title: Aspirin and the in vitro linear relationship between thromboxane A2-mediated platelet aggregation and platelet production of thromboxane A2.
abstract: BACKGROUND
  Currently, 'aspirin resistance', the anti-platelet effects of non-steroid anti-inflammatory drugs (NSAIDs) and NSAID-aspirin interactions are hot topics of debate. It is often held in this debate that the relationship between platelet activation and thromboxane (TX) A(2) formation is non-linear and TXA(2) generation must be inhibited by at least 95% to inhibit TXA(2)-dependent aggregation. This relationship, however, has never been rigorously tested.
  
  
  OBJECTIVE
  To characterize, in vitro and ex vivo, the concentration-dependent relationships between TXA(2) generation and platelet activity.
  
  
  METHODS
  Platelet aggregation, thrombi adhesion and TXA(2) production in response to arachidonic acid (0.03-1 mmol L(-1)), collagen (0.1-30 microg mL(-1)), epinephrine (0.001-100 micromol L(-1)), ADP, TRAP-6 amide and U46619 (all 0.1-30 micromol L(-1)), in the presence of aspirin or vehicle, were determined in 96-well plates using blood taken from naïve individuals or those that had taken aspirin (75 mg, o.d.) for 7 days.
  
  
  RESULTS
  Platelet aggregation, adhesion and TXA(2) production induced by either arachidonic acid or collagen were inhibited in concentration-dependent manners by aspirin, with logIC(50) values that did not differ. A linear relationship existed between aggregation and TXA(2) production for all combinations of arachidonic acid or collagen and aspirin (P < 0.01; R(2) 0.92; n = 224). The same relationships were seen in combinations of aspirin-treated and naïve platelets, and in blood from individuals taking an anti-thrombotic dose of aspirin.
  
  
  CONCLUSIONS
  These studies demonstrate a linear relationship between inhibition of platelet TXA(2) generation and TXA(2)-mediated aggregation. This finding is important for our understanding of the anti-platelet effects of aspirin and NSAIDs, NSAID-aspirin interactions and 'aspirin resistance'.
authors.affiliation: William Harvey Research Institute, Barts & London School of Medicine & Dentistry, Charterhouse Square, London, UK.
authors.forename: P C J
authors.initials: PC
authors.lastname: Armstrong
authors.forename: N J
authors.initials: NJ
authors.lastname: Truss
authors.forename: F Y
authors.initials: FY
authors.lastname: Ali
authors.forename: A A
authors.initials: AA
authors.lastname: Dhanji
authors.forename: I
authors.initials: I
authors.lastname: Vojnovic
authors.forename: Z N M
authors.initials: ZN
authors.lastname: Zain
authors.forename: D
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: M J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: A T
authors.initials: AT
authors.lastname: Tucker
authors.forename: J A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: T D
authors.initials: TD
authors.lastname: Warner