Mechanisms of Variability in Response to Antiplatelet Drugs
A thesis submitted to the Faculty of Medicine, Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2010.
A variety of antiplatelet drugs decrease the risk of thrombotic events in at risk patients. However, more recent evidence suggests that the benefit derived from to therapy. In four separate studies, we examined different components of individual variability in antiplatelet drug response. A key hypothesis was that the PIª² polymorphism of the platelet fibrinogen (GPllb/Illla) receptor modulated the response to aspirin and GPllb/Illla antagonists.
In a study of 199 patients with coronary artery disease, 30 (15%) were aspirin resistant when measured by the Platelet Function Analyser (PFA)-I 00. Non- responsiveness was related to enhanced reactivity to epinephrine (median 38% vs 23%, p < 0.05) and increased inducible platelet activation (median 66% vs 56%, p < 0.05). There was no association between the PIª² genotype and aspirin response.
In another study of the GPllb/Illla antagonist tirofiban in patients (n = 21) presenting with an acute coronary syndrome we found evidence for inadequate inhibition of platelet aggregation in the majority (66%) of patients at standard dose. There was evidence for significant interindividual variation in the antithrombotic response to tirofiban (p < 0.05), however there was poor agreement between the different assays used. No predictors of variability were detected. Consistent with a partial agonist effect, there was enhanced inducible platelet activation during tirofiban treatment (61 % versus 37%, p = 0.004).
In a third study we examined the role of GPllla promoter polymorphisms on platelet fibrinogen receptor (GPllb/Illla) expression in 207 patients with a history of an acute coronary syndrome. The promoter polymorphisms were in tight linkage disequilibrium with the PIª² polymorphism of GPllla, but did not affect GPllb/lllla receptor expression density.
Finally, to determine the effect of PIª² on the antithrombotic response to GPllb/Illla antagonists, we studied an enriched group of individuals with the PIª² genotype (n = 20). We confirmed a partial agonist effect with GPllb/Illla antagonists in vitro manifest as increased platelet P-selectin expression and thromboxane generation. Corrected p-selectin expression was significantly increased in PIª² homozygotes compared to wildtype controls after incubation with orbofiban (24.8% vs 10.1%, p = 0.02).
In conclusion, we detected variability in the response to aspirin and GPllb/Illla antagonists. Aspirin resistance was linked to increased reactivity to epinephrine and increased platelet activation. Variation in the expression of the GPllb/Illla receptor was not related to the PIª² genotype or its associated promoter polymorphisms. However PIª² appears to enhance partial agonism in the presence of small molecule GPllb/Illla antagonists, suggesting an effect of this polymorphism on outside-in signalling by the GPllb/Illla receptor.