Prevalence&Genetic Susceptibility Of Aspirin Resistance In The Old Patients

Background:Atherothrombotic diseases have become the first cause of death in old Chinese people. Aspirin is a cornerstone of treatment and prevention of ischeraic atherothrombotic diseases. In2009, Antithrombotic Trialists'(ATT) Collaboration re-emphasized a secondary prevention of cardiovascular and cerebrovascular disease of aspirin. Meta analysis showed that antiplatelet therapy can decrease1/4combined endpoint,1/3non-fatal myocardial infarction,1/4non-fatal stroke and decrease1/6vascular mortality. However, some people poorly response to aspirin application. The phenomenon is defined as aspirin resistant (AR). Patients taking regular doses of aspirin cannot reduce ischemic events, known as clinical aspirin resistance. Monitored by laboratory methods, platelet aggregation cannot be effectively inhibited after taking aspirin, known as the laboratory or biochemical aspirin resistance. Prospective analysis from clinical studies has shown that patients with laboratory aspirin resistance have an increased risk of adverse clinical outcomes. Although definition of AR by platelet function isn't standardized, it is still necessary to aspirin administration.The mechanism of aspirin resistance remains unclear. This study aimed to investigate the mechanism of genetic susceptibility to AR and prevalence of aspirin resistance in old patients.Part1. Prevalence of Aspirin Resistance in Old PatientsAims:Light transmittance aggregation and thromboelastography are routine platelet function tests in diagnosis of AR in our hospital. This study sought to determine the prevalence of aspirin resistance using those two methods.Methods:Patients:For this study, information and DNA samples were obtained from consecutive patients in Chinese Han population who were present between April 2008and June2010in Beijing with CAD, stroke and PAD. Those patients had been receiving regular aspirin therapy (75-100mg daily) for at least4weeks. Inclusion criteria were age≥65years. Exclusion criteria included:the use of Clopidogrel, Ticlopidine, Dipyridamole or other nonsteroidal anti-inflammatory drugs, heparin or low molecular weight heparin; acute vascular events; platelet count<150000000/L or>450000000/L; haemoglobin<8g/dL. All patients provided written informed consent and questionnaire before inclusion in the study.Blood Sample: Blood samples were obtained from patients for measurement of blood routine and CD62P (P-selectin) and PAC-1(activated GPⅡb/Ⅲa receptors), hs-CRP, type-B natriuretic peptide (BNP), HCY, antithrombin Ⅲ(ATⅢ) and other biochemistry measurements.Definition of aspirin resistance:On the basis of light transmitted aggregation (LTA) assay, the definition of AR was aggregation of≥70%with ADP, and of≥20%with AA. Aspirin-sensitivity was indicated by neither of these criteria being met; complete AR by both criteria being met; only one of the two criteria met was deemed semi-AR. The definition of AR by thromboelastogram is≥50%via AA-induced whole blood aggregation.Results:The prevalence of aspirin resistance varied according to the assay used:13.69%-30.16%.Conclusion:Poor correlations and agreement among AA-induced light transmitted aggregation, ADP-induced light transmitted aggregation and AA-induced whole blood aggregation by thromboelastogram defined as aspirin resistance. However, in diagnosis of complete AR, the method of AA-induced aggregation combined with AA-induced TEG is consistent with the method of AA-induced aggregation combined with ADP-induced aggregation.Part2. Aspirin Resistance and Single-nucleotide PolymorphismsAims:To detect the genetic susceptibility of AR.Methods:The correlation of AR with27single nucleotide polymorphisms (SNPs) in14candidate genes was investigated. By AA-induced LTA method,59participants are served for cases,372participants for controls. By LTAAA combined with TEGAA,36participants are served for AR,164participants for semi-AR, and231participants for aspirin sensitivity. These groups are comparable.Results:In this case-control study, HO-1rs2071746(-413A> T) significantly associated with AR or complete AR, wild type A-allele and AA-genotype is a protective factor for AR. COX1rs1330344(-1676A>G) and COX1haplotype were also significantly associated with AR. G-allele and GG-genotype are risk factors for AR. Mutant of COX1haplotype is also a risk factor to AR. ACE rs4332(14848C/T) is only associated with semi-AR, wild-type C allele and CC genotypes are risk factors for semi-AR. The remaining SNPs and haplotypes are not associated with AR and semi-AR.Conclusions:Our results indicate that AR is associated with HO-1rs2071746gene polymorphism, COX1rs1330344(-1676A>G) and COX1haplotype in Chinese Han population. ACE rs4332(547C/T) is only associated with semi-AR, the mutant T allele is a protective factor for semi-AR. The genetic susceptibility of AR between semi-AR is different.