Conundrums of Platelet Function Testing
Does Sex Matter?
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It is well established that there exists significant interpatient variability in the pharmacodynamic response to clopidogrel.1,2 In turn, multiple studies have demonstrated that higher on-treatment platelet reactivity is associated with an increased risk of cardiovascular events.3 Although thresholds for inadequate response have been proposed, the optimal therapeutic window of platelet inhibition for a patient on antiplatelet therapy after percutaneous intervention or an acute coronary syndrome has remained disputed.3,4 In part, this stems from the fact that the relationship between platelet reactivity and the risk of ischemic or bleeding events has not always been shown to be consistent across various patient populations.
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To that end, it is intuitive to assume that lower on-treatment platelet reactivity is reliably correlated with a reduced risk of thrombotic events and an increased risk of bleeding. However, studies have not always been consistent in that regard. For example, several analyses have shown that carriers of a loss-of-function CYP2C19 allele (*2, *3) that diminishes the liver’s ability to convert clopidogrel to its active metabolite are at increased risk of ischemic events after percutaneous intervention compared with wild-type carriers.5 Yet, fewer studies have been able to demonstrate that this genetic variant reduces the risk of bleeding, despite higher on-treatment platelet reactivity.6 Conversely, patients on clopidogrel who carry a gain-of-function CYP2C19 allele (*17) that confers lower on-treatment platelet reactivity have been shown in some studies to be at increased risk of bleeding but not always at reduced risk of ischemic events.7,8 One could hypothesize that the dose–response curves differ for an individual’s risk of bleeding versus their risk of …