Vitamin e suppresses enhancement of factor VIII-dependent thrombin generation by systemic hypoxia

Background and Purpose-Increased thrombin activity is an essential component of hemostatic reactions. This study elucidates how various hypoxic interventions impact endogenous thrombin generation (TG) after treatment with/without lipophilic antioxidant vitamin E. Methods-Twenty-four healthy sedentary men were randomly assigned to vitamin E (n= 12) and placebo (n= 12) groups. These subjects were randomly exposed to 12% (severe hypoxia), 15% (moderate hypoxia), 18% (light hypoxia), and 21% (normoxia) O₂ for 2 hours in a normobaric hypoxia chamber. A novel calibrated, automated thrombinography approach was used to measure TG in plasma. Results-In the placebo group, severe hypoxia enhanced plasma FVIII level/activity and TG, which was accompanied by increased urinary 15-F2t-8-isoprostane level and decreased plasma total antioxidant content and superoxide dismutase activity. However, depletion of FVIII by incubation with anti-FVIII antibodies in plasma suppressed enhancement of TG by severe hypoxia. After administration of 1000 IU vitamin E, severe hypoxia did not significantly alter urinary 15-F_2t-8- isoprostane level and plasma total antioxidant content, superoxide dismutase activity, FVIII level/activity, or TG. Moreover, redox status, FVIII level/activity, and TG were constant in response to moderate hypoxia, light hypoxia, and normoxia in the placebo and vitamin E groups. Conclusion-We conclude that severe hypoxia promotes FVIII-dependent TG, likely by elevating oxidative stress;this hypoxic effect was ameliorated by pretreatment with vitamin E.