title: Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance.
abstract: BACKGROUND
  Thrombotic events still occur in aspirin-treated patients with coronary artery disease.
  
  
  RESULTS
  To better understand aspirin "resistance," serum thromboxane B2 (TXB2) and flow cytometric measures of arachidonic acid-induced platelet activation (before and after the ex vivo addition of aspirin and indomethacin) were analyzed in 700 consecutive aspirin-treated patients undergoing cardiac catheterization. In 680 of 682 evaluable patients, serum TXB2 concentrations were reduced compared with nonaspirinated healthy donors. Twelve patients had serum TXB2 that was lower than nonaspirinated healthy donors but >10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum TXB2 (>10 ng/mL) than in patients with low serum TXB2. Addition of ex vivo aspirin reduced arachidonic acid-induced platelet activation to similar levels regardless of serum TXB2 concentrations, which suggests that patients with high residual serum TXB2 concentrations were either noncompliant or underdosed with aspirin. Among the remaining 98% of patients, ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation across all degrees of arachidonic acid-induced platelet activation and aspirin doses. Although the patients were not randomized with respect to clopidogrel treatment, multivariate analysis showed that arachidonic acid-induced platelet activation was less in patients receiving clopidogrel.
  
  
  CONCLUSIONS
  There is a residual arachidonic acid-induced platelet activation in aspirin-treated patients that (1) is caused by underdosing and/or noncompliance in only approximately 2% of patients and (2) in the remaining patients, occurs via a cyclooxygenase-1 and cyclooxygenase-2 independent pathway, in direct proportion to the degree of baseline platelet activation, and is mediated in part by adenosine diphosphate-induced platelet activation.
authors.affiliation: Center for Platelet Function Studies, Department of Pediatrics, UMass Memorial Medical Center, 55 Lake Ave N, Worcester, Massachusetts 01655, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.forename: Mark I
authors.initials: MI
authors.lastname: Furman
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Linden
authors.forename: Youfu
authors.initials: Y
authors.lastname: Li
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Fox
authors.forename: Marc R
authors.initials: MR
authors.lastname: Barnard
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology*; D016718:Arachidonic Acid / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012008:Recurrence; D015398:Signal Transduction / Q000502:physiology; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D013929:Thromboxane B2 / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D016312:Treatment Refusal
chemical_list: D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D013988:Ticlopidine; D001241:Aspirin