The usual method of assessing vitamin K nutritional status, or monitoring the efficacy of anticoagulant therapy, is a functional test of blood clotting, and hence the ability to synthesize the vitamin K-dependent clotting factors.
The standard assay measures the time taken for the formation of a fibrin clot in citrated plasma after the addition of calcium ions and thromboplastin to activate the extrinsic clotting system - the prothrombin time. The normal prothrombin time is 11 to 13 seconds; greater than 25 seconds is associated with severe bleeding.
Measurement of plasma concentrations of preprothrombin permits a more sensitive means of detecting marginally inadequate vitamin K status than simple determination of prothrombin time. Preprothrombin is not activated by thromboplastin, although it is a substrate for the protease from snake venom, which does not require phospholipid binding of the substrate for activity. When so activated, descarboxy-thrombin will catalyze clot formation from fibrinogen. This provides a means of determining the relative amounts of prothrombin and preprothrombin in blood samples. If snake venom protease is used instead of thromboplastin, the prothrombin time will be shorter, depending on how much preprothrombin is present. In normal subjects, the ratio of pro-thrombin time using thromboplastin and that using snake venom protease is >0.6, whereas in vitamin K-deficient or anticoagulant-treated subjects, it is lower.
Preprothrombin can be determined immunologically, either using antipro-thrombin antibodies, after adsorption of the y -carboxylated protein onto barium carbonate or using anti-preprothrombin antibodies that do not cross-react with prothrombin. Circulating concentrations of preprothrombin in vitamin K deficiency are of the order of 150 to 1,500 nmol per L. If elevated preprothrombin is because of vitamin K deficiency, then it will fall on administration of the vitamin, whereas if it is the result of liver disease, then vitamin K supplements will have no effect.
In deficiency, there is also undercarboxylated osteocalcin in the circulation, and this provides a more sensitive index of marginal status; it is detectable, and responds to supplements of vitamin K, in subjects with normal clotting time and no circulating preprothrombin (Sokoll and Sadowski, 1996; Binkley et al., 2000).
Measurement of the plasma concentration of phylloquinone gives some information about status, but reflects not only intake but also plasma triacyl-glycerol, because most is carried in chylomicrons and chylomicron remnants. The plasma concentration of phylloquinone is higher in older subjects, but the phylloquinone:triacylglycerol ratio is lower than in younger people (Booth andSuttie, 1998).
The urinary excretion of y-carboxyglutamate, as both the free amino acid and in small peptides, also reflects functional vitamin K status, because y -carboxyglutamate released by the catabolism of proteins is neither reutilized nor metabolized. The normal range of y-carboxyglutamate excretion is 0.2 to 0.6 [mol per mol of creatinine in adults. Children excrete more, presumably reflecting greater turnover of osteocalcin. In patients receiving anticoagulants, the urinary excretion of y-carboxyglutamate falls to half as the prothrombin time increases two- to three-fold (Suttie et al., 1988).
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