Residual platelet reactivity in atherosclerosis and its impact on patient outcomes

In this thesis, the role of platelets as potential drivers of both thrombotic and bleeding risk in patients with atherosclerosis and the influence of platelets on the immune system were investigated. The prevalence of high and low residual platelet reactivity phenotypes and the association of these phenotypes with thrombotic and bleeding risk in acute coronary syndrome (ACS) patients and patients with atherosclerotic vascular disease were examined. In ACS patients, the clinical factors that influence the residual platelet phenotype including the presence of genetic polymorphisms were tested. In addition to residual platelet reactivity, the utility of other cardiac biomarkers to predict perioperative and 1-year risk in vascular patients was also examined. To investigate the influence of platelets on the immune system, platelet-lymphocyte interactions in vascular patients and healthy volunteers were analysed. In ACS patients treated with aspirin and clopidogrel, the prevalence of high on treatment residual platelet reactivity (as identified with the Multiplate assay), was common in a New Zealand population and high residual platelet reactivity levels could be significantly reduced with prasugrel treatment. This phenotype was predicted by the presence of diabetes, high platelet count and a low clopidogrel dose. It was also demonstrated that although the prevalence of loss of function and gain of function CYP2C19 alleles were high in our population, genotype had little influence on residual platelet reactivity levels in ACS patients. Furthermore, both phenotype and diabetes were significantly and independently associated with major adverse cardiovascular events (MACE) at 1 year. Genotype was not found to be a significant driver of risk. The incidence of major bleeding in this cohort was low and not predicted by platelet reactivity phenotype or genotype. In stable vascular patients the study found the level of residual platelet reactivity on aspirin therapy was not significantly associated with MACE or bleeding following major elective surgery. However, baseline high sensitivity troponin T was the most predictive biomarker and an elevated preoperative level was significantly associated with an increased risk of MACE in both the short and long term. Bleeding was frequent and occurred early following surgery in the majority of patients and open abdominal aortic aneurysm repair surgery was the only predictor of bleeding. Investigating the interactions between platelets and lymphocytes in atherosclerosis, the study found higher levels of platelet-T cell conjugates in patients with vascular disease compared to healthy controls. There was also interesting changes in the CD4 T cell activation phenotype with a switch from a predominant memory phenotype in healthy controls to an effector activation phenotype in vascular patients. A follow on study investigated the impact of platelets on CD4 T cells in more depth and found that platelets had a potent stimulatory effect on CD4 T cell differentiation and cytokine production ex vivo in healthy volunteers. Furthermore, the CD4 T cell stimulation provided by platelets was eliminated with in vivo prasugrel treatment. The influence of platelets on the immune system demonstrated in these two studies suggests that antiplatelet therapy may modulate not only thrombosis but also inflammation.