Aspirin resistance: Fact or fiction? A point of view

Table 1 Cyclooxygenase-independent effects of aspirin

On platelets

Partially inhibits ADP2Y12 receptor activation responsible for residual arachidonic acid induced platelet activation[11]

Blocks NF-κB activation that facilitates platelet inhibition by neutrophils[12]

Anti-inflammatory effect

Inhibits release of reactive oxygen species[13]

Inhibits release of elastase and soluble ICAM-1[13]

Inhibits formation of malondialdehyde[13]

Inhibits formation of oxidized LDL antibodies[14]

Reduces inflammatory cell activity[13]

Anti-oxidant effect

Inhibits oxidized LDL formation[14]

Blocks transcription of LOX-1[15,16]

Scavenges hydroxyl radicals[17]

Induces synthesis of ferritin[18]

Inhibits nitric oxide synthase[19,20]

Inhibits expression of redox sensitive transcription factor NF-κB[19,20]

Acetylates proteins and prevents their oxidation[21,22]

Endothelial function modification

Prevents adhesion of neutrophils and monocytes[23]

Induction of VCAM-1, ICAM-1 and E-selectin[24,25]

Miscellaneous effects

Inhibits vascular smooth muscle cell function[26]

Inhibits angiogenesis[27-29]

Inhibits γ-carboxylation of coagulation factors[30]

ADP: Adenosine diphosphate; NF-κB: Nuclear factor-κB; ICAM-1: Intracellular adhesion molecule-1; LDL: Low density lipoprotein; LOX-1: Oxidized LDL receptor.

Table 2 Reported prevalence of “aspirin resistance”

	Prevalence (%)	Ref.
Healthy adults	8.3	[38]
Risk factors	0.7-23.4	[39,40]
Stable CAD	0.4-29.2	[41-48]
CVD	12.5-56	[49-55]
CABG	7.1-54	[56-60]
PCI	12.7-26.2	[61-64]
MI	0.5-70.1	[65-70]
CHF	55.0	[71]
PVD	9.6-60	[72,73]

CAD: Coronary artery disease; CVD: Cardiovascular disease; CABG: Coronary artery bypass grafting; PCI: Percutaneous coronary intervention; MI: Myocardial infarction; CHF: Congestive heart failure; PVD: Peripheral vascular disease.

Table 3 Underlying causes of “aspirin resistance”

Abnormal pharmacokinetics

Non-compliance

Inadequate dosing

Tachyphylaxis

Interaction with other drugs, such as NSAIDs and PPIs

Clinical conditions

Advanced coronary artery disease, acute coronary syndromes, CABG

Diabetes mellitus

Heart failure

Infection/inflammation

Obesity

Genetic

COX-1 gene mutation

COX-2 overexpression

GpIIb-IIIa polymorphisms

Molecular

Increased turnover of platelets

PGH2 substrate is provided to platelets by monocytes or endothelial cells

Incomplete inhibition of TXA2 formation

Increased platelet sensitivity to ADP and collagen

Increased COX-2 expression on platelets

COX: Cyclooxygenase; NSAIDs: Non-steroidal anti-inflammatory drugs; PPIs: Proton pump inhibitors; Gp: Glycoprotein; TXA₂: Thromboxane A₂; PGH₂: Prostaglandin H₂; ADP: Adenosine diphosphate.