Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.

Background and Purpose-Aspirin resistance may be relatively common and associated with adverse outcome.Meta-analysis has clearly shown that 75 mg plain aspirin is the lowest effective dose; however, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. This study was designed to determine whether enteric-coated aspirin is as effective as plain aspirin in healthy volunteers. Methods-Seventy-one healthy volunteers were enrolled in 3 separate bioequivalence studies. Using a crossover design, each volunteer took 2 different aspirin preparations. Five aspirin preparations were evaluated, 3 different enteric-coated 75-mg aspirins, dispersible aspirin 75 mg and asasantin (25-mg standard release aspirin plus 200-mg modified-release dipyridamole given twice daily). Serum thromboxane (TX) B 2 levels and arachidonic acid-induced platelet aggregation were measured before and after 14 days of treatment. Results-All other aspirin preparations tested were inferior to dispersible aspirin (PϽ0.001) in their effect on serum TXB 2 level. Treatment failure (Ͻ95% inhibition serum TXB 2 formation) occurred in 14 subjects, none of whom were taking dispersible aspirin. Mean weight for those demonstrating treatment failure was greater than those with complete TXB 2 (Ͼ99%) inhibition (PϽ0.001). Using logistic regression analysis an 80-kg subject had a 20% probability of treatment failure. Asasantin was the most potent preparation in terms of inhibition of platelet aggregation. Conclusions-Equivalent doses of the enteric-coated aspirin were not as effective as plain aspirin. Lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects. (Stroke. 2006;37:2153-2158.)

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% O 2 , maximum of 10-14% CO 2 ) 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 × 10 3 µl −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 × 10 3 µl −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. 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 CO 2 levels or by hypoxia along with hypercapnia, i.e. asphyxia. In fact, the CIH model has the disadvantage that the hypoxia is actually a...

Summary Some studies have suggested that genetic variability in the glycoprotein (GP) IIIa gene modulates expression of platelet GPIIb/IIIa (α2bβ3). We sought to determine as to whether combinations of genetic variants within the GPIIIa gene (haplotypes) influenced the expression of GPIIIa RNA and protein levels in human platelets. Three promoter polymorphisms, PlA1/A2 genotype and platelet receptor densities were determined in 207 acute coronary syndrome (ACS) patients. Allele‐specific quantitative reverse transcription‐polymerase chain reaction of platelet RNA from PlA1/A2 heterozygotes identified a greater expression of PlA2 bearing transcripts among heterozygotes. Among the patients studied, the ratio of PlA1/PlA2 RNA expression was significantly influenced by promoter haplotype (P < 0·01). However, this effect reflected carriership of rare not common haplotypes (P = 0·2). There was a threefold variation between subjects in the number of GPIIb/IIIa receptors expressed per platelet, although no association between receptor density and the PlA2 (P = 0·93) or promoter polymorphisms was demonstrated (−468A, P = 0·52; −425C, P = 0·59; −400A, P = 0·52). Among common haplotypes, PlA1/PlA2 RNA expression was negatively correlated with adjusted GPIIb/IIIa receptor density (P = 0·04). The overall trend towards higher expression of PlA2 bearing message in PlA1/A2 heterozygotes, and the existence of rare haplotypes with more pronounced changes indicate the existence of cis‐acting genetic factors that remain to be identified.

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