Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin

J Thromb Haemost. 2007 Mar;5(3):490-6. doi: 10.1111/j.1538-7836.2007.02387.x.


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.

Objectives: 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.

Publication types

  • Clinical Trial

MeSH terms

  • Adenosine Diphosphate
  • Administration, Oral
  • Adult
  • Aspirin / pharmacology*
  • Blood Platelets / drug effects*
  • Blood Platelets / enzymology
  • Blood Platelets / metabolism
  • Collagen
  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors / administration & dosage
  • Cyclooxygenase Inhibitors / pharmacology*
  • Drug Resistance*
  • Female
  • Flow Cytometry
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • P-Selectin / biosynthesis
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Function Tests
  • Platelet Glycoprotein GPIIb-IIIa Complex / biosynthesis
  • Reference Values
  • Tablets, Enteric-Coated
  • Thromboxane B2 / blood


  • Cyclooxygenase Inhibitors
  • Membrane Proteins
  • P-Selectin
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Tablets, Enteric-Coated
  • Thromboxane B2
  • Adenosine Diphosphate
  • Collagen
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Aspirin