How does aspirin work to prevent cardiac ischemia?

Aspirin's Mechanism in Preventing Cardiac Ischemia

Aspirin prevents cardiac ischemia primarily by blocking the enzyme COX-1 (cyclo-oxygenase-1) produced by platelets, which irreversibly inhibits thromboxane A2 formation and prevents platelet clumping.

Mechanism of Action

Aspirin works through a specific biochemical pathway:

1. Irreversible COX-1 Inhibition:

   • Aspirin selectively acetylates the hydroxyl group of a serine residue (Ser529) within the platelet COX-1 enzyme 1
   • This permanently inactivates the cyclo-oxygenase activity of COX-1 for the entire lifespan of the platelet (8-10 days) 1
   • The effect persists despite aspirin's short half-life of approximately 20 minutes in circulation 1

2. Thromboxane A2 Suppression:

   • Blocking COX-1 prevents the synthesis of prostaglandin endoperoxides and thromboxane A2 (TXA2) 1
   • TXA2 is a potent platelet aggregator and vasoconstrictor that promotes clot formation 2
   • Without TXA2, platelets cannot effectively clump together to form thrombi

3. Selective Inhibition at Low Doses:

   • Low-dose aspirin (75-160 mg daily) achieves complete inhibition of platelet COX-1 activity 1
   • At these doses, aspirin preferentially inhibits COX-1 over COX-2, preserving some beneficial prostacyclin (PGI2) production 2

Clinical Evidence Supporting Mechanism

The COX-1 inhibition mechanism is supported by extensive clinical evidence:

• The antithrombotic effect of aspirin is saturable at doses of 75-100 mg, consistent with the dose required for platelet COX-1 inactivation 1
• Despite aspirin's short half-life, its antithrombotic effect persists with 24-48 hour dosing intervals, reflecting the permanent nature of COX-1 inactivation 1
• Meta-analyses of randomized trials demonstrate that low-dose aspirin (75-150 mg) is as effective as higher doses in preventing cardiovascular events 1

Other Proposed Mechanisms

While COX-1 inhibition is the primary mechanism, other effects have been suggested but are less significant:

• Anti-inflammatory effects through COX-2 inhibition (requires much higher doses) 1
• Possible effects on platelet-vessel wall interactions beyond TXA2 inhibition 2

Clinical Applications

The understanding of aspirin's mechanism has important clinical implications:

• Low-dose aspirin (75-160 mg daily) is sufficient for cardiovascular protection 1
• Once-daily dosing is effective due to irreversible COX-1 inhibition 1
• Aspirin resistance may occur due to:
  • Accelerated platelet turnover in inflammatory states 1
  • Genetic polymorphisms affecting COX-1 1
  • Poor medication adherence 3

Common Pitfalls

• Using enteric-coated aspirin in acute settings (slower absorption) 4
• Assuming higher doses provide better cardioprotection (they don't, but increase bleeding risk) 1
• Failing to recognize that aspirin's effect is permanent for the platelet's lifespan, unlike other NSAIDs 1
• Overlooking potential drug interactions that may affect aspirin's antiplatelet effects 1

In conclusion, aspirin's cardioprotective effect stems primarily from its ability to irreversibly block COX-1 in platelets, preventing thromboxane A2 synthesis and subsequent platelet aggregation, which is the first answer choice in the question.