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vitamin K

Monday 16 August 2004

Vitamin K is a required cofactor for a liver microsomal carboxylase that is necessary to convert glutamyl residues in certain protein precursors to γ-carboxyglutamates.

Clotting factors VII, IX, and X and prothrombin all require carboxylation of glutamate residues for functional activity. Carboxylation provides calcium-binding sites and thus allows calcium-dependent interaction of these clotting factors with a phospholipid surface involved in the generation of thrombin.

In addition, activation of anticoagulant proteins C and S also requires glutamate carboxylation. In recent years, a diverse group of proteins with no connection to coagulation have also been found to be vitamin K-dependent. Such proteins have been found in a wide variety of tissues, including kidney, bone, placenta, and lung.

As with the proteins involved in coagulation, vitamin K serves to facilitate carboxylation of glutamyl residues in these other proteins as well. Of particular interest is osteocalcin, a noncollagenous protein secreted by osteoblasts; as with the coagulation proteins, γ-carboxylation of osteocalcin facilitates binding to calcium.

Thus, it appears that vitamin K may favor calcification of bone proteins. Studies also reveal that vitamin K can inhibit bone resorption by reducing the expression of the osteoclast differentiation factor, RANK-ligand (Chapter 26).75 On the basis of these results, there are ongoing trials of vitamin K supplementation in osteoporosis, and some studies suggest that it is beneficial, especially in combination with vitamin D.

In the course of the reaction of vitamin K with its substrate proteins, its active (reduced) form is oxidized to an epoxide but then is promptly reduced back by a liver epoxide reductase. Thus, in a healthy liver, vitamin K is efficiently recycled, and the daily dietary requirement is low. Furthermore, endogenous intestinal bacterial flora readily synthesize the vitamin. Nevertheless, there is a small but definite need for exogenous vitamin, which fortunately is widely available in the usual Western diet.

Deficiency usually occurs :
- (1) in fat malabsorption syndromes, particularly with biliary tract disease, as with the other fat-soluble vitamins;
- (2) after destruction of the endogenous vitamin K-synthesizing flora, particularly with ingestion of broad-spectrum antibiotics;
- (3) in the neonatal period, when liver reserves are small, the bacterial flora is not yet developed, and the level of vitamin K in breast milk is low;
- (4) in diffuse liver disease, even in the presence of normal vitamin K stores, because hepatocyte dysfunction interferes with synthesis of the vitamin K-dependent coagulation factors.

In patients with thromboembolic disease, therapeutically desirable vitamin K deficiency is induced by coumarin anticoagulants (e.g., warfarin). These agents block the activity of liver epoxide reductase and thereby prevent regeneration of reduced vitamin K.

The major consequence of vitamin K deficiency (or of inefficient use of vitamin K by the liver) is the development of a bleeding diathesis. In neonates, it causes hemorrhagic disease of the newborn. Its most serious manifestation is intracranial hemorrhage, but bleeding may occur at any site, including skin, umbilicus, and viscera.

The estimated 3% prevalence of vitamin K-dependent bleeding diathesis among neonates warrants routine prophylactic vitamin K therapy for all newborns. However, in normal full-term infants, by 1 week of age, endogenous flora provide sufficient vitamin K to correct any lingering deficit.

In adults suffering from vitamin K deficiency or decreased synthesis of vitamin K-dependent factors, a bleeding diathesis may occur, characterized by hematomas, hematuria, melena, ecchymoses, and bleeding from the gums.

References

- Wallin R, Hutson SM. Warfarin and the Vitamin K-Dependent gamma-Carboxylation System. Trends Mol Med. 2004 Jul;10(7):299-302. PMID: 15242675