For a long time scientists believed that its role in the synthesis of clotting factors and hence in the maintenance of blood clotting was the only essential physiological function of vitamin K. Indeed, the K in its name comes from the Danish spelling of coagulation – Koagulation. However, following the identification of specific proteins that are activated by vitamin K dependent reactions it rapidly became evident that this vitamin has a significantly broader spectrum of activity in the organism. These proteins include such diverse substances as prothrombin, needed for blood clotting, matrix Gla protein, which prevents calcification of the arteries and tissue, and osteocalcin, which is involved in bone mineralization. In more recent research discussion focuses increasingly on the importance of vitamin K for cardiovascular health, cognitive function and reproduction (1).
The function of vitamin K in the maintenance of
The best known activity of vitamin K is its function as a co-factor in the production and activation of clotting proteins like prothrombin (Factor II) and clotting factors (VII, IX and X) in the liver. The precursors of these proteins are converted into their active forms under the influence of vitamin K-dependent enzymes. Hence vitamin K functions as a co-factor for the gamma-glutamate-carboxylase enzyme, which converts the glutamic acid units of the proteins through the introduction of a carboxyl group (-COOH) to gamma-carboxyglutamic acid (GLA) (2,3). This carboxylation reaction is crucial to the calcium-binding function of vitamin K dependent proteins. The degree of carboxylation of such a protein can be used to determine vitamin K status.
The process of clotting starts with the activation of factor X, which triggers the formation of thrombin from prothrombin. Thrombin then leads to the formation of fibrin monomers from fibrinogen. Fibrin monomers form a mesh of fibrin fibers through polymerization, and these fibers accumulate in blood cells and lead to formation of a thrombus, which seals the injured blood vessel and causes bleeding to stop. It was long thought that excessive consumption of vitamin K would lead to a dangerously increased tendency to clotting, but this is now known to be untrue: the vitamin K dependent proteins possess a limited number of glutamate residues that can be carboxylated; even with high concentrations of vitamin K, no further carboxylation or excessive coagulation is possible (1).
Targeted consumption of vitamin K is recommended above all for vulnerable groups. Newborns and breastfed infants especially are exposed to a high risk of developing vitamin K deficiency and consequently to an increased risk of bleeding, in the worst case to brain-related bleeding. This may be because vitamin K does not readily cross the placental barrier, or may be due to insufficient synthesis of clotting factors, a sterile intestinal tract not yet colonized by vitamin K producing bacteria at birth or a low concentration of vitamin K in breast milk. For this reason, newborns in many countries are given oral or intramuscular vitamin K1 as standard (4). Other at-risk groups who consume too little vitamin K in their normal diet include older people and especially residents of old-age homes (5, 6). However, as yet there are insufficient studies to support concrete recommendations for dietary supplementation of these groups with vitamin K. Since older people often have to take anti-coagulation medication and the effects of such blood thinning agents (e.g. warfarin) may be partially cancelled out by vitamin K, many experts advise caution with regard to consump-tion of vitamin K via food or food supplements (7). Regular monitoring of vitamin K status is recommended for those affected and if necessary the dose of warfarin must be adjusted (8).
With the exception of these vulnerable groups, vitamin K deficiencies are rare in industrialized countries. Vitamin K supplementation is established practice for patients with cystic fibrosis, whose uptake of vitamin K from the diet is severely restricted, and whose use of antibiotics reduces their own production of vitamin K through the action of intestinal microflora (9). Nevertheless, the vitamin K status of such patients is often inadequate despite supplemental vitamin administration and, according to one recent study, a status com-parable to that of healthy individuals is only achieved with a dose of 1000 mg per day (10).
Osteoporosis is a global health problem of growing importance in view of the rising age of the world’s popu-lation. An estimated 200 million people world-wide suffer from age-related destabilization of the bones (11). The only micronutrients of interest for the prevention and treatment of osteoporosis were for a long time vitamin D and calcium. But since the Nurses Health Study it is known that there is an association between low vitamin K status, reduced bone density and increased risk of fractures (12). This study showed that the risk of fractures in the group with the highest intake of vitamin K was around 30% lower than in the group with the lowest vitamin K intake. Vitamin K is needed by the body as a co-factor for several carboxylation reactions that are important for bone mineralization, as well as blood clotting. Production of the bone matrix proteins osteocalcin and matrix Gla (MGP) requires vitamin K (13). Circulating amounts of uncarboxylated osteocalcin are higher when vitamin K status is inadequate. Osteocalcin is evidently involved in negative regulation of bone mineralization, i.e. the less osteocalcin present in the bone, the higher its density and hardness (14). Moreover, low levels of vitamin K were found in patients with low bone mineral density (13). In contrast, the reduced rates of fracture observed in studies with targeted administration of vitamin K tablets were not associated with greater bone mass. Hence dietary supplementation with vitamin K appears to improve properties of bone that strengthen it without increasing its density (14). In patients treated with warfarin administration of 100 mg vitamin K could provide a certain benefit and strengthen bones without undesirable interactions (15).
In a randomized controlled study from Japan, administration of vitamin K2 over a period of two years showed a positive effect on bone mineral density and a lowering of the risk of vertebral fracture in post-menopausal women (16). An observational study on healthy Japanese men aged over 65 years examined consumption of natto, which consists of bacterially fermented soybeans and contains vitamins K1 and K2, and the association between undercarboxylated osteocalcin, as a biomarker for vitamin K intake, and the bone mineral density of the lumbar vertebrae and hips (17). It was shown that participants who consumed greater quantities of vitamin K rich natto had lower serum levels of undercarboxylated osteocalcin and greater bone mass in hips and the neck of the femur. However, more studies are needed to confirm these results and possibly provide dietary recommendations at a later stage.
Vitamin K activates proteins that are important for calcium metabolism. Besides osteocalcin, which is needed for accumulation of calcium in the bones, vitamin K also influences matrix Gla protein (MGP), which is responsible for regulating the concentration of calcium in soft tissue such as the walls of the arteries. It is thought that a lack of vitamin K means that these proteins are not activated, leading not only to porous bones but also to calcium deposits (atherosclerotic plaque) and changes in blood vessels (18). This would also explain why patients who take anticoagulants (e.g. coumarins) that inhibit vitamin K activity are more at risk of atherosclerosis.
In a randomized controlled study, dietary supplementation with vitamin K1 plus vitamin D and a combination of minerals over a period of three years resulted in an improvement in the elasticity and pliancy of the carotid artery in postmenopausal women (19). Supplementation of older men with 500 micrograms of vitamin K1 per day together with a multivitamin product appeared to slow the progress of coronary artery calcification.
One observational study indicated that increased intakes of vitamin K2 rich food over a period of 10 years could be associated with reduced calcification of the arteries and a lower risk of dying of coronary heart disease (20). Randomized controlled studies are necessary to determine to what extent vitamin K has a clinically relevant influence on cardiovascular health and what intakes should be recommended.
Health of nervous system and brain functions
It has long been known that vitamin K is involved in the synthesis of sphingolipids in the brain. These lipids are important components of neuronal cell membranes and act as signaling molecules for motor and cognitive behavior. Numerous experimental studies indicate a role for vitamin K in the regulation of several enzymes of the sphingolipid metabolism in myelin-rich regions of the brain, although the exact mechanisms are not yet well understood (21). Based on its relevance for sphingolipids, vitamin K might support cognitive functions. An insufficient intake of vitamin K has been associated with diminished cognition as well as in-creased oxidative stress and an increase in inflammations (22).
Gas6, a vitamin K dependent gamma-carboxyglutamate-containing protein, plays an important role in the central and peripheral nervous systems as a signaling molecule. Gas6 is involved in the division, growth and myelinization of cells throughout the central nervous system. In consequence, sufficient consumption of vitamin K could help maintain an intact nervous system. The experimental finding that vitamin K dependent Gas6 activity protects neurons from cell death indicates that vitamin K could prevent age-related changes in the brain – for example the onset of Alzheimer’s disease (23). Also important is the vitamin K dependent protein S, which as a signaling molecule could support brain vascular function through anticoagulant effects and potentially contribute to the health of the nervous system through neuroprotective effects (24). The exact role of vitamin K for sphingolipids and the influence of Gas6 and protein S on brain function and nervous system as well as possible preventive effects for neurodegenerative disease have yet to be researched in detail.
Painful, excessive or irregular uterine contractions in the context of monthly periods (dysmenorrhea) are one of the most common reasons given by young women for repeated absence from school or work. Pharmaco-logical treatment includes oral non-steroidal anti-inflammatory medication and oral contraceptives. In China an injection of vitamin K into a particular acupuncture point on the lower leg, the San Yin Yao/Milz 6, has been the standard treatment for dysmenorrhea for many years. A first randomized controlled study has now shown that a vitamin K injection into the acupuncture point rapidly alleviates discomfort and reduces the use of pain killers in women aged 14 to 25 years (25). It is thought that vitamin K helps relax the uterus by reducing the muscle cramps brought on by prostaglandins. However, at present it is not known what role the vitamin plays in muscles. Moreover, the lower level of estrogens in postmenopausal women appears to influence levels of vitamin K (19). Possible connections between vitamin K and the sex hormones, as well as the role of this vitamin in maintaining reproductive health, are currently under investigation.