Factors contributing to variability in response to clopidogrel or clopidogrel resistance

Genetic factors responsible for variability in clinical response to clopidogrel include polymorphisms of CYP (Cytochrome P), GPIa (Glycoprotein Ia), P2Y₁₂ and GPIIIa (Glycoprotein IIIa). Clinical factors which contribute to a variable response to clopidogrel may be poor compliance, lower doses, poor absorption, drug-drug interactions involving CYP3A4, acute coronary syndrome, diabetes mellitus/insulin resistance and elevated body mass index. Cellular factors which may cause clopidogrel resistance may be accelerated platelet turnover, reduced CYP3A metabolic activity, increased ADP exposure, upregulation of the P2Y₁₂ pathway, upregulation of the P2Y₁ pathway and upregulation of P2Y–independent pathways (collagen, epinephrine, TX₂ or thromboxane A₂, thrombin) [Angiolillo DJ et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49):1505-16].