Sickle cell anemia
Clinical vignettes
Peter Newburger, MD
Pediatric hematology/oncology
Sickle cell anemia
From http://fig.cox.miami.edu/~cmallery/150/gene/mol_gen.htm
Sickle Cell Epidemiology
bS : Single a.a. substitution
Glutamic acid  Valine
Most common single gene disorder in African
Americans
1/375 affected (homozygous)
1/12 are heterozygous carriers (~8%)
Also affects other ethnicities: India, Middle East,
Hispanic
SICKLE CELL SYNDROMES
• Molecular pathology postulated by Pauling
in the late 1940s
• Mutation known for 50 years
• Unfinished tasks
– Explaining the clinical disorder based on the
molecular defect
– Rational and targeted treatments – still few
despite detailed knowledge of the molecular
defect
Molecular Pathophysiology
Intracellular [Hb] ~30 - 35 g/dL
Deoxygenation allows interaction of bS
subunits via abnormal hydrophobic
regions (valines)
Non-covalent bond with other bS in the RBC
Formation of 14 stranded helical fiber
Delay time ≈ k / C15
The time that elapses
between the
deoxygenation of
hemoglobin S and the
formation of polymer is
inversely proportional to
the intracellular
concentration (C) of
deoxyhemoglobin,
raised to the 15th power
Polymerization phase is sensitive to:
• O2 concentration
• Hgb concentration
• pH
• Ionic strength
(At salt concentrations spanning the physiologic
range, solubility increases with ionic strength, but
decreases markedly at high ionic strength.)
Bunn HF. NEJM 1997 337 (11)
Cellular Pathophysiology of
Sickle Cell syndromes
Polymerization leads to:
Distortion of Cell shape
Damage to RBC Membrane
Abnormal permeability
Irreversible sickling
Impairment of RBC flow = Infarction
Decreased red cell number = Anemia
Anemia
•
•
•
•
•
Most common feature of sickle cell disease
Often ignored as pathologic
Moderate to severe in almost all patients
Degree of anemia reflects clinical severity
Episodic acute anemia
Sickle complications
• Vaso-occlusive crisis
• Cerebrovascular disease
• Splenic sequestration
• Sepsis due to functional asplenia
• Acute chest syndrome
Patient vignettes
18 month old girl presents to the
ER crying inconsolably, with fever
and swollen, tender hands.
A 3 year old boy presents to the
ER with a 12-hour history of
fever to 38°C. He is slightly
irritable but looks well. Despite
IV antiobiotics, his fever
continues to rise, his blood
pressure falls, and his
extremities become cold, with
purple discoloration.
Functional asplenia
Functional
Asplenia
Sepsis Prevention:
the most effective drug for sickle cell is…
Volume 314:1593-1599. June 19, 1986. Number 25
Prophylaxis with oral penicillin in children with sickle cell
anemia. A randomized trial
MH Gaston, JI Verter, G Woods, C Pegelow, J Kelleher, G Presbury,
H Zarkowsky, E Vichinsky, R Iyer, JS Lobel, and et al.
PROPS I Prophylactic Penicillin Study
Multicenter randomized double-blind placebo-controlled trial
“Prophylactic therapy with oral penicillin by four
months of age decreases the morbidity and mortality
associated with pneumococcal septicemia.”
Vaccination: Important for adult sickle cell
and all splenectomized patients!!
“Catch-up” vaccination if Prevnar
series not complete
A fourteen year old girl with
sickle cell disease comes to
clinic because her left side is
weak. She is immediately
transferred to the ICU for
exchange transfusion.
CT scan of stoke
Cerebral blood vessels
Sickle Cell Disease: Cross
Section of Internal Carotid Artery
Intimal
hyperplasia
Normal
Age at 1st stoke in sickle syndromes
Stroke Prevention
Most clinical strokes occur in children with
increased cerebral blood vessel flow
velocities
Flow measured by transcranial Doppler
ultrasound
STOP Trial - red cell transfusions reduce the
risk of stroke in children with TCD > 200
cm/sec
Transcranial Doppler U/S
Long term treatment of
sickle cell disease
• Hydroxyurea
• Hematopoietic stem cell
transplantation
• Gene therapy
Hydroxyurea
Hydroxyurea decreases crises in patients with
severe sickle cell disease.
In 299 adults with severe sickle cell anemia:
• Hydroxyurea provided ~50% decrease in:
– frequency of hospitalization
– incidence of pain, acute chest syndrome, and blood
transfusions
• In good responders:
–
–
–
–
hemolysis and leukocyte counts fell
hemoglobin concentrations increased
Hb F increased from 5 % to 9% overall
Hb F increased to 18 % in top quartile of responders
N Engl J Med 1995;332:1317-22
Stem Cell Transplantation
– Stroke risk
– Acute chest syndrome risk
– Inexorable accrual of
chronic end organ damage
(including CHF, pulmonary
hypertension, iron overload)
Complications
of sickle cell
– Transplant-related mortality
– Infertility
– Secondary malignancy
– Graft vs. host disease
Complications
of transplantation
Gene therapy
Ely and Rainer NEJM 1997;336:1364