Sickle Cell Disease - What is New by Miguel R. Abboud, American University of Beirut Medical Center and Children’s Cancer Center of Lebanon, Beirut

1. Sickle Cell Disease What is New
Miguel R. Abboud
g
American University of Beirut Medical Center
and Children’s Cancer Center of Lebanon
Beirut, Lebanon

2. Sickle cell at the beginning
of the 20th century
● 1910
– J.B. Herrick and Irons
– “sickled cells” in the blood of Walter Clement Noel
● 1927 Hahn and Gillespie
– deoxygenated cells sickle
● 1949
– Linus Pauling
– electrophoresis
– molecular structure

3. Haemoglobin S
[6 (A3)GluVal]
H. Wajcman
Courtesy of Dr H. Wajcman.

4. STOP Prevnar Baby HUG SWiTCH SITT
1998 1999 2000 2001 2003 2004 2006 2007 2008
Hydroxyurea Hydroxyurea Pulmonary
Walk Phast
in children in infants hypertension

5. National
BMT in Phenotype matching
sickle cell
SCD and Preop Transfusions
control act
1972 1979 1984 1986 1990 1995
Penicillin Adult phase III
prophylaxis (Gaston) hydroxyurea
CSSCD
and newborn trial
screening PPV (Charache)

6. Severity of SCD varies widely
among patients
Intermediate
forms Pain
of SCD
f ACS
Stroke
Asymptomatic patients Severe forms of SCD
Penicillin, folic acid, hydration
Hydroxyurea
Chronic blood transfusion
Bone marrow transplantation
ACS = acute chest syndrome.

7. Complications of SCD in children
Polymerization of deoxy-HbS Endothelial dysfunction
Age (years)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Bacteraemia
Pain highly variable
ACS
ASS
Stroke
Chronic organ damage ?
Castro O, et al. Blood. 1994;84:643-9.
Gill FM, et al. Blood. 1995;86:776-83.
ASS = acute splenic sequestration. Ohene-Frempong K, et al. Blood. 1998;91:288-94.

8. Prophylaxis with oral penicillin reduces
morbidity and mortality of p
y y pneumoccocal
infections
● 125 SCD children aged 3–36 months
● Randomly assigned to receive either 125 mg
oral penicillin or placebo
Placebo Penicillin
group group p
Streptococcus pneumoniae
13 2 0.0025
infections
Death (S. pneumoniae) 3 0 0.003
Incidence of S. pneumoniae
0.09
0 09 0.02
0 02 < 0.05
0 05
septicaemia
Gaston MH, et al. N Engl J Med. 1986;314:1593-9.

9. Goals of newborn screening
● Reduce mortality rates from 38% due to
Pneumococcal sepsis
● Reduce incidence of complications such as
splenic sequestration

10. South Carolina: Standard Newborn
Screening Tests
● PKU 1965 3 infants/year
● hypothyroidism 1978 10
● hemoglobin 1987 100
● galactosemia 1992 1
● CAH 1992 3
● MCADD 2000 4

11. Interpreting results
● fetal hemoglobin predominates until about age
six months
● small amounts of the adult hemoglobin type are
produced in the third trimester
● qualitative results listing the predominant
hemoglobin first ( FA FS FAS FSA)
FA, FS, FAS,
● quantitative results in the first month of life are
typically F 90% S 10%
i ll F=90% S=10%

12. Earlier diagnosis positively impacts
g p y p
survival
100 HbSS
diagnosed in newborn period
98
96
Survival (%)
94
HbSS diagnosed after newborn period
92
S
90
88
86
0 10 20 30 40 10
Months Years
HbSS = haemoglobin SS. Vichinsky E, et al. Pediatrics. 1988;81:749-55.

13. Causes of death in
children with SCD
Year Country Incidence Causes
(range)
Gill 1978–98 USA 1.1/100 pt-yr 11 sepsis (9 S.pn), 2 ASS,
1 CVA
Thomas 1985 92
1985–92 France 0.29%/yr
0 29%/yr 15 sepsis (8 S pn) 3 ASS
S.pn), ASS,
(Paris) 3 CVA
Quinn 1983–04 USA 0.59/100 pt-yr 5 sepsis (4 S.pn), 3 ACS,
(Texas) 2 multi-organ failure,
1 CVA, 1 myocardial infarct
Gill FM, et al. Blood. 1995;86:776-83.
Thomas C, et al. Arch Pediatr. 1996;3:445-51.
CVA = cerebrovascular accident; pt-yr = patient years; Quinn CT, et al. Blood. 2004;103:4023-7.
S.pn = Streptococcus pneumoniae.

14. Clinical outcome in children with SCD
living in England: a neonatal cohort in
g g
East London
● 252 children identified during 1983–2005 by
universal birth screening in East London
● Followed in a hospital- and community-based
programme
● Estimated survival of children with SCD at
16 years: 99 0% (95% CI: 93 2 99 9%)
99.0% 93.2–99.9%)
● Pneumoccal sepsis rate: 0.3 (95% CI: 0.1–0.8)
episodes/100 pt-yr
i d /100 t
● Risk of overt stroke: 4.3% (95% CI: 1.5–11.4%)
Telfer P, et al. Haematologica. 2007;92:905-12.

15. Preventive care
● Neonatal screening
– immunization
– penicillin prophylaxis
● Parents and patient education
● Annual TCD ultrasound in children > 1 year old
● I children > 5–10 years old, annual
In hild 10 ld l
echocardiogram, hepatic ultrasonography,
ophthalmologic evaluation, and pulmonary
hth l l i l ti d l
function tests
TCD = transcranial Doppler.

16. Need for pneumococcal conjugate
vaccination in addition to daily penicillin
prophylaxis in children with SCD
h l i i hild ith
● Incomplete level of adherence to penicillin
prescription
– in a Tennessee study, 25–30% of Medicaid
p g
programme enrollees were likely to receive p
y penicillin
for > 270 days per year1
● Increase in percentage of p
p g penicillin-resistant
strains
1. Halasa NB, et al. Clin Infect Dis. 2007;44:1428-33.

17. Invasive pneumococcal infections
in children with SCD
● 36.5 infections/1,000 pt-yr in SCD children
1 2
1–2 years of age, 20% meningitis, 15% deaths
● 23-valent pneumococcal polysaccharide
(PVC) efficacy: 80.4% (95% CI: 39 7–93 6)
80 4% 39.7–93.6)
● 71% of serotyped isolates were PVC serotypes
● 71% of nonvaccine serotypes were
f i t
penicillin-sensitive
Adamkiewicz TV, et al. J Pediatr. 2003;143:438-44.

18. Pneumococcal conjugate vaccine reduces
j g
rate of invasive pneumococcal disease in SCD
Age Patients Rate of IPD % of
(years) with IPD (n/100,000 pt-yr)
pt yr) decrease p
Pre-PCV era Post-PCV era
<5y
All 21 2,044 134 93.4 < 0.001
<2y 16 3,630 335 90.8 < 0.001
5y 16 161 99 38 0.36
IPD = invasive pneumococcal disease;
PCV = pneumococcal conjugate vaccination. Halasa NB, et al. Clin Infect Dis. 2007;44:1428-33.

19. Increase In IPD

20. Management of Febrile Episodes
● Fever above 38.5 C needs prompt attention
● PE: Palpate spleen
● CBC retic, blood, urine culture, Chest X ray
de te y sy pto at c,
definitely if symptomatic, LP in meningitis
e gts
suspected, O2 saturation
● Ceftriaxone 50 g/ g IV obse e for se e a
Ce a o e 50mg/kg observe o several
hours
● Follow up the next day if febrile g
p y give ceftriaxone
if stable may continue on po antibiotic

21. Management of Febrile Episodes
● High risk patients have fever >40C
● Severe anemia, high WBC, appear toxic,
previous Pneumococcal sepsis,
thrombocytopenia
● Poor compliance
● ADMITT ceftriaxone 75mg/kg
ce a o e 5 g/ g
● Vancomycin not needed unless patient
extremely unstable
y
● Hemolysis my be a complication of Rocephin

22. Annual investigations
● Complete physical examination
● Complete blood counts, liver p
p profile, electrolytes, BUN, creatinine,
y
microalbuminuria, ferritin if transfused, calcium metabolism including
vitamin D and PTH, Parvovirus B19 serology until positive
● Pulmonary function tests: routinely or as clinically indicated
● TCD from 2 to 16 years of age
● Hepatic ultrasonography after 3 y
p g p y years of age
g
● Hip radiograph and echocardiography after 6 years of age
● Ophthalmological evaluation by a trained ophthalmologist
– patients with SC disease: after 6 years of age
– patients with SS disease: after 10 years of age
● Academic performance
● Adherence to treatment and appointments
BUN = blood urea nitrogen test; PTH = parathyroid hormone.

23. Treatment
of complications
● PAIN
● Infections
● Acute anaemia: ASS aplastic crisis
ASS,
● Severe vaso-occlusive events: ACS, strokes, priapism,
organ failure
● Pulmonary hypertension
● Complications in high-risk pregnancies
Transfusion therapy is a cornerstone for management of
py g
SCD complications

24. Splenic Sequestration
● Vaso-occlusion within the spleen-splenomegaly
● Pooling of red cells-marked decrease in
hemoglobin Risk of hypovolemic shock
● Droping Hemoglobin dropping platelets
Hemoglobin,
increased reticulocyte count (may occur after
Parvo infection low retic!!)
● HbSS Young children- functional spleen at risk.
● HbSC or S thal older patients at risk

25. Sequestration
● 30% of children have one episode. Initial
symptom in 20%
● May lead to early death 10-15% mortality
● Teach parents to follow spleen size
● Transfuse for acute event-Hb overshoot as
spleen shrinks
l hi k
● High rate (50%) recurrence splenectomy after
first severe event

26. Risk factors for early death in patients
with sickle cell anaemia who were
20 years of age or older*
Variable Variable estimate ± SE p value†
HbF (%) −0.09 ± 0.04 < 0.001
Acute chest syndrome‡ 0.80 ± 0.27 0.005
Renal f il
R l failure 1.10 0.47
1 10 ± 0 47 0.03
0 03
Seizures 0.91 ± 0.42 0.04
White cell count 0.10 0.04
0 10 ± 0 04 0.01
0 01
*The values shown for the variable estimates reflect the associations between age-specific mortality risks
and clinical profiles during the study in a multivariate model, with backward elimination, by proportional-
hazards regression.
†Lik lih
Likelihood ratio, 1 d
d ti degree of f d
f freedom.
‡Scored as follows: < 0.2 episode per year = 1; ≥ 0.2 episode per year = 0.
HbF = fetal haemoglobin. Platt O, et al. N Engl J Med. 1994;330:1639-44.

28. Causes of death in Athens cohort
HU patients Non-HU patients
Cause of death
(13/131 = 9.9%) (49/199 = 24.6%)
Liver dysfunction 1 10
Pulmonary hypertension 8 8
Stroke 3 10
Sudden death 3 5
Vaso-occlusion crisis 1 6
Acute chest syndrome 1 5
Sepsis 1 1
Heart failure 2 2
Intervention
I t ti 1 2
Voskaridou E, et al. Blood. 2010;115:2354-63.

29. Hydroxyurea
● Potential to increase HbF
● Have salutary effects on the adverse risk factors
● Phase 3 randomized trial
– 299 adults, 21 centres
● Decreased rate of painful crises by 50%
● Decreased rates of hospitalization for pain or
ACS and d
d decreased numbers t
d b transfusions
f i
● Led to FDA approval of hydroxyurea
pp y y
ACS = acute chest syndrome;
FDA = US Food and Drug Administration. Charache S, et al. N Engl J Med. 1995; 332:1317-22.

30. Hydroxyurea in SCD:
multiple mechanisms of action
Ware RE. Blood. 2010;115: 5300-11.

31. The Hydroxyurea
Response
Patient
1
Patient
2
Pre-treatment Dose Maximum Tolerated
Escalation Dose

32. Acute chest syndrome
● A new pulmonary infiltrate involving at least one
complete lung segment not consistent with atelectasis
p g g
● One or more of
– chest pain
– fever
– tachypnoea, wheezing, cough
– hypoxaemia compared with baseline
● Complicates 30% of admissions for painful vaso-occlusive
vaso occlusive
crises
● Most common post operative complication in patients
post-operative
with SCD

34. Medoff BD et al. Case 17-2005: A 22-Year-Old Woman with Back and Leg Pain
and Respiratory Failure. 2005;352(23):2425-34.

35. ACS is associated with higher
mortality in patients with SCD-SS
Survival of patients with SCD SS b occurrence of ACS
S i l f ti t ith SCD-SS by f
events within first 2 years of follow-up
1.0
Surviva probability
8.0
6.0
al
4.0
40
2.0 No ACS (n = 1,764)
S
ACS (n = 419)
0
0 10 20 30 40
Age (years)
Castro O, et al. Blood.
1994;84:643-9.

36. Prediction of Late events
Quinn, C. T. et al. Blood 2007;109:40-45
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

37. Flowchart for the management of ACS.
Miller S T Blood 2011;117:5297-5305

38. Flowchart for the diagnosis of ACS.
Miller S T Blood 2011;117:5297-5305

39. Role of Steroids
● Corticosteroids: Rationale
– Multiple studies have shown an inflammatory milieu in ACS
– Increased levels of adhesion molecules such as VCAM-1,
– SPLA2 which can release f
hi h l free f tt acid l di t more VCAM 1
fatty id leading to VCAM-1
– High levels of cytokines like IL-8 and G-CSF
– Asthma may a role and need to be treated adequately
● Clinical reality
– Dexamethasone 0.3 mg/kg q 12hrs for 4 doses
• Shorter hospital stays less transfusions
• increased rates of readmission
• 2 CNS bleeds
– Lower dose prednisone better tolerated no increase readmissions
– There is a trend to less steroid use
– Are asthmatic patients with SCD being under treated?
Bernini JC et al Blood 1998 92:3082 Kumar R et al JPHO 2010 32:91
Sobota A et al AJH 2010 85:24 Strousse JJ et al PBC 2007 50:1006

40. Prevention of ACS:
hydroxyurea vs HSCT
● MSH
–h d
hydroxyurea hi hl effective i th prevention of acute
highly ff ti in the ti f t
chest syndrome episodes
● HSCT
– no new episodes of acute chest syndrome
– stabilization of pulmonary function
HSCT = haemopoietic stem cell transplantation.

41. Transfusion to prevent ACS
● In the STOP study, 63 children were randomly assigned
to chronic transfusions and 67 to observation based on
cerebral blood velocity by TCD. Mean follow-up of
19.6 months
● Based on intent-to-treat analysis: hospitalization rates for
ACS 4.8 in transfused group versus 15.3 per 100
patient-years non-transfused
patient years in non transfused group (p = 0 0027)
0.0027)
● Transfusions also protective for pain when analyzed as
to treatment received 9 7 versus 27 1 events per 100
9.7 27.1
patient-years (p = 0.014)
● Transfusion remain protective of ACS 2.2 versus 15.7
events per 100 patient-years (p = 0.0001)
TCD = transcranial Doppler. Miller ST, et al. J Pediatr. 2001;139:785-9

42. ACS: an iatrogenic condition
● Multi-modal pain intervention in a large tertiary
centre
● Standardized orders staff caregiver education
● 332 admissions, 159 before and 173 after
● ACS rates declined from 25% to 12% p = 0.003
● Time to ACS increased from 0 8 to 1 7 days
0.8 1.7
p = 0.047
Reagan M, et al. Pediatr Blood Cancer. 2011;56:262-6.

43. BABY HUG – Objectives
j
• Primary: To determine
whether hydroxyurea can
prevent or reduce chronic organ damage to the
spleen and kidneys in very young children with
sickle cell anemia
• Secondary: To investigate safety; to determine
hematologic effects and effects on other
h t l i ff t d ff t th
measures of organ function; to examine effects
on adverse events
d t

44. Clinical Outcomes:
BABY HUG compared with MSH
BABY HUG† MSH
HU PL p HU PL p
n 96 97 152 147
pain 177 372 0.002 2.5/y 4.5/y <0.001
ACS 8 27 0.017 25 51 <0.001
dactylitis 24 123 <0.001 — — —
hospitalization* 232 321 0.050 1.0/y 2.4/y —
transfusion‡ 35 60 0.033 48 73 0.001
†data indicate no of episodes
no.
*in BABY HUG, all hospitalizations; in MSH, hospitalization for pain only
‡in BABY HUG, no. of transfusions; in MSH, no. of pts. receiving transfusion

45. Hydroxyurea vs transfusions
● Hydroxyurea
– one randomized t i l of h d
d i d trial f hydroxyurea i adults with
in d lt ith
SCD
– many non-randomized trials of HU in children
● Blood transfusion
– randomized trials of transfusions in SCD:
STOP, STOPII
STOP STOPII, and Preop Transfusion study
dP T f i t d
– Acute Chest Study not randomized

46. Toxicity of hydroxyurea
Toxicity Outcome Level of evidence
Leg ulcers Comparable High
Leukaemia Comparable Low
Other cancers Comparable Low
Spermatogenesis
p g Defects Insufficient
Pregnancy Comparable Insufficient

47. Silent versus ischaemic
infarcts in SCD
Silent Ischaemic
Transfusion therapy lowers risk for new
silent infarcts or stroke for children with
both abnormal TCD ultrasonographic
velocity and silent infarct
Pegelow CH, et al. Arch Neurol. 2001;58:2017-21.

48. Aims and study design
Aim: to compare 30 months of hydroxyurea and phlebotomy (alternative) with
transfusions and deferasirox (standard) for the prevention of secondary stroke and
reduction of transfusional iron overload
161 paediatric patients with sickle cell anaemia (83 male, 78 female),
documented stroke and iron overload enrolled in SWiTCH (US10)
134 patients randomized 1:1
Alternative arm Standard arm
67 patients 67 patients
Hydroxyurea + phlebotomy Transfusions + deferasirox
Prediction: increased occurrence of recurrent stroke events in alternative arm
counter-balanced by better management of iron overload with phlebotomy
Ware RE, Helms RW. Blood. 2010;116:[abstract 844].

49. Results: stroke recurrence rate
The difference in stroke rates between the
two arms was greater than expected
Treatment arm
Transfusions + Hydroxyurea +
deferasirox phlebotomy
Stroke incidence 0/66 (0%) 7/67 (10%)
Ware RE, Helms RW. Blood. 2010;116:[abstract 844].

50. Author conclusions
● Transfusions and chelation remain the gold standard
treatment for secondary stroke prevention in p
y p paediatric
SCD patients
● Phlebotomy is not superior to deferasirox in reducing
iron overload
● Pre study stroke predictions were inaccurate
Pre-study
● Study was terminated early as reduction of LIC by
phlebotomy could not compensate for the marked
increase in secondary stroke risk with hydroxyurea
Ware RE, Helms RW. Blood. 2010;116:[abstract 844].

51. Predictive value of TCD for stroke
Predictive value of TCD for stroke
Right MCA Left MCA
220 cm/s 130 cm/s
● The probability of remaining stroke-free over time of follow-up or start of
f f ff f
chronic transfusion (~ 70 months) was greatest with normal baseline TCD
The risk of stroke was higher with abnormal TCD than with normal
or conditional TCD (p < 0.01)
Adams RJ, et al. Blood. 2004;103:3689-94.

52. Importance of TCD in SCD
● Yearly stroke risk
– baseline risk from CSSCD ~ 0.5–1%
0.5 1%
– if prior stroke ~ 30%
– TIA lower baseline Hb prior and recent ACS
TIA, Hb,
(CSSCD study, no prior stroke) but yearly risk not
quantitated
– abnormal TCD 10–13% per year
– MRI “silent lesions” ~ 2–3% per y
p year
– severe arterial lesions on angiography?
• assumed to be bad, but yearly risk has not been quantitated

53. Blood transfusion prevents first
stroke in sickle cell anaemia
● Kaplan-Meier estimate of the 100
probability of not having a stroke
ree
among 130 patients with sickle cell
rcent of remaining stroke-fr
anaemia at high risk of stroke as 80
determined by transcranial Doppler.
● Patients were randomized to chronic
g
long-term transfusion therapy or 60
standard care
● There was a significant benefit from
g
40
transfusion therapy (p = 0.02)
● One patient in the standard-care
group who had an intracerebral Per 20 Transfusion
haematoma was excluded Standard care
● The tick marks represent the lengths
of observation in patients who did not 0
have a stroke
h t k 0 5 10 15 20 25 30
Months
Data from Adams RJ, et al. N Engl J Med. 1998;339:5-11.

54. Identification and management of stroke risk
g
in children with SCD: NIH guidelines
Child with HbSS, aged > 2 years, with no symptoms
Evaluate Neuropsychological TCD
educational needs testing unavailable
na ailable
based on results
TCD High risk based on
other information†
Abnormal Normal (< 200 cm/s)
Low risk Protocol treatment or
( 200 cm/s)
clinical trial
Confirm abnormal Repeat TCD every
Observation Or treatment options
3–12 months*
• Observation for
MRI/MRA progression
Abnormal • HU
Chronic transfusion examination • Transfusion
• Other (e.g.
antiplatelet agents)
*Optimal frequency of re-screening not established;
younger children with velocity closer to 200 cm/s should be
re-screened more frequently.
†Prior transient ischaemic attack, low steady-state Hb, rate
and recency of ACS, elevated systolic blood pressure. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. Accessed Nov 2010.

55. Early TCD screening
● A study from France confirmed benefits of early
TCD screening
● Reduced incidence of strokes with aggressive
management in a newborn screening cohort
ti b i h t
● TCD yearly
● MRI/A yearly after age 5 years

56. Diagram of the CHIC SCA
newborn cohort
SCA (SS/Sb0) – newborn between May 1998 and A il 2007
b b t M d April
(n = 256)
Never seen (n = 7)
Seen in the CHIC centre (n = 249)
Moved to another place (n = 24)
France (n = 21)
Africa (n = 3)
Lost to follow-up (n = 3)
TCD parental refusal (n = 2)
Patients too young for TCD ( = 3)
y g (n )
TCD screened (n = 217) Dead (n = 4)
Africa (n = 3)
Other place in France (n = 11)
Still followed at CHIC centre (n = 198) Lost to follow-up (n = 1)
Bernaudin F, et al. Blood. 2011;117:1130-40.

57. Patient therapy
● HU for patients with recurrent ACS or pain
or normal TCD and Hb < 7 g/dL
● Transfusions for abnormal TCD in 45 patients
● HSCT for patients with sibling donors
Bernaudin F, et al. Blood. 2011;117:1130-40.

58. Cumulative risk of overt stroke
10
8
Risk of stroke (%)
)
6
s
4
2
0
0 2 4 6 8 10 12 14 16 18
Age (years)
Number at risk 217 188 148 103 84 64 49 32 16 7
Bernaudin F, et al. Blood. 2011;117:1130-40.

59. Early TCD screening and intensification
of transfusion therapy allows > 5x
reduction of stroke risk by age 18 years
100 100
Risk of abnormal
mal-MRA)
Risk of stenosis
80 80
TCD (%)
60 60
s
D
(abnorm
a
40 40
20 20
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Number at risk
Age (years) Number at risk
Age (years)
217 216 186 154 120 94 82 77 67 57 50 44 39 29 24 132 132 131 128 114 96 79 67 60 53 49 38 28 20 17
100 100
CD/stenosiis/
80 80
Risk of silent
CNS risk (stroke/
troke (%)
roke (%)
60 60
40 40
abnormalTC
k
k
str
silent st
20 20
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Age (years) Age (years)
a
Number at risk Number at risk
129 129 127 125 112 94 76 63 51 43 40 33 25 17 13 217 215 184 155 126 96 74 69 58 47 42 39 36 27 23
Bernaudin F, et al. Blood. 2011;117:1130-40.

60. Conclusions
● Early TCD and transfusions effective in
preventing strokes but not silent infarcts
● Most patients who develop silent infarcts have
normal TCD
l
● Different strategies needed

61. Neurocognitive function in infants
SCA
13
14 Controls
hs)
BINS raw score (9 month
12
12
11
(
BINS raw score
10 10
w
w
9
8
8
R2 = 0 913
0.913
B
B R2 = 0 229
0.229
7 6
7.0 8.0 9.0 10.0 11.0 12.0 30 70 110 150
Haemoglobin (g/dL) MCA velocity
Hogan AM, et al. Br J Haematol. 2005;132:99-107.

62. Approach to neurological
complications in SCD
Abnormal Abnormal
Overt Silent infarct
TCD neuropsychology
stroke on MRI
(↓FSIQ)
BMT Chronic Education
Hydroxyurea
(CBT) transfusion support
SWiTCH SIT
trial trial
Intervention of proven value
Intervention of possible value
Efficacy of ‘intervention of p
y possible value’ under investigation
g
Adapted from Wang W. Curr Opin Hematol. 2007;14:191-7.

63. Special issues in transfusion
of sickle cell patients
1. Avoid hypervicosity
– sudden elevated blood pressure
– congestive heart failure
– alteration in metal status
– attributed to increase in whole blood viscosity
– see at Hb > 12 g/dL hct > 33%
g/dL,
2. Delayed haemolytic transfusion reactions
3. Iron distribution may be different than in
thalassaemia patients
– less cardiac and endocrine iron deposition

64. Approaches to transfusion therapy
Approach Applications
Simple transfusion
Transfusion of additional units of blood Severely anaemic patients
without removal of sickle blood Hb levels < 8–9 g/dL
Automated exchange transfusion
(erythrocytapheresis)
Sickle cells are removed and replaced Preferred when rapid alteration
with normal red cells of Hb levels is required
Rapid partial exchange transfusion
Whole blood removed from one arm Widely appropriate
while donor cells transfused into other
de Montalembert M, et al. Am J Hematol. 2011;86:72-5.
.

65. Effectiveness of transfusions in SCD
Criterion Outcome Level of evidence
Painful i
P i f l crises Decreased
D d Low
L
Hospitalizations Decreased Low
Acute chest syndrome Decreased High
Neurological events Decreased High
Proteinuria Decreased Low

66. Decrease in serum ferritin levels with
5 years of deferasirox therapy
Serum ferritin (µg/L) Deferasirox dose (mg/kg/day)
In ti t
I patients receiving deferasirox for ≥ 4 years, median serum ferritin
i i d f i f di f iti
significantly decreased by −591 μg/L (p = 0.027; n = 67)
Vichinsky E, et al. Blood. 2010;116:[abstract 845]. Data presented at ASH 2010.

67. Results of BMT in 4 large series
Author
A th N Median A
M di Age TRM% Rejection
R j ti EFS%
%
Walters et al 59 9.4 (3.3-14) 6 10 85
Bernaudin et 87 8.8 (2.2-22) 6.9 7 86
al
Panepinto et 67 10 (2 27)
(2-27) 3 late 13 85
al deaths
Vermylen et 50 7.5 (0.9-23) 7 10 82
al
l
Walters et al Blood 2000; 95: 1918 Updated EBMT 2008
Bernaudin et al Blood 2007; 110: 2749
Panepinto et al BJH 2007; 137: 479
Vemylen et al BMT 1998; 22: 1

68. Who was Transplanted
● Despite different age criteria most transplant
were in the pediatric age group
● Patients with severe disease. Different
definitions

69. Bernaudin et al Blood
al.
2007
Panepinto et al. BJH
P i t t l
2007
Vermylen et al. Bone
Marrow Transplant 1998
McPherson et al. Bone
Marrow Transplant 2011.
Locatelli et al. Blood
2003

70. HSCT in adult SCD patients
• A modified conditioning protocol for allogeneic haemopoietic stem cell
transplantation that does not ablate the bone marrow was used to treat
10 adults who had severe sickle cell disease
• The sickle cell phenotype was eliminated in 9 of the 10 recipients
• No deaths, no major adverse events, and no graft-versus-host disease
occurred among the recipients
g p
HLA typing performed in 169 siblings and 112 patients
88 patients did not have matched related donors
p
24 patients were eligible
4 were excluded for major ABO incompatibility
1 died before HSCT
8 are receiving optimizing medical therapy
1 is in pre-HSCT evaluation
10 underwent transplantation
Hsieh MM, et al. N Engl J Med. 2009;361:2309-17.

71. CDC-WHO Survey of 22 Countries in
MENA region
● 17/22 Responded
● 8/17 Have management guidelines
● 5/17 NBS programs one excludes
hemoglobinopathies
● 8/17 Have awareness programs
● 7/8 Provide penicillin and 8/8 hydroxyurea
EMBMT 255 HSCT All for thalassemia

72. Conclusions
● There have been significant advances in the
management of sickle cell disease leading to
increased survival and a decrease in complications
● Transfusions play a major role in preventing
complications and end-organ dysfunction
● Hydroxyurea is very useful in these patients,
but its role may be limited in certain circumstances
● HSCT is limited by availability of donors

73. β-Thalassaemia intermedia
● “Highly diverse” group of β-thalassaemia syndromes where red
blood cells are sufficiently short-lived to cause anaemia, without
patients necessarily requiring regular bl d transfusions
i il ii l blood f i
● The severity of the clinical phenotypes varies between those of
β thalassaemia
β-thalassaemia minor (TI) and β-thalassaemia major (TM)
β thalassaemia
● TI arises from defective gene(s) leading to partial suppression of
β-globin protein production
Mild Severe
Completely asymptomatic Presentation at age 2–6 years
until adult life Retarded growth and development
Taher A, et al. Br J Haematol. 2011;152:512-23.
Guidelines for the clinical management of thalassaemia. 2nd rev. ed. TIF 2008.

74. Pathophysiology summarized
Excess free Formation of haem
α-globin chains Denaturation and haemichromes
Degradation
g
Iron-mediated toxicity
Ineffective erythropoiesis
Membrane
Ineffective
Haemolysis binding of
Chronic anaemia and
erythropoiesis haemolysis
IgG and C3 Removal of
damaged red cells
Iron overload
Increased
erythropoietin Reduced tissue Anaemia Splenomegaly
synthesis oxygenation
Skeletal Erythroid
deformities, Increased
I d
marrow Iron overload
osteopenia expansion iron absorption
Olivieri NF, et al. N Engl J Med. 1999;341:99-109.

75. Overview on Practices in Thalassemia Intermedia
Management Aiming for Lowering Complication rates
Complication-rates
Across a Region of Endemicity: the OPTIMAL CARE study
● Retrospective review of 584 TI patients from
6 comprehensive care centres in the Middle East and Italy
N = 127 N = 153
N = 200 N = 51
N = 12 N = 41
Taher AT, et al. Blood. 2010;115:1886-92.

76. The OPTIMAL CARE study:
overall study population
Frequency
Parameter
n (%)
Age (years)
< 18 172 (29.5 )
18–35 288 (49.3)
> 35 124 (21.2)
Male : female 291 (49.8) : 293 (50.2) Frequency
Treatment
Splenectomized 325 (55.7) n (%)
Serum ferritin (µg/L) Hydroxyurea 202 (34.6)
< 1,000 376 (64.4) Transfusion
1,000–2,500 179 (30.6) Never 139 (23.8)
> 2,500 29 (5) Occasional 143 (24.5)
Complications Regular 302 (51.7)
Osteoporosis 134 (22.9) Iron chelation
EMH 124 (21.2) None 248 (42.5)
Hypogonadism 101 (17.3) Deferoxamine 300 (51.4)
Cholelithiasis 100 (17.1) Deferiprone 12 (2.1)
Thrombosis 82 (14) Deferiprone + deferoxamine 3 (0.5)
(0 5)
Pulmonary hypertension 64 (11) Deferasirox 21 (3.6)
Abnormal liver function 57 (9.8)
Leg ulcers 46 (7.9)
yp y
Hypothyroidism 33 (5.7)
( )
Heart failure 25 (4.3)
Diabetes mellitus 10 (1.7)
EMH = extramedullary haematopoiesis. Taher AT, et al. Blood. 2010;115:1886-92.

77. 120 Treatment-naive patients
12.0
Haemoglob (g/dL)
10.0
8.0
bin
6.0 Age vs haemoglobin level
4.0 (r = −0.679, p < 0.001)
2.0
0.0
0 20 40 60
Age (years)
3000
3,000
Serum ferritin (µg/L)
2,500
2500
2,000
2000
1,500
1500 Age vs serum ferritin level
g
1,000
1000 (r = 0.653, p < 0.001)
500
500
0
0
0 20 40 60
Age (years)
Taher A, et al. Br J Haematol. 2010;150:486-9.

78. Complications vs age
Complications in 120 treatment-naive patients with TI
<<10 years
10 years 11–20 years
11-20 years 21-32 years
21–32 years > 32 years
>32 years
45 *
40.0
40
35 33.3
*
* * 30.0
%)
equency (%
30 26.7 26.7
25
* 23.3 23.3
20 16.7 16.7
20.0 20.0 20.0 *
16.7 16.7 16.7
20.0
Fre
15 13.3 13.3 13.3 13.3 13.3
10.0 10.0 10.0 10.0 10.0
10 6.7 6.7 6.7 6.7 6.7 6.7
5 3.3 3.3 3.3 3.3 3.3 3.3 3.3
0 0 0 0 0
0
* = statistically significant trend.HF = heart failure;
PHT = pulmonary hypertension;
ALF = abnormal liver function; DM = diabetes mellitus. Taher A, et al. Br J Haematol. 2010;150:486-9.

79. Splenectomy
● Less common than in the past
– before age 5 years it carries a high risk of infection
and is therefore not generally recommended
● Main indications include
– growth retardation or poor health
– leukopenia
– thrombocytopenia
thromboc topenia
– increased transfusion demand
– symptomatic splenomegaly
● Primarily done in regularly transfused TM patients
Taher A, et al. Br J Haematol. 2011;152:512-23.
Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

80. Thromboembolic events in a large
cohort of TI patients
● Patients (N = 8,860)
– 6,670 with TM Venous 48
66
– 2,190 with TI Stroke 28
9
● 146 (1.65%) thrombotic events 23
DVT
Type of event
39
– 61 (0 9%) with TM
(0.9%)
PE 8
– 85 (3.9%) with TI 12
11
● Risk factors for developing PVT 19
T
thrombosis in TI were STP 0 TM (n = 61)
8
– age (> 20 years) TI (n = 85)
Others 30
12
– previous thromboembolic event
– family history 0 20 40 60 80
– splenectomy Thromboembolic events (%)
DVT = deep vein thrombosis;
PVT = portal vein thrombosis; STP = superficial thrombophlebitis. Taher A, et al. Thromb Haemost. 2006;96:488-91.

81. Multivariate analysis
Parameter Group OR 95% CI p value
NRBC count ≥ 300 x 106/L Group III 1.00 Referent
Group II 5.35 2.31–12.35
< 0 001
0.001
Group I 11.11 3.85–32.26
Group I had significantly higher NRBC, platelets,
Platelet count ≥ 500 x 109/L Group III 1.00 Referent
PHT occurrence and were mostly non-transfused
occurrence,
Group II 8.70 3.14–23.81
< 0.001
Group I 76.92 22.22–250.00
PHT Group III 1.00 Referent
Group II 4.00 0.99–16.13
0.020
Group I 7.30 1.60–33.33
Transfusion naivety Group III 1.00 Referent
Group II 1.67
1 67 0.82 3.38
0 82–3 38 0.001
0 001
Group I 3.64 1.82–7.30
NRBC = nucleated red blood cell;
OR = adjusted odds ratio; CI = confidence interval. Taher A, et al. J Thromb Haemost. 2010;8:2152-8.

82. Time-to-thrombosis (TTT) since
splenectomy
Time to thrombosis
1 1
ombosis-
ombosis-
NRBC count Platelet count
0.8 < 300 x 106/L 0.8 < 500 x 109/L
≥ 300 x 106/L
val
val
≥ 500 x 109/L
The median TTT following splenectomy was 8 years (range 1 33 years)
(range, 1–33
free surviv
free surviv
Cumulative thro
Cumulative thro
0.6 0.6
0.4The median TTT was significantly shorter in patients with an NRBC
0.4
0.2 count ≥ 300 x 106/L, a platelet count ≥0.2 x 109/L , and who were
500
transfusion naive
0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Duration since splenectomy (years) Taher A, et al. J Thromb splenectomy (years)
Duration since Haemost. 2010;8:2152-8.
1 1
hrombosis-
hrombosis-
Transfused Pulmonary hypertension
0.8 Yes 0.8 Yes
No No
vival
vival
0.6 0.6
free surv
free surv
Cumulative th
Cumulative th
0.4 0.4
0.2 0.2
0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Duration since splenectomy (years) Duration since splenectomy (years)
Taher A, et al. J Thromb Haemost. 2010;8:2152-8.

83. Silent brain MRI findings in 30
splenectomized adults with TI (cont.)
White matter lesions
● 18 patients (60%) had evidence
Parameter n (%) of one or more WMLs on brain
Number MRI all involving the subcortical
Single 4 (22.2) white matter
Multiple* 14 (77.8)
Location
● 11 patients (37%) had evidence
Frontal 17 (94.4)
(94 4) of mild cerebral atrophy 10 of
atrophy,
Parietal 9 (50) whom had associated WMLs
Temporal 1 (5.6)
Occipital 3 (16.7)
Internal capsule 1 (5.6)
(5 6)
External capsule 5 (27.8)
Size** White matter lesions and brain
Small (< 0.5 cm) 10 (55.5)
atrophy are a common finding in
Medium (0.5–1.5 cm)
( ) 7 (38.9)
( )
Large (> 1.5 cm) § 1 (5.6) adult, splenectomized, TI patients
d lt l t i d ti t
*Mean of 5 ± 10 lesions (range: 2 to > 40 lesions).
**For patients with multiple lesions, the largest lesion was used to define
size.
§Th possibility of misreading confluent multiple l
The ibilit f i di fl t lti l lesions was excluded
i l d d
radiologically based on lesion shape.
WML = white matter lesions. Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.

84. Risk factors for white matter lesions
No. of abnormalities
Occasionally transfused 0 1 >1
1.1
6
1.0
bility of abnormality
5
0.9 4
3
0.8 2
1
0.7
07
Patients (n)
)
0
0.6
0.5
Non-transfused
6
0.4 5
Probab
P
4
0.3
3
0.2 2
1
0.1 0
10 15 20 25 30 35 40 45 50 55 60 ≤ 30 30–40 40–50 > 50
Age (years) Age (years)
Increasing age and transfusion naivety are associated with a
higher incidence and multiplicity of white matter lesions
Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.

85. Recommendations for
iron chelation therapy in TI
Age < 4 years Age ≥ 4 years
Haemoglobin Haemoglobin
Observation
< 9 g/dL ≥ 9 g/dL
EvidenceMonitor LIC guidelines for LIC
Initiate
based Continue
Monitor
and and
chelation is serum ferritin
transfusions currently in preparation!
observation
serum ferritin
Transfusions LIC > 7 mg Fe/g dry wt LIC > 7 mg Fe/g dry wt
> 10 units or serum ferritin or serum ferritin
> 500 µg/L
/L > 500 µg/L
/L
Start iron Start iron Start iron
chelation
h l ti chelation
h l ti chelation
h l ti
therapy therapy therapy
Taher A, et al. Br J Haematol .2009;147:634-40.

86. Summary
● Our understanding of the molecular basis and pathophysiology of
TI significantly increased
● Iron overload and hypercoagulability are recently receiving
increasing attention in TI
● Despite that various treatment options are available, no clear
guidelines exist
● S
Several studies are challenging th role of splenectomy yet
l t di h ll i the l f l t t
highlighting the benefit of transfusion, iron chelation therapy, and
fetal haemoglobin induction in the management of TI; thus these
approaches merit large prospective evaluation
● The role of antiplatelets/anticoagulants in TI merits investigation

87. Early TCD screening and intervention
● Predictive factors and outcomes of cerebral
vasculopathy in the Créteil newborn SCA cohort
p y
(n = 217, SS/S0), who were early and yearly screened
with TCD 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 no
macrovasculopathy
● HSCT for those with HLA genoidentical donor
● Mean follow-up was 7.7 years (1,609 patient-years)
Bernaudin F, et al. Blood. 2011;117:1130-40.

88. Cumulative risks
● Cumulative risks by 18 years of age
– stroke: 1.9% (95% CI 0.6–5.9) compared with 11%
– abnormal T (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
● Cumulating all events
– the cerebral risk by 14 years of age was 49.9% (95% CI 40.5–59.3)
● P di ti f t
Predictive factors for cerebral risk
f b l i k
– baseline reticulocytes count
– lactate dehydrogenase
● Thus, early TCD screening and intensification therapy allowed the
reduction of stroke-risk by 18 years of age from 11% to 1.9%
● In contrast the 50% cumulative cerebral risk suggests the need for
contrast,
more preventive intervention
Bernaudin F, et al. Blood. 2011;117:1130-40.

89. Early TCD screening and intensification of
transfusion therapy allows > 5x Cumulative risk
Early TCD Screening Followed by reduction of
py
stroke risk by 18 years of age
100 100
%)
A B
ormal TCD (%
90 90
80 80
(abnormal MRA) (%)
70 70
nosis
60 60
50 50
M
Risk of sten
Risk of abno
40 40
30 30
20 20
10 10
0 0
R
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Number at risk Age (years) Number at risk Age (years)
217 216 186 154 120 94 82 77 67 57 50 44 39 29 24 132 132 131 128 114 96 79 67 60 53 49 38 28 20 17
silent stroke) (%)
100 C 100 D
%)
)
Risk of silent stroke (%
90 90
ke/abnormal
80 80
70 70
60 60
50 50
D/stenosis/s
40
CNS risk (strok 40
30 30
20 20
10 10
0 0
S
TCD
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Number at risk Age (years) Number at risk Age (years)
129 129 127 125 112 94 76 63 51 43 40 33 25 17 13 217 215 184 155 126 96 74 69 58 47 42 39 36 27 23
Bernaudin F, et al. Blood. 2011;117:1130-40.

90. Ongoing studies
● Positron emission tomography (PET)
– preliminary results
• 18 (60%) had abnormal MRI findings
• 19 (63.3%) had abnormal PET findings
• 26 (86.7%) had abnormal MRI, abnormal PET, or both
( ) , ,
● Magnetic resonance angiography
ag et c eso a ce a g og ap y
Taher AT, et al. Blood. 2009;114:[abstract 4077].

91. Cardiac iron overload in
19 Lebanese TI patients
Population: 19 transfusion independent TI patients vs
19 polytransfused TM patients
Parameter TI (n = 19) TM (n = 19) p value
Mean age ± SD, years 32.8 ± 7.9 33.0 ± 7.4
0.861
(range) (18–51) (17-49)
Male/female
M l /f l 11/8 11/8 –
Mean Hb ± SD, g/dL 8.9 ± 2.3 9.9 ± 1.6
0.241
(range) (4.9–13.1) (7.1–12.2)
Mean SF ± SD, µg/L 1,316.8 ± 652.3 3,723.8 ± 2,568.8
0.001
(range) (460–3157) (827–10,214)
Mean LIC ± SD, mg Fe/g dry wt
, g g y 15.0 ± 7.4 15.7 ± 9.9
0.095
(range) (3.4–32.1) (1.7–32.6)
Mean cardiac T2* ± SD, ms 47.3 ± 7.1 21.5 ± 15.2
< 0.001
(range) (35.0–66.9)
(35 0 66 9) (5.1–50.7)
(5 1 50 7)
Results: T2* was normal in all TI patients despite similar LIC with TM
SF = serum ferritin. Taher A, et al. Am J Hematol 2010;85:288-90.

92. NTBI in TI
35 Splenectomized 3,500 Splenectomized
Non-splenectomized Non-splenectomized
30 3,000
/L)
LIC (mg Fe/g dry wt)
25 2,500
2 500
w
Serum ferritin (µg/
20 2,000
15 1,500
,
m
10 1,000
y = 0.7787x + 6.7383 y = 74.121x + 728.69
5 500
R2 = 0.1301 R2 = 0.1556
0 0
-5 0 5 10 15 -5 0 5 10 15
NTBI (µmol/L) NTBI (µmol/L)
Significant correlations were observed between NTBI and both serum
ferritin and LIC, confirming the value of this method for assessing
iron overload in TI
Taher AT, et al. Br J Haematol. 2009;146:569-72.

93. Silent infarcts
● Prevalence: 22% ● Risk factors
– low haemoglobin
● Fronto parietal areas
Fronto-parietal – high reticulocytes
● Associated with neuro- – seizures
cognitive dysfunction – low rate of painful crises
l f i f l i
– leukocytosis
● Deep white matter
p – thrombocytosis
– SEN haplotype
● Small size
– prior silent infarcts
● Risk factor for stroke
● Management
– transfusions ? SITT

94. Strokes are a devastating
complication of SCD
Generalized brain atrophy in rare cases Rare venous system clots
“borderzone” infarction Arteriolar thickening and
capillary dilatation
Small white matter
lesions visible on MRI Cortical vessel dilatation
Large cerebral infarcts
Lenticulostriate arteries
form “moyamoya”
Subcortical infarction
Proximal arterial stenosis
at ICA, MCA, ACA
Intraventricular and
Most common site of
intraparenchymal
occlusive disease is here
haematoma
Ophthalmic artery
Subarachnoid haemorrhage Aneurysms, often multiple
from aneurysm rupture on “circle of Willis”
Dilatation of vertebrobasilar
Fat embolism system due to collateral flow
Cervical ICA usually unaffected

95. Transfusions after a stroke
● There is often progression of vasculopathy
●N
New silent i f t
il t infarcts
● The reasons are not clear

96. Children with SCD receiving regular blood
transfusion therapy for secondary
py y
prophylaxis of strokes
53 children enrolled 13 children excluded
40 children met criteria Second overt strokes
for analysis (n = 7)
No second overt strokes Silent infarcts
(n = 33) (n = 8)
TIAs without new No new
MRI lesions MRI lesions TIAs ft
TIA after silent infarct
il t i f t
(n = 1) (n = 21) (n = 1)
TIAs with silent infarct
on next MRI
(n = 2)
MRI = magnetic resonance imaging;
TIA = transient ischaemic attack. Hulbert ML, et al. Blood. 2011;117:772-9

97. Survival free of new overt or silent cerebral infarcts
in children with SCD while on transfusion therapy
for secondary stroke prophylaxis
1.0
10 1.0
10
Proportion free of new silent
Proportion fr of new
0.8 0.8
cerebral infarcts
cerebral infarcts
0.6 0.6
ree
0.4 0.4
0.2 0.2
P
0 0
0 2 4 6 8 10 0 2 4 6 8 10
Time from initial stroke Time from initial stroke
(years) (y
(years))
1.0
Proportion free of new
0.8
kes
With cerebral vasculopathy
overt strok
0.6
06
e
0.4
Without cerebral vasculopathy
0.2
P
0
0 2 4 6 8 10
Time from stroke (years) Hulbert ML, et al. Blood. 2011;117:772-9.

98. Survival free of detection of new silent cerebral infarcts
in children with SCD while on transfusion therapy for
secondary stroke prophylaxis
1.0
0.8
08
Proportion fre of new silent
0.6
w
0.4
cts
ee
bral infarc
0.2 No cerebral vasculopathy
p y
With cerebral vasculopathy
cereb
0
0 2 4 6 8 10
Time from initial stroke (years)
Hulbert ML, et al. Blood. 2011;117:772-9.

99. Coates TD. Blood. 2011;117:745-46.

100. Are transfusions really ineffective in
preventing silent strokes?
● Coates: “increased viscosity of sickle or mixed
blood in low shear areas such as post-capillary
post capillary
venules is not helped by transfusions”
– thus, does not prevent SI and microvascular events
● However, two studies have found a protective
effect in patients with only abnormal TCD but
TCD,
not stroke or vasculopathy
– thus early transfusion may be the key
thus,
Coates TD. Blood. 2011;117:745-6.
Abboud M, et al. Blood. 2008.
Gyeng E, et al. Am J Hematol. 2011;86:104-6.
Mirre E, et al. Eur J Hematol 2009;84:259-65.

101. Transfusion therapy vs standard care for
py
prevention of secondary silent brain infarcts*
Total
Subjects who New or worse No
Treatment no. of
had a stroke silent infarcts change
subjects
Transfusion 18 0 0 18
Standard care 29 9† 6 14
Total 47 9 6 32
* The difference between the 2 treatment arms was statistically significant at p < 0.001.
† Value includes 1 patient with new or worse lesion prior to stroke.
Pegelow CH, et al. Arch Neurol. 2001;58:2017-2021.