This document discusses sickle cell anemia, beginning with a description of normal hemoglobins and hemoglobinopathies. It then focuses on sickle cell anemia, caused by a point mutation replacing glutamic acid with valine in the beta globin chain, resulting in hemoglobin S (HbS). Homozygous individuals have >80% HbS and experience the full manifestations of sickle cell anemia. Clinical features include chronic hemolytic anemia, episodes of aplastic crisis and vaso-occlusive complications resulting in severe pain, as well as increased susceptibility to infections due to impaired splenic function and complement pathway defects.

1. Dr. B.V.Vydehi M.D
PROFESSOR OF PATHOLOGY
NARAYANA MEDICAL COLLEGE,NELLORE
Sickle cell Anemia

2. Normal Hemoglobins
• 750 structural hemoglobin variants are
identified
• Hb A(α2β2)- main component(96%)
• HbA2 (α2δ2)- 2-3% of adult hemoglobin
• HbF(α2γ2)- gradually decreases after 2 yrs
- in adults only traces
Increased levels of HbF are seen in SCA,Sickle
beta-Thalasemia, leukemias ( Juvenile CML,
Erythroleukemia), MPD , Normal Pregnancy

3. Hemoglobinopathies
Qualitative Disorders :
Structural abnormalities in synthesis of Hb
Eg : Sickle cell anemia, HbC, HbD etc…
Quantitative Disorders:
Decrease in globin synthesis of Hb
Eg: Thalessemias

4. Hereditary hemoglobinopathy,
characterized by production of defective
hemoglobins (Autosomal Recessive
inheritance)
Sickle cell anemia : Point mutations at 6th
position of -globin chain : Glutamic acid is
replaced with valine → Hb S
Sickle cell Disease

5. 1. Heterozygous state for HbS (only 40% of Hb
is HbS): Sickle cell trait (Asymptomatic
carrier state)
2. Homozygous state for HbS (>80%Hb is HbS):
Sickle cell anemia
3. Double Heterozygous states
Eg: Sickle -Thalassemia, Sickle-C-disease
(SC), Sickle-D-disease (SD)
Sickle cell Syndromes

7. • Deoxygenated HbS molecules undergo
aggregation & polymerization
• Reversible sickling : Initially sickling is
a reversible phenomenon
- With oxygenation HbS depolymerizes &
cell shape normalizes
• Irreversible sickling : Repeated episodes of
sickling → membrane damage →Permanent
sickling even when fully oxygenated
SCA - Pathogenesis

8. Sickle Cell Disease
Polymerization
of Hb S
Sickle cell

10. 1. Amount of HbS & interaction with other Hb
chains in the cells :
• Heterozygousstate : Only with severe hypoxia
• Homozygousstate: Full-blown SCA
• HbF : Inhibits polymerization of HbS. Hence
newbornsdo not manifest the disease until
they attain 5 to 6 monthsage
• HbC : Point mutationin -globin at 6th
position (substitutionof lysine for glutamic acid)
- Greatertendency to form aggregates with
deoxygenated HbS than HbA (HbSC disease)
Factors influencing rate & degree of sickling

11. 2. Rate of HbS polymerization is strongly
dependent upon Hb concentration per
cell (MCHC):
Eg:- Intracellular dehydration →  MCHC
→  sickling
- Sickle -thalassemia → reduces globin
synthesis →MCHC→ milder disease
3. Decrease in pH :
Oxygen affinity of Hb →sickling
Factors influencing rate & degree of sickling

12. 4. Length of time RBC are exposed to low
oxygen tension :
• Sickling of red cells is confined to
microvascular beds where blood flow is
sluggish Eg: Spleen & Bone marrow
•Inflammation &red cell adhesion → longer red
cell transit time → sickling
Factors influencing rate & degree of sickling

13. Natural protection from Malaria
• Patients with HbS are relatively protected
against Falciparum malaria
• Plasmodium infects RBC & induces quicker
sickling
• Sickled RBC with parasite inside them are
sequestered in spleen thus providing
protection

14. • Chronic hemolysis, Hyperbilirubinemia, microvascular
occlusion, infarction & thrombosis
• Expansion of bone marrow → bone resorption
& secondarynew bone formation → prominent
cheekbones& changesin skull (Crew-cut
appearancein X-ray)
• Spleen : Early phase : Splenomegaly
Micro : Marked congestion with trapping of
sickled red cells in splenic cords & sinuses
Progressive shrinkage of spleen → autosplenectomy
by adolescence or early childhood
Sickle cell Anemia Morphology

15. Peripheral smear : Sickle cells and target
cells; Features of splenic atrophy (Howell-
Jolly Bodies)
Sickling Test : Mixing of blood sample with oxygen
consuming reagent (Sodium metabisulfite)
induces sickling of red cells
if HbS is present
Reticulocytosis & Hyperbilirubinema
Hb Electrophoresis : Predominance of HbS
& 2-20 % HbF
Sickle cell Anemia - Morphology

16. Autosplenectomy

18. 1. Chronic hemolytic anemia
2. Episodes of aplastic crisis
3. Vaso-occlusive complications: Episodes of hypoxic injury
& infarction (Vaso-occlusive crisis) associated with severe
pain in affected region
4. Increased susceptibilityto infections due to :
i) Markedly impaired splenic function
ii) Defects in alternative complementpathway
Eg: Pneumococci & H.influenza → Meningitis
Clinical
Features