A patient taking a selective COX-2 inhibitor (celecoxib) for rheumatoid arthritis develops a myocardial infarction. The pharmacological mechanism linking COX-2 inhibition to cardiovascular thrombotic events is:

• A Celecoxib directly activates the coagulation cascade via vitamin K-dependent factor synthesis
• B COX-2 inhibition increases arachidonic acid availability for leukotriene synthesis, causing coronary vasospasm
• C Celecoxib competitively inhibits endothelial nitric oxide synthase reducing vasodilation
• D COX-2 inhibition blocks prostacyclin (PGI2) synthesis in vascular endothelium while platelet COX-1-derived thromboxane A2 (TXA2) remains unopposed, shifting the PGI2/TXA2 balance toward thrombosis ✓

Explanation

Vascular endothelium predominantly expresses COX-2 for constitutive prostacyclin (PGI2) synthesis; PGI2 is anti-thrombotic and vasodilatory. Platelets express mainly COX-1 for thromboxane A2 (TXA2), which is pro-thrombotic and vasoconstrictive. Selective COX-2 inhibitors suppress endothelial PGI2 while leaving platelet TXA2 synthesis intact (since platelets mainly use COX-1), creating a pro-thrombotic imbalance. This hypothesis, confirmed by the VIGOR and APPROVe trials, explains the increased cardiovascular risk of selective COX-2 inhibitors and is the basis for restricting their use.

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

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