The role of vitamin K in
Blood coagulation depends on the cascade-like activation of a series of coagulation factors (specific proteins) which stop bleeding by forming blood clots. As a cofactor for an enzyme that catalyzes the carboxylation (introduction of a carboxyl group, -COOH) of certain glutamic acid residues in the coagulation factors to gamma-carboxyglutamate (Gla), vitamin K, is of crucial importance in the activation of the in total seven coagulation factors (1). Vitamin-K-dependent gamma-carboxylation enables these coagulation factors to bind calcium ions (Ca2+) and trigger the coagulation process. Coagulation factors II (prothrombin), VII, IX and X form the center of the coagulation cascade, while protein Z appears to augment the effect of thrombin, the crucial enzyme in plasmacoagulation, by increasing its binding to phospholipids in cell membranes. Protein C, protein S and protein Z have a coagulation-inhibiting function. They are responsible for regulating (coa- gulation time) and equilibrating the coagulation cascade. Because of its dynamics and diversity of functions in the body, protein S is a particular focus of basic research into vitamin-K-dependent proteins (2).
The body stores only relatively small amounts of vitamin K, so its reserves are quickly exhausted if there is no regular intake from the diet (3). A vitamin K recycling process (vitamin K cycle) makes it possible for a small amount of vitamin K to participate several times in the gamma-carboxylation of proteins and hence reduces the need for dietary vitamin K. Coagulation disorders are the first signs of a lack of vitamin K. A marked vitamin K deficiency leads to longer coagulation times and increases the risk of heavy bleeding, blood loss, bruising, poor wound-healing and anemia. In many European countries the recommended daily vitamin K intake for adults is 60 micrograms (for women) to 70 micrograms (for men), whilst in the USA the recommended intake is 120 micrograms of vitamin K per day (for men) and 90 micrograms per day (for women) (4). The main risk group for bleeding on the brain due to vitamin K deficiency is newborns and breastfed infants, who generally only receive small amounts of vitamin K1 via breast milk, whilst their gut flora is not sufficiently developed to produce vitamin K2. For these reason, in many countries infants are given vitamin K prophylactically (5).
Since the vitamin-K-dependent coagulation factors are synthesized in the liver, severe liver disease may be associated with very low blood levels of vitamin-K-dependent coagulation factors and an increased risk of uncontrollable bleeding (hemorrhage). Some people who are at increased risk of blood clots which could block the flow of blood in the coronary arteries, the brain or the lung – potentially causing a heart attack, stroke or pulmonary embolism – take oral anticoagulants (e. g., warfarin). These have an antagonistic effect on vitamin K activity, and can reduce potential blood clotting by blocking the recycling of vitamin K. This can lead to vitamin K deficiencies in the body. Large intakes of vitamin K, on the other hand, can counteract the coagulation-inhibiting effect of vitamin K antagonists, meaning that the vitamin K status of patients taking such medication must be strictly monitored.
Maintenance of bone health
Vitamin K, as well as vitamin D, is essential to healthy bone metabolism. Three vitamin-K-dependent proteins have been isolated from bone: osteocalcin, matrix Gla protein (MGP) and protein S. Osteocalcin is synthesi- zed by bone-forming cells (osteoblasts) and is involved in bone mineralization. After collagen it is the most important protein to be incorporated into the bone matrix. Whereas vitamin D stimulates the production of osteocalcin and increases the availability of calcium, the osteocalcin is activated through the vitamin-K-de- pendent carboxylation of three of its glutamic acid residues. The active form of osteocalcin can bind calcium (hydroxylated calcium phosphate) and store it in the bones (6). Insufficient carboxylation of osteocalcin (e.g., as a result of a vitamin K deficiency) could lead to loss of bone density. Matrix Gla protein (MGP) has been found in bones, cartilage and soft tissue including blood vessels. Experimental studies indicate that MGP prevents hardening of soft tissue and cartilage, whilst it can enhance the normal growth and development of bones. The vitamin-K-dependent anticoagulant protein S is also synthesized by osteoblasts, although its role in bone metabolism has yet to be established (7). Children with an inherited protein S deficiency suffer from complications associated with increased coagulation and reduced bone density.
A number of experimental, epidemiological and clinical studies have provided evidence that a lack of vitamin K in the elderly can be associated with reduced bone mineral density (osteopenia) and an increased risk of fractures. This was observed primarily in postmenopausal women, who are no longer protected against osteoporosis (fragile bones) or its precursor osteopenia by high estrogen levels (8). Reviews indicate that the risk of fractures in older women could be reduced by dietary supplementation with vitamin K (9). Meta-ana- lyses of clinical intervention studies with vitamin K confirm the benefits of targeted administration of vitamin K on skeletal stability and a lower fracture rate for postmenopausal women – albeit through mechanisms that appear to act independently of bone mineral density and bone metabolism (10).