Effect of Vitamin E on the Anti-Coagulant Response-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS GLOBAL JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES
Fluindione is the most used Vitamin K antagonists in
France. It has been sparsely studied and few interactions have been
reported with food sources. This case reveals a significant rise in INR
when fluindione was associated to fatty acid (palmitic/oleic/linoleic
acid 2g/day) or vitamin E (1g/day).
Presentation of Case:
A 80-year-old male (weight 74 kg, body surface area
1.91 m²) with a history of severe allergic drug eruption documented with
low molecular weight heparins, vancomycin, rifamycin and netromycin was
treated and stabilized (International Normalized Ratio (INR) = 3.5)
with fluindione (10 to 15 mg once per day) for cardiovascular risks due
to a mechanical aortic heart valve and an aortic tube. During
hospitalization, the patient stopped eating dietary supplements
containing fatty acids and vitamin E (Day 0), and then, presented an
imbalance of the INR (Day 2: INR = 3.5 / Day 2: INR = 1.2). An
unexpected anticoagulant response (INR up 1.1 to 3.7) on fluindione was
observed after administration on vitamin E (1000mg once per day) for the
same patient.
Analyzes performed by high-performance liquid
chromatography on dietary supplements reveal low dose of
α/γ/δ-tocophérol (22/0.5/0.3 mg/day respectively) and unexpected high
dose of fatty acid (2 g opd containing 13/22/56% of
palmitic/oleic/linoleic acid respectively). No genetic variability in
the VKORC1 and CYP2C9 could be identified. The patient plasma
concentration of vitamin K was 328 ng/L (normal value: 150-900 ng/L).
Discussion and Conclusion:
Fatty acids and/or vitamin E associated could increase significantly the vitamin K antagonist therapy effect.
Keywords:Fluindione; Fatty
acids; Vitamin E; Tocopherol; Coagulation; VKORC1; Palmitic acid; Oleic
acid; Linoleic acid; Vitamin K antagonists
Abbreviations:VKA: Vitamin K Antagonists; INR : International Normalized Ratio; VKOR : Vitamin-K Epoxyde Reductase
Introduction
Vitamin K antagonists (VKAs) are the leading cause of
hospitalization due to iatrogenic drugs. VKAs based anticoagulant
therapies are associated with large dose response variability. This
paper reports the first case of increased prothrombin time developed in a
patient to which fluindione was administered after eating dietary
supplements (pumpkin seed oil, saw palmetto Florida, ginseng root
extract and tribulus fruit extract) and/or vitamin E.
Presentation of Case
A 80-year-old male (weight 74 kg, body surface area
1.91 m²) with a history of severe allergic drug eruption documented with
low molecular weight heparins, vancomycin, rifamycin and netromycin was
treated and stabilized (International Normalized Ratio (INR) = 3.5)
with fluindione (10 to 15 mg once per day) for cardiovascular risks due
to a mechanical aortic heart valve and an aortic tube. During
hospitalization, the patient stopped eating the dietary supplements (Day
0) and then presented an imbalance of the INR (Day 2: INR = 3.5 / Day
2: INR = 1.2). INR interfering factors were eliminated (poor adherence,
new therapy, dietary changes…). To ensure efficient anticoagulation
considering his severe allergy, a treatment with danaparoid 2000 UI
twice per day was then initiated.
The patient was suspected to be resistant to
treatment with VKAs. The city physician was contacted. He declared that
the fluindione doses needed to achieve the INR target ranged from 40 to
60 mg per day prior to taking dietary supplements. However no genetic
variability in the VKORC1 and CYP2C9 could be identified. His plasma
concentration of vitamin K was 328 ng/L (normal value: 150-900 ng/L).
Results
Fluindione dose was gradually increased: 15 mg to Day
2 (Day 5 and Day 6: INR = 1.1), 20 mg on day 6 (Day 8: INR
= 1.3) and 25 mg at Day 8 (Day 10: INR = 1.4). As estimation
based on the product-label of dietary supplements totalized
645 mg of equivalent α-tocopherol, a treatment with vitamin E
(α-tocopherol) was started on day 10 at 500 mg once per day
(Day 12: INR = 1.8) and increased at day 12 to 1000 mg opd (Day
15: INR = 2.3 / Day 18: INR = 2.9 / Day 24: INR = 3.7 / Day 29:
INR = 3.6) without changing the fluindione dose (25 mg opd)
(Figure 1). One month after initiating the vitamin E treatment,
the plasma concentration of α-tocopherol (41 μmol/L [16-35
μmol/L]), vitamin K1 (324 ng/L [150-900 ng/L]) and fluindione
(2.6 mg/L [2-6 mg/L]) were in normal range. Analyzes
performed by high-performance liquid chromatography on
dietary supplements reveal low dose of α/γ/δ-tocophérol
(22/0.5/0.3 mg/day respectively) and unexpected high dose
of fatty acid (2 g opd containing 13/22/56% of palmitic/oleic/
linoleic acid respectively) (Figure 1).
Discussion
Fluindione, an indanedione derivative, is the most used VKAs
in France. It has been sparsely studied and few interactions have
been reported with food sources. Vitamin E is used in many food
sources, dietary supplements (pumpkin seed oil, palm oil, corn
oil, safflower oil, almond, honey-roasted…) and is used as a food
preservative (E306-309) for its antioxidant properties [1]. The
prevalence of complementary and alternative medicine (CAM)
with vitamin E was reported by 24.2% of all patient taking
warfarin and 71% of those who used potentially interacting CAM
[2]. The vitamin E supplementation has an anticoagulant effect
in the presence of low vitamin K intake or VKAs treatment in
animal and human cells studies [3]. But clinical studies in human
could not associate the vitamin E exposure with an increase
of the risk of self-reported bleeding or out of range INR [2,4].
Only one case was reported with an increase prothrombin time
in a patient who was taking warfarin with self administration
of vitamin E. This case demonstrates enhanced reduction of the levels of vitamin K-dependent coagulation factors without
warfarin plasmatic level modification during the period of
vitamin E intake [5].
In parallel, warfarin treated subjects didn’t change their
INR with 400 mg opd of vitamin E [6]. Interpretation of the
available information on vitamin E-warfarin interaction is
difficult because nearly all of them are based on in-vitro data,
animal studies, individual case report or study on few patients.
This report is the first one indicating an increasing effect of
the fluindione anticoagulant efficiency by α-tocopherol. The
effects of fatty acids on hemostasis are controversial. It has been
difficult to show convincing effect of unsaturated fatty acids [7].
Studies have demonstrated contradictory effects of oleic and
linoleic acid consumption on coagulation. The mechanism of
action of oleic and linoleic acid is not completely understood,
but a dual anti-platelet and anticoagulant effect on Factor VII has
been proposed [8-11]. We report the first case of increasing the
therapeutic effect of fluindione by these fatty acids.
Recently, genetic variants (C1) of vitamin K epoxyde
reductase (VKOR), the pharmacologic target of VKAs, have been
associated to resistance to VKAs [12]. As VKORC1 genotype
strongly affected anticoagulation induced by fluindione, we emit
the hypothesis that it should affect the vitamin E and fatty acids
anticoagulation effect. But this mutation could not be found in
our patient.
Conclusion
This case reveals a significant rise in INR when fluindione was
associated to dietary supplements and/or vitamin E. Patients
undergoing anticoagulation therapy, pharmacist and physicians
should pay special attention to this potential interaction.
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