Vitamina K

Vitamin Supplement
æ

Vitamin K: the effect on health beyond
coagulation Á an overview
Cees Vermeer*
VitaK and Cardiovascular Research Institute CARIM, Maastricht University, Maastricht, The Netherlands

Abstract
Vitamin K is essential for the synthesis of proteins belonging to the Gla-protein family. To the members of
this family belong four blood coagulation factors, which all areexclusively formed in the liver. The
importance of vitamin K for hemostasis is demonstrated from the fact that vitamin K-deficiency is an acute,
life-threatening condition due to excessive bleeding. Other members of the Gla-protein family are osteocalcin,
matrix Gla-protein (MGP), and Gas6 that play key functions in maintaining bone strength, arterial
calcification inhibition, and cell growthregulation, respectively. In total 17 Gla-proteins have been discovered
at this time. Recently, it was observed that the dietary vitamin K requirement for the synthesis of the
coagulation factors is much lower than for that of the extra-hepatic Gla-proteins. This forms the basis of
the triage theory stating that during poor dietary supply, vitamins are preferentially utilized for functions thatare important for immediate survival. This explains why in the healthy population all clotting factors
are synthesized in their active form, whereas the synthesis of other Gla-proteins is sub-optimal in nonsupplemented subjects. Prolonged sub-clinical vitamin K deficiency is a risk factor for osteoporosis,
atherosclerosis, and cancer. Present recommendations for dietary intake are based on thedaily dose required
to prevent bleeding. Accumulating scientific data suggests that new, higher recommendations for vitamin K
intake should be formulated.
Keywords: phylloquinone; menaquinone; cardiovascular disease; osteoporosis; triage

itamin K received its name from the fact that it
is required for normal blood coagulation, and
during about half a century it was believed that
hemostasiswas the only metabolic process in which
vitamin K is involved. This view is obsolete now. Since
the identification of Gla as the result of vitamin K action,
it became possible to search for vitamin K-dependent
proteins on the basis of their amino acid structure: each
protein in which gammacarboxyglutamate, generally
referred to as Gla, is found contains the fingerprint of
vitamin K actionduring its biosynthesis (1). In this way a
wide variety of proteins were found ranging from
osteocalcin (the most abundant non-collagenous protein
in bone), to matrix Gla-protein (MGP, the potent
calcification inhibitor in our arteries), and the growtharrest sequence-6 protein (Gas6, a protein involved in cell
growth regulation). Whereas the proteins involved in
blood coagulation invariablyare synthesized in the liver,
the newly discovered Gla-proteins have key functions
in other metabolic processes and are synthesized in a
wide variety of tissues. An overview of the various Glaproteins and their functions (as far as they are known) is
given in Table 1.

V

The molecular function of vitamin K is precisely known:
it serves as a cofactor for the enzyme gammaglutamatecarboxylase (GGCX), which is found in the endoplasmic
reticulum of a wide variety of mammalian cells and that
catalyzes the conversion of the amino acid glutamate into
Gla. The oxidation of vitamin K hydroquinone provides
the energy required for this carboxylation reaction. All
Gla-proteins are secretory proteins found in the extracellular matrix or in body fluids. Gla-residues form strongcalcium-binding groups in the proteins to which they are
attached and in all cases in which their function is known
the Gla-residues are essential for the function of these
proteins (2).
All Gla-proteins known today contain multiple Glaresidues per molecule ranging from three in the bone
Gla-protein osteocalcin to 10 in prothrombin and as much
as 16 in Gla-rich protein (GRP). The position of the...