Resistance to Coumarin in a 55-year-old Patient with Chronic Arrhythmia

Resistance to Coumarin in a 55-year-old Patient with Chronic Arrhythmia

W. Miesbach, J. Oldenburg, M. Krause, Ch. von Auer and I. Scharrer

Retrospective studies suggest that patients with continuous chronic arrhythmia have an increased risk of stroke and, for this reason, it is recommended that they receive oral vitamin K antagonists for the long-term treatment, such as coumarin derivatives to achieve an international normalized ratio (INR) range within the the- rapeutic level.

In most clinical situations, therapeutic doses of coumarins are sufficient to con- trol this disease and prevent further thromboembolism.

Coumarins target blood coagulation by inhibiting the vitamin K epoxide reduc- tase multiprotein complex (VKOR), which is involved in the carboxylation of sever- al blood coagulation factors [1].

Presumably intestinale malabsorption or interactions with some other drugs are the most common causes of ineffective low INR levels.

Acquired resistance to Warfarin is also described in patients with enteral feed- ings [2] or with mechanical heart valve [3]. Several enteral feeding products may bind warfarin and reduce the bioavailability of the drug.

In contrary, the term warfarin failure is used in patients who develop throm- boembolic complications despite an apparently stable INR at therapeutic levels.

Hereditary resistance to coumarin is a very rare phenomena which has pre- viously been described in the literature by very few cases.

We report on a male patient, born in 1947, who appeared in our ambulance after he could not be treated sufficiently by oral anticoagulation in an external hospital.

In that hospital they could not see any prolongation of the thromboplastin time in the patient while regularly taking phenprocoumon. The patient had even occa- sionally taken considerable doses such as two tablets in the morning, three tablets in the midday and five tablets in the evening (a daily dose of 30 mg), without any effect on coagulation system being observed.

However since chronic continuous arrhythmia was diagnosed in March 2002 it was necessary to carry out efficient anticoagulation since the arrhythmia could not be converted to a regular sinus rhythm by electric or pharmaceutical means. We were also aware that the patient was suffering from chronic heart failure and hyper- lipidemia. The medical therapy consisted of acetyldigoxin, spironolacton, amio- daron and atorvastatin. Besides the daily dose of one or two tablets of phenproc- oumon the patient received also enoxaparin.

The measurement of INR was 1.02 and as a result the dose of enoxaparin was altered and a plan for dosing with phenprocoumon was set up. At his next con-

I. Scharrer/W. Schramm (Ed.)

34

Hemophilia Symposium Hamburg 2003

” Springer Medizin Verlag Heidelberg 2005

sultation the measurement of the quantitative phenprocoumon level in blood was in the highest theapeutical range with 2.4 mg/l (therapeutical range: 0.16 – 3.6 mg/l, Prof. Dr. G. Kauert, University Frankfurt). The same time we measured an INR of 1.07. After changing the treatment from phenprocoumon to coumadin and aceno- coumarol we were unable to achieve any effect on coagulation. Additional exami- nations gave negative results in terms of a dysfunction of abdominal resorption or liver function. A previously carried out nephrological examination also resulted in normal values. The other investigations of the blood were apart from slightly higher liver transaminases unremarkable, as were the values of ferrum or vitamin B12.

Under treatment with enoxaparin 60 mg twice daily the anti-Xa level remained continuously within the therapeutic range and the patient did not developed any thromboembolic or bleeding complications until now.

In conclusion, we suspect that the patient may have a genetic defect in the meta- bolism of vitamin K/coumarin since other causes could be excluded. This defect could be confirmed by Rost et al. as a genetic mutation of the first component of the VKOR complex [4].

References

1. Suttie JW. The biochemical basis of warfarin therapy. Adv Exp Med Biol 1987;214:3–16.

2. Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil 2001;82:1270–3.

3. Gotze JP, Thorsen S, Haunso S. Acquired warfarin resistance in a patient with mechanical heart valve. Ugeskr Laeger 2001;163:7075–6.

4. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EGD, Müller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004;427:537–41.

384 W. Miesbach et al.