title: Risk Factors for Nonplatelet Thromboxane Generation After Coronary Artery Bypass Graft Surgery.
abstract: 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 TXA2 generation, indicated by elevated urine 11-dehydro-TXB2 (UTXB2) 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 TXA2 generation.
  
  
  RESULTS
  Multivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin-mediated inhibition of platelet TXA2 generation. The strongest variable associated with UTXB2 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8-iso-prostaglandin (PG)F2α, 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 UTXB2 (P<0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8-iso-PGF2α correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB2. In vitro studies revealed that endothelial cells generate TXA2 in response to oxidative stress and direct exposure to 8-iso-PGF2α.
  
  
  CONCLUSIONS
  Oxidative stress-induced formation of 8-iso-PGF2α 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.
authors.affiliation: University of Massachusetts Medical School, Worcester, MA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kakouros
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Nazarian
authors.affiliation: University of Massachusetts Medical School, Worcester, MA.
authors.forename: Patrizia B
authors.initials: PB
authors.lastname: Stadler
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kickler
authors.affiliation: University of Massachusetts Medical School, Worcester, MA Johns Hopkins School of Medicine, Baltimore, MD jeffrey.rade@umassmed.edu.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rade
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000652:urine; D002478:Cells, Cultured; D001026:Coronary Artery Bypass / Q000009:adverse effects*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D005260:Female; D006083:Graft Occlusion, Vascular / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control / Q000652:urine*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018384:Oxidative Stress; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D012501:Saphenous Vein / Q000378:metabolism* / Q000503:physiopathology / Q000637:transplantation*; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000652:urine; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014654:Vascular Patency
chemical_list: D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D015237:Dinoprost
keywords: aspirin; isoprostane; oxidative stress; thrombosis; thromboxane