 880.4 ± 20.1; treated: 914.1 ± 35.2 x 103µl–1; mean ±S.E.M.), on the reduction in platelet count in response to ADP (control, reduced to 206.7 ± 49.0; treated, reduced to 193.8 ± 35.9 x 103µl–1), or on the percentage of platelets positive for CD62p (control, 5.2 ± 0.7; treated, 6.0 ± 0.8%). Chronic intermittent asphyxia significantly (P= 0.037) reduced the closure time (control, 90.9 ± 7.7; treated, 77.7 ± 3.8 s), indicating greater adhesion and aggregation. There was no significant difference in haematocrit, red cell count and haemoglobin concentration. In conclusion, chronic intermittent asphyxia has no effect on platelet count but does increase platelet aggegation in rats. These data support the idea that chronic intermittent asphyxia alters platelet function in sleep-disordered breathing.

(Received 11 October 2004; accepted after revision 10 February 2005; first published online 22 February 2005)
Corresponding author A. Bradford: Department of Physiology Royal College of Surgeons in Ireland St. Stephen's Green Dublin 2 Ireland. Email: abradfor{at}rcsi.i.e.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Sleep-disordered breathing is characterized by intermittent apnoea caused by intermittent upper airway obstruction, called obstructive sleep apnoea, or by an intermittent reduction in respiratory drive called central sleep apnoea. Each episode of apnoea can result in progressive asphyxia (Alford et al. 1986) which leads eventually to arousal and restoration of upper airway patency (Remmers et al. 1978). As these episodes of apnoea occur many times during the course of sleep, the condition is associated with chronic intermittent asphyxia (CIA). We have developed a rat model which mimics the blood gas changes associated with human sleep-disordered breathing (McGuire & Bradford, 1999, 2001; McGuire et al. 2002a,b; O'Halloran et al. 2002). In the present study, we used CIA whereas we and others have also used chronic intermittent hypoxia (CIH) as a model of sleep apnoea. This is because apnoeic periods are accompanied by either hypoxia with little change in CO2 levels or by hypoxia along with hypercapnia, i.e. asphyxia. In fact, the CIH model has the disadvantage that the hypoxia is actually accompanied by hypocapnia because of the hyperventilation evoked by the hypoxia. In addition, our CIA model has the advantage over other CIH models used elsewhere in that the duration of asphyxia mimics in rats what occurs in sleep apnoea in humans whereas other models use durations far in excess of this.

Sleep-disordered breathing is associated with a number of cardiovascular disorders including pulmonary and systemic hypertension, congestive heart failure, cardiac arrhythmias, myocardial infarction and stroke (McNicholas, 1990; Peter et al. 1995). The rat model has been shown to develop pulmonary hypertension (McGuire & Bradford, 2001), right ventricular hypertrophy (McGuire & Bradford, 1999, 2001) and systemic hypertension (Fletcher et al. 1992a,b). It is known that changes in platelet function are linked to increased cardiovascular morbidity and mortality (Thaulow et al. 1991) and previous studies have shown that patients with sleep-disordered breathing have increased platelet activation and aggregation (Bokinsky et al. 1995; Eisensehr et al. 1998; Sanner et al. 2000; Geiser et al. 2002; Von Kanel & Dimsdale, 2003; Hui et al. 2004). However, the causes of these changes in activation and aggregation are not known. It is known that acute hypoxia (Li & Guo, 1996) and chronic continuous hypoxia (Nakanishi et al. 1997) can affect platelet function and number and this raises the possibility that the alterations in platelet function in sleep-disordered breathing are caused by CIA. However, the effects of CIA on platelets have not been investigated previously. In this study, we test the hypothesis that CIA causes changes in platelet function and number.


   Methods
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 Methods
Results
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CIA model

All procedures were performed in accordance with national legislation under the Cruelty to Animals Act 1876 and European Union Directive 86/609/EC. Male Wistar rats were obtained from the Bioresources Unit, Trinity College Dublin, Ireland. They were housed four to a cage under a 12 h–12 h (light–dark) photoperiod and were given free access to rat chow and water. The treatment periods were during the day from approximately 09.00 h to 17.00 h. Animals were transferred from their home cages to a separate treatment area and transferred back to their home cages at the end of the 8-hour treatment period. Animals had no access to food or water during the treatment period. Animals were observed to be asleep for much of the time during the treatment. They were restrained in Perspex chambers without a blindfold with their heads positioned in hoods. The CIA group received 15 s of air followed by a mixture made from 100% CO2, 100% N2 and air for 15 s. The flow was regulated to give a concentration in the hood of 10–14% CO2 (maximum) and 6–8% O2 (minimum). These values were monitored continuously using an O2 analyser (Engstrom Eliza Duo, Gambro-Engstrom AB, Bromma, Sweden) and a CO2 analyser (Capstar-100 End-tidal CO2 Analyser, CWE Inc, Ardmore, PA, USA). We have shown previously that the minimum arterial blood PO2 achieved is 55–65 mmHg and that the maximum end-tidal PCO2 is 63.6 ± 8.6 mmHg (McGuire & Bradford, 2001). Timed solenoid valves were used to allow the switch between air and CO2/N2. The cycle was repeated twice per minute, 8 h per day, 5 days per week for 3 weeks. The control group received similar cycles of air switching to air for the same time period. A duration of 3 weeks was chosen as a reasonable amount of time to observe any stable chronic effects. We have shown previously that haematocrit is increased after 1 week of CIH (McGuire & Bradford, 1999) or asphyxia (McGuire & Bradford, 2001) and that it remains elevated for 4 weeks thereafter.

Platelet studies

At the end of the 3 weeks and beginning the day after the last treatment period, the rats were anaesthetized with sodium pentobarbitone (60 mg kg–1I.P.) and heparinized (1000 IU kg–1). They were artificially ventilated and a thoracotomy was performed. Blood samples were drawn from the left ventricle using heparinized syringes. The platelet count, haematocrit, red blood cell count and haemoglobin concentration were determined using a Sysmex cell counter (Sysmex, Japan).

Platelet activation was determined by CD62p expression. Platelets exist in the circulation in a resting state. When activated, they undergo degranulation. As part of this process, the alpha-granules fuse with the membrane secreting their contents. CD62p is embedded in the membrane of the alpha-granules and as a result becomes exposed on the platelet surface after activation. As it is not present on the surface of resting platelets, it is often used as a marker of platelet activation. Blood (5 µl) was incubated with 20 µl phycoerythrin (PE)-labelled CD62p for 10 min. It was then diluted with phosphate-buffered saline containing (mM): NaCl 137, KCl 2.7, Na2HPO4 8.1, KH2PO4 1.5; and analysed on a FACSCalibur flow cytometer (Becton Dickenson, Oxford, UK).

Platelet aggregation in response to adenosine diphosphate (ADP, 5 µM) was measured by the loss of single platelets method. Briefly a 200 µl sample of whole blood was incubated with ADP or buffer. The sample was stirred in a platelet aggregometer at 37°C for 5 min and the platelet count was then determined on a cell counter (Sysmex, Japan).

A platelet function analyser (PFA-100, Dade Behring, Deerfield, IL, USA) was used to measure the time taken for a given sample to occlude an aperture by clotting using the collagen–ADP cartridge (Dade Behring). This is called the closure time and it is dependent on the rate of platelet aggregation caused by high shear rate and by the collagen and ADP. The PFA-100 allows for rapid evaluation of platelet function on samples of anti-coagulated whole blood. The single-use cartridge consists of a capillary, a sample reservoir and a biochemically active membrane with a central aperture. Blood is aspirated from the reservoir through the capillary and aperture which exposes the platelets to high shear flow conditions. At the beginning of the assay, trigger solution is dispensed to wet the membrane after which platelets adhere to the collagen-coated membrane, become activated and release their granules upon contact with the agonist ADP. Platelets thus form aggregates and build to form a thrombus at the aperture thereby diminishing and finally arresting the blood flow (Kundu et al. 1995).

Gross pathology

Animals were killed by anaesthetic overdose. The heart was removed and the ventricles separated from all the surrounding tissue. The right ventricle was dissected from the left ventricle and septum. Both sides were dried and weighed and the ratio of right ventricle to left ventricle weight determined.

Statistical analysis

All values are expressed as mean ±S.E.M. and compared using ANOVA or the Mann Whitney U test where appropriate. P < 0.05 was taken as significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Before treatment, there was no significant difference in body weight between the control and CIA-treated groups (control, 342 ± 38; CIA, 354 ± 45 g), but the body weight was significantly less in the CIA-treated animals after 3 weeks of treatment (control, 308 ± 41; CIA, 278 ± 37 g). As expected, the right ventricle/left ventricle weight ratio was significantly greater in the CIA-treated group (control, 0.240 ± 0.017; CIA, 0.257 ± 0.022).

A full analysis of platelet number and function was completed in 16 control animals and in 13 CIA-treated animals. There was no significant difference in platelet count between the two groups (Fig. 1A). The percentage of platelets positive for CD62p was not significantly different (Fig. 1B). The reduction in platelet count in response to ADP also showed no significant difference between control and CIA-treated groups (Fig. 1C). The closure time was significantly less in the CIA group (Fig. 1D). There was no significant difference in haematocrit (control, 37.5 ± 0.8; CIA, 38.8 ± 0.8%), red blood cell count (control, 7.5 ± 0.2; CIA, 7.6 ± 0.2 x 106µl–1) and haemoglobin concentration (control, 13.3 ± 0.3; CIA, 13.6 ± 0.3 g per dl).



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  		Figure 1.  Effect of chronic intermittent asphyxia on platelet number, CD62 expression, platelet number following addition of ADP and PFA closure time
Effect of chronic intermittent asphyxia on platelet number (A), CD62 expression as a percentage of the total number of platelets positive for CD62p (B), platelet number following addition of ADP (C) and PFA closure time (D). Values are means ±S.E.M. for control (open bars) and for chronic intermittent asphyxia (filled bars). *Significantly different from control.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present results show that CIA had no effect on platelet number, on the reduction in platelet count in response to ADP or on the percentage of CD62p-positive platelets. There was a shortening of the platelet function analyser (PFA) closure time, indicating an increase in platelet reactivity. The absence of CD62p-positive platelets in these animals despite the shortened PFA closure time is probably due to the shedding of CD62p. Thus, in a chronic model like CIA, most of the CD62p is in the plasma not platelet bound.

Despite a decrease in body weight, our platelet count values of 880.0 ± 20.1 x 103 µl–1 and 914.1 ± 35.2 x 103 µl–1 in the control and CIA group, respectively, are comparable to those of Nakanishi et al. (1997) (600–700 x 103 µl–1), Bjerknes et al. (1990) (510 ± 35 x 103 µl–1) and Kentera et al. (1985) (approximately 850 x 103 µl–1) in Wistar rats, of Jackson & Edwards (1977) (approximately 1000 x 103 µl–1) in Long-Evans rats and of Walter (1999) (approximately 1000 x 103 µl–1) in Charles River rats. We are unaware of a comparable study in which PFA closure time was measured in rats but our values for percentage of platelets positive for CD62p of 5.2 ± 0.7 and 6.0 ± 0.8% in control and treated animals, respectively, are comparable to values of 7.0 ± 1.8 and 11.2 ± 3.3%, respectively, reported in one study in rats (Chignier et al. 1994) and 6.41 ± 0.95 and 4.51 ± 0.55, respectively, reported in another (Kuo et al. 2002).

Although we did not observe an effect of CIA on platelet number, it is well known that chronic continuous hypoxia causes initial thrombocytosis and/or long-term thrombocytopaenia in rats (Jackson & Edwards, 1977; Kentera et al. 1985; Nakanishi et al. 1997), mice (Birks et al. 1975; McDonald, 1978; McDonald et al. 1978) and humans (Gray et al. 1975; Palareti et al. 1984). Information in the literature concerning the effects of hypoxia on platelet function has been equivocal (see Bradford, 2005). We did not observe an effect of CIA on haematocrit either. It is well known that chronic continuous hypoxia increases haematocrit (Hunter et al. 1974). Furthermore, CIH for 1 h per day for 28 days (Nattie & Doble, 1984) or 30 min hypoxia/30 min normoxia for 8 h per day for 28 days (Moore-Gillon & Cameron, 1985) also causes an increase in haematocrit. We have shown previously that both CIH (McGuire & Bradford, 1999) and CIA (McGuire & Bradford, 2001) causes an increase in haematocrit. On the other hand, using a similar model to the one used in the present experiments, Fletcher et al. (1992a,b) did not observe any change in haematocrit with CIH. There appears, therefore, to be evidence for and against an effect of either CIH or CIA on haematocrit. Quantitatively, the effect in those studies where an increase was observed was small and we speculate that the absence of an effect in some studies, including the present one, is because the total amount of hypoxic exposure is less than in those showing a positive response.

Because of the amount of blood required for analysis, it was not possible to make measurements at different time points during CIA. It is possible therefore that changes in platelet number and percentage of platelets positive for CD62p and in red blood cell number may have occurred during the period prior to the 3-week sampling time.

This is the first study to show that CIA increases platelet reactivity. The relevance of this relates to human sleep apnoea in which there is CIA and in which some studies have shown alterations in platelet function. Rangemark et al. (1995) found that there was no difference in platelet aggregation (determined tubidimetrically) between sleep apnoea patients and controls and Sanner et al. (2000), using platelet aggregometry, found that platelet aggregation increased slightly during sleep in sleep apnoea patients, that treatment with continuous positive airway pressure reduced aggregation but that none of these changes was significant. However, several studies have shown an effect of sleep apnoea on platelet function. Bokinsky et al. (1995) showed that during the night, there was an increase in platelet aggregation and activation (measured using a marker of both CD62p and CD41) in sleep apnoea patients and that treatment with continuous positive airway pressure caused a reduction in activation and aggregation. Hui et al. (2004) found that platelet activation (measured using an index derived from percentage of the total platelets positive for CD62p and from the extent of CD62p expression per platelet) was correlated with the severity of the sleep apnoea and that treatment with continuous positive airway pressure reduced platelet activation. Geiser et al. (2002) found that the percentage of platelets positive for CD62p was higher in sleep apnoea patients than in controls during sleep and that this value was also higher during sleep compared to awake values. None of these studies reported on platelet number so we cannot draw any conclusions on the lack of effect of CIA on platelet count in the present experiments until data are available on platelet counts in patients with sleep apnoea.

The implications of an increase in platelet reactivity are that this could contribute to cardiovascular disease. It has been shown that there is a correlation between platelet reactivity and coronary heart disease mortality (Thaulow et al. 1991) and that inhibitors of platelet reactivity reduce coronary heart disease mortality (Gregg & Goldschmidt-Clermont, 2003). Patients with sleep-disordered breathing have an increased cardiovascular disease morbidity and mortality (Hung et al. 1990; Dyken et al. 1996; Bassetti & Aldrich, 1999; Peker et al. 2000) and also have increased platelet activation and aggregation (Bokinsky et al. 1995; Eisensehr et al. 1998; Sanner et al. 2000; Geiser et al. 2002; von Kanel & Dimsdale, 2003; Hui et al. 2004). Therefore, although caution should be exercised in extrapolating to the effects of CIA in humans, the significance of the present finding is that CIA may be at least partly responsible for the increased platelet activation seen in patients with sleep-disordered breathing and therefore may contribute to the association of this condition with cardiovascular disease.


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   Acknowledgements
 
This work was supported by the Royal College of Surgeons in Ireland.




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