title: Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals.
abstract: Aspirin administration decreases the risk of vascular ischemic problems. However, aspirin withdrawal may temporarily increase this risk. Previous studies reported that high dilutions of aspirin might cause a pro-thrombotic effect. This paper studies the effect of the lower end of the aspirin dose-response curve, its possible mechanism and clinical implications.
  
  
  METHODS
  Wistar rats were distributed into 100 groups of 10 rats each. Aspirin was injected at 100 mg/kg, 1 mg/kg and at several different aspirin dilutions along with cyclooxygenase (COX) 1 (SC-560), COX 2 (NS-398) or both selective inhibitors simultaneously using a laser-induced thrombosis model.
  
  
  RESULTS
  The higher doses of aspirin decreased thrombosis. An opposite trend was observed with the lowest doses. SC-560 produced an anti-thrombotic effect antagonized by the highest aspirin dilutions. NS-398 created a pro-thrombotic effect that was antagonized by aspirin at higher doses. Simultaneous inhibition of COX 1 and 2 produced changes similar to COX 1 inhibition.
  
  
  CONCLUSIONS
  COX 2 inhibition induced a pro-thrombotic effect that was antagonized by aspirin at 1 mg/kg or 100 mg/kg. The administration of the lowest aspirin doses induced a pro-thrombotic effect stronger than the antithrombotic effect of COX 1 selective inhibition. The mechanism of this last pro-thrombotic effect is induced by residual aspirin and is independent of COX 1 inhibition. This study may explain the cause of the paradoxical thrombo-embolic complications observed after aspirin discontinuation, an effect of residual aspirin rather than a rebound effect, and highlights the importance of low doses of substances as a barely studied source of side-effects.
authors.affiliation: Laboratoire d'Hématologie, Université Victor Segalen, Bordeaux 2, Bordeaux, France. christian.doutremepuich@heph.u-bordeaux2.fr
authors.forename: Christian
authors.initials: C
authors.lastname: Doutremepuich
authors.forename: Omar
authors.initials: O
authors.lastname: Aguejouf
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Eizayaga
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology* / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000209:etiology; D013449:Sulfonamides / Q000494:pharmacology; D013927:Thrombosis / Q000139:chemically induced* / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D001241:Aspirin