Impaired response to P2Y12 receptor antagonists, such as clopidogrel and prasugrel, can have devastating consequences for patients that require prolonged or indefinite therapy with these agents, including those with a left ventricular assist device (LVAD). While loss-of-function (LOF) alleles in CYP2C19 have been elucidated as contributing to high on treatment platelet reactivity (HTPR) during clopidogrel therapy, genetic variations in the metabolic pathway of prasugrel have not been shown to elicit this same effect. Moreover, limited studies have assessed the effect of coexisting genetic variations in pharmacokinetic and pharmacodynamic pathways. Herein, we report a left ventricular assist device patient exhibiting high on treatment platelet reactivity during clopidogrel and prasugrel therapy. Genotyping revealed variants in pharmacokinetic (CYP2B6), and pharmacodynamic pathways, with multiple variants in P2Y12, the target receptor.