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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Role of Reticulated Platelets and Platelet Size Heterogeneity on Platelet Activity After Dual Antiplatelet Therapy With Aspirin and Clopidogrel in Patients With Stable Coronary Artery Disease

Sasidhar Guthikonda, MD, MPH, FACC^_*, Carlos L. Alviar, MD^_*, Muthiah Vaduganathan, BS^_*, Mehmet Arikan, MD^_*, Armando Tellez, MD^_*, Timothy DeLao, MLT^_*, Juan F. Granada, MD^_*, Jing-Fei Dong, MD, PhD, Neal S. Kleiman, MD, FACC^_*,_* and Eli I. Lev, MD^_*

^_* Department of Cardiology, Methodist DeBakey Heart and Vascular Center and Methodist Hospital Research Institute, Houston, Texas
Department of Thrombosis, Baylor College of Medicine, Houston, Texas.

Manuscript received April 7, 2008; revised manuscript received May 12, 2008, accepted May 12, 2008.

^_* Reprint requests and correspondence: Dr. Neal S. Kleiman, Methodist DeBakey Heart and Vascular Center, 6565 Fannin, F-1035, Houston, Texas 77030. (Email: nkleiman{at}tmhs.org).

Objectives: The aim of this study was to evaluate the relationship between reticulated platelets (RPs), platelet size, and platelet function in patients with stable coronary artery disease (CAD) taking aspirin and clopidogrel.

Background: Reticulated platelets are young platelets that are larger and possibly more active than non-RPs.

Methods: Flow cytometry was used to measure RPs after staining with thiazole orange and to define the upper 20% and lower 20% of platelets by size. Platelet aggregation was measured with light transmission aggregometry (LTA); platelet activation was assessed by measuring activated platelet surface expression of P-selectin and glycoprotein (GP) IIb/IIIa.

Results: Ninety patients were recruited and stratified into tertiles of %RPs. Patients in the upper tertile displayed greater platelet aggregation to 5-µmol/l adenosine diphosphate (ADP) (50.7 ± 16.4% vs. 34.2 ± 17.3%, p < 0.001), 1.5-mmol/l arachidonic acid (AA) (27.3 ± 16.9% vs. 11.7 ± 9.3%, p < 0.001), and 1-µg/ml collagen (18 ± 11.6% vs. 12.1 ± 8.7%, p < 0.05) and greater expression of GP IIb/IIIa (4.7 ± 1.8% vs. 3.1 ± 2.2%, p < 0.001). Frequency of low response to aspirin (AA LTA >20%) was higher in the upper tertile (53% vs. 17%, p < 0.001) compared with the lower tertile; low response to clopidogrel (ADP LTA >50%) was also elevated in the upper tertile (50% vs. 13%, p = 0.003). The larger platelet gate had a higher % of RPs compared with the smaller gate (15.4 ± 16.7% vs. 1.7 ± 2.3%, p < 0.001) and greater GP IIb/IIIa (5.7 ± 3.1 vs. 2.1 ± 1.2, p < 0.001) and P-selectin expression (7.8 ± 4.9 vs. 4.6 ± 2.7, p < 0.001).

Conclusions: The proportion of circulating RPs strongly correlates with response to antiplatelet therapy in patients with stable CAD. Large platelets exhibit increased reactivity despite dual antiplatelet therapy, compared with smaller platelets.

Key Words: aspirin • platelets • coronary artery disease

Abbreviations and Acronyms   AA = arachidonic acid   ADP = adenosine diphosphate   CAD = coronary artery disease   CHF = congestive heart failure   COX = cyclooxygenase   GP = glycoprotein   LTA = light transmission aggregometry   MPV = mean platelet volume   RP = reticulated platelet

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