Undergraduate Lecture

1. Sickle Cell Disease

2. Quick Definition
It is a disorder of red blood cell
production that gives red blood cells a
sickle shape during hypoxia

3. Lets go back in time…
 James Herrick
 Hahn and Gillespie
1927
 Genetic Mutation
 Inherited, not contagious

4. Sickle Cell Disease
 Group of genetic disorders characterized by:
 Hemolytic anemia - not enough red blood cells in
the blood
 Vasculopathy - disorder of blood vessels
 In US, predominantly with African-Americans
(i.e., 1 in 400)
 Also occurs in descendents of Mediterranean,
Indian, Asian, and Caribbean cultures

5. Sickle Cell Syndromes
Sickle Cell Trait (HbS gene/Hb A gene)
Sickle Cell Anemia (HbS/HbS)
Hgb SC Disease
Sickle Beta-Thalassemia

6. SCA: Impact on Red Blood Cells
With low oxygen levels, the shape of red
cells becomes distorted
They appear elongated and sickle
shaped
Red blood cells become very fragile,
short lived, and can clog blood vessels

7. Genetics
Hb-S result from
point mutation
for the sixth
amino acid in the
β-chain result in
substitution of
glutamic acid by
valine.

9. Deoxyhemoglobin S Polymer Structure
A) Deoxyhemoglobin S
14-stranded polymer
(electron micrograph)
D) Charge and size
prevent
6β Glu from binding.
C) Hydrophobic pocket
for 6β Val
B) Paired strands of
deoxyhemoglobin S
(crystal structure)
Dykes, Nature 1978; JMB 1979
Crepeau, PNAS 1981 Wishner, JMB 1975

12. 1. Young RBCs with HbS can
alternate between the
sickled and normal
formation.
2. However, sickling causes
oxidative damage to the
RBCs cell membrane (and
to the cells around it).
3. Eventually, RBCs become
irreversibly sickled.

13. SCA: Complications
Clinical manifestations do NOT appear
until after ~ 6 months
Vaso-occlusive pain crises

14. Sickle Cell Anaemia
“It is a specific type of sickle cell
disease in which there is homozygosity
for the mutation that causes HbS”.
SS

15. Sickle cell disease crises

16. Vaso-occlusive complications
 Most frequent
 Occur in areas with:
• Prolonged, low oxygen
tension
• Decreased pH
• Inflammation
• Low blood flow
 Bones ,lungs, spleen and
the brain commonly
affected.
Source: Robbins

17. Hand-foot syndrome
Painful dactylitis caused by infarcts of the
small bones.
Painful swelling of hands and feet.
Early complication of sickle cell disease.
Digits of varying lengths
Highest incidence 6 months to 2 years.

19. Visceral sequestration crises
 These are caused by sickling within organs
 The acute sickle chest syndrome is a
feared complication and the most common
cause of death after puberty.
 Spleen and liver sequestration may lead to
severe illness

21. Aplastic crises
Paravirus B19
Divides in RBCs precursors and destroys
them
Stops erythropoiesis for two or three
days
Causes reticulocytopenia
Disappears within one week with
management and blood transfusions
 A sudden fall in haemoglobin, usually
requiring transfusion.

22. Haemolytic crises
These are characterized by an
increased rate of haemolysis with a
fall in haemoglobin but rise in
reticulocytes and usually accompany a
painful crisis.

23. Medical Complications
1. pain episodes
2. strokes
3. increased infections
4. leg ulcers
5. bone damage
6. yellow eyes or
jaundice
7. early gallstones
8. lung blockage
9. kidney damage and
loss of body water in urine
10. painful erections in men
(priapism)
11. blood blockage in the spleen
or liver (sequestration)
12. eye damage
13. low red blood cell counts
(anemia)
14. delayed growth

26. Lab Findings
CBC:
• Hb, PCV, RBCs count: low
• MCV, MCH, MCHC: normal
• T.WBCs count: increased and
neutrophilia is common.
• PLT count: increased

27. PBP
 Sickle cells
 Target cells
 Polychromatic cells and nucleated
RBCs.
 Inclusions: basophilic stippling, Howell-
Jolly bodies and Pappenheimer bodies.
 If infection is present a left-shift may
present.

30. Sickling Test

32.  Special haematological tests:
• Sickling test: positive
• Hb-S solubility test: positive
• Hb electrophoresis: confirm the presence of Hb S.
• ESR: low
StateState Hb-AHb-A Hb-FHb-F Hb-SHb-S
normalnormal 9595--98%98% >>1%1% 00
Hb S traitHb S trait 5555--70%70% >>2%2% 3030--40%40%
Hb-SSHb-SS 00 11--10%10% 8080--90%90%

33.  B.M: erythroid hyperplasia with decreased M:E
ratio.
Che m istry:
• Indirect bilirubin: increase
• LDH: increase
• S.haptoglobin: decrease
• Urobilinogen and stercobilin: increase
• DNA diagnosis

34. PCR

35. Treatment
Blood transfusions:
Acute chest crisis
Decreases the risk for strokes
Defrasirox: iron chelator
Folic acid daily intake
Penicillin
Malaria chemoprophylaxis

36.  Hydroxyurea.
 Reactivates fetal Hb production
 Decreases severity of attacks
 Increases life span
 More effective with Erythropoietin.
 Bone marrow transplant during childhood.
 5-HMF. This natural compound binds to red blood
cells and increases their oxygen. This helps prevent
the red blood cells from sickling.

37. How does hydroxyurea work?
Steinberg, MH, NEJM, 340:1021-1030, 1999

40. What about a future?
 Stem Cell research
 Gene therapy

41. Sickle cell trait
 No anaemia
 Normal appearance of red cells on a blood film.
 Haematuria is the most common symptom and is
 Thought to be caused by minor infarcts of the renal
 papillae.
 Hb S varies from 25 to 45% of the total
haemoglobin
 Care must be taken with anaesthesia, pregnancy
and at high altitudes.