Abstract 11336: Racial Differences in Resistance to P2Y12 Receptor Antagonists in Thrombin-Stimulated Diabetic Platelets
Background: Thrombin mediates potent effects on platelet activation via Protease-Activated Receptors (PARs), PAR1 and PAR4. Thrombin stimulates feed forward release of the secondary agonist ADP, which activates P2Y12. Diabetic platelets display heightened activation and are resistant to inhibition with Clopidogrel. Genetic alterations in metabolism of clopidogrel only partly account for clopidogrel resistance. Prior studies have been in predominantly Caucasian populations and have not investigated the role of PARs in diabetes and resistance to direct P2Y12 antagonists.
Methods: 132 Human subjects from both Vanderbilt and Thomas Jefferson Universities were recruited. 52 were non-diabetic and 80 diabetic (Type II); 54% Caucasian, 44% African -American (AA), and 2% Hispanic/Asian. Platelet aggregation, secretion from dense and alpha granules, and GPIIbIIIa activation in response to thrombin and PAR1 and 4 agonist peptides were measured. To circumvent alterations in metabolism with clopidogrel, we examined the effect of the direct P2Y12 antagonist 2MeSAMP on platelet activation.
Results: Inhibition of 2 nM thrombin-mediated GPIIbIIIa activation by 2MeSAMP was greater in non-diabetics versus diabetics (56 +/- 3.5% inhibition vs. 28 +/- 5.9%, respectively). Resistance to 2MeSAMP inhibition in diabetics was observed when stimulating with PAR agonist peptides 1 and 4 and with other indices of platelet activation. Sub-group analysis revealed diabetic AAs displayed normal inhibition to 2MeSAMP in sharp contrast to decreased inhibition observed in diabetic Caucasians. Multivariable analysis demonstrated that other variables such as obesity, age or gender could not account for the observed differential racial resistance to 2MeSAMP.
Conclusions: Diabetic platelets are resistant to direct P2Y12 antagonists when stimulated with PAR activation. These findings provide an explanation for the observation that alterations in metabolism of clopidogrel cannot fully account for resistance to P2Y12 antagonists. In contrast, AA diabetic platelets display normal inhibition with direct P2Y12 antagonists. These findings have potential clinical implications as newer more potent P2Y12 antagonists become clinically available.
- © 2011 by American Heart Association, Inc.