Multiple recurrent ischaemic strokes in a patient with cancer: is there

Novel treatment (new drug/intervention; established drug/procedure in new situation)
Case report
Multiple recurrent ischaemic strokes in a patient
with cancer: is there a role for the initiation
of anticoagulation therapy for secondary
stroke prevention?
Giselle Alexandra Suero-Abreu,1,2 Jia Zhen Cheng,2 Ryna Karina Then2
Department of Medicine,
Rutgers University New Jersey
Medical School, Newark, New
Jersey, USA
Department of Neurology,
Cooper University Hospital,
Camden, New Jersey, USA
Correspondence to
Dr Ryna Karina Then,
Accepted 16 May 2017
A 52-year-old woman with a medical history of cervical
and thyroid cancer, hypertension, dyslipidaemia,
uncontrolled diabetes and heavy smoking was diagnosed
with a new metastatic cholangiocarcinoma. While
undergoing palliative chemotherapy, she developed
dysarthria and left-sided weakness. Imaging studies
showed multiple bilateral ischaemic strokes. On hospital
days 2 and 5, she developed worsening neurological
symptoms and imaging studies revealed new areas
of ischaemia on respective days. Subsequent workup
did not revealed a clear aetiology for the multiple
ischaemic events and hypercoagulability studies were
only significant for a mildly elevated serum D-dimer
level. Although guidelines are unclear, full-dose
anticoagulation with low molecular weight heparin was
initiated given her high risk of stroke recurrence. She was
discharged to acute rehabilitation but, within a month,
she experienced complications of her malignant disease
progression and a new pulmonary thromboembolism.
The patient died soon after being discharged home with
hospice care.
To cite: Suero-Abreu GA,
Cheng JZ, Then RK. BMJ Case
Rep Published Online First:
[please include Day Month
Year]. doi:10.1136/bcr-2016218105
Patients with cancer have a substantial risk of
ischaemic strokes, increasing their morbidity and
mortality by more than twofold. This is a commonly
recognised but poorly studied clinical situation,
which represents a significant management challenge and brings together several medical fields.
Ischaemic stroke is the second most common brain
lesion in patients with cancer and, after an initial
ischaemic stroke, accounts for 31% of all recurrent
thromboembolic incidents in these patients.1 2 The
pathophysiology of cancer-associated ischaemic
stroke has been described, but the specific mechanisms linked to distinct patient and disease characteristics are not well known.3–6 There are no
current diagnostic or therapeutic guidelines for
the prevention and treatment of cancer-associated
strokes. Initiation of anticoagulation therapy for
secondary stroke prevention in such circumstance
remains controversial and clinical management of
these patients is challenging. We describe a case of
multiple recurrent ischaemic strokes in a patient
with cholangiocarcinoma. We present this case to
emphasise the need for more studies that could
shed light on the risk stratification and appropriate
management of recurrent strokes in patients with a
history of remote or current cancer. We also want
to highlight the lack of current guidelines for the
initiation of anticoagulation therapy for secondary
stroke prevention in cancer-associated strokes.
Case presentation
This is the case of a 52-year-old woman with a
recently diagnosed liver mass with multiple bilateral metastatic pulmonary nodules (figure 1A,B).
She had a history of cervical and thyroid cancer
10 and 4 years ago, respectively, both currently in
remission. The malignancy was initially detected
as a new unexpected liver finding on surveillance
imaging for her cervical cancer history. MRI with
MR cholangiopancreatography and pathology via
CT-guided percutaneous core biopsy confirmed the
diagnosis of cholangiocarcinoma. The patient also
had a medical history of hypertension, uncontrolled
diabetes mellitus, dyslipidaemia, asthma, morbid
obesity, hypothyroidism, neuropathy and arthritis,
as well as a 62 pack-years smoking history. The
patient underwent systemic palliative chemotherapy
with cisplatin and gemcitabine for 5 months, and
6 days after her eighth cycle of chemotherapy, she
presented to the emergency department with altered
mental status, sudden onset of left upper and lower
extremities’ weakness and slurred speech for 1 day.
The patient also described having mild shortness of
breath for a few days and diffuse bilateral wheezing
was noted during examination. The patient was not
in acute respiratory distress; vital signs and oxygen
saturation on room air were within normal limits
during this admission. The patient had a medical
history of asthma and received a combination of
beta-adrenergic and anticholinergic bronchodilator
(DuoNeb) which improved her symptoms. With
regard to the neurological symptoms, the last known
normal (LKN) time was determined as 7 hours prior
to admission. A non-contrast head CT scan was
unremarkable; however, brain MRI findings were
consistent with acute multiple non-haemorrhagic
strokes. These infarcts involved the right frontal
and temporoparietal areas, in the vascular territory of the right middle cerebral artery bilaterally
(figure 2A,B). Infarcts also involved the left cerebellum corresponding to the vascular distribution of
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105
Novel treatment (new drug/intervention; established drug/procedure in new situation)
Figure 1 Non-contrast abdominal MRI showing a mass on the left
liver lobe (arrow) as a typical hypointense lesion on a T1-weighted
image (A). Non-contrast chest CT showing discrete multiple bilateral
lung nodules at the time of diagnosis (B; arrowheads).
the posteroinferior cerebellar artery (figure 2C,D). The patient
was admitted to the neurology stroke service for stroke workup
and poststroke care. On the second day of hospitalisation, she
experienced agitation, worsening dysarthria and left-sided weakness. MRI studies showed a new small infarct in the deep white
matter of the right hemisphere, specifically in the right parasagittal frontal lobe (figure 3). On hospital day 5, the patient re-experienced worsening dysarthria and increased weakness at the
left upper and lower extremities. There was also sensory deficits
to light touch and proprioception at the left side. A repeat brain
MRI demonstrated a new stroke within the body of the corpus
callosum and right cingulate gyrus (figure 4A,B), as well as the
superior aspect of the right cerebellar hemisphere (figure 4C,D).
When compared with the patient’s prior brain imaging studies,
the remaining acute and subacute strokes were essentially stable
in appearance. After this clinical event, the patient had a stable
hospital stay until discharge to an acute rehabilitation centre.
Figure 3 Hospital day 2, brain MRI showed small newly developed
strokes in the right parasagittal frontal lobe. ADC, apparent diffusion
coefficients; DWI, diffusion weighted imaging.
At the acute presentation and after the two episodes of sudden
neurological deterioration, the patient underwent urgent
non-contrast head CT and brain MRI studies. Initial tests
were performed and showed that haemoglobin A1c was 6.8%,
low-density lipoprotein was 100 mg/dL and high-density lipoprotein was 51 mg/dL. They also showed pancytopenia associated with the recent chemotherapy treatments and elevated
alkaline phosphatase levels due to the underlying cholangiocarcinoma. Extensive workup to investigate the stroke aetiology
was conducted, and the relevant findings are discussed below in
relation to each differential diagnosis.
Differential diagnosis
Several differential diagnoses wereconsidered, as described in
the following sections.
Embolic strokes due to cardiac aetiology
Figure 2 Hospital day 1, brain MRI showed bilateral middle cerebral
artery strokes (A,B) and left posterior inferior cerebellar artery strokes
(C,D: ADC, apparent diffusion coefficient ; DWI, diffusion weighted
The patient had history of several major conventional vascular
risk factors such as hypertension, uncontrolled diabetes mellitus,
heavy smoking and dyslipidaemia. Imaging studies confirmed
recurrent acute ischaemic strokes in multiple vascular territories,
suggestive of embolic or—less likely—hypotensive or watershed
aetiologies. Workup was done to investigate a cardioembolic
aetiology for the acute stroke: head and neck CT angiography
with and without contrast was unremarkable. Continuous ECG
did not reveal any concomitant acute myocardiac ischaemia or
arrhythmias, and cardiac enzymes were unremarkable. A transthoracic echocardiogram (TTE) showed no atrial enlargement
and no evidence of intracardiac thrombus or patent foramen
ovale. However, there was moderate hypokinesis in the anterior septal wall with a left ventricular ejection fraction of 40%.
This mild left ventricular systolic dysfunction was considered
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105
Novel treatment (new drug/intervention; established drug/procedure in new situation)
comorbidities and high risk of bleeding. Early in the inpatient
management, the patient had severe thrombocytopenia due to
recent chemotherapy. Later, after the multiple recurrent episodes
of acute ischaemic events, the patient was placed on full dose
anticoagulation for secondary stroke prevention. The TEE was
going to be pursued as outpatient, but after discharge the patient
discontinued any interventions and opted for supportive care
only. Since conducting a more sensitive TEE was not possible in
this patient, the diagnosis of NBTE cannot be completely rule
Brain metastasis in the setting of advanced
Notably, multiple, non-specific, left-sided hyperintensities
were seen in the initial brain MRI fluid-attenuated inversion recovery (FLAIR)images and, given the patient’s known
advanced cancer state, these findings suggested the possibility of metastatic brain disease. For further investigation, a
complete non-contrast and contrast brain MRI was conducted.
This study confirmed the prior ischaemic findings, and the
multiple areas of mild contrast enhancement observed were
considered to be due to blood–brain barrier breakdown rather
than brain metastases.
Ischaemic stroke associated with the chemotherapy agents
Figure 4 Hospital day 5, brain MRI showed two foci of new ischaemia
within the body of the corpus and right cingulate gyrus, as well as the
superior aspect of the right cerebellar hemisphere. DWI= diffusion
weighted imaging; ADC= apparent diffusion coefficient .
to be a result of the recent use of chemotherapeutic agents and
less likely to be the predisposing source for thrombus formation. After discussion with cardiology team, no loop recorder
was implanted at the moment given the patient’s cancer diagnosis, poor prognosis and immunocompromised state. Instead,
an event monitor was to be considered prior to discharge for the
purpose of long-term rhythm monitoring.
Embolic strokes due to infective endocarditis
Given the immunocompromised state of the patient secondary to
recent chemotherapy, blood cultures, erythrocyte sedimentation
rate (ESR) and C reactive protein (CRP) studies were obtained
to address a suspicion of endocarditis. A high ESR of 45 mg/
dL (normal range 0–20 mg/dL) and a high CRP of 1.52 mg/dL
(normal <0.5 mg/dL) were found. There was one positive blood
culture for Gram-positive cocci in clusters, coagulase negative,
but subsequent blood cultures were negative which favoured
the probability of a contaminated specimen. Throughout the
hospital stay, there was no evidence of bacteraemia and no clinical findings sustained suspicion for endovascular infection.
In light of her advanced malignancy, non-bacterial thrombotic
endocarditis (NBTE) was also considered as a manifestation of
the cancer-associated hypercoagulability. In contrast to infectious endocarditis, in NBTE there is deposition of small, sterile
and friable vegetations on valvular surfaces leading to a thrombogenic state and embolic strokes. Notably, no valve vegetations
or murmur were reported in this patient on the TTE.4 7 8 But,
the lesions on the heart valves in NBTE are commonly missed
and transoesophageal echocardiography (TEE) has been shown
to be more sensitive in detecting vegetations than TTE.7 The
team considered conducting a TEE once the patient was in a
more stable clinical condition, but this was not done due to
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105
There is a likely relationship between ischaemic stroke and
malignancy, and the risk elevates even higher in patients treated
with chemotherapy. This has been reported in association with
cisplatin-based chemotherapy and in some cases with gemcitabine. Our patient was undergoing a regimen combining these
two medications and therefore there was a chance of ischaemic
stroke as an adverse effect of the chemotherapy itself. Similar to
published reports, the initial stroke developed within 1–2 weeks
after the last chemotherapy session; however, it is not common
to have multiple recurrent strokes linked to chemotherapy
agents and a definitive proof of causality is difficult to establish.9
Although less likely, another possible aetiology was chemotherapy-induced thrombotic microangiopathy such as thrombotic
thrombocytopenic purpura related to gemcitabine exposure, but
the patient did not have the clinical features indicative of this
clinical scenario.10–12
Embolic source due to hypercoagulable state in the setting of
remote and active malignancy
After the multiple recurrent ischaemic events, and in the setting
of malignancy and obesity, hypercoagulable states were investigated. Main coagulation studies (prothrombin time, partial
thromboplastin time, and international normalised ratio) were
within normal ranges. Duplex ultrasonogram of the lower
extremities ruled out deep venous thrombosis (DVT) as the
source of the embolic events, and notably the patient was undergoing DVT prophylaxis since admission. Extensive hypercoagulable workup was conducted and results for fibrinogen, antithrombin III, protein C, protein S, factor V Leiden, prothrombin
gene mutation analysis, dilute Russell’s venom viper time screen,
cardiolipins, antiphospholipid antibodies and heparin-induced
antibodies were all found to be normal. The only significant
finding was an elevated D-dimer level of 3.19 mg/dL (normal
value <0.5 mg/dL). Similarly, a second D-dimer level was
measured and found to be elevated at 5.7 mg/dL after the third
recurrent stroke. Interestingly, several studies have reported
elevated D-dimer levels in recurrent cancer-associated strokes
and have suggested it as a biomarker of a hypercoagulable state
Novel treatment (new drug/intervention; established drug/procedure in new situation)
and a predictor of the short-term risk of ischaemic strokes in
cancer patients.13–20
In cancer-associated thrombosis, the Khorana score is the most
validated method that helps to assess venous thromboembolism
(VTE) risk in cancer outpatients receiving chemotherapy and
to inform recommendation for thromboprophylaxis.21 22 The
calculated Khorana score for our patient using baseline data at
the time of chemotherapy was 1 point (body mass index >35 kg/
m2) for an intermediate VTE risk of 1.8%–2.0% at 2.5 months.
Our patient developed three ischaemic strokes and one VTE all
within 6 months after initiation of chemotherapy. Of note, to the
best of our knowledge, there is no published data on large cohort
studies using this score for risk prediction of arterial events such
as ischaemic strokes in patients with cancer.
Following the first diagnosis of acute ischaemic stroke, the
patient was stabilised clinically and was promptly initiated on
the early key poststroke medical protocol according to national
guidelines. The patient had a LKN time of more than 4.5 hours
and also had pancytopenia with a low platelet count secondary to
the recent chemotherapy treatments. Thrombolytic therapy was
not appropriate, and she was admitted to a dedicated stroke unit
for medical management. Treatment included blood pressure
and glucose control, fluid management and swallowing assessment. Antihypertensives were withheld on day 1 of admission
to facilitate permissible hypertension given a mild hypotensive
state; they were then resumed to achieve moderate blood pressure control during the rest of the hospital course. She was also
initiated antithrombotic therapy with aspirin and statin therapy,
as well as inpatient DVT prophylaxis with subcutaneous heparin.
After the third stroke, full-dose anticoagulation with therapeutic
low molecular weight heparin (LMWH) was initiated (enoxaparin 120 mg twice a day subcutaneously). Although guidelines
about anticoagulation for stroke prevention in patients with
are unclear, this approach was initiated by consensus between
neurology and haematology–oncology in view of the patient’s
dramatic high-stroke recurrent risk. The possible hypercoagulable state due to the advanced malignancy and the potential for
bleeding on anticoagulation were also discussed with the patient.
With regard to the metastatic cholangiocarcinoma, the
patient’s most recent cycle of palliative chemotherapy was 6 days
prior to the onset of the first neurological event, and further
oncological regimen was put on hold until acute neurological
issues were resolved. In general, the prognosis of patients with
unresectable stage IV cholangiocarcinoma is poor, and therapies
such as systemic chemotherapy have failed to show any significant increase in survival. Thus, the benefit of palliative measures
should always be weighted against the potential side effects of
the therapy. Prior to discharge, the goals of cancer care were
discussed with the oncology team and the patient. It was recommended a multidisciplinary supportive care to achieve clinical
stabilisation and a close follow-up with oncology as outpatient to decide about resuming palliative chemotherapy. Also,
it was discussed additional palliative measures such as relief of
symptoms, placement of a biliary stent to bypass obstructions
and management of cholangitis to address future quality-of-life
concerns due to possible progression of the malignancy.
Outcome and follow-up
After a 7-day hospitalisation, the patient was discharged to
acute rehabilitation with instructions to receive continuous anticoagulation with enoxaparin (120 mg subcutaneously, twice a
Figure 5 Contrast chest CT and pulmonary embolism protocol
showing disease burden and significant progression of the multiple
bilateral lung metastasis (A) and filling defect consistent with
pulmonary embolism in the right lower lobe pulmonary artery (B).
day). The patient followed up with haematology–oncology as
an outpatient 2 weeks after discharge, and still had significant
residual dysarthria and weakness in the left upper and lower
extremities. Given her overall medical status, the patient decided
not to resume the palliative chemotherapy treatments and to
continue supportive care at the rehabilitation centre. One month
later, the patient presented to the ED complaining of abdominal
pain, nausea, vomiting and anorexia for 3 days. She was found
to have sepsis secondary to acalculous cholecystitis, progression
of the cancer and a complicated urinary tract infection related to
long-term Foley catheterisation and chronic urinary retention.
The patient also had shortness of breath and mild hypoxaemia,
and subsequent workup found remarkable progression of her
multiple lung metastases and a new onset pulmonary embolism
(figure 5A,B); despite being prescribed anticoagulation therapy
with enoxaparin as an outpatient. Due to her advanced cholangiocarcinoma, overall disease burden and multiple comorbidities, the patient was not a surgical candidate for cholecystectomy or for additional palliative chemotherapy. She opted
for a cholecystostomy tube placement for symptomatic relief,
and after achieving clinical stability, the patient and her family
decided on her discharge home with hospice assistance and with
the appropriate comfort measures. The patient died 2 days after
being discharged.
In this report, we present a patient who developed multiple early
recurrent ischaemic strokes while undergoing chemotherapy for
metastatic cholangiocarcinoma. As in this case, patients with
active cancer may have multiple conventional vascular risk
factors which could be the main underlying stroke aetiology.5 6
However, compared with the general population, patients with
cancer are in a hypercoagulable state that increases their risk of
events such as venous thromboembolism, arterial thrombosis,
migratory superficial thrombophlebitis, NBTE and disseminated
intravascular coagulation.7 23 24 In addition, besides coagulation disorders, other mechanisms such as direct cancer effect,
paraneoplastic syndrome and complications of cancer treatment
have been identified as possible causes of stroke in patients with
cancer.1 25–27 In our patient, a number of factors pointed towards
the probability of an embolic stroke aetiology due to cancer-associated thrombosis. These factors included the patient’s negative workup for the main traditional stroke risk factors, the presence of advanced-stage cancer, the occurrence of multiple early
recurrent strokes in distinct vascular territories and the elevated
D-dimer levels. In regard to D-dimer levels, several groups have
studied D-dimer as a marker of a cancer-associated hypercoagulable state and in some cases high levels of D-dimer have been
correlated with an increased risk of early recurrent events in
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105
Novel treatment (new drug/intervention; established drug/procedure in new situation)
patients with cancer after an initial acute ischaemic stroke.13–18
However, it is important to note that the predictive utility of
this biomarker is not always this straightforward. This is because
D-dimer levels could also be influenced by the advanced malignancy itself (such as large tumour burden, progression and
metastasis without thrombosis), increased age, diabetes and
other factors.14 15 28–31 Nonetheless, elevated D-dimer levels may
be helpful in recognising ischaemic stroke as the initial presentation of an underlying malignancy in patients with cryptogenic
stroke and multiterritorial brain lesions.32 33 That being said, in
this patient, the suspicion of cancer-associated thrombosis was
further strengthened when the patient also developed a new
pulmonary embolism, a manifestation of hypercoagulability
more frequently identified in patients with active cancer.
Further research is needed to better understand cancer-specific prothrombotic effects and how active inflammatory and
immune response mechanisms may play a role in the pathogenesis of stroke.26 27 There are only a few large-scale epidemiological reports that systemically study the incidence, mechanism
and appropriate treatment of recurrent stroke in patients with
cancer. One of the most recent comprehensive studies determined that the majority of patients with cancer with recurrent
thromboembolic events after ischaemic stroke had reached a
metastatic disease stage. In addition, the most common histological tumour type was adenocarcinoma and the most common
type of malignancy was lung cancer.1 Prior studies have determined that other common cancer types linked to recurrent
stroke in patients are breast, gastrointestinal and gynaecological
cancers.1 27 34 In the literature, we only found one reported case
of recurrent ischaemic stroke in the setting of cholangiocarcinoma.35 Some studies found that the median time from diagnosis
of underlying cancer to stroke was about 1 year, but in a number
of patients with stroke could occur as early as 1 month or as
late as several years after the cancer diagnosis. Interestingly, in
some patients with stroke can be the initial sign of cancer, and
approximately 84% of such patients had a second stroke within
the following 4 months.1 2 32–34
Anticoagulation in high-risk vascular events is an established
treatment. However, the use of risk-stratified thromboprophylaxis in patients with active malignancy as a strategy for the
prevention of arterial, as well as venous, thromboembolic events
is a less common intervention. Most clinical trials of cancer-associated thrombosis and the use of anticoagulation have focused
on the treatment and prevention of cancer-associated venous
thrombosis and clear guidelines have been established.36 37
Several large studies have focused on the risk assessment, safety
and compliance with thromboprophylaxis for VTE in patients
with cancer.38–42 However, it is uncertain how much these data
can be extrapolated to guide clinical decision making for the use
of anticoagulation in regards to arterial thrombotic events such
as ischaemic strokes.
Controversies remain concerning the initiation of anticoagulation therapy and the optimal choice of medication for
secondary stroke prevention in the setting of active malignancy. The goal of anticoagulation therapy in these patients
would be to decrease their substantial risk of short-term
stroke recurrence while also considering their risk of bleeding.
However, there is not enough data to support the claim that
early anticoagulation would be beneficial. One retrospective
study suggested that treatment with LMWH may be more
effective than warfarin for lowering the risk of stroke recurrence, but it was limited by a small sample size, confounding
factors and a short study period.16 There is also an ongoing
randomised phase I/II trial evaluating enoxaparin versus
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105
aspirin in patients with active cancer and first-ever acute ischaemic stroke to compare these treatments’ safety and efficacy
in preventing recurrent thromboembolic events (​
ClinicalTrials.​gov, NCT01763606). But, currently, the role of thromboprophylaxis for secondary stroke prevention in patients
with active cancer is not addressed in current stroke or cancer
treatment guidelines. Since this is an important evolving
area of research, large-scale randomised prospective studies
are needed to establish patient-specific and disease-specific
diagnostic and treatment algorithms for acute and recurrent
strokes in patients with cancer.
In closing, the interrelationship between ischaemic stroke and
cancer is a complex one. As the life expectancy of the general
population increases and the survival rate of patients with cancer
improves, the coexistence of stroke and cancer in adult patients
will continue to be common. This report seeks to highlight the
intricacies of this correlation. It emphasises the relevance of
establishing a distinct stroke aetiology on a patient-by-patient
basis, especially when active malignancy is present. This, in turn,
can have important implications for the prognosis, therapeutic
management and prevention of recurrent stroke in patients with
Learning points
►► Clinicians should remain alert for thromboembolic events
(both arterial and venous) in patients with cancer as a
possible cause of any clinical deterioration. Even though
their risk is significantly increased with advanced cancer,
delay in diagnosis is not uncommon and may negatively
impact patient morbidity and mortality.
►► Identifying stroke aetiology in the setting of malignancy
can be complex due to the presence of traditional
cerebrovascular risk factors in many adult oncology patients,
but this is crucial to defining treatment and prevention
►► Some studies have associated elevated D-dimer levels with a
high risk of early recurrent ischaemic strokes in patients with
cancer. Thus, it can be beneficial to consider D-dimer levels
for risk stratification of recurrent events as part of the acute
inpatient stroke management of certain patients with active
►► There are no current recommendations to support any
benefit of early anticoagulation for secondary stroke
prevention after acute stroke in patients with cancer.
However, it should be considered if cancer-associated
hypercoagulability is likely to be the main stroke aetiology.
Contributors GAS-A: substantial contributions to the conceptualisation of the
work, data acquisition and interpretation; drafting and revision of the work, final
approval of the final version and analysis or interpretation of data; agreement to
be accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately investigated and
resolved. JZC: substantial contributions to the conceptualisation of the work, data
acquisition and interpretation; revision of the work, approval of the final version;
agreement to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved. RKT: substantial contributions to the conceptualisation
and design of the work and data supervision and interpretation; revision of the work,
approval of the final version; agreement to be accountable for all aspects of the
work in ensuring that questions related to the accuracy or integrity of any part of the
work are appropriately investigated and resolved.
Competing interests None declared.
Patient consent Detail has been removed from this case description to ensure
anonymity. The editors and reviewers have seen the detailed information available
and are satisfied that the information backs up the case the authors are making.
Novel treatment (new drug/intervention; established drug/procedure in new situation)
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work
is properly cited and the use is non-commercial. See: http://​creativecommons.​org/​
© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)
2017. All rights reserved. No commercial use is permitted unless otherwise expressly
1 Navi BB, Singer S, Merkler AE, et al. Recurrent thromboembolic events after ischemic
stroke in patients with Cancer. Neurology 2014;83:26–33.
2 Navi BB, Reiner AS, Kamel H, et al. Association between incident Cancer and
subsequent stroke. Ann Neurol 2015;77:291–300.
3 Seok JM, Kim SG, Kim JW, et al. Coagulopathy and embolic signal in Cancer patients
with ischemic stroke. Ann Neurol 2010;68:n/a–9.
4 Schwarzbach CJ, Schaefer A, Ebert A, et al. Stroke and Cancer: the importance
of cancer-associated hypercoagulation as a possible stroke etiology. Stroke
5 Kim SG, Hong JM, Kim HY, et al. Ischemic stroke in cancer patients with and without
conventional mechanisms: a multicenter study in Korea. Stroke 2010;41:798–801.
6 Dearborn JL, Urrutia VC, Zeiler SR. Stroke and Cancer- A complicated relationship. J
Neurol Transl Neurosci 2014;2:1039.
7 el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer
patients: pathogenesis, diagnosis, and treatment. Oncologist 2007;12:518–23.
8 Bang OY, Seok JM, Kim SG, et al. Ischemic stroke and cancer: stroke severely
impacts cancer patients, while cancer increases the number of strokes. J Clin Neurol
9 Li SH, Chen WH, Tang Y, et al. Incidence of ischemic stroke post-chemotherapy: a
retrospective review of 10,963 patients. Clin Neurol Neurosurg 2006;108:150–6.
10 Govind Babu K, Bhat GR. Cancer-associated thrombotic microangiopathy.
Ecancermedicalscience 2016;10:649.
11 Werner TL, Agarwal N, Carney HM, et al. Management of cancer-associated
thrombotic microangiopathy: what is the right approach? Am J Hematol
12 Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with
targeted Cancer agents. Clin Cancer Res 2011;17:5858–66.
13 Lee MJ, Chung JW, Ahn MJ, et al. Hypercoagulability and mortality of patients with
stroke and active cancer: the OASIS-CANCER study. J Stroke 2017;19:77–87.
14 Nam KW, Kim CK, Kim TJ, et al. D-dimer as a predictor of early neurologic
deterioration in cryptogenic stroke with active cancer. Eur J Neurol
15 Nam KW, Kim CK, Kim TJ, et al. Predictors of 30-day mortality and the risk of
recurrent systemic thromboembolism in cancer patients suffering acute ischemic
stroke. PLoS One 2017;12:e0172793.
16 Jang H, Lee JJ, Lee MJ, et al. Comparison of Enoxaparin and Warfarin for Secondary
Prevention of Cancer-Associated Stroke. J Oncol 2015;2015:1–6.
17 Kono T, Ohtsuki T, Hosomi N, et al. Cancer-associated ischemic stroke is associated
with elevated D-dimer and fibrin degradation product levels in acute ischemic stroke
with advanced Cancer. Geriatr Gerontol Int 2012;12:468–74.
18 Mytnik M, Stasko J. D-dimer, plasminogen activator inhibitor-1, prothrombin
fragments and protein C - role in prothrombotic state of colorectal cancer.
Neoplasma 2011;58:235–8.
19 Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state. Lancet Oncol
20 De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev
Oncol Hematol 2004;50:187–96.
21 Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a
predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902–7.
22 Angelini D, Khorana AA. Risk Assessment scores for cancer-associated venous
thromboembolic disease. Semin Thromb Hemost 2017.
23 Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349:109–11.
24 Bick RL. Cancer-associated thrombosis: focus on extended therapy with dalteparin. J
Support Oncol 2006;4:115–20.
25 Matijevic N, Wu KK. Hypercoagulable states and strokes. Curr Atheroscler Rep
26 Cestari DM, Weine DM, Panageas KS, et al. Stroke in patients with cancer: incidence
and etiology. Neurology 2004;62:2025–30.
27 Zhang YY, Cordato D, Shen Q, et al. Risk factor, pattern, etiology and outcome in
ischemic stroke patients with cancer: a nested case-control study. Cerebrovasc Dis
28 Nwose EU, Richards RS, Jelinek HF, et al. D-dimer identifies stages in the progression
of diabetes mellitus from family history of diabetes to cardiovascular complications.
Pathology 2007;39:252–7.
29Ebara S, Marumo M, Yamabata C, et al. Inverse associations of HDL cholesterol and
oxidized HDL with d-dimer in patients with type 2 diabetes mellitus. Thromb Res
30 Tardy B, Tardy-Poncet B, Viallon A, et al. Evaluation of D-dimer ELISA test in elderly
patients with suspected pulmonary embolism. Thromb Haemost 1998;79:38–41.
31Righini M, Goehring C, Bounameaux H, et al. Effects of age on the performance of
common diagnostic tests for pulmonary embolism. Am J Med 2000;109:357–61.
32 Goedee S, Naber A, Rovers JM, et al. Ischaemic stroke as initial presentation of
systemic malignancy. BMJ Case Rep 2014;2014:bcr2013202122.
33 Bond LM, Skrobo D. Multiple embolic cerebral infarcts as the first manifestation of
metastatic ovarian cancer. BMJ Case Rep 2015;2015:bcr2015211521.
34 Taccone FS, Jeangette SM, Blecic SA. First-ever stroke as initial presentation of
systemic Cancer. J Stroke Cerebrovasc Dis 2008;17:169–74.
35 Chaiyasit K, Wiwanitkit V. Ischemic stroke in a patient with cholangiocarcinoma: a
case study. Arq Neuropsiquiatr 2012;70:833.
36 Lyman GH, Bohlke K, Falanga A; American Society of Clinical Oncology. Venous
thromboembolism prophylaxis and treatment in patients with Cancer: American
Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol Pract
37 Donnellan E, Khorana AA. Cancer and venous thromboembolic disease: a review.
Oncologist 2017;22:199–207.
38 Spyropoulos AC, McGinn T, Khorana AA. The use of weighted and scored
risk assessment models for venous thromboembolism. Thromb Haemost
39Rabinovich E, Bartholomew JR, Wilks ML, et al. Centralizing care of cancerassociated thromboembolism: the Cleveland clinic experience. Thromb Res
40 Kuderer NM, Culakova E, Lyman GH, et al. A validated risk score for venous
thromboembolism is predictive of cancer progression and mortality. Oncologist
41 Khorana AA, Yannicelli D, McCrae KR, et al. Evaluation of US prescription patterns:
are treatment guidelines for cancer-associated venous thromboembolism being
followed? Thromb Res 2016;145:51–3.
42 Khorana AA, Dalal M, Lin J, et al. Incidence and predictors of venous
thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing
chemotherapy in the United States. Cancer 2013;119:648–55.
Copyright 2017 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit
BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.
Become a Fellow of BMJ Case Reports today and you can:
►► Submit as many cases as you like
►► Enjoy fast sympathetic peer review and rapid publication of accepted articles
►► Access all the published articles
►► Re-use any of the published material for personal use and teaching without further permission
For information on Institutional Fellowships contact
Visit for more articles like this and to become a Fellow
Suero-Abreu GA, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218105