Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin.
BACKGROUND
The mechanisms for the variability in antiplatelet effects of aspirin are unclear. Immature (reticulated) platelets may modulate the antiplatelet effects of aspirin through uninhibited cyclooxygenase (COX)-1 and COX-2.


OBJECTIVE
To evaluate the role of reticulated platelets in the antiplatelet effects of aspirin.


METHODS
Sixty healthy volunteers had platelet studies performed before and 24 h after a single 325-mg dose of aspirin. Platelet studies included light transmission aggregometry; P-selectin and integrin alpha(IIb)beta(3) expression, and serum thromboxane B(2) (TxB(2)) levels. Reticulated platelets and platelet COX-2 expression were measured using flow cytometry.


RESULTS
Subjects were divided into tertiles based on the percentage of reticulated platelets in whole blood. Baseline platelet aggregation to 1 microg mL(-1) collagen, and postaspirin aggregations to 5 microm and 20 microm ADP and collagen, were greater in the upper than in the lower tertile of reticulated platelets. Stimulated P-selectin and integrin alpha(IIb)beta(3) expression were also higher in the upper tertile both before and after aspirin. Platelet COX-2 expression was detected in 12 +/- 7% (n = 10) of platelets in the upper tertile, and in 7 +/- 3% (n = 12) of platelets in the lower two tertiles (P = 0.03). Postaspirin serum TxB(2) levels were higher in the upper (5.5 +/- 4 ng mL(-1)) than in the lower tertile (3.2 +/- 2.5 ng mL(-1), P = 0.03), and decreased even further with ex vivo additional COX-1 and COX-2 inhibition. The incidence of aspirin resistance (>or= 70% platelet aggregation to 5 microm ADP) was significantly higher in the upper tertile (45%) than in the lower tertile (5%, P < 0.0001).


CONCLUSIONS
Reticulated platelets are associated with diminished antiplatelet effects of aspirin and increased aspirin resistance, possibly because of increased reactivity, and uninhibited COX-1 and COX-2 activity.
Guthikonda
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Department of Cardiology, Emory University, Atlanta, GA 77030, USA. nkleiman@tmh.tmc.edu
Lev
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Patel
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DeLao
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Bergeron
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Dong
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Kleiman
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D000244:Adenosine Diphosphate; D000284:Administration, Oral; D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003094:Collagen; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D019007:P-Selectin / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000096:biosynthesis; D012016:Reference Values; D013608:Tablets, Enteric-Coated; D013929:Thromboxane B2 / Q000097:blood
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013608:Tablets, Enteric-Coated; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D003094:Collagen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001241:Aspirin