2. Prevalence/Incidence of SCD
In African-Americans the incidence of SCD is 1 in
375 for HbSS, 1 in 835 for HbSC and 1 in 1,667 for
Sickle beta-thalassemia. In addition, 1 in 12
African-Americans are carriers for the disorder
In other U.S. populations, the prevalence of sickle
cell disease is 1 in 58,000 Caucasians; 1 in 1,100
Hispanics (eastern states); 1 in 32,000 Hispanics
(western states); 1 in 11,500 Asians; and 1 in 2,700
Native Americans
4. What Is Sickle Cell Disease?
An inherited disease of red
blood cells
Affects hemoglobin
Polymerization of hemoglobin
leads to a cascade of effects
decreasing blood flow
Tissue hypoxia causes acute
and chronic damage
β-globin gene (chromosome 11q)
mutation GAGGTG at 6th codon
Glutamic Acid Valine at the 6th amino
acid along the β-globin chain
5. Why Do Cells Sickle?
Sickling Mechanism
1. Deoxygenation HgbS protein
conformational change
2. Hydrophobic Valine exposed at
molecular surface
3. Val6 of B2 chain of 1st Hgb S chain
forms hydrophobic bond with
Phe85 and Leu88 of a 2nd Hgb S B1
chain
4. Pairing Hgb S monomers
polymerize to form Hgb S chains
5. Hgb S polymers precipitate in
RBCs as long, rigid fibers.
6. Pathophysiology
HgbS fibers are rigid
Hgb S fibers deform
RBC membranes
Membrane disruption
exposes transmembrane
proteins and lipids that
are pro-inflammatory
Progressive sickling
makes cells dense and
inflexible
Frenette et al., Journal of Clinical Investigation 117(4): 850-858, 2007
7. Pathophysiology
Factors that Promote Hgb S polymerization:
Low pO2 / Hypoxia
Prolonged “Delay Time” – time RBC spends in microcirculation
Low pH
High Hgb S concentration
Genotype-dependent
Cellular “Dehydration”
Volume depletion (total body)
Sickling Activation K+ / Cl- cotransporter and
Gardos Ca2+- activated K+ efflux channels ion and water efflux
Low Hgb F concentration
α2γS: gamma globin chains bind Hgb S chains and inhibit Hgb S
polymerization, thus countering sickling process
8. Normal Vs. Sickle Red Cells
Normal
Disc-Shaped
Deformable
Life span of 120 days
Sickle
Sickle-Shaped
Rigid
Lives for 20 days or less
9. Clinical Syndromes
Disease Severity is Genotype –Dependent
Genotype
Hgb SS
Hgb S / β0 thalassemia
Hgb SC
Hgb S / α thalassemia
Hgb S / D
Hgb S / A
Hgb S / E
Hgb S / β+ thalassemia
Hgb S / HPFH
WorseningDiseaseSeverity
Asymptomatic
+ / - Mild Anemia
10. Interpreting Newborn Screening Results
Sickle Hemoglobinopathies
Screening Results* Associated Disorder
FS SS or Sβ°thalassemia
FSC SC
FSA S ß+ thalassemia
FSE S Hemoglobin E
FS Variant S Variant
FAS Sickle Cell Trait
FAC Hb C Carrier
FAE Hb E Carrier
FA Variant Hb Variant Carrier
onfirmation.
11. Hemolysis and Vaso-occlusion
Vaso-occlusion:
Occurs when the rigid
sickle shaped cells fail to
move through the small
blood vessels, blocking
local blood flow to a
microscopic region of
tissue. Amplified many
times, these episodes
produce tissue hypoxia.
The result is pain, and
often damage to organs.
Hemolysis:
The anemia in SCD is
caused by red cell
destruction, or
hemolysis, and the
degree of anemia varies
widely between patients.
The production of red
cells by the bone marrow
increases
dramatically, but is
unable to keep pace with
the destruction.
12. Chronic Manifestations:
Anemia
Jaundice
Splenomegaly
Functional asplenia
Cardiomegaly and functional
murmurs
Hyposthenuria and enuresis
Proteinemia
Cholelithiasis
Delayed growth and sexual
maturation
Restrictive lung disease*
Pulmonary Hypertension*
Avascular necrosis
Proliferative retinopathy
Leg ulcers
Transfusional hemosiderosis*
Acute Manifestations:
Bacterial Sepsis or meningitis*
Recurrent vaso-occlusive pain
(dactylitis, muscoskeletal or
abdominal pain)
Splenic Sequestration*
Aplastic Crisis*
Acute Chest Syndrome*
Stroke*
Priapism
Hematuria, including papillary
necrosis
Hemolysis and Vaso-occlusion
(continued)
*Potential cause of mortality
13. Fever and Infection
Fever > 38.5° C (101°F)
is an EMERGENCY
Basic laboratory
evaluation:
CBC with differential and
reticulocyte
count, blood, urine, and
throat
cultures, urinalysis, chest
x-ray
Indications for
hospitalization & IV
antibiotics:
-Child appears ill
-Any temperature > 40°C
-Abnormal laboratory
values
Start IV antibiotics
IMMEDIATELY if child
appears ill or temperature
> 40°C (DO NOT WAIT
FOR LABS)
14. Acute Chest Syndrome
Clinically:
Acute onset of fever, respiratory distress, chest
pain, new infiltrate on chest x-ray.
Causes
Infection
Fat emboli
Lung infarct
Since you cannot distinguish between acute chest
syndrome and pneumonia clinically there is no change
in treatment.
A leading cause of death in sickle cell disease
16. Priapism: INVOLUNTARY ERECTION FOR>30 min
STUTTERING&REFRACTORY
Treatment is difficult
Opioid pain medication
Intravenous fluids
Aspiration and irrigation of the corpus
cavernosum(>4hr)
Blood Transfusions
Impotence with severe disease or
recurrent episodes
Prevention: Hydroxyurea,Etilefrine
Surgical shunt procedures
Urethr
a
Corpus cavernosum
Commonly occurs in children and adolescents with SS or SC
Age of onset is 5-35 yrs.
Early morning
17. Stroke: Any focal neuro deficit>24hr&/or↑intT2W MRI
Historically 8 to 10% of
children with SS
“Silent Stroke” in 22% of
children with
hemoglobin SS
Any acute neurologic symptom other than mild headache, even if
transient, requires urgent evaluation.
Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or
below 30%
18. Splenic Sequestration
Sudden trapping of blood within the spleen
Usually occurs in infants under 2 years of age with
SS
Spleen enlarged ,hypovolemia, Hb↓>2%
,reticulocytosis ,↓pl atelet count,may not be
associated with fever, pain, respiratory, or other
symptoms
Circulatory collapse and death can occur in less
than thirty minutes •Recurrence very common (50%)
•Associated with high mortality (20%)
19. Splenic Sequestration
Hemoglobin SS
Incidence increased: 6 and 36 months
Overall incidence about 30%
Hemoglobin SC
Incidence increased: 2 and 17 years
Mean age 8.9 years
Can occur in adolescence and adulthood
Incidence about 5%
20. Treatments For Splenic
Sequestion
Intravenous fluids
Maintain vascular volume
Cautious blood
transfusion
Treat anemia with 5ml/kg
of PRBC
splenectomy
If indicated
22. PRECIPTATING FACTORS: physical stress, infection
, dehydration,hypoxia ,exposure to cold, acidosis
Pain is an emergency
Hospital evaluation:
Hydration: 1.5 times maintenance unless acute
chest syndrome suspected
Assess pain level and treat
Do not withhold opioids
Frequently reassess pain control
Assess for cause of pain/complications
23. Pain Management
Mild-moderate pain
Acetaminophen
Hepatotoxic
Non-steroidal anti-inflammatory agents
(NSAIDs)
-Contraindicated in patients with gastritis/ulcers
and renal failure
-Monitor renal function if used chronically
24. Pain Management
Moderate-severe pain
Opioids are first-line treatment
Morphine sulfate or hydromorphone
Meperidine NOT recommended
(Metabolite causes seizures & renal toxicity)
Moderate or less severe pain
Acetaminophen or NSAID's in combination with opioids
Other adjuvant medications (sedatives, anxiolytics)
May increase efficacy of analgesics
25. Hand Foot Syndrome - Dactylitis
Early complication of
sickle cell disease
Highest incidence 6
months to 2 years
Painful swelling of hands
and feet
Treatment involves fluids
and pain medication
Fevers treated as medical
emergency
27. Gall Bladder and Liver
Gall stones and biliary sludge
Monitor by ultrasound every 1-2 years
Cholestasis
May progress, leading to bleeding disorders or liver
failure
Iron overload
Due to chronic transfusions
Chronic hepatitis
28. Bone Disease Diagnosis and
Treatment
Avascular necrosis of hips and shoulders
Index of suspicion
Persistent hip or shoulder pain
Plain film or MRI
Treatment
Conservative
NSAID’s and 6 weeks of rest off affected limb
Physical therapy
30. GENETIC COUNSELLING
Who should receive counseling?
-Parents of newborns with sickle disorders or traits
-Pregnant women/ prenatal counseling
What is the purpose of counseling?
-Education
-Informed decision-making
Content should include:
-Genetic basis, chances of disease or trait (potential
pregnancy outcome), disease-related health
problems, variability/unpredictability of disease, family
planning, average life span
31. Health Maintenance Frequent visits: every 3 to 6 months
Immunizations
Routine immunizations
Hib- 6 months and older
23 valent Pneumovax at five years
Penicillin prophylaxis beginning no later than two
months
Nutrition and fluids
Folate supplementation is controversial
32. Health Maintenance
Physical exam with attention to:
Growth and development, jaundice, liver/spleen
size, heart murmur of anemia, malocclusion from
increased bone marrow activity, delayed puberty
Lab evaluations:
CBC with differential and reticulocyte
count, urinalysis, renal & liver function
33. Health Maintenance
Special studies
Brain- Transcranial doppler
ultrasonography, MRI/MRA
Lungs- Pulmonary function tests, Echo
cardiogram for pulmonary hypertension
Neurologic- neuropsychological testing
34. Current Recommendations
Penicillin Prophylaxis: SS, S ºThalassemia
2 months to 3 years: 125 mg PO BID
Over 3 years: 250 mg PO BID
When to discontinue is controversial
Penicillin Prophylaxis: SC and S + Thalassemia
SC warrants penicillin prophylaxis similar to SS
S + Thalassemia: penicillin prophylaxis can be safely
discontinued at 5 years
Routine use in infants and children is controversial
Special Circumstances
History of repeated sepsis, surgical splenectomy
35. Therapy
Hydroxyurea
S-phase cytotoxic, myelosuppressive drug: inhibits ribonucleotide
reductase
Induces proliferation of early erythroid progenitors
Leads to ↑ Hgb F production (α2γ2)
γ subunit production α2 γS does not polymerize
Additional effects of hydroxyurea:
↓ Neutrophil numbers and neutrophil activation
↓ stress reticulocytes, ↓ reticulocyte adhesion
↓ endothelial adhesion properties (↓VCAM-1, ↓ laminin, ↓thrombospondin)
Improved RBC hydration and MCV
Increased [Hgb]
36. Therapy
Hydroxyurea Dosing:
Initiation of Treatment:
Hydroxyurea 15-20mg/kg/day in single daily dose
Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q 2-4 wks
May require
Tx Continuation: If no major toxicity, escalate dose Q 6-8wk by 2.5-5 mg/kg
until desired endpoint reached may go upto 35mg/kg
Reduces painful episodes, ACS by 50%.
Treatment Endpoints:
Decreased pain / pain crises
Hgb F 15-20%
Acceptable myelotoxicity:
<2500 neutrophils / ul
< 90,000 platelets / ul
Hgb < 5.3 g/dL
37. Therapy
Other Hgb F – inducing Agents
Short-chain fatty acids (sodium butyrate)
Mechanism: Histone deacetylation
Baboons: ↑ Hgb F
Phase II study (N=15): 11 responders, Increased Hgb F 7% 21%
5-Azacytidine and 5-Aza-2’deoxycytidine
Mechanism: Demethylation of DNA
9-month Phase I/II study (N=7): Increased Hgb F 3.1% 13.9%
Erythropoietin
38. Therapy
Allogeneic Stem Cell Transplantation
Only Therapy Offering Curative Potential for sickle cell disease
As of 2002, only ~150 patients had undergone SCT
Patient recruitment hindered by:
Difficult pt selection - Absence of early prognostic markers in SCD
Majority of patients do not have donor
High mortality risk of SCT
Risk of long-term treatment-induced malignancy
Risk of GVHD
Pts >16 have demonstrated poor outcomes d/t comorbidities
Two multicentre series of allogeneic SCTs have been undertaken,
1 in US, 1 in Europe