***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: OBJECTIVES We studied the modifier effect of platelet antigen polymorphism ( PlA2 ) on platelet inhibition by acetylsalicylic acid ( ASA , i.e. , aspirin ) , clopidogrel , or their combination in patients with coronary heart disease . BACKGROUND Clopidogrel , when administered with ASA , was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA . We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2 . Hence , an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or , like acetylsalicylic acid , more selective . METHODS Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned r and omly to ASA 325 mg/day , clopidogrel 75 mg/day , or both . After 10 days , platelet function was studied . RESULTS Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist , and combination therapy result ed in greater inhibition than either inhibitor used alone ( p < 0.0001 ) . The use of ASA result ed in greater inhibition compared with clopidogrel with epinephrine ( p < 0.0001 ) and collagen as agonists ( p < 0.0001 ) . With collagen as the agonist , platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA ( p = 0.005 ) . In contrast , with clopidogrel , no significant difference could be detected between inhibition of Pl(A1/A1 ) and Pl(A1/A2 ) platelets . CONCLUSIONS The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function . Pl(A2 ) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel . These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease Background — Thrombotic events still occur in  aspirin-treated patients with coronary artery disease . Methods and Results — To better underst and aspirin “ resistance , ” serum thromboxane B2 ( TXB2 ) and flow cytometric measures of arachidonic acid – induced platelet activation ( before and after the ex vivo addition of aspirin and indomethacin ) were analyzed in 700 consecutive aspirin-treated patients undergoing cardiac catheterization .  In 680 of 682 evaluable patients , serum TXB2 concentrations were reduced compared with nonaspirinated healthy donors . Twelve patients had serum TXB2 that was lower than nonaspirinated healthy donors but > 10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum TXB2 ( > 10 ng/mL ) than in patients with low serum TXB2 . Addition of ex vivo aspirin  reduced arachidonic acid – induced platelet activation to similar levels regardless of serum TXB2 concentrations , which suggests that patients with high residual serum TXB2 concentrations were either noncompliant or underdosed with aspirin . Among the remaining 98 % of patients , ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation across all degrees of arachidonic acid – induced platelet activation and aspirin doses . Although the patients were not r and omized with respect to clopidogrel treatment , multivariate analysis showed that arachidonic acid – induced platelet activation was less in patients receiving clopidogrel . Conclusions — There is a residual arachidonic acid – induced platelet activation  in aspirin-treated patients that ( 1 ) is caused by underdosing and /or noncompliance in only ≈2 % of patients and ( 2 ) in the remaining patients , occurs via a cyclooxygenase-1 and cyclooxygenase-2 independent pathway , in direct proportion to the degree of baseline platelet activation , and is mediated in part by adenosine diphosphate – induced platelet activation Aspirin prevents the production of thromboxane A2 ( TXA2 ) by irreversibly inhibiting platelet cyclooxygenase , exhibiting antiplatelet actions . This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infa rct ion via this action mechanism . However , there are individual differences in this action , and aspirin is not effective in some patients , which is referred to as ‘ aspirin resistance ’ . In this study , we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms ( SNPs ) of nine genes involved in platelet aggregation/hemorrhage . Among SNPs involved in platelet aggregation , aspirin  was less effective for 924 T homozygote of a TXA2 receptor , 924T > C , and 1018C homozygote of a platelet membrane glycoprotein GPIbα , 1018C > T , suggesting that 924 T and 1018C alleles are involved in aspirin resistance Background —Mechanisms by which the PlA2 ( Leu33Pro ) polymorphism of & bgr;3 integrins could lead to an increased risk for coronary events are unclear . This study was design ed to examine the effect of this polymorphism on blood coagulation . Methods and Results —In normal subjects ( 12 with PlA1A1 , 9 with PlA1A2 , and 3 with PlA2A2 )  , we evaluated the activation of prothrombin , factor V , and factor XIII and fibrinogen removal by quantitative immunoblotting ; thrombin-antithrombin III complex generation using ELISA ; and levels of fibrinopeptide A and B by high-performance liquid chromatography in blood collected every 30 seconds at sites of st and ardized microvascular injury before and after 7 days of aspirin ingestion ( 75 mg/d ) . Compared with the PlA1A1 subjects , the PlA2 carriers exhibited higher maximum rates of thrombin B-chain generation ( by 31.6%;P = 0.005 ) , thrombin-antithrombin III complex generation ( by 30.7%;P = 0.003 ) , fibrinogen consumption ( by 31.3%;P = 0.002 ) , prothrombin consumption ( by 26.1%;P = 0.011 ) , and activation of factor V ( by 14.1%;P = 0.033 ) and factor XIII ( by 27.0%;P = 0.012 ) . In the PlA1A1 homozygotes , aspirin ingestion result ed in reductions in the velocity of thrombin B-chain formation ( by 32.1%;P = 0.007 ) , prothrombin consumption ( by 30.4%;P = 0.018 ) , factor Va generation ( by 28.9%;P = 0.014 ) , fibrinogen removal ( by 41.2%;P = 0.001 ) , and factor XIII activation ( by 22.6%;P = 0.026 ) . In the PlA2 carriers , aspirin did not alter the velocity of all these processes . After aspirin ingestion , fibrinopeptide A and B concentrations in the last 30-second interval were significantly reduced , but only in the PlA1A1 subjects . Conclusions —The presence of the PlA2 allele is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin , which might favor coronary thrombosis in the PlA2 carriers Platelet membrane receptors play a pivotal role in thrombus formation . Expression of platelet membrane receptors are under genetic control and gene sequence variations of receptors pivotal to thrombotic formation have been hypothesized to contribute to different degrees of individual response to aspirin . The aim of the present study was to investigate the impact of functional genetic polymorphisms of platelet membrane receptors on aspirin sensitivity assessed by means of the PFA-100 system in patients with coronary artery disease . Gene sequence variations of three platelet membrane receptors ( GPIa/IIa , P2Y12 , GPIIb/IIIa ) pivotal to thrombus formation were assessed in 76 patients with coronary artery disease on chronic aspirin treatment . Patients with reduced sensitivity to aspirin were defined when closure-times of collagen/epinephrine cartridges ≤193 seconds and coined as PFA-100 non-responders . PFA-100 non-responders were observed in 33 % of patients . Patients with diabetes mellitus were more frequently PFA-100 non-responders . Closure times of collagen/ADP coated cartridges were reduced in PFA-100 non-responders . The genotype distribution was similar in PFA-100 responder and non-responder patients for all three genotypes and did not vary in contemporaneous carriers of allelic variants . In conclusion , in vitro determined sensitivity  to aspirin assessed using PFA-100 is not associated with gene sequence variations of platelet membrane receptors key to thrombus formation BACKGROUND Aspirin ( acetylsalicylic acid ) irreversibly inhibits platelet cyclooxygenase (COX)-1 , the enzyme that converts arachidonic acid ( AA ) to the potent platelet agonist thromboxane ( TX ) A2 . Despite clear benefit from aspirin in patients with cardiovascular disease ( CAD ) , evidence of heterogeneity in the way individuals respond has given rise to the concept of ' aspirin resistance . ' AIMS To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance . PATIENTS AND METHODS Aspirin response , determined by serum TXB2 levels and AA-induced platelet aggregation , was prospect ively studied in patients ( n = 144 ) with stable CAD taking aspirin ( 75 - 300 mg ) . Patients were genotyped for five single nucleotide polymorphisms in COX-1 [ A-842 G , C22 T ( R8W ) , G128A ( Q41Q ) , C644A ( G213 G ) and C714A ( L237 M ) ] . Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood . The four most common haplotypes were considered separately and less common haplotypes pooled . RESULTS COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation ( P = 0.004 ; 4 d.f . ) . Serum TXB2 generation was also related to genotype ( P = 0.02 ; 4 d.f . ) . CONCLUSION Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation . Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype INTRODUCTION There is wide variability in the responses of individual patients to aspirin and clopidogrel . Polymorphisms of several platelet receptors have been related to increased platelet aggregation . We therefore aim ed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel . MATERIAL S AND METHODS Patients ( n=120 ) undergoing percutaneous coronary intervention who received aspirin for > or = 1 week but not clopidogrel were included . Blood sample s were drawn at baseline and 20 - 24h after a 300-mg clopidogrel dose . Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or = 70 % and 0.5 mg/mL arachidonic acid-induced aggregation > or = 20 % . Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or = 10 % in response to 5 and 20 microM ADP . PlA polymorphism of glycoprotein IIIa , T744C polymorphism of the P2Y(12 ) gene and the 1622A > G polymorphism of the P2Y(1 ) gene were genotyped by polymerase chain reaction . RESULTS There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients . There were also no significant differences in response to aspirin  ( assessed by arachidonic acid-induced aggregation ) or to  clopidogrel  ( assessed by ADP-induced aggregation or activation markers ) when patients were grouped according to genotype . The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2 ) carriers ( P=0.065 ) . CONCLUSIONS We did not find an association between polymorphisms in the platelet receptors GP IIIa , P2Y(12 ) or P2Y(1 ) and response to aspirin or clopidogrel in cardiac patients . These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations We determined the prevalence and clinical predictors of aspirin resistance by prospect ively study ing 325 patients with stable cardiovascular disease who were receiving aspirin ( 325 mg/day for > or = 7 days ) but no other antiplatelet agents .  We also compared the detection of aspirin resistance with optical platelet aggregation , a widely accepted method , with a newer , more rapid method , the platelet function analyzer (PFA)-100 
    Output:
    
Our data support a genetic association between the PlA1/A2 molecular variant and  aspirin resistance in healthy subjects , with the effect diminishing in the presence of cardiovascular disease .
The laboratory methodology used influences the detection of aspirin resistance .