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
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
6.
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
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
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
