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An adverse vitamin E–vitamin K interaction was reported among patients taking coumarin-based oral anticoagulants, such as warfarin and phenprocoumon (1–3). The mechanism of the apparent enhancement by vitamin E of the action of coumarin is unknown, although Dowd and Zheng (4) proposed a competitive inhibition between tocopherol quinone and the phylloquinone hydroquinone for the vitamin K–dependent -carboxylase. The vitamin K–dependent carboxylase is required for conversion of specific glutamyl residues to -carboxyglutamyl residues in certain proteins, including factors II, VII, IX, and X, and proteins C and S, which are involved in normal hemostatic function (5).
Vitamin E in the reduced, alpha-tocopherol form shows very modest anticlotting activity. By contrast, vitamin E quinone is a potent anticoagulant. This observation may have significance for field trials in which vitamin E is observed to exhibit beneficial effects on ischemic heart disease and stroke. Vitamin E quinone is a potent inhibitor of the vitamin K-dependent carboxylase that controls blood clotting. A newly discovered mechanism for the inhibition requires attachment of the active site thiol groups of the carboxylase to one or more methyl groups on vitamin E quinone. The results from a series of model reactions support this interpretation of the anticlotting activity associated with vitamin E.
From numerous publications on the "prophylactic" and "therapeutic" use of vitamin E, it may be concluded that the toxicity of vitamin E is very low. It has been demonstrated in animal experiments that vitamin E has neither mutagenic, teratogenic nor carcinogenic properties. Based on studies in humans, a daily dosage of 100-300 mg vitamin E can be considered harmless from a toxicological point of view. Using double-blind studies involving a large number of subjects, it has been demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. From a large body of published data, dosage ranges have been deduced which can be characterized as safe for human subjects even where their use extends over a long period of time. It should, however, be noted that oral intake of high levels of vitamin E can exacerbate the blood coagulation defect of vitamin K deficiency caused by malabsorption or anticoagulant therapy. High levels of vitamin E intake are, therefore, contraindicated in these subjects.
Rats rendered lightly vitamin K deficient with warfarin (0.01 mg/100 g, IP) and given the equivalent of 1000 units of vitamin E/kg IM for 7 days, showed a marked reduction in functional factor II activity, but normal factor II levels using Echis venom on coagulation analysis. In 12 humans receiving warfarin, vitamin E was administered in doses of 100 or 400 units/day orally for 4 wk. The results in these patients showed no significant change in the prothrombin time, factor II coagulant activity, or factor II antigen (by electroimmunoassay). However, by using a ratio of factor II coagulant activity to immunoreactive protein, significant reduction was observed when compared to pretreatment ratios. These data suggest that vitamin E acts at the step mediated by vitamin K and not in the synthesis of the factor II precursor. Although the administration of high doses of vitamin E in animals, and possibly humans, with vitamin K deficiency potentiates the vitamin K deficiency, this effect is not clinically obvious with 400 IU/day or less.
In this study, we investigated whether vitamin E at concentrations achievable in blood after supplementation inhibits platelet function in humans. Gel-filtered platelets were incubated 30 minutes with scalar concentrations (50 to 250 mmol/L) of vitamin E and then stimulated with collagen. Compared with controls, vitamin E inhibited collagen-induced platelet aggregation and thromboxane A2 formation in a dose-dependent manner. Furthermore, vitamin E inhibited, in a dose-dependent manner, Ca2+ mobilization and formation of inositol 1,4,5-triphosphate. Because it was previously shown that hydrogen peroxide formation mediates arachidonic acid metabolism and phospholipase C activation in collagen-induced platelet activation, we investigated whether vitamin E was able to blunt hydrogen peroxide. In experiments performed in unstimulated platelets supplemented with hydrogen peroxide and in collagen-stimulated platelets, vitamin E was able to blunt hydrogen peroxide. In 6 healthy subjects given vitamin E for 2 weeks (600 mg/d), we found a significant decrease of collagen-induced H2O2 formation, platelet aggregation, and calcium mobilization. This study demonstrated in vitro and ex vivo that vitamin E inhibits collagen-induced platelet activation by blunting hydrogen peroxide formation.
A review of the literature concerning the safety of oral intake of vitamin E indicated that the toxicity of vitamin E is low. Vitamin E supplementation has resulted in inconsistent effects in serum lipid and lipoprotein levels. Animal studies showed that vitamin E is not mutagenic, carcinogenic, or teratogenic. In human studies with double- blind protocols and in large population studies, oral vitamin E supplementation resulted in few side effects even at doses as high as 3200 mg/d (3200 IU/d).
when you're on warfarin, it works so especially well that you need to keep your doctor in the loop. there are studies that say vitamin e doesn't really change anything, but they are talking about isolated and probably synthetic alpha tocopherol, not the e8 complex.
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