Written in Blood
A Closer Look at CancerAssociated Venous Limb Gangrene
Warfarin-induced venous limb
gangrene (VLG) in patients with
cancer with deep-vein thrombosis
(DVT) is an uncommon, poorly
understood complication of anticoagulant therapy. While warfarin
and other vitamin K antagonists
have been implicated in the development of VLG because they
impair synthesis of the vitamin
K-dependent coagulation factors
– the most common complication of which is bleeding – there
is limited information about the
clinical features and pathogenesis
of this syndrome.
In a recent study published in
Blood, Theodore E. Warkentin,
MD, BSc, from the Departments
of Pathology and Molecular
Medicine at McMaster University
in Hamilton, Ontario, and his colleagues evaluated 10 patients with
cancer-associated severe VLG to
better characterize the clinical
and laboratory picture of this rare
and unpredictable condition.
All of the patients had metastatic cancer and cancer-associated disseminated intravascular
coagulation (DIC) and were being
evaluated for suspected heparininduced thrombocytopenia
(HIT). In eight patients, the diagnosis of cancer was not known or
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suspected at initial DVT presentation. The researchers hypothesized that warfarin-induced VLG
would be associated with marked
thrombin generation (determined
by elevated thrombin-antithrombin (TAT) complexes) together
with severe deficiency of the
natural anticoagulant protein C.
“The patients with VLG in this
study exhibited a novel, clinically
and platelet fall (median = 69%)
after stopping heparin.”
They also found that VLG
occurred in the same limb with
recent or concurrent symptomatic
DVT. When both lower limbs
had DVT, the limb with the most
recent DVT, or the one with the
greatest burden of thrombosis,
was the one that developed VLG.
Despite an elevated INR,
thrombin generation persisted,
indicated severe protein C depletion. “This clinical picture thus
strongly resembles that of hepa-
"This clinical picture strongly
resembles that of heparininduced thrombocytopenia–associated venous limb
gangrene associated with
warfarin therapy."
—THEODORE E. WARKENTIN, MD, BSc
distinct syndrome,” the authors
noted, including “warfarin-associated supratherapeutic international normalized ratio (INR;
median = 6.5) at onset of limb
ischemia, rising platelet count
during heparin anticoagulation,
rin-induced thrombocytopenia–
associated VLG associated with
warfarin therapy,” Dr. Warkentin
and authors explained. “Those
patients also develop venous limb
ischemic necrosis after stopping
heparin and during warfarin
therapy associated with a supratherapeutic INR, and those patients
also develop acral limb ischemic
necrosis in the same limb with a
recent DVT.”
There is one key difference
between patients in the present
study and those with HIT-associated VLG,: Blood samples from
HIT patients contain heparindependent platelet-activating
antibodies, whereas the patients
with warfarin-associated VLG
had negative testing for HIT
antibodies. This indicates that the
hypercoagulable state in HIT is
the result of procoagulant effects
of HIT antibodies, rather than the
pathobiologic consequences of
cancer.
Ultimately, for a patient with
warfarin failure with evidence for
DIC, vitamin K antagonist therapy should not be re-administered
due to the risk of limb loss.
“The hypercoagulable state of
malignancy has been documented
for more than a century, yet it
seems we continue to find new
manifestations,” wrote Alok A.
Khorana, MD, from Cleveland
Clinic, in an editorial accompanying the paper by Dr. Warkentin
and colleagues. “Regardless of
whether this is truly a clinically
distinct syndrome or not, the
lethal complication of warfarinassociated venous gangrene is
a grave complication of which
clinicians should be aware.”
While Dr. Khorana listed the
“exhaustive chart review” and
“comprehensive” hemostatic
testing as strengths of the current
report, he did note some weaknesses with how the 10 patients
were selected: “If only those
patients who are being worked up
for HIT (the entry point for study
inclusion) are sought out, then
necessarily the ‘syndrome’ will include only those patients with an
‘HIT-like’ presentation. This process would exclude patients, for
instance, with venous gangrene
but without thrombocytopenia.”
Also, because Dr. Warkentin et al.
included only patients with malignancy, he added, “it is unclear
whether a similar picture exists in
patients without malignancy.”
REFERENCES
• Warkentin TE, Cook RJ, Sarode R, et al. Warfarininduced venous limb ischemia/gangrene complicating
cancer: a novel and clinically distinct syndrome.
Blood. 2015;126:486-93.
• Khorana AA. The wacky hypercoagulable state of
malignancy. Blood. 2015;126:430-1.
September 2015