Advertisement

Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects

Leon J. Schurgers, Martin J. Shearer, Karly Hamulyák, Elisabeth Stöcklin and Cees Vermeer

Article Figures & Data

Figures

  • Figure 1.

    Dose-response plots of coagulation indices versus log vitamin K1 dose for study phase I. (A) Plot of mean change in INR from baseline after 7 days of supplementation with each dose of vitamin K1 (•). For each subject, the data set represents the means of 4 INR values taken during the week. Plot of mean change in INR from baseline after first 24 hours (□). (B) Plot of the mean change in FIIc from baseline after 7 days of supplementation with each dose of vitamin K1. (C) Reciprocal plot of the mean change in INR after 7 days of supplementation with each dose of vitamin K1.

  • Figure 2.

    Effect of increasing vitamin K1 supplement doses on plasma concentrations of undercarboxylated prothrombin and undercarboxylated osteocalcin in study phase I. The values represent the mean plus or minus the standard error of the mean (SEM) change after 7 days' supplementation with each vitamin K1 dose. ucFII indicates undercarboxylated prothrombin (•); ucOC indicates undercarboxylated osteocalcin (▪). The arrows represent the vitamin K1 doses that resulted in significant decreases from baseline for ucFII (100 μg) and ucOC (300 μg), respectively.

  • Figure 3.

    Effect of increasing vitamin K1 supplement doses on plasma concentrations in study phase I. (▪) Plasma K1 concentrations 4 hours after each incremental vitamin K1 dose had been taken with breakfast on the first day of the 7-day supplementation period. (□) Fasting plasma K1 concentrations after 7 days of supplementation with each incremental dose of vitamin K1 and 24 hours after the last dose had been taken. Values represent the mean ± SEM.

Tables

  • Table 1.

    Protocol scheme

    Study phase and weekVitamin K intake, μg/day
    Adjustment
    1 0
    2 0
    3 0
    4 0
    Phase I: vitamin K from dietary supplements
    5 50
    6 100
    7 150
    8 200
    9 250
    10 300
    11 500
    Washout phase
    12 0
    13 0
    Phase II: vitamin K from foods (single meals)
    14 1500*
    15 700*
    16 103
    17 1000
    • Vitamin K intakes shown are the supplement doses that each subject received above the intakes obtained from the regular diet (≈ 55 μg/day). In each week the INR was measured 4 times (on Mondays, Tuesdays, Wednesdays, and Fridays), whereas FIIc, FVIIc, ucFII, ucOC, cOC, vitamin K, and TAG were measured twice weekly (on Mondays and Tuesdays).

    • * K1.

    • MK-9.

    • MK-7.

  • Table 4.

    Effects of single meals of different vitamin K-rich food items on the INR and vitamin K-dependent proteins after OAC treatment

    Food and dayINRFIIc, %FVIIc, %ucFII, AU/L × 103ucOC, ng/mLcOC, ng/mL
    Washout
    Mon 2.02 ± 0.40 47.3 ± 8.0 52.7 ± 23.5 26.2 ± 15.0 20.2 ± 7.5 3.7 ± 1.4
    Tue 2.05 ± 0.29
    Wed 1.97 ± 0.26
    Fri 2.19 ± 0.44
    Mon 1.97 ± 0.30 49.9 ± 8.2 47.3 ± 11.3 27.3 ± 20.9 19.0 ± 7.1 3.8 ± 1.3
    Spinach
    Mon 1.97 ± 0.30 49.9 ± 8.2 47.3 ± 11.3 27.3 ± 20.9 19.0 ± 7.1 3.8 ± 1.3
    Tue 1.70 ± 0.16 56.5 ± 6.3 71.1 ± 22.6 25.0 ± 12.7 18.0 ± 7.9 4.3 ± 1.4
    Wed 1.91 ± 0.38
    Fri 1.86 ± 0.34
    Mon 2.03 ± 0.27 47.7 ± 10.1 57.0 ± 18.9 22.0 ± 16.2 20.2 ± 7.6 4.3 ± 1.1
    Broccoli
    Mon 2.03 ± 0.27 47.7 ± 10.1 57.0 ± 18.9 22.0 ± 16.2 20.2 ± 7.6 4.3 ± 1.1
    Tue 1.62 ± 0.20 61.6 ± 9.8 76.5 ± 23.1 21.0 ± 13.0 17.4 ± 7.4 4.2 ± 1.4
    Wed 1.87 ± 0.28
    Fri 1.89 ± 0.28
    Mon 1.98 ± 0.31 52.0 ± 7.0 47.0 ± 15.8 26.8 ± 15.7 18.4 ± 5.7 4.3 ± 1.1
    Curd cheese
    Mon 1.98 ± 0.31 52.0 ± 7.0 47.0 ± 15.8 26.8 ± 15.7 18.4 ± 5.7 4.3 ± 1.1
    Tue 1.84 ± 0.23 53.0 ± 9.4 54.4 ± 20.6 25.0 ± 9.2 22.4 ± 7.6 3.7 ± 1.4
    Wed 1.81 ± 0.31
    Fri 1.88 ± 0.28
    Mon 2.01 ± 0.57 50.5 ± 11.3 51.3 ± 23.3 21.0 ± 21.3 23.1 ± 7.7 3.6 ± 1.2
    Natto
    Mon 2.01 ± 0.57 50.5 ± 11.3 51.3 ± 23.3 21.0 ± 21.3 23.1 ± 7.7 3.6 ± 1.2
    Tue 1.50 ± 0.21 55.2 ± 9.0 87.9 ± 30.2 24.8 ± 16.6 26.0 ± 8.5 3.7 ± 1.1
    Wed 1.49 ± 0.26 56.2 ± 9.4 81.2 ± 27.8 22.9 ± 12.4 22.8 ± 7.4 4.3 ± 1.7
    Thu* 1.42 ± 0.13 54.6 ± 8.4 73.7 ± 19.3 11.4 ± 7.0 21.3 ± 6.7 4.3 ± 2.2
    Fri 1.44 ± 0.21 58.0 ± 8.6 78.1 ± 28.2 25.3 ± 16.5 21.5 ± 8.0 3.8 ± 1.7
    Mon 1.75 ± 0.38 52.3 ± 10.6 54.0 ± 27.6 24.9 ± 17.9 22.9 ± 8.4 3.8 ± 1.9
    • Values shown are the mean ± standard deviation for 12 volunteers: —indicates not determined.

    • * In the natto supplementation week, an additional blood sampling was performed on Thursday because of the more potent and sustained effect of natto on vitamin K-dependent proteins.

    • For each meal, indicates group values (n = 12) that differ significantly (P < .05) from the baseline (premeal) value.

  • Table 2.

    Description of study population

    AllMaleFemale
    Anthropometric data
    No. of subjects 12 6 6
    Age, y 27.8 ± 1.8 28.3 ± 1.5 27.3 ± 2.07
    Weight, kg 75.5 ± 14.8 85.8 ± 9.4 65.2 ± 11.8
    BMI, kg/m2 24.2 ± 2.6 25.0 ± 2.8 23.4 ± 2.4
    Biochemical markers at baseline
    INR 1.02 ± 0.07 1.04 ± 0.06 1.01 ± 0.08
    FIIc, % 103 ± 11 103 ± 7 103 ± 15
    FVIIc, % 109 ± 22 107 ± 18 110 ± 25
    ucFII, AU/mL < 150 < 150 < 150
    ucOC, ng/mL 3.4 ± 1.7 3.9 ± 1.6 3.0 ± 1.9
    cOC, ng/mL 9.4 ± 3.4 10.7 ± 3.7 8.2 ± 2.8
    Vitamin K1, nM 1.27 ± 0.4 1.36 ± 0.5 1.18 ± 0.5
    Vitamin K2, nM ND ND ND
    Triacylglycerol, mM 1.02 ± 0.48 1.18 ± 0.59 0.87 ± 0.33
    OAC dose at stable anticoagulation, mg* 3.1 ± 0.7 3.3 ± 0.7 2.8 ± 0.7
    • Values are the mean ± standard deviation.

      ND indicates not detectable (< 0.05 nM).

    • * The OAC dose at stable anticoagulation was the dose required to maintain the INR at a value of 2.0 ± 0.4.

  • Table 3.

    Effects of vitamin K1 supplements on the INR and vitamin K-dependent proteins after OAC treatment

    Dose and dayINR, %FIIc, %FVIIc, %ucFII, AU/L × 103ucOC, ng/mLcOC, ng/mL
    0 μg/day
    Mon 2.04 ± 0.31 46.3 ± 9.0 52.7 ± 23.5 24.4 ± 6.4 31.5 ± 8.1 2.2 ± 0.9
    Tue 2.08 ± 0.38 45.7 ± 10.8 47.8 ± 23.0 23.6 ± 8.9 33.1 ± 9.2 2.1 ± 0.8
    Wed 2.02 ± 0.41
    Fri 2.04 ± 0.50
    Mon 1.93 ± 0.26 45.7 ± 7.1 49.4 ± 16.6 26.9 ± 10.4 29.9 ± 8.8 2.1 ± 0.5
    50 μg/day
    Tue 1.95 ± 0.36 51.8 ± 10.6 58.6 ± 36.1 27.3 ± 14.0 32.4 ± 8.8 2.1 ± 0.8
    Wed 1.81 ± 0.29
    Fri 1.73 ± 0.27
    Mon 1.85 ± 0.31 50.0 ± 8.4 50.3 ± 23.6 22.4 ± 17.9 30.6 ± 9.9 2.0 ± 0.9
    100 μg/day
    Tue 1.86 ± 0.30 52.8 ± 7.0 54.7 ± 20.1 19.1 ± 9.2* 33.4 ± 9.1 2.0 ± 1.1
    Wed 1.78 ± 0.29
    Fri 1.67 ± 0.22
    Mon 1.75 ± 0.26 48.3 ± 17.2 44.3 ± 17.2 20.5 ± 11.8 33.0 ± 8.2 2.4 ± 1.6
    150 μg/day
    Tue 1.75 ± 0.24 55.1 ± 8.7 62.8 ± 25.3 19.2 ± 8.2 32.6 ± 7.8 2.7 ± 1.2
    Wed 1.59 ± 0.26*
    Fri 1.56 ± 0.27
    Mon 1.58 ± 0.20 55.0 ± 8.0* 66.4 ± 43.5 15.1 ± 8.2 31.0 ± 9.2 2.4 ± 1.1
    200 μg/day
    Tue 1.57 ± 0.23 56.7 ± 8.8 69.3 ± 26.7 15.4 ± 9.6 32.3 ± 6.2 2.9 ± 1.1
    Wed 1.54 ± 0.16
    Fri 1.50 ± 0.21
    Mon 1.53 ± 0.18 59.3 ± 7.5 61.9 ± 19.4* 16.3 ± 9.8 32.7 ± 8.2 3.1 ± 1.4
    250 μg/day
    Tue 1.55 ± 0.24 61.1 ± 5.2 69.4 ± 19.2 12.1 ± 5.9 29.8 ± 8.5 3.0 ± 1.0*
    Wed 1.50 ± 0.15
    Fri 1.53 ± 0.16
    Mon 1.47 ± 0.24 61.9 ± 6.7 75.8 ± 39.1 14.3 ± 8.2 27.9 ± 9.9 2.9 ± 1.6
    300 μg/day
    Tue 1.47 ± 0.15 57.9 ± 5.6 61.3 ± 29.9 10.4 ± 6.5 20.8 ± 8.1 3.6 ± 1.6
    Wed 1.51 ± 0.13
    Fri 1.57 ± 0.11
    Mon 1.42 ± 0.17 64.5 ± 9.5 75.4 ± 30.1 9.4 ± 10.3 19.2 ± 4.3* 4.3 ± 1.2
    500 μg/day
    Tue 1.39 ± 0.13 64.0 ± 6.9 60.3 ± 12.0 6.1 ± 4.0 18.5 ± 5.4 4.4 ± 1.2
    Wed 1.41 ± 0.14
    Fri 1.37 ± 0.12
    • Mena group values are given ± the standard deviation for 12 volunteers. The first point (t = 0) of each new dose was identical to the last point (t = 7 days) of the previous dose. — indicates not determined.

    • * Indicates dose and day on which the group value (n = 12) for each measurement first became significantly (P < .05) different from the baseline (presupplementation, 0 μg/day) value. See the text (“Study phase I : daily supplementation with synthetic vitamin K”) for differences between men and women.