Vitamins and Thrombosis (VITRO) study—homocysteine lowering with B vitamins

To the editor:

Den Heijer et al¹  present their randomized, placebo-controlled, double-blind trial for homocysteine lowering with B vitamins as a measure for secondary prevention of deep vein thrombosis and pulmonary embolism. Of the 8 water-soluble B vitamins, they used folic acid (5 mg), cyanocobalmin (0.4 mg), and pyridoxine (50 mg).

In the context of the known genotype-phenotype relation between the MTHFR (OMIM [Online Inheritance in Man] *607093), the homocysteine level, and thrombophilia (OMIM #188050), there remain some problems and questions.

What is the share of patients homozygous for the MTHFR C677T genotype? This genetic variant renders this enzyme thermolabile and affects its noncovalent binding of its prosthetic group FAD.^2–5  Vitamin B₂, or riboflavin, is the biosynthetic precursor of FMN or FAD, the coenzymes or prosthetic groups of diverse oxidoreductases.

If there is a link between folate and riboflavin mediated by the MTHFR^6–9  as a flavoprotein, what effect or benefit for the cohort of patients in that study could an additional riboflavin supplementation to the aforementioned vitamin B cocktail have? In most of the published studies for lowering homocysteine with B vitamins, riboflavin supplementation is neglected.

What are the scientific rationales for choosing the mentioned doses of the 3 vitamins used? Following Ames et al's proposal⁴  of high-dose vitamin therapy, it may be an underdosing. The MTHFR C677T is an FAD-responsive mutant,^2,3  and this should guide future trials for homocysteine lowering by vitamin supplementation with at least folic acid, riboflavin, pyridoxin, and cyanocobalamin in proper dosing.