The potential adverse effects of multivitamin and mineral supplements have not been systematically determined in well-designed randomized, controlled trials. Because of uncertainties regarding design (for example, doses and outcome monitoring) and ethical constraints, such studies may never be performed. A few adverse effects of nutrients in multivitamin preparations may be interpreted as common responses in the general population because they occurred with certain consistency in different primary prevention trials. Examples include [...] minor bleeding, particularly epistaxis, with vitamin E supplementation. However, there was no consistent evidence to suggest that vitamin E supplementation results in more serious bleeding events, such as hemorrhagic stroke (36, 43). [...]

We examined whether vitamin E increased adverse effects due to bleeding (gastrointestinal bleeding, hematuria, easy bruising, epistaxis) because of the potential for vitamin E to inhibit platelet function,52 gastrointestinal symptoms (gastric upset, nausea, diarrhea, constipation), or fatigue. There were no differences between reported adverse effects for any of these variables among women in the 2 groups, apart from a small, but significant, increase in the risk of epistaxis [nosebleeds] (RR, 1.06; 95% CI, 1.01-1.11; P = .02).

Nutrient interactions

Large doses of vitamin A and vitamin E have been found to antagonize vitamin K (8). Excess vitamin A appears to interfere with vitamin K absorption, whereas a form of vitamin E (tocopherol quinone) may inhibit vitamin K-dependent carboxylase enzymes. One study in adults with normal coagulation status found that supplementation with 1,000 IU of vitamin E for 12 weeks decreased gamma-carboxylation of prothrombin, a vitamin K-dependent protein (52). A vitamin E-vitamin K interaction has also been reported in patients taking anticoagulatory drugs like warfarin. Hemorrhage (excessive bleeding) was reported in a man taking 5 mg of warfarin and 1,200 IU of vitamin E daily (53).

Background: Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants. Although a vitamin E–vitamin K interaction was proposed to underlie this effect, it has not been systematically investigated in adults with normal baseline coagulation status.
[...]
Design: Vitamin K status, which was assessed with the use of plasma phylloquinone concentrations, the degree of under--carboxylation of prothrombin (proteins induced by vitamin K absence–factor II, PIVKA-II), and the percentage of undercarboxylated osteocalcin (ucOC), was determined in 38 men and women with rheumatoid arthritis (study A) and in 32 healthy men (study B) participating in 2 independent, 12-wk randomized clinical trials of vitamin E supplementation (1000 IU/d).

Results: Mean (± SD) PIVKA-II increased from 1.7 ± 1.7 to 11.9 ± 16.1 ng/mL (P < 0.001) in study A and from 1.8 ± 0.6 to 5.3 ± 3.9 ng/mL (P < 0.001) in study B in response to 12 wk of vitamin E supplementation. An increase in PIVKA-II is indicative of poor vitamin K status. In contrast, the other measures of vitamin K status (ie, plasma phylloquinone concentration and percentage of ucOC) did not change significantly in response to the supplementation.

Conclusions: High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy. The clinical significance of these changes warrants further investigation, but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined.