Platelet Glycoprotein IIIa Pl Polymorphism and Effects of Aspirin on Thrombin Generation

Effects of Aspirin on Thrombin Generation To the Editor: Michelson et al1 recently reported differences in platelet glycoprotein IIb/IIIa function in relation to the common Pl polymorphism. Pl-positive platelets showed a lower threshold for activation. This was supported by the gene dosage effect: P1 homozygotes had the highest activation of their platelets using a range of ADP concentrations. We are concerned about the conclusions regarding the antiplatelet effects of aspirin reached by the authors. At a low concentration of epinephrine (0.4 mmol/L), there was no difference in platelet aggregation between the Pl and Pl genotypes, whereas increased aggregation was observed in the Pl group. Unexpectedly, the inhibitory effect of aspirin on epinephrine-induced (2.0 mmol/L) platelet aggregation was found in the Pl group, but the opposite was found in Pl subjects. Two facts could explain this inconsistency. First, in experiments on the platelet aggregation response to aspirin, the number of Pl subjects included in the final analysis was diminished by 35%, because 7 of the 20 subjects did not achieve .60% aggregation at 10.0 mmol/L epinephrine. Because platelet response to aspirin was calculated as a percent of aggregation determined in the absence of the inhibitor, the exclusion of “weak responders” could be the cause of a relevant bias. We wonder whether the results obtained could be attributed to an altered sensitivity to epinephrine, which was used in 3 different concentrations. Second, experiments performed in platelet suspensions do not necessarily reflect the wide array of platelet functional responses observed in vivo, particularly the reaction to vascular injury. The limitations of in vitro studies on platelet glycoprotein activation have been critically reviewed.2 Platelets contribute to the explosive generation of thrombin by providing membrane surfaces for the assembly of the prothrombinase complex, which converts prothrombin to thrombin. In our study on the effects of aspirin on the formation of thrombin at the site of microvascular injury,3 we found that P1 carriers, most of them heterozygotes, had an impaired response to 75 mg of aspirin administered for 7 days. In fact, the odds for a failure of aspirin treatment in our study tripled in P1 carriers. A recent report4 on the increased risk of restenosis after coronary stent placement in P1 carriers treated with aspirin and ticlopidine corroborates our observations. Moreover, these results are consistent with the finding that in patients treated with aspirin after coronary artery bypass surgery, the P1 allele is a hereditary risk factor for bypass occlusion, myocardial infarction, and death.5 Given the high frequency of the P1 allele in the general population and growing evidence for lower clinical efficacy of aspirin treatment in P1 carriers with atherosclerotic vascular disease, the results of the in vitro platelet aggregation experiments reported by Michelson et al1 should be interpreted with caution.