title: Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin.
abstract: 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.
authors.affiliation: Department of Cardiology, Emory University, Atlanta, GA 77030, USA. nkleiman@tmh.tmc.edu
authors.forename: S
authors.initials: S
authors.lastname: Guthikonda
authors.forename: E I
authors.initials: EI
authors.lastname: Lev
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: T
authors.initials: T
authors.lastname: DeLao
authors.forename: A L
authors.initials: AL
authors.lastname: Bergeron
authors.forename: J-F
authors.initials: JF
authors.lastname: Dong
authors.forename: N S
authors.initials: NS
authors.lastname: Kleiman
mesh_terms: 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
chemical_list: 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