Mechanisms of aspirin resistance

Pharmacol Ther. 2014 Jan;141(1):69-78. doi: 10.1016/j.pharmthera.2013.08.005. Epub 2013 Aug 29.


Aspirin is integral to the secondary prevention of cardiovascular disease and acts to impair the development of platelet-mediated atherothromboembolic events by irreversible inhibition of platelet cyclooxygenase-1 (COX-1). Inhibition of this enzyme prevents the synthesis of the potent pro-aggregatory prostanoid thromboxane A2. A large number of patients continue to experience atherothromboembolic events despite aspirin therapy, so-called 'aspirin treatment failure', and this is multifactorial in aetiology. Approximately 10% however do not respond appropriately to aspirin in a phenomenon known as 'aspirin resistance', which is defined by various laboratory techniques. In this review we discuss the reasons for aspirin resistance in a systematic manner, starting from prescription of the drug and ending at the level of the platelet. Poor medication adherence has been shown to be a cause of apparent aspirin resistance, and may in fact be the largest contributory factor. Also important is high platelet turnover due to underlying inflammatory processes, such as atherosclerosis and its complications, leading to faster regeneration of platelets, and hence of COX-1, at a rate that diminishes the efficacy of once daily dosing. Recent developments include the identification of platelet glycoprotein IIIa as a potential biomarker (as well as possible underlying mechanism) for aspirin resistance and the discovery of an anion efflux pump that expels intracellular aspirin from platelets. The absolute as well as relative contributions of such factors to the phenomenon of aspirin resistance are the subject of continuing research.

Keywords: AA; Aspirin; CABG; COX; Cardiovascular; LTA; MRP4; NSAID; PGE(2); PGH(2); PGI(2); PPI; Platelet; Resistance; TXA(2); TXB(2); Thrombosis; arachidonic acid; coronary artery bypass graft; cyclooxygenase; light transmission aggregometry; multidrug resistant protein 4; non-steroidal anti-inflammatory drug; prostaglandin E(2); prostaglandin H(2); prostaglandin I(2) (prostacyclin); proton pump inhibitor; thromboxane A(2); thromboxane B(2).

Publication types

  • Review

MeSH terms

  • Aspirin / pharmacokinetics
  • Aspirin / pharmacology*
  • Aspirin / therapeutic use
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Cyclooxygenase 1 / drug effects
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase Inhibitors / pharmacokinetics
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cyclooxygenase Inhibitors / therapeutic use
  • Drug Interactions
  • Drug Resistance*
  • Humans
  • Integrin beta3 / drug effects
  • Integrin beta3 / metabolism
  • Medication Adherence
  • Tachyphylaxis
  • Thromboembolism / drug therapy*
  • Thromboembolism / prevention & control
  • Thromboxane A2 / antagonists & inhibitors
  • Thromboxane A2 / metabolism
  • Treatment Failure


  • Cyclooxygenase Inhibitors
  • Integrin beta3
  • Thromboxane A2
  • Cyclooxygenase 1
  • Aspirin