1. health and fitness
2. disease

Sickle Cell Anemia
JFK Pediatric Core Curriculum
Edited by
Venée Tubman, MD
HEARTT
Department of Pediatrics
Children’s Hospital Boston
Definition and Molecular Basis of
Disease

Sickle cell disease (SCD): a recessively inherited
chronic hemolytic anemia

Caused by a single nucleotide substitution in the
β globin gene on chromosome 11
– Hemoglobin S (most common): GTG  GAG results in
substitution of valine (hydrophobic) for glutamate
(hydrophilic)
– Many other variant hemoglobins are described

Mutant hemoglobin polymerizes under low
oxygen conditions and form bundles that distort
red cells into the classic sickle shape
Pathophysiology
Deoxygenation
polymerization of hemoglobin
sickling of red cells
endothelial damage/activation
RBC and leukocyte adhesion to
endothelium, vasoconstriction
vascular occlusion, organ
ischemia and end-organ
damage
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Pathophysiology

Severity of disease varies widely among
individuals and disease type:
SS disease is most severe
SC and S-beta thal0 disease portend
intermediate severity
SA (one normal allele=trait) is generally
asymptomatic
Sickle Cell Anemia and Malaria
Children with sickle trait (heterozygotes) have a milder course of
P. falciparum. However, children with SS disease have more
severe courses with a very high mortality rate.
Epidemiology
Hb S, thalassemia, G6PD, HPHF all confer
malaria survival advantage
 Up to 30% of population carriers for Hb S
allele in many parts of West Africa
 Hb S carrier estimate for Liberia: 15%

Prognosis
Over the past 30 years in US/Europe,
median survival has increased from 14yrs
to 45-55yrs for SS disease
 Figures not available for Africa but
estimated 50% of affected die before 5yrs
 WHO estimates that SCD complicates up
to 9% of under 5 deaths in West Africa

Initial Clinical Presentation

Typically presents in infancy after 6 months of
age, when Hb F is waning
– Birth hemoglobin F: α2γ2
– Hemoglobin A: α2β2
– Hemoglobin S: α2S2

Pain and anemia are hallmarks of disease
Initial Clinical Presentation

Suggestive historical findings:
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Family history of known SCD
Family history of sudden death in young child
Frequent pain
Frequent chest infections
Failure to gain weight despite good nutrition
Persistent jaundice
Classic sequelae (hand/foot syndrome, priapism)
Initial Clinical Presentation

Physical Exam findings are nonspecific:
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scleral icterus
pale mucous membranes
systolic murmur throughout precordium
splenomegaly
Initial Clinical Presentation

Predictors of adverse outcome at presentation:
– dactylitis in infant <1y/o
– Hb<7g/dL
– leukocytosis absent infection
– priapism
Laboratory Findings and Diagnosis
Hemolytic anemia: low hemoglobin, high
reticulocyte count, elevated LDH and
decreased haptoglobin
 Peripheral blood smear:

Diagnosis: Sodium metabisulfite

Screening for SCD with sodium
metabisulfite
– Add Na metabisulfite to blood
– Seal mixed sample in airtight container or
under coverslip
– Look for sickling under microscope

Does not differentiate trait from disease
Diagnosis: Hemoglobin Electrophoresis
Sequelae: Vaso-occlusive/pain crisis
Occurs in 60% of SS patients when vasoocclusion tissue ischemia
 May be triggered by infection, temperature
extremes, dehydration or stress but usually w/o
identifiable cause.
 Characterized by severe pain often in
extremities, involving the long bones, or the
abdomen. May last hours to days.
 Number of pain crises/year varies widely
between individuals with some patients w/
constant low level pain.

Sequelae: Vaso-occlusive/pain crisis
Management:
 Hydration: 20cc/kg NS bolus, then PO/IV
hydration at 1.5 x maintenance (not for acute
chest)
 Pain ladder:
Paracetamol 15mg/kg PO q4hr ADD
Ibuprofen 10 mg/kg PO q6hr ADD
Codeine 1mg/kg PO q4hr
CHANGE Codeine to Tramadol (need dose)
CHANGE Tramadol to Morphine 0.1mg/kg q4hr
Ambulation to prevent acute chest
 Oxygen to maintain O2 sat > 95%

Sequelae: Infection
By age 1 30% of Hb SS pts are asplenic,
by age 6, 90% are asplenic due to
microinfarcts.
 This makes children especially vulnerable
to infection/sepsis with encapsulated
organisms, esp. Strep pneumoniae (400x
higher risk vs. general population)
 Sickle Cell patients are also more
susceptible to osteomyelitis (Salmonella
and Staph spp.)

Sequelae: Infection(cont’d)
Management of fever:
 For T ≥38, send: Hb, malaria smear, CXR,
UA (under 2 years or symptoms)
 Administer Ceftriaxone 50 mg/kg QD until
clinically improving OR 3 days
 Change to amoxclav or ampicillin to
complete 14 days
Sequelae: Acute Chest Syndrome
Characterized by new respiratory distress,
CXR infiltrate, hypoxia(O2<95%) and/or
chest pain
 Occurs in 40% of patients with SS disease
 Can progress rapidly to ARDS
 May be caused by viral or bacterial
infection, fat embolism(2/2 bone marrow
infarction), cause unknown in most cases

Sequelae: Acute Chest Syndrome
Management :

Ceftriaxone 50mg/kg IV daily, then when
pain improving ampicillin or amoxclav

If O2<94 and Hb < 6 g/dL, consider
transfusion

Do not hydrate > 1x maintenance
(furosemide with transfusion)
Sequelae: Stroke
11% of SS patients have a stroke by age
20 with peak incidence between 2 and 10
 Presents as focal neurologic deficit or
seizure
 Management: Transfusion

Sequelae: Acute Splenic Sequestration
Sudden enlargement of the spleen accompanied
by a >2g/dL decrease in Hb from baseline, often
w/ thrombocytopenia
 Occurs in children <3y/o
 Can cause sudden circulatory collapse

Management:
 Immediate volume expansion with crystalloid
 Transfusion
 If >2 episodes splenectomy
Sequelae: Aplastic Crisis
Caused by infection with Parvovirus B19 (fifth
disease) which invades young erythroblasts in
bone marrow
 Often presents with fever, URI sx and drop in
Hb
 RBC life expectancy in SS disease is 10-20 days,
thus decrease in RBC production has profound
effect.
 Bone marrow recovery typically within 7-10 days
Management:
Transfusion if symptomatic with Hb drop.

Sequelae: Anemia
Compensated anemia at baseline
 Baseline Hb normally 8-9 g/dl
 Overtransfusion can predispose to
transfusion transmitted infections and iron
overload
Management
 Transfuse for Hb < 5g/dL or <6g/dL with
cardiac decompensation

Indications for Simple Transfusion
Final hematocrit after transfusion <30%.
 Simple Transfusion for:

– aplastic crises
– splenic sequestration
– Acute chest syndrome
– Before surgery
– Priapism resistant to medical management
– Stroke
– Persistent pain despite proper pain
management
Indications for Exchange Transfusion

For stroke, severe ACS
Other Sequelae
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Priapism: May require surgical drainage,
phenylephrine injection, exchange transfusion
Dactylitis (hand-foot syndrome): painful swelling
of hands and feet which occurs in infants.
Avascular necrosis of the humeral/femoral head
Cholelithiasis
Retinopathy
Chronic leg ulcers
Preventive Care:
Daily Penicillin VK 125mg BID from time of
diagnosis (ideally<3mos) through 5 years
of age (increase dose to 250mg BID at
age 3yrs.)
 May use erythromycin in penicillin allergic
patients
 Folic Acid 1mg daily started by 1y/o
 Pneumococcal Vaccine (if available)
 All standard vaccines

Preventive Care:
Stroke Prevention Trial in SCD (STOP):

A two year trial of children 2-16y/o screened with transcranial
Doppler ultrasonography and found to be high risk (flow
velocity>200cm/sec)

The children then randomly assigned to receive either standard care
or prophylactic transfusions to keep their HbS concentrations<30%

In the group that received prophylactic transfusions, 2% had
strokes, compared with 16% in the control group.

Therefore, current recommendations are to screen all children
>2y/o with transcranial doppler ultrasound and offer prophylactic
transfusion to children with a flow velocity>200cm/sec (high risk of
stroke)
Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle
cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM
1998;339:5-11
Definitive Treatment:
Hydroxyurea therapy
• Indicated for children
>5y/o who have severe
complications of SCD
• Effective because
increases HbF, decreases
leukocytes, platelets and
reticulocytes
• CBC must be monitored
regularly when on
therapy for leukopenia
Definitive Treatment:
Bone Marrow Transplant
Definitive cure for SCD
 Only 14% of SCD patients have a humanleukocyte antigen matched donor
 Associated with a peri-transplant morbidity
of ~10%
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References
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
Driscoll, C. Sickle Cell Disease. Pediatrics in Review
2007;28:259-267
Steinberg, M Management of Sickle Cell Disease. New

England Journal of Medicine 1999; 340: 1021-1030
Claster, S Managing Sickle Cell Disease. British Medical
Journal 2003; 327:1151-1155
Serjeant, G Mortality from sickle cell disease in Africa.
British Medical Journal 2005; 330:432-433
Distenfeld, A Sickle Cell Anemia. eMedicine.com

Paediatric Treatment Protocols in Island Hospital, 2007
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Adapted from a lecture by: Kevin Schwartz, MD