Correct Answer: C. Thromboxane
Aspirin causes occult gastrointestinal bleeding by irreversibly inhibiting cyclooxygenase (COX), which blocks the synthesis of thromboxane A₂ (TXA₂) in platelets. TXA₂ is a potent platelet aggregator and vasoconstrictor synthesized from arachidonic acid via the COX pathway. By preventing TXA₂ formation, aspirin impairs platelet aggregation and hemostasis, leading to prolonged bleeding time and increased susceptibility to mucosal bleeding—especially in the gastric mucosa where aspirin also causes direct irritation. This is the mechanism behind aspirin-induced GI bleeding, a common adverse effect seen in Indian patients on chronic aspirin therapy for cardiovascular prophylaxis. The bleeding is typically occult (microscopic) rather than frank hematemesis, and occurs even at low doses (75–100 mg daily) used for antiplatelet effect. The inhibition is irreversible because aspirin acetylates serine residues on COX enzymes, and platelets cannot synthesize new COX, making the effect persist for the platelet lifespan (~7–10 days).
Why the other options are wrong
A. Phospholipase D — Phospholipase D is not the primary target of aspirin's antiplatelet action. While PLD is involved in cell signaling and lipid metabolism, aspirin does not inhibit it as a mechanism of action. This is a distractor that confuses the phospholipase cascade with the COX-arachidonic acid pathway. NBE uses this to test whether students can distinguish between different phospholipase enzymes and their roles. B. Phospholipase A2 — This is a classic NBE trap. PLA₂ does release arachidonic acid from membrane phospholipids (the first step in eicosanoid synthesis), but aspirin does NOT inhibit PLA₂. Aspirin acts downstream at the COX step, not at PLA₂. Students who confuse the arachidonic acid cascade may incorrectly select this, thinking aspirin blocks the entire pathway at its origin. D. Phospholipase C — Phospholipase C is involved in the IP₃/DAG signaling pathway and is not the target of aspirin. PLC inhibition would affect intracellular calcium mobilization and protein kinase C activation, not platelet aggregation via the TXA₂ pathway. This distractor tests whether students confuse different second-messenger systems with eicosanoid metabolism.
High-Yield Facts
- Aspirin irreversibly inhibits COX, blocking thromboxane A₂ synthesis in platelets, causing prolonged bleeding time and occult GI bleeding.
- Occult GI bleeding (not frank hematemesis) is the most common adverse effect of chronic aspirin use in Indian cardiovascular patients on 75–100 mg daily.
- Thromboxane A₂ is a potent platelet aggregator and vasoconstrictor; its inhibition impairs hemostasis and increases mucosal bleeding risk.
- Aspirin's effect on platelets is irreversible and lasts 7–10 days because platelets cannot synthesize new COX enzymes after acetylation.
- Phospholipase A₂ releases arachidonic acid (upstream step), but aspirin inhibits COX (downstream), not PLA₂—a key distinction in the eicosanoid pathway.
Mnemonics
COX → TXA₂ → Platelets (ASPIRIN BLOCKS HERE) Arachidonic acid → [PLA₂ releases it] → [COX-1 converts it] → Thromboxane A₂ → Platelet aggregation. Aspirin blocks COX, not PLA₂. Remember: COX is the target, TXA₂ is the victim. GI Bleed from Aspirin = Two Hits
- 1.Direct mucosal irritation (topical effect), 2) Impaired hemostasis (TXA₂ inhibition). Both contribute to occult bleeding in chronic users.
NBE Trap
NBE pairs phospholipase options (A₂, C, D) with aspirin to trap students who know aspirin affects the arachidonic acid cascade but confuse which enzyme is actually inhibited. Students may incorrectly choose PLA₂ because it releases arachidonic acid, not realizing aspirin acts downstream at the COX step.
Clinical Pearl
In Indian clinical practice, elderly patients on aspirin 75 mg daily for secondary stroke prevention often present with iron-deficiency anemia from chronic occult GI bleeding—a diagnosis easily missed if stool occult blood testing is not done routinely. Switching to gastroprotection (PPI) or alternative antiplatelet agents may be necessary.
_Reference: KD Tripathi Pharmacology Ch. 12 (Autacoids & NSAIDs); Harrison Ch. 139 (Antiplatelet agents)_