BACKGROUND

Approximately half of all patients receiving warfarin therapy fail to remain stable in their given target range, with the resultant risks of either thromboembolic complications or complications relating to bleeding.1 Possible complications of overcoagulation, especially in older patients who are most likely to have indications for warfarin, often preclude its use in these patients. Any method to improve stability and thus the safety profile of warfarin would be welcomed by the many doctors who manage unstable international normalised ratios (INRs) on a daily basis.

Recently, the effect of tissue body stores of vitamin K on anticoagulation stability has been investigated, and it is has been shown that the mean daily intake of vitamin K in unstable patients is considerably lower than that in stable patients.2 It has subsequently been shown that supplementation of vitamin K can improve the stability of the INR in those patients with unstable INRs.3

This case illustrates a relatively new approach to managing patients with highly unstable INR levels and provides extra understanding of the factors influencing INR stability.

CASE PRESENTATION

We describe the case of a 57-year-old woman receiving anticoagulation for a metallic mitral valve replacement secondary to rheumatic heart disease with a target INR of 3.0. Her INR stability was very poor, seemingly unexplained by other medication or compliance. Large variability in INR had previously contributed to minor bleeding complications including multiple haematomas and an embolic cerebrovascular accident, which was successfully treated with embolectomy.

Her concurrent medical conditions include hypothyroidism, discoid lupus and coeliac disease. Medications include thyroxine and hormone replacement therapy. She does not drink alcohol.

INVESTIGATIONS

A review of the literature revealed that poor INR stability is multifactorial and often associated with reduced body stores of vitamin K. In the absence of any other obvious cause for our patient’s highly variable INR, we pursued this hypothesis.

Following presentation to the casualty department with a fall and subsequent hip haematoma, plasma vitamin K, plasma warfarin and INR levels were checked concurrently. The results are as given in table 1.

The notable finding is that a markedly elevated INR result was seen despite a normal plasma warfarin level with an absence of detectable vitamin K. This result confirmed that non-compliance with warfarin was not the issue and that warfarin dosage, as defined by the therapeutic warfarin level, was not excessive.

Therefore her prolonged prothrombin time (PT) ratio reflected an absence of the underlying vitamin K substrate that is necessary for functional vitamin K dependent factor synthesis (factor II, VII, IX, X, protein C and protein S). In the absence of vitamin K no factor synthesis can occur, distinct from the situation where warfarin effect in the presence of normal vitamin K levels will result in the synthesis of dysfunctional vitamin K dependent factors that cannot partake in normal clotting due their inability to bind calcium and adhere to platelet surfaces.4^,5

The absence of detectable plasma vitamin K levels in our patient after oral dosing suggests malabsorption as the cause of her absent vitamin K levels. This was also suggested by an over-responsiveness to low dose subcutaneous and intravenous vitamin K previously administered to this patient to correct overprolongation of prothrombin time on other occasions (data not shown). Serology revealed an anti-gliadin antibody level of >100 units and an anti-tissue transglutaminase level of >100 units, suggesting poor adherence to a gluten-free diet. Malabsorption was further supported by low levels of vitamin B12 (109 pmol/litre; normal range 148–443) and folate (1.9 ng/ml; normal range 3.5–16.1).

TREATMENT

Based on this, we gave daily supplementation of oral vitamin K, first at 50 μg/day for 6 weeks, then 100 μg/day. Our patient has now been maintained on 100 μg/day vitamin K for 2 months to date. As can be seen by the graph (fig 1), vitamin K supplementation resulted in an improvement in anticoagulation stability (mean (SD) 3.41 (1.68) vs 4.68 (3.34)). The percentage time spent within target INR range has doubled following vitamin K supplementation.

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Figure 1

International normalised ratio (INR) readings over the course of 11 months prior to, and after, commencing 50 μg/day vitamin K (red arrow) and then 100 μg/day vitamin K (orange arrow).

DISCUSSION

Vitamin K is required for the production of functional clotting factors II, VII, IX and X. These factors require addition of a carboxyl group to enable calcium induced binding of the factors to the platelet surface in vivo or to phospholipids in the prothrombin time test system. This carboxylation requires the presence of the reduced form of vitamin K, the production of which is inhibited by oral anticoagulants such as warfarin. Therefore a body deficiency of vitamin K induced by dietary deficiency or malabsorption, or an inhibition of its carboxylation by warfarin, will have the same consequence of an absence of necessary functional vitamin K dependent factors for clotting.

Stable anticoagulation is characterised by a reduction of active vitamin K dependent factor levels to approximately 30% of normal,6 and achieving this reflects continued supply and absorption of a basal vitamin K intake, in addition to the above-mentioned effect of warfarin on vitamin K metabolism. It is therefore not surprising that variable availability of vitamin K as evident in diet or absorptive capacity will influence sensitivity to warfarin as judged by PT testing.

This principle has been recently illustrated by a number of studies. Cushman et al have shown that warfarin sensitivity at onset of therapy is proportional to baseline body vitamin K status.7 Sconce et al showed that patients with unstable control of anticoagulation have a consistently and significantly lower intake of vitamin K than matched stable counterparts,2 while Kurnik et al showed that a daily dose of just 25 μg of vitamin K for 4 weeks in patients with vitamin K depletion significantly reduced INR, while having no effect on the INR of patients with normal vitamin K stores.8 Sconce et al further investigated the hypothesis that supplementation with vitamin K may increase the stability of INR control in a double-blinded randomised placebo controlled trial in which a cohort of 70 patients with unstable anticoagulation control were assigned a daily supplementation of 150 μg vitamin K or placebo for 6 months. Supplementation with vitamin K resulted in a significantly greater decrease in standard deviation of INR compared with placebo and a significantly greater increase in percentage time within target INR range.3

It should be noted that Ford et al found that vitamin K supplementation at a dose of 500 μg per day had unpredictable effects on the magnitude of INR change and the need for warfarin dose increases.9 Due to the variation in INR responses to vitamin K supplementation, such treatment needs to be performed under careful monitoring, particularly during the vitamin K initiation phase, in order to safely achieve improved anticoagulant control.

Factors contributing to low vitamin K body stores include poor dietary intake, or an underlying medical reason causing malabsorption of vitamin K. In this case, low vitamin K stores were attributed to poorly controlled coeliac disease. Our patients serology showed an anti-gliadin antibody level of >100 units and an anti-tissue transglutaminase level of >100 units, suggesting poor adherence to a gluten-free diet and subsequent malabsorption. This was further supported by low levels of vitamin B12 (109 pmol/litre; normal range 148–443) and folate (1.9 ng/ml; normal range 3.5–16.1).