1. DR SANDIP GUPTA
PGT, PEDIATRICS

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

3. Sickle Cell Disorders in India

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 GAGGTG 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

15. ACS : Treatment
 Oxygen ( Spo2>90%)
 Blood transfusion therapy
 Emperical antibiotics( cephalosporin+ macrolides)
 Cont respiratory therapy( incentive
spirometry,physio)
 Optimum pain control
 Fluid management.

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

21. Pain Management
Acute pain
 Hand-foot syndrome (dactylitis)
 Painful episodes: vasoocculsion
 Splenic sequestration
 Acute chest syndrome
 Cholelithiasis
 Priapism
 Avascular necrosis
 Right upper quadrant syndrome

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

26. Renal Disease
 Renal findings
 Decreased ability to concentrate urine
 Decreased ability to excrete potassium
 Inability to lower urine pH normally
 Hematuria / papillary necrosis
 Risk factors for progressive renal failure
 Anemia, proteinuria, hematuria

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

29. Chronic Complications
 Anemia/Jaundice
 Brain Damage/Stroke
 Kidney failure
 Decreased lung function
 Eye disease (bleeding, retinal detachment)
 Leg ulcers
 Chronic pain management

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

39. 2002 NIH Guidelines for SCT Eligibility in Sickle Cell Disease

40. Therapy
Gene Therapy
 Goal: Transfer anti-sickling β-globin genes
 Obstacles:
 poor onco-retroviral vector stability
 low viral titres and gene transfer efficiency
 difficulty packaging large β-globin gene and regulatory
elements
 safety concerns

41. THANK YOU