title: Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients.
abstract: OBJECTIVE
  Although the concept of aspirin resistance is extensively reported in medical literature, its precise mechanisms and clinical outcomes are largely unknown. In this study, we examined individual thromboxane biosynthesis and platelet aggregation in aspirin-treated patients, and whether the results of a platelet aggregation test influenced clinical outcomes.
  
  
  RESULTS
  Subjects taking 81 mg of aspirin (n = 50) and controls (n = 38) were evaluated for platelet aggregation and platelet cyclooxygenase-1 (COX-1) activity by measuring collagen-induced thromboxane B2 production. For aggregometry, both light transmission (LT) and laser-light scattering methods were employed to quantitatively evaluate aggregate sizes and numbers. Aspirin treatment resulted in the inhibition of collagen-induced platelet aggregation, particularly the transition from small to large platelet aggregates. Although platelet COX-1 activity seemed to be uniformly inhibited in all patients, platelet aggregation studies showed great inter-individual differences; variation in platelet COX-1 activity only accounted for 6-20% of the individual aggregations. Factor analysis revealed the existence of a common factor (other than platelet COX-1) that explained 48.4% of the variations in platelet aggregation induced by collagen, adenosine diphosphate (ADP), and collagen-related peptide. We then prospectively enrolled 136 aspirin-treated patients in our study, and we found that being in the upper quartile level of LT, or with large aggregate formation induced by collagen, was an independent risk factor for developing cardiovascular events within 12 months [hazard ratio (HR) = 7.98, P = 0.008 for LT; HR = 7.76, P = 0.007 for large aggregates]. On the other hand, the existence of diabetes mellitus was an independent risk factor for overall outcomes (HR 1.30-11.9, P = 0.015-0.033).
  
  
  CONCLUSIONS
  Aspirin resistance expressed as unsuppressed platelet COX-1 activity is a rare condition in an out-patient population. Other factor(s) affecting collagen-induced platelet aggregation may influence early outcomes in aspirin-treated patients.
authors.affiliation: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, Minamikawachi, Tochigi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohmori
authors.forename: Y
authors.initials: Y
authors.lastname: Yatomi
authors.forename: T
authors.initials: T
authors.lastname: Nonaka
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Madoiwa
authors.forename: J
authors.initials: J
authors.lastname: Mimuro
authors.forename: Y
authors.initials: Y
authors.lastname: Ozaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000368:Aged; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology / Q000652:urine; D003094:Collagen / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D010979:Platelet Function Tests / Q000379:methods; D011446:Prospective Studies; D012307:Risk Factors; D015398:Signal Transduction; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D016896:Treatment Outcome
chemical_list: D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D003094:Collagen; D051545:Cyclooxygenase 1; D001241:Aspirin