The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Departments of Pathology (M.L.,
E.M.V.) and Radiology (M.H.L.), Massachu-
setts General Hospital; and the Depart-
ments of Pathology (M.L., E.M.V.) and Ra-
diology (M.H.L.), Harvard Medical School.
N Engl J Med 2007;356:174-82.
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174
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 1-2007: A 40-Year-Old Woman
with Epistaxis, Hematemesis,
and Altered Mental Status
Michael Laposata, M.D., Ph.D., Elizabeth M. Van Cott, M.D.,
and Michael H. Lev, M.D.
Pr e sen tat ion of C a se
Dr. Amy Jo Chien (Medicine): A 40-year-old woman was admitted to the emergency
department of this hospital because of the sudden onset of headache, loss of con-
sciousness, and coagulopathy.
The patient had been in her usual state of good health until approximately
6 months earlier, when menorrhagia developed, with menstrual periods lasting for
2 weeks. Approximately 2 weeks before admission to the emergency department of
this hospital, she vomited blood clots after a meal. During the next several days,
intermittent epistaxis, gingival bleeding, and easy bruising occurred. Eight days
before admission to the emergency department of this hospital, she went to the
emergency department of a local hospital, where a physical examination was normal.
Results of liver- and renal-function tests were normal, as were the white-cell count,
differential count, and levels of serum protein, electrolytes, glucose, calcium, and
phosphorus; results of additional laboratory tests are shown in Table 1. She left
against medical advice to care for her children but returned 3 days later, after she
was called by a member of the emergency department staff; she was admitted to
that hospital (6 days before admission to the emergency department of this hospi-
tal). Overnight, she experienced hoarseness, tightness in her throat, and difficulty
swallowing; physical examination on the second hospital day showed enlargement
of the left tonsil and swelling in the left side of the neck. Results of liver- and
renal-function tests were normal, as were levels of serum protein, electrolytes,
glucose, calcium, phosphorus, and ferritin and iron-binding capacity; the serum
iron level was 22 μg per deciliter (3.9 μmol per liter), the erythrocyte sedimentation
rate was 114 mm per hour, and the lactate dehydrogenase level was 235 U per liter
(normal range, 100 to 190); results of additional laboratory tests are shown in
Table 1. Two units of fresh-frozen plasma were transfused, and the patient was
transferred to the intensive care unit of this hospital later that day (5 days before
the second admission to this hospital).
Computed tomographic (CT) scanning of the neck showed a left parapharyngeal
mass that was thought to be a hematoma. Vitamin K was administered orally,
subcutaneously, and intravenously, and multiple units of fresh-frozen plasma and
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The New England Journal of Medicine
 case records of the massachuset ts gener al hospital
5000 units of a concentrate of factors II, IX, and
X and small amounts of factor VII (35%) (Profil-
nine SD, Grifols) were given. Results of laboratory
tests on the next 2 days are shown in Table 1.
There was no evidence of new bleeding. The pa-
tient was discharged on the fourth hospital day
with no medications and with instructions to re-
turn to the other hospital the next day for follow-
up laboratory tests.
The patient returned to the outpatient hema-
tology clinic at this hospital 2 days later at the
request of her hematologist because of abnormal
results of laboratory tests (Table 1). She was feel-
ing well. An intravenous infusion of 5000 units
of a prothrombin complex concentrate was given
without immediate complications. During the car
trip home from the clinic (1 day before admission
to the emergency department of this hospital),
she told her husband that she had abdominal
cramps and a headache and then rapidly became
confused and lost consciousness. Her husband
reported transient twitching of her left leg but no
clear seizure activity. She was taken to a commu-
nity hospital emergency department, where she
was reported to be agitated, combative, and unable
to follow commands. Her trachea was intubated
for airway protection with the use of vercuronium
and succinylcholine during intubation. She was
transferred to the emergency department of this
hospital.
On arrival, the patient was intubated, sedated,
and paralyzed. The temperature was 36.2°C, blood
pressure 148/81 mm Hg, pulse 75 beats per min-
ute, and oxygen saturation 100% while the patient
was breathing 100% oxygen. On physical exami-
nation, there was no sign of head trauma, but
there was blood on the oral mucosa and there
were ecchymoses on both arms and under the
blood-pressure cuff. Petechiae were present dif-
fusely on the chest, arms, legs, and back. There
was bleeding at the sites of peripheral intravenous
administration. The neurologic examination was
limited by sedation. The pupils were 2 mm in
diameter, equal, round, and reactive. The patient
was able to move all four extremities; there was
equivocal movement of the toes in response to
noxious stimuli. Muscle bulk and tone were nor-
mal. All reflexes were decreased. Examination of
the chest, heart, and abdomen showed no abnor-
malities. Peripheral pulses were normal.
The patient had no other medical problems,
took no medications or nutritional supplements,
and had no known drug allergies. She had had
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three pregnancies: two full-term deliveries and one
miscarriage. She was married and had two sons
who were well. She did not smoke, drink alcohol,
or use illicit drugs. She worked as a dog groomer.
There was no family history of bleeding disorders.
A complete metabolic panel, results of liver-
function tests, and a lipid profile were normal.
Serum and urine toxicologic screening tests were
negative. Serum levels of creatine kinase and MB
isoenzyme were normal; the level of folic acid
was 11 ng per milliliter (25 nmol per liter; normal
range, 150 to 450 ng [340 to 1020 nmol]), vitamin
B12 473 pg per milliliter (350 pmol per liter; nor-
mal value, >250 nmol [>180 pmol]), lactate dehy-
drogenase 362 U per liter, and troponin T 0.72 ng
per milliliter. The results of other laboratory tests
are shown in Table 1.
An electrocardiogram showed a normal sinus
rhythm with no acute ischemic changes. A chest
radiograph obtained at the bedside showed clear
lungs and a correctly placed endotracheal tube.
CT scanning of the head without the administra-
tion of contrast material showed no evidence of
an acute territorial infarction or intracranial hem-
orrhage. A CT angiogram and venogram of the
head showed no stenosis or aneurysm of the in-
tracranial arteries. A laminar filling defect was
seen in the right superior ophthalmic vein. There
was no evidence of venous sinus thrombosis.
In the emergency department, the patient was
given 4 units of fresh-frozen plasma, 10 units
of cryoprecipitate, recombinant factor VIIa, and
20 mg of intravenous vitamin K. The serum level
of haptoglobin was normal; results of other labo-
ratory tests are shown in Table 1. CT scanning of
the abdomen and pelvis showed no evidence of
intraabdominal bleeding. Vancomycin, cefepime,
and metronidazole were given intravenously for
possible pneumonia. On the same day, the patient
was admitted to the intensive care unit of this
hospital. Results of laboratory tests are shown
in Tables 1 and 2.
Vitamin K (10 mg) was administered intrave-
nously three times daily. A test for the presence
of warfarin in a specimen of blood that had been
obtained on the third day of the first hospitaliza-
tion was reported to be negative. An electroen-
cephalogram showed no epileptiform activity.
Magnetic resonance imaging (MRI) of the head
before and after the administration of contrast
material showed multiple foci of restricted diffu-
sion involving the pons, and bilateral cerebellum.
On the second hospital day, a repeated CT
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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Results of Hematologic and Coagulation Laboratory Tests.

Normal Range First Admission

Variable at This Hospital to Other Hospital First Admission to This Hospital
8 Days
before Second 5 Days 4 Days 3 Days
Admission to before Second before Second before Second
This Hospital Admission Admission Admission
Hematocrit (%) 36.0–46.0 42.1 32.2 29.0 31.0
Platelet count (per mm3) 150,000–350,000 232,000 188,000 179,000 210,000
Prothrombin time (sec) 11.3–13.3 >60.0 24.4 23.4 28.1
Prothrombin-time mixing study* Corrected Corrected
Partial-thromboplastin time (sec) 22.1–35.1 110.5 48.5 48.8 48.9
Partial-thromboplastin–time mixing Corrected Corrected
study*
Fibrinogen (mg/dl) 150–400 773
Fibrin split products (μg/ml) <5
D-Dimer (ng/ml) <500 700
Antithrombin III (%) 80–130
Factor II (%) 60–140 2
Factor V (%) 60–140 60
Factor VII (%) 60–140 <1
Factor VIII (%) 50–200 177
Factor IX (%) 60–140 <0.9
Factor X (%) 60–140 1
Protein S (%) 70–140
Protein C (%) 70–140
Activated protein C resistance >2.0

* Mixing study denotes 1:1 mix of patient’s plasma with normal plasma and multiple measurements during a 1-hour period.

angiogram of the head and neck showed stable
left pontine and cerebellar infarcts and no evi-
dence of new infarction or acute intracranial
hemorrhage. A transcranial Doppler study showed
normal flow velocities, spectral configurations,
and directions of flow in the left and right, mid-
dle, anterior, and posterior cerebral arteries, with
no spontaneous emboli detected during a 30-min-
ute recording. No emboli were detected after the
injection of agitated saline or with the the pro-
vocative maneuvers of abdominal compression,
inspiratory pause, and suctioning with coughing.
Treatment with unfractionated heparin was
initiated, with a target partial-thromboplastin time
of 40 to 50 seconds. Treatment with vitamin K
was continued intravenously, and fresh-frozen
plasma was transfused as needed on the basis
of the prothrombin and partial-thromboplastin
times. The patient was alert, behaved normally,
and was able to follow commands. The trachea
was extubated. Neurologic examination revealed
mild weakness of the right arm and left side of
the face, with no other abnormalities. On ques-
tioning, she specifically reported that she had
not been exposed to warfarin or rat poison; she
had had occupational exposure to canine flea and
tick solutions containing fipronil, imidacloprid,
and permethrin. She drank four to five glasses
of bottled iced tea with ginseng daily. Tests for
lupus anticoagulant, heparin–PF4 antibodies, and
the prothrombin gene mutation G20210A were
negative. Results of other laboratory tests are
shown in Tables 1 and 2. No blood products were
required after the second hospital day.
On the fifth hospital day, swelling of the left
arm developed; ultrasonography showed a super-
ficial cephalic-vein thrombus with no evidence of
deep venous thrombosis. A transthoracic echocar-

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 case records of the massachuset ts gener al hospital

On Visit to Hematology
2 Days before Second Clinic at This Hospital
Admission to This (1 Day before Second
Hospital Admission to This Hospital) Second Admission to This Hospital

In On
Emergency Admission
Department to the ICU Day 2 Day 3 Day 5 Day 8
31.5 32.0 23.4 26.6 28.2 29.2
201,000 125,000 119,000 70,000 98,000 137,000
18.6 23.0 28.5 >50.0 11.0 14.4 18.8 13.5

37.5 39.9 47.6 >150.0 33.3 28.3 36.4 43.8

<50 240 386 557

>20
>10,000 >10,000 8,696 3,227
32
31 43
85 104
<1 59
150
7.0 54.0
25 41
20
14
3.0

diogram obtained after injection of agitated saline which had resolved by the time of discharge. On
on the sixth hospital day showed no evidence of the second admission, a CT angiogram obtained
a patent foramen ovale. On the seventh hospital for the evaluation of neurovascular symptoms
day, the serum warfarin level in a specimen of showed poor filling of the right superior oph-
blood that had been obtained on admission to the thalmic vein, a finding suggestive of thrombosis.
emergency department the second time was re- This finding did not resolve on follow-up exami-
ported to be negative. Evaluation by the psychiat- nation (Fig. 1B). Both T2-weighted (Fig. 1C) and
ric service on the eighth hospital day showed that diffusion-weighted (Fig. 1D) MRI scans showed
the patient had no evidence of acute psychiatric punctate acute infarction of the pons and left
illness and no indication of suicidal intent or a cerebellum, although no hemorrhage was seen
desire to harm herself. on a magnetic resonance susceptibility sequence
The results of a diagnostic test were reported (not shown). CT scanning of the pelvis, performed
on the 10th hospital day. because of excessive bleeding after an attempted
femoral-line placement, showed an extensive su-
Differ en t i a l Di agnosis perficial soft-tissue hematoma. A transcranial Dop-
pler ultrasound study, which was performed the
Dr. Michael H. Lev: CT scanning of the neck on the next day to confirm the patency of the cerebral vas-
first admission to this hospital showed a high- culature, was normal. On the fifth hospital day,
density supraglottic soft-tissue hematoma (Fig. 1A), a deep-vein thrombosis ultrasonographic exami-

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 The n e w e ng l a n d j o u r na l
Table 2. Serum Levels of Brodifacoum and Results of Coagulation Tests during Therapy with Vitamin K after Second Admission
to This Hospital.
Normal
Variable Range Day 2
Brodifacoum (ng/ml) Not detected 93
Prothrombin time (sec) 11.1–13.1 14.1
Partial-thromboplastin time (sec) 22.1–35.1 29.0
* This was 10.5 months after the initial onset of the bleeding.
nation of the arms revealed a superficial cephalic
vein thrombosis. On the fifth hospital day, ultra-
sonographic examination of the arms revealed a
superficial cephalic vein thrombosis. In summary,
this patient had radiologic evidence of both bleed-
ing and thrombosis, including hemorrhage in
the regions of the neck and groin and thrombo-
sis of the superior ophthalmic vein, posterior ce-
rebral microvasculature, and left cephalic vein.
Dr. Michael Laposata: This 40-year-old woman
presented with a hemorrhagic coagulopathy in
the absence of a personal or family history of
bleeding and taking no identifiable medications
or nutritional supplements that would predispose
her to a bleeding disorder. The bleeding began at
least 6 months before her initial presentation,
with menstrual periods lasting 2 weeks. Excessive
menstrual bleeding can be associated with non-
hematologic disorders, but such disorders are un-
likely in this patient, since she later vomited
blood clots after a meal and began to have inter-
mittent epistaxis, gingival bleeding, and easy bruis-
ing. These additional clinical findings strongly
suggested the presence of a hemorrhagic coagu-
lopathy, which could be due to a low platelet
count, defective platelet function, or a coagulation-
factor deficiency.
Causes of Hemorrhagic Coagulopathy
Laboratory test results 8 days before admission
showed markedly prolonged prothrombin and
partial-thromboplastin times, both of which were
corrected in mixing studies. The patient had a
normal platelet count, and the results of liver-
function tests were normal. These findings rule
out a decreased platelet count as a likely explana-
tion for the hemorrhagic coagulopathy and pro-
vide evidence of multiple coagulation-factor defi-
ciencies. A less likely possibility is an acquired,
single coagulation-factor deficiency in the com-
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of m e dic i n e
2 Months after 4.5 Months after
Day 11 Day 14 Admission Admission*
78 74 Not performed <5
16.8 25.8 13.0 13.0
48.4 37.7 35.7 30.1
mon pathway of the coagulation cascade (fibrin-
ogen, factor II, factor V, or factor X), which could
prolong both the prothrombin and partial-throm-
boplastin times. Impaired platelet function would
not prolong the prothrombin and partial-throm-
boplastin times, and neither a deficiency or an
inhibitor of factors VIII, IX, XI, or XII nor von
Willebrand’s disease would prolong the prothrom-
bin time. A selective deficiency or inhibitor of
factor VII would not prolong the partial-thrombo-
plastin time. In this patient, the coagulation-factor
deficiency is probably acquired rather than con-
genital, given the absence of a personal and fam-
ily history of bleeding.
Acquired Deficiency of Vitamin K–Dependent
Coagulation Factors
The seriousness of the bleeding disorder became
apparent 5 to 6 days before the second admission
to this hospital, when a parapharyngeal hemato-
ma developed. Factor assays at that time showed
low or undetectable levels of the vitamin K–depen-
dent factors, with normal values for non-vitamin
K–dependent coagulation factors. Treatment with
2 units of fresh-frozen plasma shortened the pro-
thrombin and partial-thromboplastin times, but
did not normalize the values for these two tests.
Relatively small amounts of plasma can shorten
the prothrombin and partial-thromboplastin times,
but much larger amounts are required for normal-
ization or even near normalization. The hemato-
crit had fallen, suggesting that the patient had
blood loss. At that time, it was clear that she had
a hemorrhagic coagulopathy caused by multiple
acquired deficiencies of the vitamin K–dependent
factors.
The differential diagnosis includes surrepti-
tious or inadvertent ingestion of warfarin or a
warfarin-related compound or a very severe vita-
min K deficiency. Vitamin K (Fig. 2) is a cofactor
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 case records of the massachuset ts gener al hospital

A B

Figure 1. CT and MRI Studies of the Head and Neck.

An axial CT scan of the neck, obtained after the administration of contrast material (Panel A), shows a left supraglottic
high-density soft-tissue hematoma (arrow) measuring 68 Hounsfield units. The appearance was the same on the
images obtained before and after the administration of contrast material. An axial CT scan of the head, obtained
after the administration of contrast material (Panel B), shows an unopacified right superior ophthalmic vein (arrow),
a finding consistent with the presence of a thrombus. An axial T2 -weighted MRI scan (Panel C) shows hyperintensity
of the left pons (long arrow) and superior cerebellum (short arrow). An axial diffusion-weighted MRI scan (Panel D)
confirms the presence of an acute stroke in these locations (long arrow and short arrow).

in the reaction in which the enzyme gamma car-
boxylase catalyzes the production of factors II,
VII, IX, and X, as well as the natural anticoagu-
lants, protein C and protein S. Vitamin K is con-
verted to an inactive vitamin K epoxide in this
reaction, and the enzyme vitamin K epoxide re-
ductase regenerates the active form. This enzyme
is the target of warfarin and warfarin-related
animal poisons. The warfarin-related poisons can
have a much greater potency than warfarin and
are thus called “superwarfarins.”
Superwarfarin Pesticide Poisoning
Five days before the second admission, the patient
was treated with large amounts of vitamin K. She
also received multiple units of fresh-frozen plas-

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 The n e w e ng l a n d j o u r na l
Vitamin K1
(phytonadione)
Epoxide reductase Reductase
inhibited by or NAD(P)H-
warfarin, dependent
brodifacoum dehydrogenase
Vitamin K2,3- Vitamin K
epoxide hydroquinone
Carboxylase+oxygen+
carbon dioxide
Carbon dioxide is added to glutamate
on factors II, VII, IX, and X
(carboxylation)
Figure 2. The Vitamin K Cycle.
Vitamin K1 (also called phylloquinone or phytonadione),
acquired from the diet or from medical administration,
is reduced to its active form (hydroquinone) by one of
two reductases. One of the reductases is not sensitive
to warfarin and requires NAD(P)H; the other reduc-
tase is partially sensitive to warfarin. Active vitamin K
is required for carboxylation of coagulation factors II,
VII, IX, and X (as well as protein C, protein S, protein
Z, and certain bone proteins). A carboxylase enzyme
performs the carboxylation step using oxygen and carbon
dioxide, and in the process, active vitamin K becomes
oxidized to an inactive form called vitamin K2,3- epox-
ide. Epoxide reductase reduces vitamin K 2,3- epoxide
back to vitamin K1, which permits the regeneration of
active vitamin K. Epoxide reductase is inhibited by warfa-
rin or warfarin-like agents, including superwarfarins
such as brodifacoum.
ma and a prothrombin-complex concentrate, which
contains some activated coagulation factors and
carries with it the potential complications of
thrombosis and disseminated intravascular coagu-
lation.1,2 After all of this therapy (3 days before
the second admission), the patient had a markedly
reduced but still prolonged prothrombin time
(18.6 seconds) and a nearly normal partial-
thromboplastin time (37.5 seconds). Furthermore,
follow-up studies indicated that these times were
gradually increasing, findings that are consistent
with the persistent activity of a residual substance
that inhibits the action of vitamin K–dependent
clotting factor. The failure of very large amounts
of vitamin K to correct the problem makes the
diagnosis of vitamin K deficiency or surreptitious
or inadvertent warfarin ingestion unlikely, since
these disorders would have been effectively treat-
ed with much smaller amounts of vitamin K. The
fact that large amounts of vitamin K did not cor-
rect the problem provides strong support for the
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of m e dic i n e
surreptitious or inadvertent ingestion of a super-
warfarin pesticide.3,4
Because the patient’s prothrombin and partial-
thromboplastin times continued to rise, she re-
ceived a second treatment with a prothrombin-
complex concentrate. Shortly thereafter, abdominal
cramps, headache, and loss of consciousness oc-
curred; she had evidence of both bleeding and
thrombosis, with a thromboembolic stroke and
thrombosis in the right superior ophthalmic vein.
The results of coagulation studies, including the
prothrombin and partial-thromboplastin times,
were elevated. There were also signs of dissemi-
nated intravascular coagulation, with a low fi-
brinogen level, an elevated D-dimer level, a low
platelet count, and a low antithrombin level (32%).
Disseminated intravascular coagulation is one of
the major side effects of prothrombin-complex
concentrates.1,2
At this point, the management issues became
especially challenging, since the thrombotic stroke
and coagulopathy had to be treated simultane-
ously. The most appropriate management strat-
egy, which was applied in this case, was to nor-
malize or nearly normalize the coagulation factors
and then to administer anticoagulation therapy
in a standard fashion as treatment for stroke.
After treatment with fresh-frozen plasma, cryo-
precipitate, and large quantities of intravenous
vitamin K, the patient’s prothrombin and partial-
thromboplastin times became normal for the
first time, and the fibrinogen level rose to the
normal range. Several risk factors for hyperco-
agulable states were ruled out, and both the bleed-
ing and disseminated intravascular coagulation
resolved. A serum test for warfarin was negative.
This result was consistent with the presence of a
superwarfarin pesticide, which was not likely to
be detected in an assay to identify and quantitate
warfarin.
Conclusions
I suspect that the diagnostic test result that was
reported on the 10th hospital day was the detec-
tion of a superwarfarin compound, possibly brodi-
facoum, in the plasma. Ingestion of brodifacoum
does not cause gastrointestinal symptoms, and
it can be ingested in large quantities; neverthe-
less, once poisoning occurs, abdominal pain is
common. Both brodifacoum and warfarin are
4-hydroxycoumarins; chemical differences outside
the 4-hydroxycoumarin structure differentiate war-
farin from the superwarfarins. The 4-hydroxycou-
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 case records of the massachuset ts gener al hospital
marin superwarfarins include brodifacoum,5 bro-
madiolone,6 coumafuryl,7 and difenacoum.8
I think that the events occurred in the follow-
ing sequence. The patient was exposed to a super-
warfarin, either accidentally or intentionally. There
was a marked reduction in vitamin K–dependent
coagulation factors. With replacement of vita-
min K and vitamin K–dependent factors, the ad-
ditional use of a prothrombin-complex concen-
trate resulted in the desired hemostasis as well
as the undesired side effects of thrombosis and
disseminated intravascular coagulation. It would
be informative to learn from the patient how her
exposure to large amounts of a superwarfarin
might have occurred.
Dr. Nancy Lee Harris (Pathology): Dr. Ellman, you
were this patient’s hematologist; will you tell us
your thinking at the time of her admission?
Dr. Leonard Ellman (Hematology and Oncology):
My thinking very closely paralleled Dr. Laposata’s,
and although the patient vehemently denied any
exposure, I thought she must have ingested a
superwarfarin. Specimens of blood were sent to
a reference laboratory for testing. Before her ad-
mission, I was very concerned about the risk of
serious bleeding, and the decision to give her the
concentrate of factors II, VII, IX, and X was
made in consultation with the director of the
blood bank.
Cl inic a l Di agnosis
Multiple vitamin K–dependent coagulation-factor
deficiencies due to ingestion of brodifacoum.
DR . MICH A EL L A P O S ATA’S
DI AGNOSIS
Multiple vitamin K–dependent coagulation-factor
deficiencies due to ingestion of brodifacoum.
Pathol o gic a l Dis cus sion
Dr. Elizabeth M. Van Cott: The results of an assay for
brodifacoum from a specimen of blood obtained
on the first hospital day were reported to the
hematologist on call on the 10th hospital day.
The level was 93 ng per milliliter (threshold for
detection, 5 ng per milliliter).
Brodifacoum is the most commonly used su-
perwarfarin in the United States. The number of
superwarfarin exposures (defined as ingestion or
inhalation without coagulation abnormalities or
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bleeding) or poisonings (defined as exposure with
coagulation abnormalities and bleeding) is in-
creasing, with 5133 exposures or poisonings re-
ported in 1988, 13,423 in 1995, and 16,109 in
1998.9,10 The vast majority of these cases have
been exposures, and only 24 cases were classified
as poisonings in adults.10 Ninety percent of expo-
sures are in children, usually those under 6 years
of age and usually with no consequent coagula-
tion abnormalities.10,11 Minor exposures in chil-
dren may not require treatment.11,12
Cases of exposure to brodifacoum have includ-
ed accidental exposure, suicide attempts with the
substance, Munchausen’s syndrome, exposure of
factory workers, and exposure from smoking
marijuana or “crack” cocaine.10,13,14 In addition to
ingestion or inhalation, absorption through the
skin can occur.
Brodifacoum is lipophilic. It is 100 times as
potent as warfarin and has a very long half-
life15,16; in this patient, the half-life was estimat-
ed to be 30 days. In contrast, the half-life of
warfarin is approximately 40 hours. The duration
of coagulation abnormalities and the dosage of
vitamin K1 required to correct them vary among
reported cases, probably at least in part because
of variations in the amount of brodifacoum con-
sumed, deliberate or unintentional noncompliance
with vitamin K1 therapy in some cases, continued
exposure to brodifacoum in some cases, and the
variable metabolism of brodifacoum, like that of
warfarin. With brodifacoum poisoning, every car-
boxylation reaction requires a new vitamin K1
molecule, because vitamin K1 cannot regenerate
(Fig. 2).9 For these reasons, the treatment of brodi-
facoum poisoning requires large doses of vitamin
K1, ranging from 50 to 800 mg per day, admin-
istered for an extended period.10,13,16-21 In this
patient, coagulation abnormalities resolved within
4.5 months after her second admission (Table 2),
and the highest vitamin K dose she received was
60 mg per day.
Dr. Harris: Dr. Ellman, will you give us the fol-
low-up information?
Dr. Ellman: The patient continued to deny that
she had accidentally or intentionally ingested
brodifacoum or that anyone could have been try-
ing to poison her. The only explanation she could
offer was the ingestion of strange-tasting lun-
cheon meat about 1 week before her initial visit
to the local emergency department. The case was
reported to her city’s health department and to
law enforcement officials. To the best of my
january 11, 2007 181
 case records of the massachuset ts gener al hospital

knowledge, no additional information has been
obtained.
Treatment with vitamin K and anticoagulation
therapy initially with heparin and later with
fondaparinux were continued, and the patient
was discharged home on the 15th hospital day.
At the time of discharge, she had no focal neuro-
logic deficits. She was well, with no further
bleeding or clotting problems, at the last follow-
up visit, 8 months later.
PATHOL O GIC A L DI AGNOSIS
Multiple vitamin K–dependent coagulation-factor
deficiencies due to ingestion of brodifacoum.
Dr. Laposata reports receiving consulting fees from BD Preana-
lytical Systems, Cubist Pharmaceuticals, T2 Biosystems, Roche
Point-of-Care Coagulation, Instrumentation Laboratory, Procter
& Gamble, and Catalyst Oncology; having equity and ownership in
American Medical Diagnostics, MedPacks, and Pocket Medicine;
having anticipated stock options in T2 Biosystems; receiving lecture
fees from GlaxoSmithKline, Diagnostica Stago, InVein Treatment
& Techniques, Gerson Lehrman, Novo Seven, Ortho, and Lab Info-
Tech; serving as an expert witness in areas related to laboratory
testing and coagulation; receiving royalties from ASCP Press and
Pocket Medicine, Lexi-Comp, ASCP, American Medical Diagnostics,
and Thomas Weisel Venture Partners; and being a nonpaid advi-
sory board member for DiagnosisONE. Dr. Van Cott reports receiv-
ing lecture fees from Novo Nordisk, bioMerieux, and Diagnostica
Stago; grant support from Diagnostica Stago; and royalties from
American Medical Diagnostics. Dr. Lev reports serving on medical
advisory boards for GE Healthcare, Bracco Diagnostics, and CoAxia
and receiving lecture fees from GE Healthcare and Bracco Diagnos-
tics, and educational support from GE Healthcare. No other poten-
tial conflict of interest relevant to this article was reported.

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