• resistance;
  • vitamin K epoxide reductase;
  • vitamin K antagonist

Resistance to vitamin K antagonists including warfarin was first described in man in 1964 [1] and its hereditary pattern (autosomal dominant) has been hypothesized as causing warfarin resistance in rats [2]. The knowledge of the mechanism of action of vitamin K led to an hypothesis of an alteration of a component of the enzyme that is the therapeutic target site of warfarin, the vitamin K epoxide reductase complex subunit-1 (VKORC1). In the 1980s and afterward, very rare cases of severe constitutional bleeding associated with combined deficiency of all vitamin K-dependent blood coagulation factors were reported and by the same thinking process could be explained by alterations of the same enzyme or γ-glutamyl carboxylase.

The VKORC1 gene is located on the short arm of chromosome 16 (chromosomal location: 16p11.2) and Fregin et al. in 2002, suggested that warfarin resistance phenotype in mice and rats and certain familial constitutive deficiency of vitamin K-dependent clotting factors in humans may be an allelic mutation in the same gene [3]. Li et al. and Rost et al. reported in 2004 the identification of the VKOR [4,5]. The latter described four cases of warfarin resistance associated with four different gene mutations of VKORC1:Val29Leu, Val45Ala, Arg58Gly and Leu128Arg respectively [5]. A Val66Met substitution in the VKORC1 polypeptide has been recently identified in one patient who required more than 25 mg of warfarin daily for therapeutic anticoagulation and in two asymptomatic family members who had never received warfarin [6]. Combined deficiencies of vitamin K-dependent clotting factors can also be associated with mutations in VKORC1 gene as reported by Rost et al. [5].

Now, we report a sixth case of warfarin resistance associated with a VKORC1 gene mutation. This mutation was suspected because the patient was resistant to several different vitamin K antagonists (warfarin, acenocoumarol, fluindione, and phenprocoumon). In a previous work, published in 1997 [7], we hypothesized an alteration of one of the enzymes of the vitamin K cycle:VKOR.

The patient is a 63-year-old man with recurrent pulmonary embolism and deep vein thrombosis without known hereditary or acquired thrombophilia who was found resistant to warfarin (up to 45 mg day−1), fluindione (up to 80 mg day−1), acenocoumarol (up to 12 mg day−1), and phenprocoumon (up to 30 mg day−1; Table 1). With phenprocoumon, a long-acting vitamin K antagonist, the drug concentration reached in plasma 85 mg L−1 (usual range: 1–6) but the International Normalized Ratio (INR) remained about 1.0. Daily low-molecular weight heparin (LMWH) was continued for 3 months. Treatment was discontinued on two occasions and recurrent thrombotic episodes were observed. Careful biochemical investigation has demonstrated high concentrations of plasmatic phenprocoumon, subnormal levels of vitamin K, and low levels of epoxide. These data led to an absence of blockade of VKOR by phenprocoumon (Table 1). We hypothesized the existence of a VKOR mutation. We recently sequenced the three exons of VKORC1 in this patient and detected a heterozygous T383G transversion resulting in a leucine to arginine substitution (L128R). This mutation is most likely responsible for the so-called warfarin resistance as it was not found in 259 control subjects that we tested. Resistance to all vitamin K antagonists, including warfarin up to 45 mg day−1 is extremely rare and the mutation T383G of the VKORC gene has been reported in only one patient before the case reported here [5]. Both cases of this mutation exhibit total warfarin resistance, making the connection of genotype and phenotype even more secure.

Table 1.  Phenotypic data and laboratory tests of the patient resistant and the control group (n = 22) as published in 1997 [7]
Biochemical measurementPatient resistant to oral anticoagulantReference group (22 subjects treated by oral anticoagulant)
  1. The International Normalized Ratio (INRs) for the patient resistant during the prolonged oral anticoagulant treatment remained around 1.

Vitamin K1 plasma level1202 ± 546 ng L−1524 ± 425 ng L−1
Ratio: vitamin K1 epoxide/vitamin K1<1.2Approximately 4
Decarboxyprothrombin plasma concentration1449 ± 923 μg L−14062 ± 1350 μg L−1
Phenprocoumon maximum daily dose30 mg1–6 mg
Plasma phenprocoumon concentration85 mg L−11–5 mg L−1
Estimated phenprocoumon half-life350 H120–150 H
Fluindione maximum daily dose80 mg20–40 mg
Warfarin maximum daily dose45 mg4–10 mg
Acenocoumarol maximum daily dose10 mg4–8 mg

Progress in genetics has been very useful in order to understand the mechanism of resistance to four different vitamin K antagonists and testing for mutation in VKORC1 will help in explaining some more cases of resistance to vitamin K antagonists. The patient we report is now receiving a single daily dose of LMWH (80 mg Enoxaparin, body weight 120 kg, 67 IU kg−1 once a day) for the past 10 years without thrombotic or bleeding episodes. Bone density tests were normal after 9 years of treatment.

Further studies are warranted to know if genetic abnormalities of VKOR can explain all vitamin K antagonists resistance and combined coagulation factor deficiency. These cases explain how through progress in scientific investigation, new facts emerge, and illuminate old questions with no answer.


  1. Top of page
  2. Acknowledgements
  3. References

Thanks are due to Florence Parent MD (Paris) for referring the patient, to Philippe Beaune PharmD, PhD (Paris), Earle Rothbell MD of Colonia, New Jersey (USA), and Jacqueline Conard PharmD, PhD (Paris) for their help in the revision of this paper.


  1. Top of page
  2. Acknowledgements
  3. References
  • 1
    O'Reilly RA, Aggeler PM, Hoag MS, Leong LS, Kropatkin ML. Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs. The first reported kindred. N Engl J Med 1964; 271: 80915.
  • 2
    Greavses JH, Ayres P. Heritable resistance to warfarin in rats. Nature 1967; 215: 8778.
  • 3
    Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J. Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood 2002; 100: 322932.
  • 4
    Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 5414.
  • 5
    Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 53741.
  • 6
    Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 236.
  • 7
    Kereveur A, Leclercq M, Trossaert M, Dupeyron JP, Parent F, Horellou MH, Conard J, Bachmann F, Samama MM. Vitamin K metabolism in a patient resistant to vitamin K antagonists. Haemostasis 1997; 27: 16873.