Vitamin E Suppresses Enhancement of Factor VIII-Dependent Thrombin Generation by Systemic Hypoxia

Abstract

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 (nϭ12) and placebo (nϭ12) groups.These subjects were randomly exposed to 12% (severe hypoxia), 15% (moderate hypoxia), 18% (light hypoxia), and 21% (normoxia) O 2 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

Effects of normoxic and hypoxic exercise regimens on monocyte-mediated thrombin generation in sedentary men

“…Dynamic TG in plasma or MRP treated with/without ox-LDL was measured by calibrated, automatic thrombinography (Synapse Thrombinoscope), as described in our previous studies [15,23,24]. Briefly, 80 μl of various plasma samples were allocated into the wells of round bottom 96-well microtitre plates (Nunc).…”

“…The following parameters were recorded: (i) endogenous thrombin potential (ETP): area under the curve, which stands for the total amount of thrombin generated over the time; (ii) the lag time of TG: time to burst of TG, which roughly represents the clotting time; (iii) the peak height of TG: the highest thrombin concentration reached during the time course of thrombin formation and inhibition; and (iv) the rate of TG: peak height divided by the difference between time to peak and lag time, which represents the initial slope of TG [15,22,23].…”

“…Activated prothrombinase complex catalyses the generation of thrombin (TG) from prothrombin, resulting in the formation of a fibrin clot [12]. The authors' previous study has demonstrated that an acute exposure to 12 % O 2 , but not 15 % O 2 , may promote blood coagulant FVIII-dependent TG by elevating circulatory oxidative stress [15]. Furthermore, intermittent exposure to 12 % O 2 for 4 weeks resulted in an impairment of vascular haemodynamics by suppressing vascular endothelial function.…”

Effects of normoxic and hypoxic exercise regimens on cardiac, muscular, and cerebral hemodynamics suppressed by severe hypoxia in humans

“…The O 2 concentrations of 15%, and 21% correspond to altitudes of ϳ2,733 m and sea level, respectively. The hypoxia chamber was maintained at a temperature of 22 Ϯ 0.5°C with a relative humidity of 60 Ϯ 5%; a CO 2 scrubber eliminated CO2 in the air (Յ3,500 ppm) (43)(44)(45). Interventional conditions in various normoxic and hypoxic regimens are shown in Table 1 and Fig.…”

“…Additionally, acute or chronic severe hypoxic exposure may have detrimental effects on thrombotic and vascular disorders (26). More recently, we (45) found that acute hypoxic exposure affected coagulant factor VIII-mediated thrombin generation in a concentration-dependent manner; it was enhanced by exposure to 12% O 2 but not by exposures to 15%, 18%, or 21% O 2 . In the chronic hypoxic intervention, our previous investigation (44) of healthy sedentary males demonstrated an impairment of vascular hemodynamics by suppression of vascular endothelial function after 4 wk of intermittent exposure to 12% O 2 ; when the concentration of O 2 was set to 15%, the risk of vascular complications became negligible.…”