Neurocritical Care
Copyright © 2006 Humana Press Inc.
All rights of any nature whatsoever are reserved.
ISSN 1541-6933/06/5:210–212 ISSN 1556-0961 (Online)
DOI: 10.1385/Neurocrit. Care 2006;05:210–212

Practical
Pearl
Practical Pearl
Multiple Hemorrhagic Strokes From DIC Associated With Occult
Large Cell Carcinoma
Matthew A. Koenig,1,* Joseph Maleszewski,2 and Brad Winters3
1

Division of Neurosciences Critical Care, 2Department of Pathology, and 3Department of Anesthesia and Critical
Care Medicine, Johns Hopkins Hospital, Baltimore, MD

Abstract:
Background and Purpose: Multiple hemorrhagic strokes are a rare presentation of
paraneoplastic disseminated intravascular coagulation (DIC). We present a case of DIC
occurring in a patient with occult large cell carcinoma.
Summary of Case: A 77-year old Asian-American man presented with 1 month of vision
disturbance followed by acute onset of left hemiparesis and encephalopathy. He was
found to have three strokes of varying ages, and was placed on aspirin and clopidogrel.
He returned 4 days later with hemorrhagic conversion of the strokes and laboratory
abnormalities suggestive of DIC. Over the hospital course, he suffered recurrent ischemic
strokes and intracerebral hemorrhages despite management of his coagulopathy. On
autopsy, an occult large cell carcinoma was found in the hilar lymph nodes, as well as
multiple intravascular thrombi.
Conclusions: Recurrent hemorrhagic strokes associated with DIC may be the initial
presentation of occult malignancy. Although adenocarcinoma is classically associated with
paraneoplastic DIC, this case demonstrates that large cell carcinoma may also be
implicated.
Key Words: Disseminated intravascular coagulation; large cell carcinoma; ischemic stroke;
intracerebral hemorrhage; paraneoplastic.
(Neurocrit. Care 2006;05:210–212)
*Correspondence and reprint
requests to:
Matthew A. Koenig
Division of Neurosciences
Critical Care
600 N. Wolfe St.
Meyer 8-140
Baltimore, MD 21287.
E-mail:
mkoenin1@jhmi.edu

A 77-year old Asian-American man presented with acute onset of left hemiparesis
and confusion to a local emergency department. He had been involved in a motor
vehicle collision 1 month previously, and his
vision had been abnormal since that time.
Past medical history included hypertension,
hypercholesterolemia, and recent multistage
oral surgery. His medications were lisinopril
and simvastatin. He had a long history of
tobacco use. Review of systems included
easy bruising and recent unintentional weight
loss. Initial laboratory studies were normal,
including coagulation and hematology

210

profiles. Examination revealed mild left
hemiparesis and right homonymous hemianopsia. Magnetic resonance imaging (MRI)
of the brain showed subacute infarcts in the
left posterior cerebral artery (PCA) territory,
left subcortical frontoparietal region, and an
acute infarct in the right operculum. Transthoracic echocardiography (EKG) and intracranial and extracranial MR angiography
were normal. The patient was discharged on
clopidogrel and aspirin. He returned to the
emergency department 4 days later, after a
generalized seizure. Head computed tomography (CT) showed hemorrhagic conversion

Multiple Hemorrhagic Strokes From DIC

211

of the prior strokes (Figure 1). Laboratory evaluation revealed
an international normalized ratio (INR) of 1.9 and an elevated
D-dimer.
The patient was transferred to the Johns Hopkins Neurosciences Critical Care Unit for further evaluation. Admission
laboratory studies revealed an INR of 2.5, fibrinogen less than
50 mg/dL, D-dimer 3784 mg/L, lactate dehydrogenase 350
U/L, hemoglobin 7.7 g/dL, and the presence of schistocytes
on a peripheral blood smear. Von Willibrand factor (vWF)cleaving protease activity was normal and vWF-cleaving protease inhibitor was absent. Creatinine, platelet count, cardiac
enzymes, and EKG were normal. Anticardiolipin and circulating anticoagulant immunoglobulin titers were within normal
limits. The laboratory studies were interpreted as consistent
with disseminated intravascular coagulation (DIC). In consultation with the Hematology service, he was given vitamin K
and transfused blood products to maintain fibrinogen greater
than 150 mg/dL and INR less than 1.5. The initial differential
diagnosis for DIC included endocarditis related to recent dental procedures, occult malignancy, and an idiosyncratic reaction to clopidogrel. A transesophageal EKG demonstrated no
valvular vegetations and multiple blood cultures had no
growth. CT of the chest, abdomen, and pelvis revealed a 2.1 ´
1.7 cm2 left hilar lymph node. Esophagogastroduodenoscopy
and colonoscopy demonstrated no mass. A positron emission
tomography scan showed hypermetabolism and enlargement
of multiple mediastinal and supraclavicular lymph nodes.

Fig. 1. Unenhanced head CT showing hemorrhagic infarcts in the
anterior left MCA, posterior right MCA, and left PCA territories
with ischemic right PCA infarct.

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Despite treatment of the coagulopathy, the patient continued bleeding from multiple regions, including venopuncture
sites, urethra, and upper gastrointestinal tract. Over subsequent days, his neurological function progressively declined
and a second brain MRI demonstrated multiple new ischemic
strokes in the right middle cerebral artery territory. In consultation with the Hematology service, the patient was placed on
intravenous unfractionated heparin, titrated to a partial thromboplastin time (PTT) ratio of 1.5 to 2.0. Given declining neurological function and poor prognosis for recovery, however,
the family opted to withdraw supportive measures and the
patient quickly expired. Autopsy revealed multiple small
thrombi within the vasculature of the brain, heart, kidneys, spleen,
and lungs. Gross lymphadenopathy was present in the lung
hila and paratracheal region. On microscopic examination, a
poorly differentiated large cell carcinoma was seen infiltrating
these lymph nodes (Figure 2). The immunohistochemical
staining pattern strongly argued in favor of a primary lung
cancer; however, exhaustive sectioning of the lungs revealed
no identifiable tumor. An occult salivary gland neoplasm
could not be entirely excluded because limitations placed on
the autopsy precluded head and neck examination.

Discussion
Remote cancer is associated with an increased risk of thrombosis and stroke through a variety of mechanisms including
vascular compression and infiltration, nonbacterial thrombotic
endocarditis, and antiphospholipid antibody syndrome (1–3).
Based on review of the literature, this is the first reported case
of DIC-related recurrent strokes associated with occult large
cell carcinoma. Paraneoplastic DIC has been widely reported
in the literature, most commonly in association with hematological malignancies, especially acute promyelocytic leukemia
(1,2). Intraabdominal and lung adenocarcinoma is the solid

Fig. 2. 10X magnification of hilar lymph node Hematoxylin and
Eosin stain showing large cell carcinoma morphology.
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Koenig

tumor histology most commonly associated with DIC (4).
The incidence of chronic, low-grade DIC in solid tumors was
reported as 6.8% in a study of 1117 patients with solid tumors
referred for Oncology consultation (4). Although 5% of patients with paraneoplastic DIC experience a central nervous
system hemorrhage, ischemic strokes only rarely occur in this
condition (4).
DIC is a clinical syndrome characterized by excessive bleeding and thrombosis with a unique pattern of laboratory abnormalities. It is caused by microvascular deposition of fibrin
leading to ischemic organ failure and intravascular shearing of
erythrocytes (5). Thrombotic consumption of fibrinogen, platelets, and prothrombin also lead to hemorrhage (5). Excessive
fibrinolysis yields a detectable rise in fibrin degradation products, including D-dimer. The syndrome includes episodes of
thrombosis and hemorrhage in the setting of elevated PTT, fibrin degradation products, schistocytes, LDH, and D-dimer,
as well as low fibrinogen and platelets.
The mechanism of paraneoplastic DIC is not fully understood, but undoubtedly differs from sepsis-related DIC, in
which widespread endothelial injury is pathogenic (1,2). Tissue
factor expression on cancer cells appears essential for initiating DIC (6). Tissue factor interacts with tenase and prothrombinase complexes to generate excessive circulating thrombin
(7). The overproduction of thrombin leads to consumption of
coagulation factors, increased fibrin production, and release
of tissue plasminogen activator from endothelial cells (8).
Elevation of tumor necrosis factor (TNF), interleukin (IL)-1,
and IL-6—either by the tumor itself or as a systemic immunological response to tumor cells—has also been implicated
(9,10).
In this case, the other diagnostic possibility of primary
concern was thrombotic thrombocytopenic purpura (TTP).
Although the patient was symptomatic prior to clopidogrel
exposure, the development of laboratory abnormalities within
1 week of its initiation is provocative. At least 50 cases of TTP
have been associated with clopidogrel use in postmarketing
analysis (11). Drug-induced TTP is caused by autoantibodies
against vWF-cleaving protease (12). Impaired degradation of
vWF leads to the formation of abnormally large multimers,
which subsequently bind to platelets and form microthrombi
(13). Patients with clopidogrel-induced TTP have demonstrated undetectable levels of vWF-cleaving protease activity

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and the presence of IgG inhibitors of the protease (13). In this
case, vWF-cleaving protease activity was normal and the inhibitory IgG was absent. TTP can also be distinguished from
DIC by the relative normalcy of the PTT and fibrinogen and
the presence of thrombocytopenia (5). Based on these criteria,
the laboratory abnormalities and clinical history were highly
suggestive of DIC, rather than TTP, although clopidogrel cannot be excluded as a contributory factor.

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