A 44-Year-Old Woman With Hematemesis and Cutaneous Hemorrhages as ...

CASE REPORT
A 44-Year-Old Woman With Hematemesis and Cutaneous Hemorrhages
as a Result of Superwarfarin Poisoning
Elizabeth K. Dolin, DO
Damon L. Baker, DO
Steven C. Buck, DO
The authors present the case of a 44-year-old American
The patient then visited an outlying tertiary care center,
Indian woman with hematemesis, spontaneous cutaneous
where measurements were made of her prothrombin (coag-
hemorrhages, and multiple ecchymoses. Coagulation factor
ulation factor II) time (PT) and partial thromboplastin time
analyses demonstrated both prolonged prothrombin time
(PTT). To restore normal coagulation activity, the patient’s
(PT, 40 s) and prolonged partial thromboplastin time
therapy included fresh frozen plasma and vitamin K. The dis-
(PTT, 120 s). Measurement of the serum level of brodi-
charge summary from the hospitalization lists a diagnosis of
facoum (37 ng/mL), one of the superwarfarin agents com-
possible Munchausen syndrome (factitious disorder with
monly used in rodenticides, confirmed poisoning as the
physical symptoms) and ingestion of warfarin, a synthetic
cause of the patient’s symptoms. Substantial amounts of
anticoagulant. The hospital’s treatment course indicated that
fresh frozen plasma and vitamin K were required to obtain
the patient’s serial warfarin levels were negative, while mixing
normal coagulation parameters and maintain these param-
studies indicated correction of her PT with coagulation factor
eters over a 3-week inhospital period. Oral administra-
replacement. Quantification of the amount of fresh frozen
tion of vitamin K (100 mg daily) maintained normal PT
plasma and vitamin K administered to the patient during this
(14.1 s), PTT (33.0 s), and international normalized ratio
hospitalization was not provided in the discharge summary.
(INR, 1.48) at 2 weeks after the patient was discharged
The patient’s hospitalization ended after 10 days, when she was
from the hospital. By 2 months postdischarge, PT, PTT,
denied smoking privileges and left against medical advice.
and INR returned to elevated levels because of patient
One week after discharge, the patient noted a recurrence
noncompliance with the prescribed tapering vitamin K
of diffuse spontaneous skin hemorrhages and ecchymoses
regimen.
over her upper and lower extremities and oral mucosa. She
also had an incident of uncontrolled bleeding after acciden-
J Am Osteopath Assoc. 2006;106:280–284
tally cutting her hand with a kitchen knife while preparing
http://www.jaoa.org/content/vol106/issue5/
a meal. In addition to developing lesions, she began to have
A44-year-old American Indian woman was admitted to bilateral calf pain associated with bruising and swelling.
the intensive care unit (ICU) for management of a coag-
These complaints prompted her to report to the Indian Health
ulopathy requiring coagulation factor replacement therapy.
Service clinic in Tulsa, Okla, where prolongation of her PT and
The patient reported an episode of hematemesis approxi-
PTT was once again noted. She received subcutaneous
mately 2 months prior to admittance. During this episode, the
vitamin K (25 mg) and was transferred to our tertiary care hos-
patient underwent an esophagogastroduodenoscopy (EGD),
pital (Tulsa Regional Medical Center) for additional evalua-
which revealed severe esophagitis. She was prescribed a reg-
tion and management.
imen of lansoprazole and sucralfate at the time. The 4 weeks
following her EGD were uneventful.
Evaluation and Management of Case
At the end of this 4-week period, the patient experienced
Upon admission to the Tulsa Regional Medical Center, the
a sudden recurrence of hematemesis and noticed sponta-
patient appeared to be well nourished. Physical examina-
neous cutaneous hemorrhages (1–4 mm) and ecchymoses
tion revealed scattered purpuric lesions on her scalp, with
(1–4 cm) in areas of minimal trauma on her body.
some areas of excoriation that were actively bleeding. She
also had a small hematoma on the left corner of her lower lip
and purpuric lesions scattered on her oral mucosa. Exami-
nation of her skin revealed numerous cutaneous hemor-
rhages on both her upper and lower extremities, her
From Scott and White Memorial Hospital in Temple, Tex (Dolin), and Okla-
homa State University College of Osteopathic Medicine in Tulsa (Baker, Buck).
abdomen, and her back. In addition, multiple areas of ecchy-
Address correspondence to Elizabeth K. Dolin, DO, Scott and White
moses in several stages of healing were noted. No evidence
Memorial Hospital, 121 Meadowbrook Dr, Temple, TX 76502-5582.
of hemearthrosis was observed. A neurovascular examination
E-mail: bethdolin@aol.com
revealed no abnormalities.
280 • JAOA • Vol 106 • No 5 • May 2006
Dolin et al • Case Report

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CASE REPORT
soning me.” The patient further reported
Table 1
her belief that she probably had been
Initial Laboratory Test Results of Patient
poisoned numerous times by her hus-
band, whom she had not seen in 4
Factor Tested
Test Result
Reference Range
weeks. (Although we were able to estab-
lish superwarfarin ingestion as the cause
of the patient’s symptoms, we were not
▫ Fibrinogen, mg/dL
339
200–420
able to definitively establish the cause of
▫ Hematocrit, %
27.6
36.1–44.3 (female)
this ingestion.)
▫ Hemoglobin, g/dL
9.5
12.1–15.1 (female)
The patient’s initial treatment
▫ International normalized ratio*
...
...
course at our hospital continued for 2
▫ Partial thromboplastin time, s
weeks. During this time, she was closely
120 25–35
▫ Platelet count, /µL
386,000
150,000–400,000
observed both in the ICU and on the
▫ Prothrombin time, s†
general medical floor for any sign of
40 10.4–12.6
self-medication. However, no such ques-
▫ Qualitative D-dimer
Negative
...
tionable behavior was observed.
▫ Thrombin time, s
13.8
14.5–18.9
Because of her prolonged PT and PTT,
▫ White blood cell count, /µL
9600
4500–10,000
continual replacement of coagulation
factors via plasma transfusion was nec-
* International normalized ratio was not initially tested because prothrombin time was greater than
essary. In total, the patient required 56
40 seconds.
† A subsequent 1:1 mixing study for coagulation factor deficiency showed a correction in prothrombin
units of fresh frozen plasma, averaging
time to 12.1 seconds.
six units daily for 10 days. She also
received daily doses (5 mg) of vitamin
K. This regimen corrected the patient’s
The results of our initial laboratory evaluation of the
PT to an average time of 18 seconds, and her PTT to an
patient are reported in Table 1. The coagulation factor analyses
average of 40 seconds. Her INR tested at an average of 2.5 (ref-
demonstrated both prolonged PT ( 40 s; reference range,
erence range, 0.8–1.2)
10.4–12.6 s) and prolonged PTT ( 120 s; reference range,
Although substantial corrections of the patient’s PT and
25–35 s). It was not necessary to initially test for the interna-
PTT were obtained with treatment, an incomplete correc-
tional normalized ratio (INR), which is useful for confirming
tion was suggested by a 50:50 mixing study on serial dilutions,
PT results, because of the extremely elevated PT level.
which pointed to a possible circulating inhibitor as a com-
Additional medical history obtained in the initial evalu-
ponent of the patient’s anticoagulated state. The possibility of
ation of the patient included hypertension, which had pre-
an autoimmune process behind the symptoms was consid-
viously been managed with amlodipine, and depression,
ered, and the patient was prescribed the corticosteroid sol-
which had been managed with inpatient psychiatric hospi-
umedrol for immunosuppression.
talization. The patient denied having a prior history of
Superwarfarin toxicity was also considered. Superwar-
bleeding into a joint or elongated bleeding after surgery or
farins are a class of rodenticides that include brodifacoum, bro-
tooth extraction. No recent history of snake bite or hyper-
madiolone, chlorophacinone, difenacoum, and difethiacone.1
thermia were reported. Other medications used by the patient
We contacted the national hotline of the American Associa-
in her previous hospitalizations included sucralfate (1 g orally
tion of Poison Control Centers (AAPCC), to learn what sero-
before meals and at bedtime) and lansoprazole (30 mg orally
logic tests are available for ingestion of superwarfarins and
four times per day). The patient denied using over-the-counter
where these tests could be performed (Figure). Serologic tests
medications, alcohol, or recreational drugs. Ingestion of
for two of the more common superwarfarins—brodifacoum
Coumadin (Bristol-Myers Squibb Co; Princeton, NJ) (war-
and difenacoum—were referred out to a recommended lab-
farin sodium) or derivatives was also adamantly denied—a
oratory. Laboratory evaluation for these substances is per-
denial that was supported by negative test results for
formed using reversed-phase high-performance liquid chro-
Coumadin upon admission to our hospital.
matography (HPLC) or radioimmunoassay/enzyme-linked
After this information was obtained in the patient’s ini-
immunosorbent assay (RIA/ELISA). The patient’s brodifa-
tial evaluation, a psychiatric consultation was obtained. The
coum level by HPLC was 37 ng/mL—a positive result indi-
consultation revealed that the patient’s depression had been
cating poisoning.
managed with several different regimens in the past. Con-
Within 24 hours of contacting the AAPCC hotline, empiric
cerning her past inpatient psychiatric hospitalization, the
treatment with oral vitamin K (100 mg daily) was initiated.
patient remarked, “I was either crazy or my husband was poi-
Laboratory tests performed within 24 hours of the initial
Dolin et al • Case Report
JAOA • Vol 106 • No 5 • May 2006 • 281

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CASE REPORT
normalize on the patient’s sixth day of hospitalization. The
patient’s serum albumin level was normal, at 4.5 g/dL. Test
Laboratories Performing Tests for Superwarfarin Toxicity*
results for hepatitis A, B, and C were negative.
Computed tomography scans of the patient’s abdomen
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Evaluation for autoimmune disease in the patient revealed
a positive result in the test for antinuclear antibody, with a
nucleolar pattern suggestive of autoimmune disease seen at
* Source: American Association of Poison Control Centers (AAPCC),
titers of 1:640 (negative result, 1:40). Test results were neg-
http://www.aapcc.org/. For more information on poisoning emergencies,
call the AAPCC hotline: (800) 222-1222.
ative for rheumatoid arthritis factor, extractable nuclear anti-
gens, and antibodies for Sjögren syndrome A and B. The
Russell Viper Venom Test, a test for lupus anticoagulant,
Figure. Laboratories performing serologic tests for superwarfarin tox-
revealed an elevated clotting time of 44.4 seconds (reference
icity, as noted by the American Association of Poison Control
range, 0–42.8 s), with a normal viper venom ratio and detec-
Centers.
tion of a factor VII inhibitor. Other study results for lupus anti-
coagulant are reported in Table 2.
When all laboratory results were reviewed as a whole, ele-
vitamin K dose revealed corrected PT (16.3 s), PTT (29.0 s), and
vation of cardiolipin immunoglobulin A and immunoglob-
INR (1.3). All fresh frozen plasma support was discontinued
ulin M antibodies (Table 2) were interpreted as being part of
at this point. The patient was discharged after 5 days of the
a reactive process. The test result for serum protein elec-
100 mg vitamin K regimen.
trophoresis was negative, as was the urine drug screen. A
peripheral blood smear revealed microcytic normochromic
Diagnostic Findings
anemia.
Treatment of the patient with fresh frozen plasma decreased
clinical bleeding and improved INR, consistent with a
Comment
decreased level of coagulation factor production. The patient’s
The patient in the present case report had a clinical history and
PT became repeatedly elevated in 24-hour intervals after
symptoms consistent with Coumadin overdose. The persis-
transfusions of fresh frozen plasma were discontinued. Sub-
tence and reoccurrence of a coagulopathy related to vitamin
sequent attempts to identify coagulation factor deficiencies
K deficiency, however, led to the suspicion of superwarfarin
revealed inconsistent results. Because both PT and PTT were
intoxication. Upon review of the literature,1,4–9 it became
elevated, the activity level of factor V (proaccelerin) was eval-
apparent that coagulation parameters resulting from
uated. The level of factor V activity was found to be 90%
coumadin overdose are distinguishable from those resulting
(reference range, 50%–150%). The level of factor VIII (anti-
from superwarfarin intoxication. The brodifacoum level
hemophilic factor) activity was 168% (50%–150%).
(37 ng/mL) revealed by the evaluation of the patient’s serum
Initial evaluation of the level of factor VII (proconvertin)
with HPLC clearly indicated superwarfarin poisoning.
activity indicated 7%, but there was reversal of this level
We presumed that the patient had no exposure to brod-
with further dilution, suggesting the presence of an inhibitor.
ifacoum since her initial hospitalization at our tertiary care
The Bethesda unit measurement of the inhibitor was
center. Therefore, at the time of discharge from our center, she
extremely low (0.2 U/mL). (One Bethesda unit is the amount
was nearing completion of at least 3 weeks of half-life with-
of inhibitor that inactivates 50% [0.5 unit] of a coagulation
drawal from the vitamin K deficiency that was induced by
factor during a given incubation period.) We believed that this
brodificoum. Twenty-four hours after receiving her first dose
degree of inhibitor activity was not sufficient to explain the
of 100 mg oral vitamin K, tests showed complete normal-
severe coagulopathy that was present in the patient. If a non-
ization of her INR (1.3). Oral vitamin K therapy was admin-
specific inhibitor was present, it would be expected to affect
istered without complications for the next 5 days, during
factor VIII as well.2
which evidence of cutaneous hemorrhages and ecchymoses
The patient’s renal function was normal. However, liver
were resolved.
function studies revealed mild aminotransferase elevation,
The patient was discharged from our hospital with pre-
with an aspartate aminotransferase level of 88 U/L and an ala-
scriptions for a tapering dose of vitamin K over a period of 4
nine aminotransferase level of 92 IU/L. These levels began to
weeks (100 mg for 14 days, 10 mg for 7 days, and 5 mg for 7
282 • JAOA • Vol 106 • No 5 • May 2006
Dolin et al • Case Report

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CASE REPORT
days) and weekly INR measurements. If these follow-up mea-
ring in patients younger than 6 years. All of the superwar-
surements were to detect marked elevation of the INR, the pre-
farins work by inhibiting the generation of the activated form
vious dosing level would be maintained for an additional 2
of vitamin K1 via inhibition of vitamin K1 reductases.4 Acti-
weeks; then, another attempt at tapering would be made.
vation of the coagulation factors II, VII, IX, and X require the
At outpatient follow-up 2 weeks after discharge, the
presence of vitamin K as a cofactor. When vitamin K cannot
patient’s coagulation parameters remained within normal
be regenerated, the coagulation factors cannot be activated,
or near-normal ranges (PT, 14.1 s; PTT, 33.0 s; INR 1.48), with
and a coagulopathy results involving both the extrinsic and
a normal platelet count of 349,000/µL. By 2 months after
intrinsic coagulation pathways.5
discharge, the patient had missed her serial INR measure-
Superwarfarins have a half-life of approximately 6 to 8
ments on multiple occasions. Laboratory evaluations at that
weeks.6 Of the vitamin K–dependent factors, factor VII has the
time showed elevated coagulation parameters (PT, 31.8 s;
shortest half-life, at 5 hours.6 Therefore, factor VII levels are
PTT, 57.0 s; INR 3.22). The primary care physician reported
used to monitor synthesis of vitamin K–dependent coagula-
that the patient admitted to noncompliance with her oral
tion factors.7 Patients are able to tolerate a reduction in coag-
vitamin K regimen.
ulation factor synthesis of as much as 70% before manifesting
coagulation disorders.7
Pathologic Considerations
Chronic exposures and overdoses of superwarfarins may
According to the AAPCC,3 exposures to superwarfarins in
result in bleeding from any organ system. However, more
2004 numbered 16,054, with 14,229 of these poisonings occur-
than one system is usually involved. Other possible results of
chronic exposure include ecchymoses, epis-
taxis, friable gums, hematemesis, hematuria,
Table 2
hemoptysis, melena, petechiae, and vaginal
Lupus Anticoagulant Study Results of Patient*
bleeding.8 Measurements of specific coagula-
tion factors support the diagnosis of super-
Factor Tested
Test Result
Reference Range
warfarin toxicity if all vitamin K–dependent
factors (II, VII, IX, and X) are decreased while
PTT Studies
others remain normal in the absence of
▫ Heparin adsorption, U/mL
45.8
20.9–37.4
Coumadin therapy, liver disease, or the use
▫ aPTT (heparin adsorption), s
51.7
43.0
of an inhibitor.4 In addition to using HPLC
▫ aPTT (patient), s
48.5
20.9–37.4
and RIA/ELISA to make diagnoses of toxi-
▫ PTT (lupus), s
55.5
43.0
city, the vitamin K1(2,3-epoxide):K1 ratio can be
used, with a ratio of 2:3 (normal, 0.1:0.2) indi-
Mixing Studies, s
cating ingestion of superwarfarins.9
▫ PTT (1:1 NP) mix
35.5
25–35
There is no specific therapeutic regimen
▫ PTT (1:1 NP) RT
32.0
25–35
for patients diagnosed with superwarfarin
Cardiolipin Antibody Studies
poisoning other than restoration of normal PT
▫ Cardiolipin IgA, APL U/mL
18.0
0–12
and coagulation factor levels. In patients with
▫ Cardiolipin IgG, GPL U/mL
5.2
0–15
active bleeding, treatment involves adminis-
▫ Cardiolipin IgM, MPL U/mL
19.0
0–12.5
tering fresh frozen plasma and/or coagula-
tion factor concentrates, in addition to packed
Other Studies
red blood cells and oral vitamin K.5 In patients
▫ Antidouble-stranded
who no longer demonstrate active bleeding
DNA antibody, IU/mL
83
0–200
or life-threatening hemorrhage but continue to
▫ Fluorescent treponemal
antibody
Nonreactive
...
have prolongation of PT, supratherapeutic
▫ Complement activity CH50, U/mL
442
400–700
doses of oral vitamin K ( 100 mg daily) have
been demonstrated to normalize PT.5 Moni-
▫ Complement protein C3, mg/dL
134
73–183
toring of broudifacoum concentrations are
▫ Complement protein C4, mg/dL
17
15–59
useful for predicting when to terminate
therapy.7
* APL indicates immunoglobulin A phospholipid level; aPTT, activated partial thromboplastin
time; C, complement; CH, hemolytic complement; GPL, immunoglobulin G phospholipid level;
IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IU, international
Conclusion
units; MPL, immunoglobulin M phospholipid level; NP, normal plasma; PTT, partial
Of the 16,054 reported cases of superwarfarin
thromboplastin time; and RT, reptilase time.
exposure in 2004, 15,339 exposures were unin-
tentional, according to the AAPCC.3 Patients
Dolin et al • Case Report
JAOA • Vol 106 • No 5 • May 2006 • 283

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CASE REPORT
with unexplained anticoagulation and evidence of abnormal
4. Chua JD, Friedenberg WR. Superwarfarin poisoning. Arch Intern Med.
bleeding should be evaluated using both an individual his-
1998;158:1929–1932.
tory and a physical examination focusing on the considera-
5. Burkhart KK. Anticoagulant rodenticides. In: Ford MD, ed. Clinical Toxi-
tion of possible superwarfarin exposure. Prolongation of
cology. 1st ed. Philadelphia, Pa: WB Saunders; 2000:848–853.
both the PT and PTT with requirement for continual coagu-
6. Weitzel JN, Sadowski JA, Furie BC, Moroose R, Kim H, Mount ME, et al. Sur-
lation factor replacement—despite treatment with fresh frozen
reptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brod-
plasma—is also a clue to possible superwarfarin exposure.
ifacoum: clinical and metabolic studies of three cases. Blood.
1990;76:2555–2559. Available at: http://www.bloodjournal.org/cgi/reprint/
Reference laboratories are available to perform diagnostic
76/12/2555. Accessed April 5, 2006.
tests for superwarfarin toxicity.
7. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anti-
coagulant overdose: brodifacoum kinetics and optimal vitamin K dosing.
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Available at: http://www.aapcc.org/2004.htm. Accessed April 5, 2006.
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