Vitamin K metabolism in a patient resistant to vitamin K antagonists

Haemostasis. 1997 Jul-Aug;27(4):168-73. doi: 10.1159/000217450.

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.

Publication types

  • Case Reports

MeSH terms

  • Drug Resistance
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors
  • Phenprocoumon / blood
  • Vitamin K / antagonists & inhibitors*
  • Vitamin K / blood
  • Vitamin K / metabolism*
  • Vitamin K 1 / blood
  • Warfarin / blood

Substances

  • Vitamin K
  • Warfarin
  • Vitamin K 1
  • NAD(P)H Dehydrogenase (Quinone)
  • Phenprocoumon