Cerebral Infarcts in Patients
with Sickle Cell Disease
Miguel R. Abboud, MD
Professor of Pediatrics
Hematology-Oncology
Chairman, Department of Pediatrics and
Adolescent Medicine
American University of Beirut Medical Center
Beirut, Lebanon
Definitions
Term
Definition
Imaging
Stroke
Acute neurologic syndrome that
results from either vascular
occlusion or haemorrhage,
resulting in ischaemia and
neurologic symptoms or signs
lasting >24 hours
Positive
Transient
ischaemic
attack
Acute neurologic syndrome with
deficits lasting <24 hours
Negative
Silent infarct
Small infarct (typically <15 mm)
evidenced by MRI but no
neurologic deficits
Area of increased
signal on
intermediate or
T2-weighted MRI
pulse sequences
Adams RJ, et al. Hematology Am Soc Hematol Educ Program. 2001:31-46.
Stroke Subtype by Age
• Ischaemic stroke1
– 54% of cerebrovascular accidents
– Highest in 1st decade and after 30 years
– Peak incidence at 2–5 years
• Haemorrhagic stroke1
– Highest in 2nd decade
• Silent stroke/infarct
– Radiologic findings consistent with white matter disease1
– 10%–30% of patients with sickle cell disease (SCD)1
– Associated with cognitive deficiencies1 and higher stroke risk2
1. Verduzco LA, et al. Blood. 2009;114:5117-5125. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.
Risk Factors for Infarctive Stroke
● Multivariate predictors (P <.05 for each)1
– Prior transient ischaemic attack (TIA): Relative risk
(RR) = 56
– Anaemia: RR = 1.85 per 1 g/dL Hb decrease
– Recent acute chest syndrome: RR = 7
– Acute chest syndrome rate: RR = 2.39 per event/year
– Hypertension: RR = 1.31 per 10 mmHg increase
● Additional predictors
– Silent infarcts: RR = 142
– Nocturnal hypoxia: Hazard ratio (HR) = 0.85 per 1%
increase in O2 saturation3
1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.
3. Kirkham FJ, et al. Lancet. 2001;357:1656-1659.
Stroke Recurrence Risk After Initial
Simple vs Exchange Transfusion
Patients with Recurrent
Strokes (%)
100
80
60
All children received scheduled chronic blood
transfusion therapy for at least 5 years after the
first stroke and initial therapy
RR = 5.0 (1.3–18.6; P = .02)
57
40
21
20
0
8/14
8/38
Simple
Exchange
Transfusion Type
Hulbert ML, et al. J Pediatr. 2006;149:710-712.
Management of Stroke and
Prevention of Recurrence
100
Patients with Recurrent
Strokes (%)
● Ischaemic stroke is
treated with emergent
simple or exchange
blood transfusion1
● Without transfusion,
70% will recur within
2–3 years1
● With chronic
transfusion, risk of
recurrence is reduced
by 90%1
Cumulative observation time =
191.7 patient-years
80
67
60
40
20
1. Josephson CD, et al. Transfus Med Rev. 2007;21:118-133. 0
2. Pegelow CH, et al. J Pediatr. 1995;126:896-899.
3. Powars D, et al. Am J Med. 1978;65:461-471.
Study population with
transfusion vs
historical control subjects
without transfusion2
13
8/60
10/15
Transfusion2
No
Transfusion3
Hydroxyurea for Secondary Stroke
Prevention—SWiTCH
Aim of study: [hydroxyurea + phlebotomy = alternative arm] vs
[transfusions + deferasirox = standard arm] for 30 months to prevent
secondary stroke and reduce transfusional iron overload
161 paediatric
patients with SCD
and documented
stroke and iron
overload enrolled in
SWiTCH
133 patients
randomized
1:1
Alternative arm
Hydroxyurea + phlebotomy
n = 67
Standard arm
Transfusions + deferasirox
n = 66
Prediction: increased recurrence of stroke events
in alternative arm but counterbalanced by better management of
iron overload with phlebotomy
Ware RE, et al. Blood. 2010;116:Abstract 844.
SWiTCH—Stroke Recurrence Higher with
Hydroxyurea than with Transfusions1
Patients with
Recurrent Strokes (%)
20
15
Study was terminated early2 due to the
marked increase in secondary stroke risk
with hydroxyurea compared with transfusion
therapy and no benefit of phlebotomy over
chelation in reducing iron overload
10.4
10
5
0
0
0/66
Transfusion +
Deferasirox
7/67
Hydroxyurea +
Phlebotomy
1. Ware RE, et al. Blood. 2010;116:Abstract 844. 2. NIH. Press release. June 4, 2010. Accessed
11/21/11 at: http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2709.
Importance of Transcranial
Doppler Screening in SCD
Annual Stroke Risk
● Baseline risk from Cooperative Study of Sickle Cell Disease
(CSSCD) is approximately 0.5%–1%1
−If prior stroke, annual stroke risk is approximately 30%2
● Increased risk of infarctive stroke with TIA, lower baseline Hb,
prior and recent acute chest syndrome (CSSCD study, no prior
stroke), but yearly risk not quantitated1
● If abnormal transcranial Doppler (TCD), annual risk is
10%–13% per year3
● If MRI “silent lesions,” annual risk is approximately 2%–3%4
● Severe arterial lesions on angiography?
−Assumed to be bad,5 but yearly risk has not been quantitated
1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Powars D, et al. Am J Med. 1978;65:461-471.
3. Adams RJ. Arch Neurol. 2007;64:1567-1574. 4. Miller ST, et al. J Pediatr. 2001;139:385-390. 5. Abboud
MR, et al. Blood. 2011;118:894-898.
Patients with Strokes (%)
Stroke-free Probability Is Increased
with Long-Term Transfusions
in Children with SCD
Paediatric patients with SCD and abnormal TCD
20 velocity were randomized to transfusion or standard
care to prevent first stroke.
18
16.4
16
14
Median follow-up =
21.1 months
12
10
9.2
P <.001
8
6
4
2
0
1.6
12/130
1/63
11/67
Total
Transfusion
Standard*
*Includes 1 patient with intracerebral hematoma.
Adams RJ, et al. N Engl J Med. 1998;339:5-11.
Early TCD Screening and Intervention
● Predictive factors and outcomes of cerebral vasculopathy in
the Créteil newborn SCA cohort (n = 217, SS/Sβ0)
● Screened with TCD early and yearly since 1992
● MRI/MRA every 2 years after age 5 years (or earlier in case
of abnormal TCD)
● Transfusions for abnormal TCD and/or stenoses
● Hydroxyurea to symptomatic patients with no
macrovasculopathy
● Stem cell transplantation for those with HLA genoidentical
donor
● Mean follow-up 7.7 years (1609 patient-years)
Bernaudin F, et al. Blood. 2011;117:1130-1140.
Cumulative Risks in SCD Cohort
with TCD Screening
• Cumulative risks by 18 years of age
–
–
–
–
Stroke: 1.9% (95% CI 0.6%–5.9%) compared with 11%
Abnormal: TCD 29.6% (95% CI 22.8%–38%) plateau at age 9 years
Stenosis: 22.6% (95% CI 15.0%–33.2%)
SI: 37.1% (95% CI 26.3%–50.7%) age 14 years
• All cerebral event risk by 14 years 49.9% (95% CI 40.5%–59.3%)
• Independent predictive factors for cerebral risk
– Baseline reticulocytes count: HR 1.003 per 1 x 109/L increase
– Lactate dehydrogenase: HR 2.78 per 1 IU/mL increase
• Conclusion: Early TCD screening and intensification therapy
reduced risk of stroke by age 18 years from 11% to 1.9%
– 50% cumulative cerebral risk suggests more preventive intervention
is needed
Bernaudin F, et al. Blood. 2011;117:1130-1140.
TCD and Transfusions in Patients
with Silent Infarcts—Conclusions
• Early TCD and transfusions effective in
preventing strokes
• TCD does not screen for risk of silent infarcts
• Most patients who develop silent infarcts have
normal TCD
• Different strategies needed
Bernaudin F, et al. Blood. 2011;117:1130-1140.
● 79 subjects having
normalized TCD under
transfusion were
randomized1
– 38 to continue cRCT
therapy
– 41 to discontinue cRCT
therapy
● No neurologic events in
the cRCT group1
Patients with Neurologic
Events (%)
STOP II Trial—Transfusion and
Stroke Prevention
50
45
40
35
30
25
20
15
10
5
0
Ischaemic stroke
4.9%
High-risk TCD
34.1%
0%
No RCT
cRCT
STOP II trial terminated after 2 years and concluded that it is unsafe to
stop blood transfusions in patients who are at high risk of stroke2
Abbreviations: cRCT, chronic red cell transfusion; TCD, transcranial Doppler.
1. Adams RJ, et al. N Engl J Med. 2005;353:2769-2778. 2. NIH. Press release. December 5, 2004.
Accessed 11/21/11 at: http://www.nhlbi.nih.gov/new/press/04-12-05.htm.
Graphic courtesy of Dr. Miguel R. Abboud.
STOP Trial—Transfusion Therapy vs
Standard Care for Prevention of
Secondary Silent Brain Infarcts
Outcome after observation for 36 months in patients who had
silent infarcts at baseline and who were randomized to
transfusion or standard care
Transfusion
Standard
Care
Total
Stroke
0
9*
9
New or worse
silent infarcts
0
6
6
No change
18
14
32
P-value
<.001
*Includes 1 patient with new or worse lesion prior to stroke.
Pegelow CH, et al. Arch Neurol. 2001;58:2017-2021.
STOP II Trial—Effect of Discontinuing
Transfusion on Silent Brain Infarcts on MRI
Baseline: Silent Infarct*
11 (26.8%)
No
Transfusion
(n = 41)
Baseline: Normal MRI
30 (73.2%)
Baseline: Silent Infarct
10 (26.3%)
Transfusion
(n = 38)
Baseline: Normal MRI*
28 (73.7%)
*1 patient had no follow-up MRI.
†3 patients had lesion number decrease; 1 reverting to normal scan.
Abboud MR, et al. Blood. 2011;118:894-898.
New Lesion
5 (50%)
No Change
5 (50%)
New Lesion
6 (20%)
No Change
24 (80%)
New Lesion
3 (30%)
No Change†
7 (70%)
New Lesion
0 (0%)
No Change
27 (100%)
STOP II Trial—Effect of Discontinuing
Transfusion on Silent Brain Infarcts on MRI
Baseline: Silent Infarct*
11 (26.8%)
No
Transfusion
(n = 41)
Baseline: Normal MRI
30 (73.2%)
Baseline: Silent Infarct
10 (26.3%)
Transfusion
(n = 38)
Baseline: Normal MRI*
28 (73.7%)
*1 patient had no follow-up MRI.
†3 patients had lesion number decrease; 1 reverting to normal scan.
Abboud MR, et al. Blood. 2011;118:894-898.
New Lesion
5 (50%)
No Change
5 (50%)
New Lesion
6 (20%)
No Change
24 (80%)
New Lesion
3 (30%)
No Change†
7 (70%)
New Lesion
0 (0%)
No Change
27 (100%)
Patients with Strokes (%)
Consequence of Stroke Prevention
with Blood Transfusions
Paediatric patients with SCD and abnormal TCD
20 velocity were randomized to transfusion or standard
care to prevent first stroke.
18
16.4
16
14
Median follow-up =
21.1 months
12
10
9.2
Initial serum ferritin
164 ± 155 ng/L
P <.001
8
1-year serum ferritin
1804 ± 773 ng/L
6
4
2
0
1.6
12/130
1/63
Total
Transfusion
*Includes 1 patient with intracerebral hematoma.
Adams RJ, et al. N Engl J Med. 1998;339:5-11.
2-year serum ferritin
2509
11/67± 974 ng/L
Standard*
Organ Dysfunction in
Sickle Cell Disease and β-Thalassaemia
Patient Characteristics
Group
Age*
(y)
Transfusion
Duration (y)
Serum Ferritin
(ng/mL)
Liver Iron*
(mg/g dry wt)
SCD
14.8 ± 1.0
6.0 ± 0.6
2916 ± 233
14.33 ± 1.38
β-Thal
18.37 ± 2.1
12.2 ± 1.8
2122 ± 289
14.79 ± 2.15
Liver Disease
Organ Dysfunction
Group
Cardiac Growth
Disease Delay*
SCD
β-Thal
Gonadal Group
Failure
0
9%
0
20%
27%
33%
Viral
Hepatitis
ALT
>65 U/L
Fibrosis
Score >0
SCD
2%
7%
39%
β-Thal
33%
37%
81%
SCD n = 43
β-Thal n = 30
*P-value = not significant; P-value significant for all other comparisons.
Vichinsky E, et al. Am J Hematol. 2005;80:70-74.
Why Do SCD Patients Demonstrate Less Organ
Injury than β-Thalassaemia Patients?
● Organ injury may require a critical iron level with
prolonged exposure
● SCD biology and its secondary inflammatory state may
be protective factors
● Inflammation may decrease organ injury by restricting
iron to shielded sites within the reticuloendothelial
system (RES) and delaying the release of iron from the
RES system
● The 2 diseases may have different transport and storage
proteins
Vichinsky E, et al. Am J Hematol. 2005;80:70-74.
Possible Explanations for Absence
of Cardiac Iron Overload in SCD
● Nontransferrin-bound iron higher in
thalassaemia major than SCD
● Other factors
–
–
–
–
Splenic tissue
Ineffective erythropoiesis
Gastrointestinal iron metabolism
Urinary iron loss
Vichinsky E, et al. Am J Hematol. 2005;80:70-74.
Hepatocyte Siderosis
With permission from Pierre Brissot, MD.
Kupffer Cell Siderosis
How to Monitor Iron Status
● Serum ferritin
– Noninvasive, available, inexpensive
– Confounded by several parameters
– Use long-term trends and avoid using acute-phase values
● Liver biopsy
–
–
–
–
Gold standard
Reveals pathology
Invasive
Sampling error
● Magnetic resonance
– Accurate
– Expensive
How to Manage Iron Overload
● Chelating agents
– Desferrioxamine
– Deferasirox
– Deferiprone
 Licensed for thalassaemia major only1
● Nonpharmacologic techniques
– Erythrocytapheresis
– Phlebotomy
1. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999.
Chronic Transfusion Methods
Simple
Transfusion1
Features
Iron overload
Safety
• Easy to
perform
• 1 venous
access
+++
Manual
Exchange
Transfusion1
Erythrocytapheresis1,2
• Time-consuming • Expensive
• Manual
• Requires
2 good venous
accesses
• Good clinical
tolerance
+
No iron overload
Allo-immunization +++
Infections
1. Sickle Cell Society. Standards for the clinical care of adults with sickle cell disease in the UK. 2008.
Accessed 11/29/11 at: http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf.
2. Kim HC, et al. Blood. 1994;83:1136-1142.
Iron Chelation Therapy is Needed to
Treat Iron Overload
Properties
Desferrioxamine1
Deferasirox2
Deferiprone3
Usual dose
(mg/kg/d)
20–60
20–30
75 (total daily dose)
SC, IV
(8–12 h, 5–7 d/wk)
Oral, once daily
Oral, TIW
6h
8–16 h
2–3 h
Urinary, faecal
Faecal
Urinary
Local reactions,
ophthalmologic,
auditory, growth
retardation, allergic
Gastrointestinal
disturbances, rash,
creatinine increase,
ophthalmologic,
auditory, elevated
liver enzymes
Gastrointestinal
disturbances,
agranulocytosis/
neutropaenia,
arthralgia, elevated
liver enzymes
Licensed for SCD
Licensed for SCD
Not licensed for SCD
Route
Half-life
Excretion
Key adverse
effects
Status
1. Desferal (desferrioxamine). Summary of product characteristics. Camberly, UK: Novartis; 2010. 2. Exjade (deferasirox). Summary of product characteristics.
Nuremberg, Germany: Novartis; 2006. 3. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999.
Graphic courtesy of Dr. Miguel R. Abboud.
Deferasirox vs Desferrioxamine—
Measures of Iron Overload
LIC Reduction (SQUID)
Deferasirox Desferrioxamine
(n = 117)
(n = 56)
0
-2
-4
-6
-8
-10
Deferasirox Desferrioxamine
(n = 83)
(n = 33)
-3
-2.8
P = NS
Mean Reduction in Serum
Ferritin (g/L)
Mean Reduction in LIC
(mg Fe/g dw)
0
Serum Ferritin Reduction
-100
-200
-183
-300
P = NS
-400
-500
-600
-558
Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine.
Abbreviations: LIC, liver iron concentration; SQUID, superconduction quantum interference device.
Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.
Deferasirox vs Desferrioxamine—
Measures of Satisfaction and Adherence
N
Risk Ratio:
Deferasirox vs
Desferrioxamine
Patient satisfaction
195
3.13 (95% CI 1.99–4.93)
Convenience
195
3.85 (95% CI 2.28–6.47)
Patient’s estimate of
likelihood to continue
treatment
195
6.86 (95% CI 3.38–13.91)
Discontinuations
390
1.17 (95% CI 0.56–2.44)
Measure
Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine.
Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.
Conclusions
• Infarctive strokes are a devastating complication of SCD
• Chronic transfusion regimens are very effective in
preventing stroke recurrence as well as new strokes in
patients with abnormal transcranial Doppler
• Early transfusions seem effective in preventing
development and progression of silent infarcts
• Iron accumulation in sickle cell disease is different
compared with thalassaemia
• Iron chelators are effective in preventing iron overload in
these patients