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Vitamin K metabolism in a patient resistant to vitamin K antagonists
A Keréveur1, M Leclercq, M Trossaërt
1Service d'Hématologie biologique, Hôtel-Dieu, Paris, France.
Abstract:
We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.
Insights
This study explores a patient resistant to multiple vitamin K antagonist anticoagulants. The resistance is likely due to a mutation in the vitamin K reductase, affecting drug binding.
Area of Science:
- Pharmacology
- Clinical Biochemistry
- Genetics
Background:
- Oral anticoagulants (e.g., warfarin, phenprocoumon) are crucial for preventing thromboembolic events.
- Warfarin resistance is rare but poses a significant clinical challenge.
- Understanding the mechanisms of anticoagulant resistance is vital for patient management.
Observation:
- A 63-year-old male patient exhibited resistance to warfarin, fluindione, acenocoumarol, and phenprocoumon.
- High doses of phenprocoumon resulted in elevated drug concentrations and prolonged half-life, without achieving therapeutic anticoagulation (International Normalized Ratio ≈ 1).
- Vitamin K1 levels were adequate, and decarboxyprothrombin was low, ruling out malabsorption, accelerated metabolism, or vitamin K deficiency as causes of resistance.
Findings:
- The patient's vitamin K epoxide to vitamin K ratio was significantly lower than in sensitive individuals, suggesting unimpeded vitamin K cycling.
- This indicates that phenprocoumon did not block the vitamin K reductase enzyme.
- The observed resistance to all tested vitamin K antagonists points towards a reduced drug affinity to a mutant vitamin K reductase.
Implications:
- This case highlights a potential genetic basis for resistance to multiple vitamin K antagonists.
- Identifying mutations in the vitamin K reductase could lead to personalized anticoagulant therapy.
- Further research is needed to characterize the specific mutation and its impact on drug efficacy.