Illustrative Teaching Cases
Section Editors: Sophia Sundararajan, MD, PhD, and Shadi Yaghi, MD
More Than Meets the Eye
Cerebrovascular Disease in Sickle Cell Disease Is About
More Than Sickling
Sneha Jacob, MD; Amelia Adcock, MD; Ann Murray, MD; Joanna Kolodney, MD
A 56-year-old male with a known history of sickle cell
disease (SCD) with HbSC and progressive deafness
presented to the hospital with increased left-sided weakness
accompanied by worsening confusion for the past 5 days.
He experienced a multiorgan crisis requiring plasmapheresis
10 years prior.
He had lived independently until moving in with his
brother because of progressive cognitive problems.
On presentation, he appeared mildly confused, with mild
bilateral proximal weakness, and scored a 3 on the National
Institutes of Health Stroke Scale.
Laboratories
Hemoglobin was 12.9, and peripheral blood smear showed
occasional sickle cells. Serum electrophoresis demon-
strated 52% hemoglobin S (HbS) and 44.7% hemoglobin
C (HbC).
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Imaging
Magnetic resonance imaging (MRI) brain revealed multifo-
cal punctate areas of restricted diffusion of acute infarction
affecting the deep white matter and the cortex. These were
superimposed on diffuse volume loss and multifocal areas of
old lacunar infarction (Figure 1). Computer topographic angi-
ography showed severe stenosis in the right superior division
of the middle cerebral artery and moderate stenosis in the dis-
tal aspect of bilateral anterior, middle, and posterior cerebral
arteries (Figure 2). His transesophageal echocardiogram was
normal, and transcranial Doppler (TCD) showed no evidence
of vasospasm or elevated velocities.
Clinical Course
He appeared stable with no obvious changes on clini-
cal examination. The hematology team was consulted, but
they did not think he was a candidate for exchange transfu-
sion given his normal HgB, normal MCV, few peripheral
sickle cells, and most importantly, because of compound
heterozygosity with HbC. Given the uncertainty of stroke
pathogenesis and lack of treatment consensus, repeat
Received February 7, 2018; final revision received March 21, 2018; accepted March 26, 2018.
From the Departments of Neurology (S.J., A.A., A.M.) and Hematology and Oncology (J.K.), West Virginia University, Morgantown.
Correspondence to Sneha Jacob, MD, Department of Neurology, West Virginia University, 1 Medical Center Dr, Suite 7500, PO Box 9180, Morgantown,
WV 26506. E-mail snjacob@hsc.wvu.edu
(Stroke. 2018;49:e224-e227. DOI: 10.1161/STROKEAHA.118.021057.)
© 2018 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
e224
brain imaging was performed demonstrating new punctate
areas of restricted diffusion (Figure 3). Updated TCDs
remained stable.
Considering his progressive injury, further hematologic
opinion was pursued and partial RBC exchange transfusion
initiated. After 2 rounds of exchange transfusion, repeat elec-
trophoresis showed HbC decreased to 27% and HbS to 32.9%.
He was discharged to a skilled nursing facility.
Unfortunately, 3 months later, the patient passed away
because of urosepsis. His serum electrophoresis showed an
HbS of 37%.
Discussion
SCD is an inherited hemoglobinopathy where there is a quali-
tative disorder in either the α or the β globin chain. HbS is
the most important inherited hemoglobinopathy in the United
States followed by HbC. β-Globin gene can be homozy-
gous (HbSS), commonly referred to as sickle cell anemia ,
or heterozygous sickle cell trait, HbSC and HbS-thalassemia.
Stroke is a major complication of SCD and most frequently
seen in HbSS in up to 25% in these patients followed by the
thalassemias and HbC.1,2 Understanding the mechanism of
stroke is crucial to prevent their recurrence. Several risk fac-
tors increase the likelihood of strokes in patients with SCD,
including cerebral vasculopathy, elevated TCD velocities,
anemia, leukocytosis, evidence of silent infarcts, and tradi-
tional cardiovascular risk factors.2
Our patient’s presentation of a progressive cognitive
decline is consistent with the severe leukoaraiosis seen on
MRI. The lateralizing findings on his neurological examination
corresponded to his acute multifocal strokes. The presentation
of multifocal recurrent strokes within 2 weeks of maximal
medical management did not fit the typical pattern observed in
intracranial atherosclerosis. Although his leukoaraiosis could
be partially attributed to his one known vascular risk factor
(hypertension), his symptom progression and history of HbSC
suggested the alternative pathogenesis of symptomatic SCD.
Underlying pathogenesis of cerebrovascular disease in
SCD involves both large vessel as well as penetrating (small)
DOI: 10.1161/STROKEAHA.118.021057

Figure 1. Axial diffusion-weighted imaging showing multiple
areas of restricted diffusion consistent with multifocal acute
ischemia.
artery disease. Small-vessel infarction in SCD is thought to
involve immature red cell congestion at the postcapillary
venules. This causes backward propagation, delayed transit
and, ultimately, more red cell sickling.3 Large artery vasculop-
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athy seen in SCD is not clearly understood although proposed
hypotheses include a mechanical response because of a mix-
ture of oxygenated and deoxygenated, polymerized clumped
red cells, platelets, white blood cells, and thrombin. Both
large-vessel vasculopathy and small-vessel occlusion have
been attributed to abnormal adherence to the endothelium,
Figure 2. Computed tomographic angiogram showing multifocal
stenosis in different vascular territories most pronounced in the
left internal carotid artery terminus.
Jacob et al   Stroke and Sickle Cell Disease   e225
reperfusion injury, promotion of a hypercoagulable state,
hemolysis, and impaired vasomotor tone.4 Silent infarcts often
contribute to the progressive cognitive decline that affect
patients with SCD.
The primary event in the pathogenesis of sickle cell ane-
mia is the polymerization of the sickle cell (HbS) mainly in
the deoxygenated state of the erythrocyte. Thus, the sickle cell
obstructs the vessels and shortens the erythrocyte’s life span,
leading to diffuse vasculopathy and tissue damage in various
organs.5
Downstream hypoxia, however, is not the same phenom-
enon that occurs in HbSC patients. Heterozygosity with HbS
or HbC traits are associated with a less severe phenotype and
therefore generally considered benign.
However, the combination of these 2 relatively benign
conditions (HbSC) result in significant clinical and physiolog-
ical abnormalities that are distinct from HbSS. HbC enhances
the formation of intracellular polymer of HbS by dehydrat-
ing the cell. Moreover, a slower rate of hemolysis and longer
erythrocyte half-life in HbSC result in a higher hemoglobin
level and MCHC-generating hyperviscosity.5
The clinical manifestations seen in HbSC disease are gen-
erally milder than HbSS and occur later in life. Nonetheless,
retinitis proliferans, osteonecrosis, and acute chest syndrome
often have a higher incidence in HbSC disease than in HbSS.
Ischemic stroke rates are 2% to 3% and are higher than the
general population.6 Increased blood viscosity compromis-
ing the blood oxygen delivery to the terminal arteries in the
cochlea is a possible explanation of the patient’s progressive
hearing loss.5 It could be argued that a similar mechanism
explains central nervous system ischemic insult although this
remains to be established.
Given the uncertainty of pathogenesis, many questions
remain on how to treat, or better yet, prevent the ischemic
complications seen in SCD. Initially, the hematology team
did not think that our patient was a candidate for exchange
transfusion or phlebotomy based on lack of anemia (HGB
>10). However, the proportion of HbS rather than abso-
lute blood counts is more relevant. The role for exchange
transfusion in the prevention of stroke is clearly established
in pediatric population with SCD. When TCD velocities
>200 cm/s are demonstrated on 2 repeated studies, chil-
dren should undergo exchange transfusion. More than a
10-fold reduction in recurrent stroke is observed if HbS
concentration is maintained <30% of their total hemoglobin.
Prophylactic transfusions are supported until the age of 16
years.7 Discontinuation of exchange transfusions has been
associated with an increased incidence of strokes, creating
controversy on when (if ever) to stop prophylactic transfu-
sions. Chronic transfusion therapy must be weighed against
the risks of blood borne pathogens, alloimmunization, and
hemosiderosis.
The appropriate primary and secondary stroke preven-
tion strategies in adults with SCD have not been widely
studied. A TCD velocity criterion is still lacking in adults.
Adult studies concluded that TCD velocities in adults were
lower than in children with SCD, and velocity criterion
 e226  Stroke  June 2018
Figure 3. Axial diffusion-weighted imaging (DWI; left) at initial presentation demonstrating scattered restricted diffusion consistent with
acute ischemia. Axial DWI (right) obtained 1 wk later illustrates new areas of restricted diffusion in the left lentiform nuclei.
used in children cannot be used to stratify stroke risk in
adults.8
The American Heart Association and American Stroke
Association recently recommended treating all SCD patients
with intravenous alteplase after reviewing new evidence for
the first time this year.9 Otherwise, the initial acute manage-
ment of strokes in adults remains blood transfusion if MRI
shows evidence of acute stroke. If the Hgb <10 g/dL, simple
blood transfusion is performed followed by exchange transfu-
sion.10 If Hgb >10 g/dL, a partial or complete exchange trans-
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fusion can be offered.
Specific management recommendations of HbSC disease
do not exist. Many physicians think that HbSC disease is a
mild form of SCD without any significant clinical conse-
quence as occurred in our case. However, HbSC disease is a
unique disease entity from sickle cell anemia. Management of
HbSC disease is under investigation. Some preliminary data
suggest rehydrating HbS to decrease polymerization, as well
as the effects of oral magnesium supplementation to optimize
the K-Cl transport system.6
Secondary prevention of stroke includes repeat MRI brain
in 30 days to assess for recurrent strokes and if there is evi-
dence of new infarcts, initiation of monthly exchange or sim-
ple transfusions. Guidelines for the long-term use of partial
RBC exchanges and the subsequent use of hydroxyurea have
not been determined in this disease. Simple therapeutic phle-
botomy to target the Hgb to 9.5 to 10.0 g/dL has also been
used successfully in the prevention of multisystem organ dam-
age in HbSC disease. However, management of HbSC disease
is currently based on treatment of sickle cell anemia with a
goal to reduce HbS to <30%. Annual MRI scans are reason-
able in patients with no obvious clinical changes. Aggressive
treatment of all cardiovascular risk factors is warranted in all
patients with SCD; however, it is important to note that anti-
platelet therapy in patients with SCD is generally contraindi-
cated because of the increased risk of hemorrhagic strokes.
The goal of therapy is to either reduce polymerization of HbS
or hyperviscosity.
TEACHING POINTS
• Patients with sickle cell disease and acute ischemic
stroke symptoms who are otherwise lytic candidates
should receive alteplase.
• Exchange transfusions in the acute phase to achieve
hemoglobin S <30% followed by prophylactic sim-
ple transfusions are reasonable secondary prevention
measures.
• Other vascular risk factors should be managed aggres-
sively, and routine follow-ups should be performed in
patients with sickle cell disease to rule out any silent
infarctions that could also trigger transfusions because
this might prevent long-term cognitive decline.
• HbSC disease should not be considered a benign
entity or a mild form of sickle cell anemia but as a
separate hemoglobinopathy disorder with its own
pathogenesis and presentation.
Disclosures
None.
References
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Jacob et al   Stroke and Sickle Cell Disease   e227
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KEY WORDS: anemia, sickle cell ◼ cognitive dysfunction ◼ hemoglobinopathies
◼ magnetic resonance imaging ◼ stroke