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Massive warfarin overdose management in an adolescent patient

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 Clinical Toxicology

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Massive warfarin overdose management in an

adolescent patient

Andrea Setiawan, Varun Vohra & Emily Jaynes Winograd

To cite this article: Andrea Setiawan, Varun Vohra & Emily Jaynes Winograd (2022):
Massive warfarin overdose management in an adolescent patient, Clinical Toxicology, DOI:
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CLINICAL TOXICOLOGY
https://doi.org/10.1080/15563650.2022.2116337

TEACHING CASE

Massive warfarin overdose management in an adolescent patient

Andrea Setiawana, Varun Vohrab,c and Emily Jaynes Winograda
a
Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA; bMichigan Poison & Drug Information Center, Detroit, MI, USA;
c
Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, USA

ABSTRACT ARTICLE HISTORY

Introduction: Warfarin is a widely used oral anticoagulant with established reversal guidelines in the Received 5 May 2022
setting of a supratherapeutic international normalized ratio (INR). Limited literature exists on managing Revised 16 August 2022
acute warfarin overdoses in patients who are not chronically anticoagulated. Accepted 18 August 2022
Case: A 15-year-old male, with no indication for anticoagulation, presented to a pediatric emergency
KEYWORDS
department after an acute 1,000 mg warfarin ingestion. He had no significant complaints upon presen- Warfarin; acute overdose;
tation aside from a mild intermittent headache. His past medical history was significant for anxiety, vitamin K;
depression, Tourette syndrome, attention deficit hyperactivity disorder, and polysubstance misuse. pediatrics; reversal
Computed tomography of his head was unremarkable and serum acetaminophen, salicylate, and etha-
nol concentrations were negative. Approximately 16 h post-ingestion, his INR was 1.9 with an increase
to 3.3 by 26 h. The regional poison center was consulted and recommended, consistent with the
CHEST guidelines, holding treatment with vitamin K until INR was >10 or if signs or symptoms of
bleeding occurred. The patient was admitted for monitoring and by hospital day (HD) #4, his INR had
risen to >11.8 at which point oral vitamin K 10 mg was administered. On HD #7, the patient was
deemed stable for transfer to inpatient psychiatry after repeat INRs of 2.9 and 3.4.
Discussion: Case reports have demonstrated early administration of vitamin K can temporarily lower
INR and prevent detection of rebound. The CHEST warfarin reversal guidelines describe the risks and
benefits with respect to bleeding and thrombosis in the non-intentional overdose patient. Application
and extrapolation of these guidelines to acute overdose in patients who lack an indication for anticoa-
gulation may or may not be warranted.
Conclusion: While established clinical guidance exists on reversing a supratherapeutic INR in patients
chronically anticoagulated with warfarin, the risks and benefits of extrapolating this approach are
unclear in those who lack an indication for anticoagulation.

Introduction majority of which occurred in adults (622 cases). In pediat-

Warfarin is a widely used oral anticoagulant indicated for the
treatment and prevention of thromboembolic disease. It
functions as a vitamin K antagonist, preventing activation of
vitamin K-dependent clotting factors. It exhibits wide interpa-
tient variability combined with a narrow therapeutic index
(NTI). Bleeding is the major adverse effect of warfarin with
greater risk associated with higher international normalized
ratio (INR), particularly when >4.5 [1]. Consequently, warfar-
in’s NTI and potential for severe toxicity requires frequent
INR monitoring and close patient follow-up.
While venous thromboembolism incidence rates range
from 10 to 1,200 per 100,000 adults 30 years and older, it is
comparatively rare in pediatric patients with an incidence of
0.7 to 4.9 per 100,000 children [2]. As a result, use of anticoa-
gulants in pediatrics is limited. A study evaluating anticoagu-
lant use in children found warfarin was only used in 3–4% of
pediatric patients with an indication for anticoagulation [3].
According to the 2020 Annual Report of the American
Association of Poison Control Centers’ National Poison Data
System, there were 799 single exposure warfarin cases, the
rics, warfarin exposures were more common in children
5 years and represented 87 of 119 cases in patients
<20 years old. The majority of all reported warfarin expo-
sures were classified as unintentional [4].
Acute warfarin toxicity and treatment present a clinical
challenge due to warfarin’s unique pharmacokinetics.
Warfarin is rapidly absorbed from the gastrointestinal tract
with a long half-life (36 to 42 h), resulting in a duration of
action of approximately five days. INR changes secondary to
warfarin are predicated upon the half-life differences of six
vitamin K-dependent clotting factors (II, VII, IX, X, and
Proteins C and S), with factor VII having the shortest half-life.
Therefore, although increases in INR may be apparent within
18–24 h due to reduced factor VII production, there is signifi-
cant variation and a maximal increase may not occur for two
to three days due to the longer half-lives of the other factors
[1]. As such, vitamin K1 (phytonadione) is a first-line warfarin
reversal agent for patients with a supratherapeutic INR with
or without signs and symptoms of bleeding.
While established guidelines address supratherapeutic INR
management in the setting of chronic warfarin use,

CONTACT Emily Jaynes Winograd ejaynes@med.umich.edu Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA
ß 2022 Informa UK Limited, trading as Taylor & Francis Group
2 A. SETIAWAN ET AL.
treatment of acute overdose in warfarin-naïve patients is not
well described. Further, treatment approaches following
acute massive warfarin ingestions are even less well charac-
terized, presenting a potential clinical quandary. We present
a rare case of an intentional massive warfarin overdose in
an adolescent.
Case presentation
A 15-year-old male (64.9 kg), with no history of chronic anti-
coagulation, presented to an emergency department (ED)
after an intentional massive warfarin overdose. His past med-
ical history was significant for anxiety, depression, Tourette
syndrome, attention deficit hyperactivity disorder, and poly-
substance use. On presentation, patient was afebrile with an
oral temperature of 36.7  C, heart rate of 92 beats per
minute, blood pressure of 161/86 mm Hg, and respiratory
rate of 24 breaths per minute. Physical exam was otherwise
unremarkable aside from facial tics consistent with patient’s
Tourette syndrome. He was noted to be in no apparent dis-
tress and conversational. The patient ingested his grandfa-
ther’s warfarin in a suicide attempt, reportedly ingesting 180
warfarin 5 mg tablets and 100 warfarin 1 mg tablets over the
course of five hours for a cumulative 1,000 mg dose (Table 1).
The regional poison center was consulted and recommended
administering activated charcoal, trending INR levels every
12 h, avoiding empiric administration of vitamin K, and
obtaining routine toxicology labs and diagnostics (e.g. com-
plete metabolic panel, acetaminophen, salicylate, and etha-
nol levels, urine drug screen, and electrocardiogram).
Approximately three hours post-ingestion, his initial INR was
1.1 and he was given a dose of activated charcoal. Due to
complaints of a mild headache, computed tomography (CT)
of the head was performed along with additional laborato-
ries, including acetaminophen, salicylate, and ethanol levels
and a urine drug screen, all of which were negative.
Approximately 16 h post-ingestion, the patient’s INR was 1.9.
He was subsequently transferred to a pediatric ED for fur-
ther evaluation and management.
Upon arrival to the pediatric ED, his repeat INR was 3.3
and a comprehensive blood count and coagulation panel
were ordered every 12 h, based on initial poison center rec-
ommendations. Additionally, the poison center recom-
mended, in accordance with the CHEST guidelines, holding
vitamin K for reversal until INR was >10 or the patient
became symptomatic. In the case of an acute bleed, man-
agement options included intravenous (IV) vitamin K along
with prothrombin complex concentrate, fresh frozen plasma
(FFP), or factor VIIa. The patient was admitted to a general
care floor for further observation and psychiatric evaluation.
His INR trended upward to 8.5 approximately 51 h post-
ingestion, prompting a repeat consult with the poison cen-
ter, which recommended continuing to hold vitamin K unless
bleeding developed or INR exceeded 10 (Figure 1).
The following morning on hospital day (HD) #4, the
patient’s INR was >11.8 (maximum measurable value at insti-
tution), therefore 10 mg oral vitamin K was administered. A
subsequent downtrend in INR to 2.9 occurred 22 h post-
vitamin K administration but was followed by an increase to
3.4 approximately 48 h after vitamin K dose. By HD #7, the
patient was deemed stable for transfer to inpatient psych-
iatry since he did not require additional doses of oral vitamin
K 48 h post-initial administration and demonstrated no signs
or symptoms of bleeding despite an up-trending INR. A
repeat INR was checked on HD #18 and found to be normal
at 1.0.
Discussion
Acute warfarin ingestions in warfarin-naïve patients are infre-
quently reported in the literature, with acute massive over-
doses even less well described. Despite established
guidelines providing clinicians with reversal strategies in the
setting of chronic warfarin use, management of acute over-
doses in patients not chronically anticoagulated presents a
clinical dilemma, namely whether to administer vitamin K as
soon as possible post-ingestion to prevent INR elevation and
a potential bleeding event, or to hold vitamin K until a cer-
tain INR or symptom threshold is reached. Our case involved
a large acute warfarin overdose in a pediatric patient with
no indication for anticoagulation who received vitamin K
once the INR exceeded 10. It is unknowable if treatment
with vitamin K prevented an adverse bleeding event, or if
earlier “prophylactic” administration of vitamin K would have
prevented INR elevation.
Case reports have cautioned that early administration of
vitamin K may generate false reassurance among clinicians
by normalizing the INR, thereby precluding the subjective
need for prolonged INR monitoring. Consequently, clinicians
may not detect a rebound increase in INR caused by inher-
ent pharmacokinetic differences between vitamin K and war-
farin [5–10]. In an acute overdose in patients not chronically
anticoagulated, some authors recommend administering vita-
min K for minimal INR elevations to mitigate bleeding risk
[11]. However, if vitamin K is administered within 48 h post-
ingestion, patient monitoring for at least 5 days post-vitamin
K administration is prudent due to the long duration of
effect of warfarin [12,13]. While these recommendations are
predicated upon warfarin’s pharmacokinetic profile, appropri-
ate management also depends on the amount of warfarin
ingested as well as co-ingestions and/or chronic concomitant
medications affecting warfarin’s absorption and metabolism,
such as antifungals, antibiotics, anticonvulsants, and
antiarrhythmics.
Acute bleeding events are the primary concern of a
rebound increase in INR due to inadequate monitoring.
Previous case reports describe rebound INRs following war-
farin overdoses (range, 50 mg to 260 mg) when oral or paren-
teral vitamin K administration occurred within 48 h post-
ingestion [5–10]. A 50-year-old male, on warfarin for history
of a massive pulmonary embolism, presented after an acute
ingestion of an unknown amount of warfarin, received IV
vitamin K 6 mg and was discharged at 40 h post-ingestion.
He was readmitted the following day at 69 h post-ingestion
with epistaxis and an increase in INR to 7.8 requiring add-
itional doses of IV vitamin K over the next 48 h [5]. Montanio
 CLINICAL TOXICOLOGY 3

Table 1. Patient hospitalization course.

Hospital Day Event Summary
1 Reported warfarin 1,000 mg ingestion
Initial INRa 1.1 three hours post-ingestion
Received 50 g activated charcoal x 1 dose
Labs and imaging unremarkable
2 Transferred to pediatric emergency department
Consulted regional poison center
Repeat INR 3.3 at 24 h post-ingestion
Admitted to general medicine floor
3 INR checked every 12 h and increased to 6.4 and 8.5 at 41- and 51-hours post-ingestion, respectively
Repeat consult with poison center
4 INR >11.8 approximately 63 h post-ingestion
Oral vitamin K 10 mg administered 65 h post-ingestion
Subsequent INR 4.3, 75 h post-ingestion
5 INR decreased to 2.9 and 3.0 at 24- and 36-hours post-vitamin K administration, respectively
6 INR increase to 3.4, 48 h post-vitamin K administration
7 Transferred to inpatient psychiatry
18 INR 1.0 upon re-testing 14 days post-vitamin K administration
a
INR: International normalized ratio.

Figure 1. INR trend post-warfarin overdose.

et al. described a 20-month-old male who ingested 50 mg of
warfarin and was managed with activated charcoal plus
intramuscular (IM) vitamin K. Although the patient did not
have any signs or symptoms of bleeding, his prothrombin
time was elevated three days post-ingestion and he was initi-
ated on a three-day course of IM vitamin K [6]. Similarly,
Ramanan et al. reported a 15-year-old male with an ingestion
of 350 mg warfarin plus 300 mg allopurinol and an initial INR
of 1.1; IV vitamin K was empirically administered. By HD #3,
no bleeding symptoms were noted but his INR increased to
5.0 and he was given FFP. Due to the allopurinol-warfarin
drug interaction, he continued to have INR fluctuations
and required an additional dose of FFP and IV vitamin K
before levels normalized by HD #5 [7]. These cases
highlight the importance of subsequent monitoring following
vitamin K administration given warfarin’s pharmacokinetics
and potential for INR rebound despite improvement with
initial management.
Withholding vitamin K does not ensure a shorter monitor-
ing period, however. Watson and colleagues described a
15-year-old female who ingested 100–200 mg of warfarin.
Vitamin K was held until INR was >4.5 and dosed at 2.5 mg
orally 60 h post-ingestion. Her INR continued to trend up and
the patient was given a second dose of oral vitamin K
2.5 mg 85 h post-ingestion when her INR was 6.67. The
patient was not medically cleared until HD #8 once the INR
was <2.0 [11].
Our patient ingested 1,000 mg of warfarin, a dose mark-
edly higher than those described in previous case reports,
placing him at risk for ongoing anticoagulation and a poten-
tially protracted course of vitamin K treatment. Oral vitamin
K was administered 65 h post-ingestion and the INR
decreased to 2.9 but was trending upwards (INR 3.4) at the
time of transfer to inpatient psychiatry suggesting a potential
rebound. The lack of regularly scheduled INR monitoring
between the observed rebound and subsequent INR check
12 days later (14 days post-vitamin K administration) pre-
cluded an accurate assessment of both the time course and
degree of INR rebound. This highlights a limitation of this
report since an accurate timeline of the effects of vitamin K
on warfarin kinetics could not be inferred. Further, this case
highlights the need for frequent INR monitoring post-vitamin
4 A. SETIAWAN ET AL.
K administration to assess for a rebound effect, evaluate its
extent, and mitigate the potential for supratherapeutic INR-
associated bleeding events.
Vitamin K is a fat-soluble vitamin and cofactor for
gamma-glutamyl carboxylase, an enzyme essential for the
activation of clotting factors inhibited by warfarin [1]. There
are minimal adverse effects or toxicity risks associated with
oral vitamin K [14]. While anaphylactoid type reactions have
occurred after vitamin K administration, it is relatively
uncommon with an incidence of 3 per 10,000 doses and
more likely following IV administration [15]. The exact mech-
anism is unclear, but increased risk is associated with higher
doses or administration as a rapid, undiluted IV bolus [15].
Despite these concerns, the benefits of vitamin K to reverse
anticoagulation outweigh the risks, particularly in the setting
of an acute overdose where precipitating a thrombotic event
with liberal vitamin K use is not a concern.
This case highlights the significance of verifying an exist-
ing indication for anticoagulation to guide clinical patient
management in an acute overdose setting. The CHEST 2012
guidelines provide management recommendations on supra-
therapeutic INR due to warfarin therapy. Vitamin K is only
recommended if INR is >10 or if there are signs and symp-
toms of bleeding [16]. Low doses of vitamin K are recom-
mended in patients with an indication for anticoagulation
due to consideration of thrombosis versus bleed risk.
Excessive vitamin K in these patients results in prolonged
resistance to reestablishing therapeutic anticoagulation once
warfarin is reintroduced, increasing the risk of precipitating a
thrombotic event. Extrapolation of traditional reversal guide-
lines may or may not be warranted in patients, like ours,
who lack an indication for anticoagulation and have no signs
or symptoms of bleeding following acute warfarin overdose.
Conclusion
Acute warfarin overdoses in warfarin-naïve patients are
uncommon. Available guidelines focus on managing patients
with acute-on-chronic warfarin toxicity with elevated INR
and/or bleeding during warfarin therapy, however it remains
unclear whether these recommendations are suitable for
those without an indication for anticoagulation. While some
providers advocate for early vitamin K administration to pre-
vent coagulopathy in patients with no indication for anticoa-
gulation, our patient responded well with INR reduction after
a single dose of oral vitamin K when INR exceeded 10.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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tured in this article.
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