The stratification of platelet reactivity and activation in patients with stable coronary artery disease on aspirin therapy

Abstract

Condensed abstract: Heightened platelet reactivity may affect the occurrence of ischemic events in patients with coronary artery disease on aspirin therapy. However, a definition to stratify platelet reactivity in this group of patients has not been previously reported. We studied platelet reactivity and activation by measuring platelet aggregation and the expression of p-selectin, total GP IIb/IIIa and active GP IIb/IIIa (n=96). Patients were divided into quartiles by each of the markers; correlations were made between the markers; and a definition of heightened platelet reactivity was proposed. Marked variability in activation and reactivity were observed despite aspirin therapy.

Background: Heightened platelet reactivity and activation may affect the occurrence of ischemic events in patients with coronary artery disease on aspirin therapy. However, a definition to stratify platelet reactivity has not been previously reported. Methods and results: Platelet aggregation (5 and 20 μmol/l ADP), total GP IIb/IIIa, active GP IIb/IIIa and the expression of maximally stimulated p-selectin were measured in patients about to undergo elective coronary stenting (n=96). All patients had received aspirin (325 mg). There was marked variability in platelet reactivity and activation as measured by all markers. The highest quartile was defined by 77±1% and 98±1% aggregation by 5 and 20 μmol/l ADP, respectively; 65±2% p-selectin positivity; 508±15 MFI for total GP IIb/IIIa; and 23.0±1.8 MFI for active GP IIb/IIIa. Conclusions: There is a wide range in platelet reactivity and activation as measured by multiple markers in stable coronary disease patients on aspirin therapy. From these indices, we can define those patients at the extremes of reactivity and activation and thus, the greatest potential risk of thrombosis and bleeding. These indices will serve as a guide to future studies investigating the relationships of platelet reactivity, activation, drug-induced inhibition and clinical outcomes.

Introduction

Platelets play a major role in the genesis of acute thrombosis [1]. Therefore, heightened platelet reactivity and activation would be expected to be important risk factors associated with acute arterial thrombotic diseases. However, there have been no conclusive studies thus far linking those patients with the most reactive platelets to adverse ischemic outcomes [2]. Moreover, low reactivity following aspirin therapy may be a risk factor for bleeding from the addition of clopidogrel. One explanation for the paucity of data relates to the complexity of performing sensitive analyses of platelet function in large scale investigations [2]. The established methods to assess platelet reactivity—light transmittance aggregometry and flow cytometric detection of surface receptors—are laborious and expensive. The predictive value of simpler point-of-service assays to measure platelet reactivity have also not been validated in clinical trials [3]. Despite the repeated use of the term, “ heightened reactivity” in the literature, an accepted definition of it is not readily available.

In the current investigation, we studied patients on aspirin therapy. We stratified platelet reactivity by light transmittance aggregometry and by flow cytometry to detect stimulated p-selectin expression. Activation was determined by measurement of total and active GP IIb/IIIa expression. The primary goal of our study was to examine the variability of platelet inhibition in patients with stable coronary artery disease on aspirin therapy and to propose a definition of heightened platelet reactivity and activation to be used as a reference for future investigations linking the latter to adverse ischemic events.