Genetic (VKORC1) sensitivity to warfarin may predict limited effect of daily vitamin K supplementation on the INR

Henry I. Bussey, Pharm.D., FCCP, FAHA
September, 2008

Reference: Sconce EA, Avery PJ, Wynne HA, Kamali F. Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study. J Thromb Haemost 2008; 6:1226-1228.

The bottom line of this report is that those with the "resistant" genotype (GG) who typically require a higher dose of warfarin show the greatest fall in the INR (or require the largest upward dose adjustment of warfarin) when daily vitamin K supplementation (150 mcg) is initiated to help stabilize the INR. On the other hand, those who are more sensitive to warfarin (GA and AA genotype), show less of a change - or no change - in the INR with daily vitamin K supplementation. Although a variety of other factors may influence the response to vitamin K supplementation, the mean increase in warfarin dose that was required was 25% for resistant (GG) patients, 8% for GA patients, and 0% for sensitive AA patients following the implementation of daily vitamin K supplementation. These percentage changes represented an absolute change in the daily dose of 0.82 mg, 0.34 mg, and 0 mg for those with GG, GA, and AA genotypes, respectively.

I must admit that my clinical experience and intuition led me to anticipate that those patients who require very low doses of warfarin (and therefore are likely to have the AA genotype or be relatively vitamin K deficient) would be the patients most likely to benefit from daily vitamin K supplementation; and also would show the greatest change in the INR with vitamin K supplementation. It appears that the exact opposite may be the case since those with the GG genotype apparently have a form of VKORC1 that is better able to regenerate vitamin K hydroquinone (required for carboxylation of the clotting factors) from the vitamin K 2,3-epoxide. Therefore, the warfarin-resistant "GG patients" can better utilize - or regenerate - whatever vitamin K is available while the more warfarin sensitive "AA patients" apparently can not "utilize" the additional vitamin K as well.

Additional observations and limitations of this paper:

1. The sample sizes were small: 11 patients with GG, 18 patients with GA, and 6 with AA.
   
   
2. The warfarin doses before vitamin K were not significantly different between the 3 groups and, in fact, the absolute mean dose was lower in the GG group than in the GA or the AA group (3.23 mg, 4.52 mg, and 3.50 mg, respectively).
   
   
3. The warfarin doses after the addition of vitamin K also were not significantly different (mean daily doses of 4.05 mg, 4.86 mg, and 3.50 mg for GG, GA, and AA, respectively) - and the mean dose for the "resistant" group remained lower than the mean dose for the "average" (GA) group.
   
   
4. Whether genotype influenced the impact of vitamin K supplementation on INR stability was not examined in this report.