Aspirin resistance associated with platelet Pl^A (GPIIIa) polymorphism in coronary heart disease

Aspirin is commonly used to reduce the risk of ischemic events in patients with cardiovascular disease. Aspirin inhibits platelets by irreversibly binding to cyclooxygenase-1 and blocking the synthesis of thromboxane A2. However, patients treated with aspirin still can suffer ischemic events, and laboratory assessment of platelet function reveals persistent platelet aggregation despite regular aspirin therapy in a significant proportion of patients at high risk of ischemic events. Multiple mechanisms appear to account for aspirin resistance one of them is the genetic abnormality involving the platelet surface membrane glycoproteins essential for platelets adhesion and aggregation with subsequent thrombus formation. The present work aimed to study GPIIb/IIIa genetic polymorphism by PCR-RFLP assay in patients with coronary heart disease in relation to their clinical response to therapeutic dose of aspirin. The impact of this genetic risk and other endogenous and environmental determinants of platelet aggregability on aspirin resistance were also assessed. The present study included 31 patients with coronary heart disease and they were all receiving prophylactic 75mg/day aspirin. According to their clinical response they were classified into two groups; aspirin resistant and aspirin sensitive. This study showed that aspirin resistance could be a considerable problem in patients with coronary heart disease (CHD) relying on aspirin for antiplatelet protection. Aspirin resistance involved 35% of the studied patients with CHD without certain age or sex prevalence. Hypertension, diabetes mellitus, hypercholesterolemia, obesity and smoking were not associated with increased risk of aspirin resistance in the studied patients. Aspirin resistance was not also influenced by the number of the diseased coronaries as revealed by coronary angiography. GPIIb / IIIa is known as the receptor for fibrinogen, or vonWillebrand factor that mediates platelet aggregation. This receptor is characterized by several heritable dimorphisms. Pl^A1 and Pl^A2 alleles are the two most common and clinically important β3 alleles with individuals being Pl^A1 / Pl^A1 homozygous, Pl^A1 /Pl^A2 heterozygous, or Pl^A2 /Pl^A2 homozygous. In the present work, none of the studied patients or controls had the homozygous Pl^A2 / pl^A 2 genotype. Twenty percent of the controls had Pl^A1 / Pl^A2 genotype with one Pl^A2 allele and this was significantly less frequent than that in the studied group of patients where 48% of them had PL^A1/ PL^A2 genotype. Despite the higher frequency of at least one PL^A2 allele among the studied patients, yet it was not associated with increased risk of ischemic cardiovascular disease. Regarding the impact of P1A genetic polymorphism on developing aspirin resistance, the present work showed a significantly increased frequency of pL^A1/ pL^A2 genotype among patients with aspirin resistance with strong association between this genotype and risk of aspirin resistance. In conclusion, diagnosing aspirin resistant patients due to GPIIb / IIIa genetic polymorphism before their clinical failure on aspirin could prevent the possible associated adverse outcome especially with the presence of safe alternative antiplatelet agents for long term administration.