The relationship between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity with warfarin.

Abstract

1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41‐99 ng ml‐1 for the 0.2 mg dose and 157‐292 ng ml‐1 for the 1 mg dose. 3 There was a significant prolongation of the mean prothrombin time (0.9 s) after 1 mg warfarin daily, but no significant change in prothrombin time after 0.2 mg warfarin daily. There was no significant change in individual clotting factor activity (II, VII, IX or X) with either dose of warfarin. 4 Following the administration of a pharmacological dose of vitamin K1 (10 mg), all seven volunteers had detectable levels of vitamin K1 2,3‐epoxide with both doses of warfarin (Cpmax 31‐409 ng ml‐1). 5 Both the Cpmax and the AUC for vitamin K1 2,3‐ epoxide were significantly greater on 1 mg of warfarin daily than 0.2 mg daily (P less than 0.01). 6 The apparent dissociation between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clotting factor concentration.

The long‐term effects of the rodenticide, brodifacoum, on blood coagulation and vitamin K metabolism in rats

“…The apparent dissociation between the effect on vitamin KO reductase and blood coagulation activity may partly be caused by the insensitivity of the coagulation tests for small changes in blood clotting factor levels (Choonara et al, 1988). Fully carboxylated clotting factors contain 10-12 Gla residues (Suttie, 1987).…”

“…It was suggested that a partial inhibition of vitamin KO reductase may not interfere with the clotting factor synthesis (Park et al, 1986). A threshold for vitamin KO inhibition was also suggested by Choonara et al (1988) (Thijssen, 1987) and were stored at -70'C. The protein content was measured by the Lowry method, with bovine serum albumin as a reference.…”

Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin

“…4 Warfarin is an effective anticoagulant because it inhibits the regeneration of vitamin K hydroquinone from vitamin K epoxide by inhibiting the reductase enzymes in the vitamin K cycle. 5 Dietary changes in vitamin K intake influence anticoagulation response to warfarin; even a brief period of reduced intake of vitamin K has been demonstrated to cause warfarin sensitivity, while increased intake of vitamin K-containing foods can reduce anticoagulation, which can last for several days thereafter. 6 We have recently demonstrated that patients with unstable control of anticoagulation have a consistently and significantly lower intake of vitamin K than their matched stable counterparts.…”

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

“…7 Warfarin exerts its anticoagulant effect by reducing the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase. 8 This protein is encoded by the recently identified vitamin K epoxide reductase complex subunit 1 gene (VKORC1) in which rare mutations associated with clotting factor deficiencies and warfarin resistance have been identified. 9 More recently, genotype for several noncoding polymorphisms in this gene has been shown to influence coumarin anticoagulant dose requirements.…”