What is the effect of aspirin (acetylsalicylic acid) on platelets?

Aspirin's Effect on Platelets

Aspirin permanently and irreversibly inactivates platelet cyclooxygenase-1 (COX-1) by acetylating a serine residue at position 529, which blocks thromboxane A2 production and prevents platelet aggregation for the entire lifespan of the platelet. 1

Mechanism of Action

Irreversible Enzyme Inhibition

• Aspirin selectively acetylates the hydroxyl group of serine 529 (Ser529) within the polypeptide chain of platelet prostaglandin H-synthase (COX-1), permanently destroying the enzyme's cyclooxygenase activity 1
• This acetylation prevents arachidonic acid from accessing the catalytic site at tyrosine 385, resulting in irreversible inhibition of platelet-dependent thromboxane formation 2
• The hydroperoxidase activity of the enzyme remains unaffected by aspirin 1

Thromboxane A2 Suppression

• COX-1 is responsible for converting arachidonic acid to prostaglandin H2 (PGH2), the precursor of thromboxane A2 (TXA2) 1
• TXA2 provides a mechanism for amplifying platelet activation signals by being synthesized and released in response to various platelet agonists 1
• By blocking TXA2 formation, aspirin prevents this amplification pathway of platelet aggregation 1

Clinical Manifestations

Functional Platelet Defect

• Aspirin induces a long-lasting functional defect in platelets that is clinically detectable as a prolonged bleeding time 1
• This effect persists for the entire 7-10 day lifespan of the platelet because platelets cannot synthesize new COX-1 enzyme 1

Duration of Effect

• Despite aspirin's half-life of only approximately 20 minutes in human circulation, its anti-thrombotic effect lasts 24-48 hours due to the permanent nature of platelet COX-1 inactivation 1
• This "hit-and-run" mechanism allows once-daily dosing while limiting extra-platelet effects 1

Dose-Response Characteristics

Optimal Antiplatelet Dosing

• The anti-thrombotic effect of aspirin is saturable at doses in the range of 75-100 mg daily, as demonstrated by extensive clinical trial data 1
• Low-dose aspirin (75-150 mg) is as effective as higher doses (300-1500 mg) for preventing vascular events 1
• Aspirin is approximately 150-200 fold more potent at inhibiting COX-1 than COX-2, explaining the different dose requirements for antiplatelet versus anti-inflammatory effects 1, 2

Biochemical Selectivity

• Low-dose aspirin achieves biochemical selectivity through presystemic acetylation of platelet COX-1 in portal blood before first-pass metabolism 1, 3
• This pharmacokinetic advantage allows platelet inhibition while relatively sparing vascular prostacyclin (PGI2) synthesis 1

Limitations and Resistance

COX-2 in Newly Formed Platelets

• Mature platelets contain only COX-1, but newly formed platelets (approximately 10% of circulating platelets) also contain COX-2 1
• During periods of increased platelet turnover, COX-2-derived thromboxane can be produced in an aspirin-insensitive fashion since aspirin is 150-fold less potent against COX-2 1
• This may contribute to aspirin resistance in certain clinical conditions 1

Aspirin Resistance Prevalence

• Laboratory evidence of aspirin resistance occurs in 5-14% of stable cardiovascular disease patients, but rises to 28-29% in acute coronary syndrome patients 1
• Aspirin resistance is associated with increased risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio 3.12) 1
• Multiple factors contribute to resistance including cigarette smoking, drug-drug interactions with NSAIDs, inadequate dosing, and genetic variability in COX-1 1, 4

Non-Thromboxane Pathways

• Aspirin only blocks the thromboxane-mediated pathway of platelet activation 1, 2
• Platelet activation by other mechanisms (shear stress, ADP, collagen, thrombin) remains unaffected, which can result in incomplete platelet inhibition 2

Clinical Implications

Bleeding Risk

• Any effective antiplatelet dose of aspirin increases bleeding risk, particularly upper gastrointestinal bleeding 1
• The risk of major GI bleeding is estimated at 1-2 events per 1000 patients per year, representing a 2-3 fold increase over baseline 1
• Both COX-1-dependent mechanisms contribute: inhibition of TXA2-mediated platelet function and impairment of PGE2-mediated gastrointestinal mucosal cytoprotection 1