What is the primary mechanism by which aspirin prevents platelet aggregation?

Mechanism of Aspirin's Antiplatelet Action

Aspirin prevents platelet aggregation primarily through the inactivation of platelet cyclooxygenase-1 (COX-1), which is answer choice B. 1

Detailed Mechanism of Action

Aspirin works through a specific biochemical pathway that involves:

• Permanent inactivation of COX-1: Aspirin selectively acetylates the hydroxyl group of a serine residue (Ser529) within the platelet COX-1 enzyme, permanently inactivating its cyclooxygenase activity 1, 2

• Blockade of thromboxane synthesis: This inactivation prevents the formation of prostaglandin endoperoxides and thromboxane A2 (TXA2), a potent platelet aggregator and vasoconstrictor 1

• Irreversible effect: The acetylation of COX-1 is permanent and lasts for the entire lifespan of the platelet (8-10 days), despite aspirin's short half-life of approximately 20 minutes in circulation 2, 3

Why Other Options Are Incorrect

• A. Inactivation of PGI2 (prostacyclin): Incorrect - PGI2 is actually antithrombotic and produced mainly by vascular endothelium. Aspirin at higher doses may reduce PGI2 production, but this would promote rather than prevent platelet aggregation 1

• C. Amplification of PGI2: Incorrect - Aspirin does not amplify PGI2; in fact, at higher doses it may reduce PGI2 production 1

• D. Inability of megakaryocytes to synthesize COX-1: Incorrect - Aspirin does not prevent megakaryocytes from synthesizing COX-1. Rather, it inactivates the enzyme that is already synthesized 1, 3

Clinical Implications of COX-1 Inhibition

• Low-dose aspirin (75-100 mg) is sufficient to achieve complete inhibition of platelet COX-1 activity 2

• This effect is dose-independent for daily doses above 30 mg, meaning that once COX-1 is inhibited, higher doses do not provide additional antiplatelet benefits 1

• The antiplatelet effect persists for the lifespan of the platelet due to the irreversible nature of COX-1 inhibition 1, 4

Potential Limitations and Resistance

• Aspirin resistance may occur in approximately 5-60% of patients, depending on the definition and testing methods used 1

• Mechanisms of resistance include:

  • Poor medication adherence
  • Accelerated platelet turnover in inflammatory states
  • Genetic polymorphisms affecting COX-1
  • Drug interactions (e.g., NSAIDs blocking aspirin's access to COX-1) 1, 5

In summary, aspirin's antiplatelet effect is primarily due to the irreversible inactivation of platelet COX-1, which prevents the synthesis of thromboxane A2 and subsequent platelet aggregation.