CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012
e10
AFRICA
105/75
mmHg and a pulse rate of 92 beats/min. Heart and
respiratory auscultation findings were normal. The patient was
in a depressive mood over his family problems and had never
received treatment for depression. He had oral mucosal bleeding,
numerous bruises over the arms, legs and abdomen, and an
abdominal tenderness, together with melena.
Electrocardiography (ECG), abdominal ultrasonography
(
USG) and abdominal X-ray showed no pathological
findings. Laboratory tests revealed a haemoglobin level of
12.3
g/dl, leucocyte count of 9.1
×
10
9
/
l, haematocrit of 28%
and platelet count of 280
×
10
9
/
l. The prothrombin time (PT)
was
>
200
s (normal range 10.5–15.2 s) and the activated partial
thromboplastin time (aPTT) was 91 s (normal range 20–45 s).
The INR (international normalised ratio) was
>
17 (
normal range
0.8–1.2).
The thrombin time and plasma fibrinogen levels were
in the normal range. All coagulation deficits were corrected by
mixing with normal pooled plasma in a 1:1 ratio.
The liver, renal and thyroid function tests, and serum protein
electrophoresis were normal, but urinalysis revealed microscopic
haematuria. The results of factor assays were consistent with
vitamin K deficiency: factor II: 68% (79–150), factor VII: 28%
(67–175),
factor IX: 40% (82–162), factor X: 46% (68–153),
factor V: 98% (73–150), and factor VIII: 82% (59–150). Because
no other cause of vitamin K deficiency could be determined,
warfarin abuse was suspected. However, analysis of two blood
samples for warfarin gave negative results with reversed-phase
liquid chromatography.
The endoscopic examination performed for his melena
revealed mucosal erosion in the antrum, and pantoprazole
infusion was started along with 30 mg/day intravenous vitamin
K
1
and two units of fresh frozen plasma. Over the next five days,
the melena resolved and his INR and aPTT levels decreased to
1.62
and 41 s, respectively.
The patient was psychiatrically evaluated and he was put on
alprazolam 0.5 mg three times a day. He started psychotherapy
sessions for his depressive mood. Two days after the second
measurement of coagulation parameters, the patient had epistaxis
and his INR level was found to be elevated again (
>
17).
Two units
of fresh frozen plasma along with 10 mg intravenous vitamin K
1
were given twice a day in order to control the acute bleeding, and
phenobarbital 200 mg/day was given for microsomal enzyme
induction. The patient’s failure to respond to vitamin K treatment
and the negative blood test result for warfarin led to a suspicion
of superwarfarin poisoning.
A serum sample was sent to a reference laboratory for
investigation by reversed-phase liquid chromatography.
7
The
results showed the presence of brodifacoum at a concentration
of 61 ng/ml. The patient’s INR level showed fluctuations and
it remained high for his entire hospital stay of 72 days (Fig. 1).
When his INR levels increased concomitant with active bleeding,
fresh frozen plasma and intravenous vitamin K
1
treatments were
increased up to three units/day and/or 40 mg/day, respectively.
The patient was discharged from hospital on 30 mg/day oral
vitamin K
1
,
with an INR level of 2.6. During follow-up visits
over a period of 92 days, the INR level regressed to the normal
range. A repeat brodifacoum level of 15 ng/ml was found 92 days
after hospital discharge. The vitamin K
1
treatment was stopped
and the patient was referred to a psychiatric clinic for medical
and psychotherapeutic treatment of major depression.
Discussion
Warfarin was first identified by Karl Link in 1933 as the
active component of mouldy sweet clover and has since been
used as a rodenticide. Increasing resistance to warfarin in
rats has led to the development and use of the superwarfarins
(
derivatives of 4-hydroxycoumarin, such as difenacoum,
bromadiolone and brodifacoum, and indanedione derivatives
such as chlorophacinone, pindone and diphacinone).
1
Superwarfarins are long-acting, colourless, odourless and
fat-soluble anticoagulants with a terminal half-life varying
between 16 and 220 days and are 100 times more potent than
warfarin.
3,10
They show their anticoagulant effect by inhibiting the
conversion of vitamin K 2,3-epoxide to vitamin K hydroquinone,
the co-factor required by r-glutamyl carboxylase for the post-
translational modification of coagulation factors II, VII, IX and
X, and protein C and protein S, thereby leading to decreased
functional activities and antigenic levels of vitamin K-dependent
coagulation factors and proteins.
Brodifacoum, which is a derivative of 4-hydroxy coumarin,
is the most commonly used rodenticide worldwide, especially
in homes and businesses. It is more potent than warfarin as
a vitamin K antagonist and the elimination half-life in rats is
156
hours compared to the 17-hour half-life of warfarin.
11
In
humans, the half-life varies between 243 and 1 656 hours for
brodifacoum,
12,13
compared to 17 and 37 hours for warfarin.
The main side effect of brodifacoum is toxicity leading to
coagulopathy, which can be encountered with relatively small
doses.
14
The most common clinical feature of superwarfarin
intoxication is bleeding from any mucosal site or organ. Epitaxis,
haematuria, gingival bleeding, ecchymosis, gastrointestinal
bleeding, haemoptysis, and intracranial haemorrhage have been
reported in studies by Chua
et al
.
4
and Spahr
et al
.
8
In our case,
gastrointestinal haemorrhage and gingival bleeding were present.
We also found reduced levels of vitamin K-dependent factors II,
VII, IX and X.
The incidence of superwarfarin poisoning has increased
over the past 10 years.
7,8
While the most common cause of this
poisoning is accidental ingestion, especially in children, other
causes include suicide, homicide, surreptitious administration,
and usage as a drug of abuse. Since most adult cases are related
to suicide,
5,8,12,15
obtaining a psychiatric consultation is needed
18
16
14
12
10
8
6
4
2
0
0
50
100
150
200
Fig. 1. INR level showing elevation and fluctuations
during the hospital stay of 72 days.
