CLINICAL NEWS
Literature Scan
New and noteworthy research from the
medical literature landscape
A New Source of “Superwarfarin” Poisoning:
Increased Bleeding Risk After Synthetic
Cannabinoid Use
In the New England Journal
of Medicine (NEJM), authors
reported a case series of patients
with synthetic cannabinoid–
associated coagulopathy, iden-
tifying contamination with
brodifacoum, or “superwarfarin”
(a potent vitamin K antagonist
routinely used as a rodenticide), as
the culprit of increased bleeding
risk in these patients. Synthetic
cannabinoids are sold under
names such as “K2” and “spice”;
public officials note that brodifa-
coum is sometimes added because
of a perception that it prolongs
a cannabinoid-induced “high.”
The use of vitamin K 1 replace-
ment therapy could be an effective
option for symptom control in
this population, according to the
findings.
Synthetic cannabinoid–
associated coagulopathy is a
growing clinical concern, as
Thomas G. DeLoughery, MD,
and Joseph Shatzel, MD, from
the Oregon Health and Science
University Knight Cancer Institute,
wrote in a guest commentary for
ASH Clinical News.
“Over the past decade, the
use of synthetic cannabinoids/
marijuana has increased. … The
appeal of such products is that
they are inexpensive, available in
states without legalized marijuana,
and undetectable in urine drug
screens,” they wrote. “However, the
risk to users can be substantial be-
cause synthetic marijuana does not
routinely undergo any regulatory
quality control, chemical content
evaluation, or inspection.”
The first cases of synthetic
cannabinoid–associated coagu-
lopathy were observed in Illinois,
where, in March and April 2018,
more than 150 patients presented
to hospitals with coagulopathy and
bleeding diathesis.” In the NEJM
case study, Amar Kelkar, MD,
from the University of Illinois
College of Medicine at Peoria,
reviewed data from 34 patients
(median age = 37 years; range =
ASHClinicalNews.org
27-46 years) who presented with
suspected synthetic cannabinoid–
associated coagulopathy at Saint
Francis Medical Center, a tertiary
care hospital in Peoria, between
March 28 and April 21, 2018.
Study inclusion criteria were as
follows:
• presence of vitamin K–
dependent factor coagulopathy
(i.e., a prothrombin time
of ≥14.8 seconds plus an
international normalized ratio
[INR] of ≥1.3)
• exposure to synthetic cannabi-
noids in the previous 30 days
• active bleeding symptoms
• exposure to contaminated
synthetic cannabinoids
obtained from a person
with known superwarfarin
poisoning
Positivity for superwarfarin was
confirmed on an anticoagulant
poisoning panel, and researchers
also collected anonymized epide-
miologic, historic, diagnostic, and
treatment data for all patients.
The frequency of exposure to
synthetic cannabinoids varied great-
ly: Almost half of patients (47%)
reported daily use of synthetic
cannabinoids, while 12 percent of
patients reported first-time use.
At time of presentation, the
most common bleeding and
nonbleeding symptoms were gross
hematuria (56%) and abdominal
pain (47%), respectively. The
average INR was 15.8, and 33
patients (73%) had blood pressure
readings of >130/80 mm Hg at
presentation.
During hospitalization, 13 pa-
tients were found to have anemia
(defined as hemoglobin level of
<13 g/dL in men and <12 g/dL
in women). Five patients (15%)
received red-cell transfusion,
either for active blood loss or for a
hemoglobin level <7 g/dL.
Urinalysis results during
a total of 42 hospitalizations
showed that many patients tested
positive for hematuria (n=35) and
proteinuria (n=24). “Studies in rat
models have shown that a bimodal
pattern of hematuria – with early
dosedependent transient hemo-
globinuria and late recurrence of
hematuria days after exposure – is
a unique biomarker for brodifa-
coum poisoning,” the researchers
explained. “The suspected cause
of hematuria is increased capillary
permeability.”
Management varied according
to clinical presentation, the authors
noted, but was guided by recom-
mendations from the Illinois Poison
Center, guidelines for anticoagulant
reversal, and previous case reports.
The most common treatment ap-
proaches were as follows:
• oral vitamin K 1 therapy, or
phytonadione (n=34; 100%)
• intravenous vitamin K 1 (n=23;
68%)
• fresh-frozen plasma infusion
(n=19; 56%, median of 3 units)
• four-factor prothrombin com-
plex concentrate, comprising
human coagulation factors II,
VII, IX, and X (n=1; 3%)
To improve compliance and poten-
tial outcomes, clinicians provided
patients with discharge patient
education, interfaced with local
pharmacies and insurance compa-
nies regarding the high prices of oral
vitamin K 1 therapy, and “arranged
for delivery of oral vitamin K 1 to
counter local shortages.”
Six patients were readmitted to
the hospital during the study period
– all of whom were discharged
against medical advice or were un-
able to fill their vitamin K 1 prescrip-
tion. In this subgroup of patients,
clinicians noted recurrent use of the
same synthetic cannabinoid batch
in two patients, whereas one patient
was readmitted due to prolonged
bleeding after attempting to donate
plasma. Each patient was treated to
stop bleeding, except for one patient
who died following readmission.
The patient who died was a
37-year-old woman without a known
medical history who presented to
the emergency department with
a reduced level of consciousness.
She had recent use of synthetic
cannabinoids and amphetamines
but no history of prescribed anti-
coagulation. During admission,
her laboratory testing revealed a
prothrombin time >150 seconds,
an INR >20, and a hemoglobin
level of 14 g/dL. Despite treatment
with intravenous vitamin K 1 10 g,
four units of fresh-frozen plasma,
and 2,300 units of coagulation
factors, she died 15 hours after
presentation.
“Our data indicate that super-
warfarin adulterants of synthetic
cannabinoids can lead to clinically
significant coagulopathy,” the au-
thors concluded. While symptoms
were controlled with the use of vita-
min K 1 replacement therapy, there
are numerous barriers that preclude
access to long-term treatment.
These include the lack of consensus
guidelines about the management
of synthetic cannabinoid–associated
coagulopathy and limited access to
primary care after hospitalization.
Cost also is a concern: “The cost
and availability of longterm oral
vitamin K 1 therapy, quoted to some
of our patients as $24,000 to $34,000
per month, makes management dif-
ficult and underscores the value of
confirmatory laboratory superwar-
farin testing,” they wrote.
Limitations of this analysis in-
cluded the small number of patients,
the limited follow-up, the retrospec-
tive nature of data analysis, and its
single-center design.
The authors report no conflicts of
interest.
REFERENCE
Kelkar AH, Smith NA, Martial A, et al. An outbreak of
synthetic cannabinoid-associated coagulopathy in Illinois.
N Engl J Med. 2018;379:1216-23.
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