Selective COX-2 inhibitors (coxibs) increase cardiovascular risk. Which prostanoid imbalance is the most accepted molecular explanation?

• A Increased PGE2 from constitutive COX-1 in macrophages causes vasoconstriction by activating EP3 receptors
• B Accumulation of arachidonic acid due to COX-2 blockade increases 5-LOX activity, elevating leukotriene B4 in the vasculature
• C Unopposed TXA2 production from platelet COX-1 is enhanced by COX-2 inhibition releasing free arachidonate for platelet use
• D Suppression of endothelial prostacyclin (PGI2) synthesis without affecting platelet thromboxane A2 (TXA2), tipping the balance toward platelet aggregation and vasoconstriction ✓

Explanation

The prostanoid imbalance hypothesis: COX-2 is constitutively expressed in vascular endothelium and is the principal isoform responsible for prostacyclin (PGI2) synthesis by endothelial cells. PGI2 inhibits platelet aggregation (via IP receptor/Gs/cAMP in platelets) and causes vasodilation. Platelet TXA2 (synthesized by COX-1, since platelets lack a nucleus and cannot upregulate COX-2) promotes aggregation and vasoconstriction. Selective COX-2 inhibitors block endothelial PGI2 production while sparing platelet COX-1-derived TXA2, creating an unbalanced prothrombotic/vasoconstrictive environment. This mechanism was confirmed by the VIGOR, APPROVe, and APC trials and led to rofecoxib withdrawal. Small daily aspirin blocks platelet COX-1 permanently but does not offset the endothelial PGI2 deficit.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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