Risk Factors for Nonplatelet Thromboxane Generation After Coronary Artery Bypass Graft Surgery

BACKGROUND: Persistent thromboxane (TX) generation while receiving aspirin therapy is associated with an increased risk of cardiovascular events. The Reduction in Graft Occlusion Rates (RIGOR) study found that aspirin‐insensitive TXA (2) generation, indicated by elevated urine 11‐dehydro‐TXB (2) (UTXB (2)) 6 months after coronary artery bypass graft surgery, was a potent risk factor for vein graft thrombosis and originated predominantly from nonplatelet sources. Our goal was to identify risks factors for nonplatelet TXA (2) generation. METHODS AND RESULTS: Multivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin‐mediated inhibition of platelet TXA (2) generation. The strongest variable associated with UTXB (2) 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8‐iso‐prostaglandin (PG)F (2α), an arachidonic acid metabolite generated nonenzymatically by oxidative stress (standardized coefficient 0.442, P<0.001). Age, sex, race, lipid therapy, creatinine, left ventricular ejection fraction, and aspirin dose were also significantly associated with UTXB (2) (P<0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8‐iso‐PGF (2α) correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB (2). In vitro studies revealed that endothelial cells generate TXA (2) in response to oxidative stress and direct exposure to 8‐iso‐PGF (2α). CONCLUSIONS: Oxidative stress–induced formation of 8‐iso‐PGF (2α) is strongly associated with nonplatelet thromboxane formation and early vein graft thrombosis after coronary artery bypass graft surgery. The endothelium is potentially an important source of oxidative stress–induced thromboxane generation. These findings suggest therapies that reduce oxidative stress could be useful in reducing cardiovascular risks associated with aspirin‐insensitive thromboxane generation.