Covert poisoning with difenacoum: clinical and toxicological observations

Abstract

<jats:p> 1 The coumarin anticoagulant difenacoum was detected by high performance liquid chromatography (HPLC) with multi-wavelength UV detection in plasma from a 41 year old man who presented with a severe deficiency of vitamin K-dependent clotting factors of unknown aetiology. A longitudinal toxicological study of the consequent coagulopathy is described. </jats:p><jats:p> 2 Plasma concentrations of difenacoum declined from 0.97 to 0.11 mgl<jats:sup>-1</jats:sup> in 47 days with a terminal half life of 11.7 days. Rifampacin (300 mg bd) had no apparent effect on the terminal half life of the drug. Subsequently plasma concentrations of difenacoum and descarbox yprothrombin (DCP) unexpectedly increased. </jats:p><jats:p> 3 Seven months after exposure clotting times were prolonged. The patient continued to have episodes of epistaxis, haematoma, purpurae and bruising and he required frequent treatment with Fresh Frozen Plasma in additional to oral phylloquinone (200 mg day<jats:sup>-1</jats:sup>). </jats:p><jats:p> 4 Intermittent and unexpected increases in plasma concentrations of difenacoum and descarboxypro thrombin suggested that covert, repeated ingestion of the anticoagulant was the most likely cause of the poisoning. The measurement of low concentrations of plasma phylloquinone except following supervised ingestion ofthe vitamin indicated that as an outpatient, the subject was not compliant with treatment despite his protestations to the contrary. He continued to deny this even when confronted by laboratory findings and at no time did he ever admit to self-poisoning. </jats:p>

Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection

“…For the supplementation studies, the subjects took different forms of vitamin K orally at doses previously used for the treatment or prevention of several pathologies. The vitamin K compounds used were K 1 (2 mg and 50 mg) (29); two homologs representative of the MK series, MK-4 (45 mg) (30) and MK-7 (1 mg) (31); and K 3 (20 mg) (5). The amounts of 5C-and 7C-aglycone excreted in the urine were measured before and after supplementation.…”

Superwarfarins

“…Other serum methods have been reported; for example, detection limits of 3-12 ng/mL for fluorescence and 20-75 ng/mL for UV detection (Mura et al, 1992;Kuijpers et al, 1995;McCarthy et al, 1997;Feng et al, 1999). Tissue methods include a solid phase cartridge extraction from liver, with recoveries ranging from 52% for difenacoum to 78% for warfarin.…”

“…Serious poisoning has been reported in adults with massive overdoses. These long-acting anticoagulants have produced rapid and persistent bleeding due to hypoprothrombinemia (Chong et al, 1986;Hoffman et al, 1988;Katona and Wason, 1989;Wallace et al, 1990;Routh et al, 1991;Barnett et al, 1992;Exner et al, 1992;Mack, 1994;Morgan et al, 1996;McCarthy et al, 1997;Gallo, 1998;Berry et al, 2000). There is a risk of spontaneous abortion with long-acting anticoagulants (Lipton and Klass, 1984;Zurawski and Kelly, 1997;Nelson et al, 2006).…”

Rodenticides

“…Recent reports of cases of poisoning indicate that selfpoisoning was the most frequent cause of intoxication (McCarthy et al, 1997;Soubiron et al, 2000;Terneu, et al, 2003).…”