Vitamin K deficiency and requirements
Apart from deliberate experimental manipulation, vitamin K deficiency is unknown, and determination of requirements is complicated by a lack of informa-tion on the importance of menaquinones synthesized by intestinal bacteria.
The classical way of determining vitamin K status, and monitoring the efficacy of anticoagulant therapy, is by measuring the time required for the formation of a fibrin clot in citrated blood plasma after the addi-tion of calcium ions and thromboplastin: the pro-thrombin time. A more sensitive index is provided by direct measurement of preprothrombin in plasma, most commonly by immunoassay using antisera against preprothrombin that do not react with prothrombin.
Based on determination of clotting time, and direct measurement of prothrombin and preprothrombin, an intake of 1 μg/kg body weight per day is consid-ered adequate; this forms the basis of reference intakes of between 65 and 80 μg/day for adults.
A small number of newborn infants have very low reserves of vitamin K and are at risk of potentially fatal hemorrhagic disease. It is therefore generally rec-ommended that all neonates should be given a single prophylactic dose of vitamin K.
It has long been known that treatment of pregnant women with warfarin or other anticoagulants can lead to bone abnormalities in the child: the fetal war-farin syndrome. Two proteins in bone matrix contain γ-carboxyglutamate: osteocalcin and a less well char- acterized protein simply known as bone matrix Gla protein. Osteocalcin is interesting in that as well as γ-carboxyglutamate, it also contains hydroxyproline, so its synthesis is dependent on both vitamins K and C; in addition, its synthesis is induced by vitamin D, and the release into the circulation of osteocalcin provides a sensitive index of vitamin D action. It constitutes some 1–2% of total bone protein, and modifies the crystallization of bone mineral. The matrix Gla protein is found in a variety of tissues, and acts to prevent mineralization of soft connective tissue.
The fetal warfarin syndrome involves neurological as well as bone abnormalities. The vitamin K-dependent carboxylase is expressed in different brain regions at different times during embryological devel-opment, and the product of the growth arrest-specific gene 6 (Gas6) is a Gla-containing growth factor that is important in the regulation of growth and development, and the regulation of apoptosis and cell survival.