Does high on-treatment platelet aggregability reflect poor individual response to clopidogrel?

On-treatment platelet aggregability represents the major form of functional assessment for patients treated with P2Y₁₂ receptor antagonists, with "high" on-treatment platelet aggregability (HTPA) predicting thrombotic risk. However HTPA reflects a variable combination of pre-treatment hyperaggregability and poor response to P2Y₁₂ antagonists. We have previously shown that integrity of platelet adenylate cyclase/cAMP signaling, assessed with PGE₁, is a strong predictor of individual responses to clopidogrel. We therefore sought to determine the extent to which HTPA reflects impaired platelet responsiveness to clopidogrel.

Using data from our previous investigations of acute and sub-acute effects of clopidogrel, we analyzed the relationship between on-treatment aggregability and acute/steady state responsiveness to clopidogrel, utilizing ADP, the thromboxane A₂ mimetic U46619, and thrombin receptor-activating peptide (TRAP) as pro-aggregants. The relationship between anti-aggregatory response to PGE₁ and both on-treatment and pre-treatment aggregability was also examined.

With all 3 pro-aggregants, (1) response to clopidogrel after 4 h, as measured by ΔADP response, exhibits a strong inverse relationship with on-treatment aggregation, with a similarly inverse relationship between pre-treatment PGE₁ response and on-treatment aggregability; (2) there is a weaker inverse relationship between clopidogrel response and pre-treatment platelet aggregability, and a significant inverse relationship between pre-treatment PGE₁ response and pre-treatment platelet aggregability. Furthermore, pre-treatment PGE₁ response also predicts on-treatment platelet aggregability in response to ADP at steady state. Thus, HTPA largely represents clopidogrel resistance.