SICKLe CELL
ANAEMIA
INTRODUCTION
• The most important and widely prevalent type of
haemoglobinopathy is due to the presence of sickle
haemoglobin (HbS) in the red blood cells.
• The red cells with HbS develop ‘sickling’ when they are
exposed to low oxygen tension.
• Sickle syndromes have the highest frequency in black
race and in Central Africa where falciparum malaria is
endemic.
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• Sickle syndromes occur in 3 different forms:
1. As heterozygous state for HbS: sickle cell trait
(AS).
2. As homozygous state for HbS: sickle cell
anaemia (SS).
3. As double heterozygous states e.g. sickle β-
thalassaemia, sickle-C disease (SC), sickle-D
disease (SD).
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1. Heterozygous state for HbS: sickle cell trait (AS)
• Sickle cell trait (AS) is a benign heterozygous state of
HbS in which only one abnormal gene is inherited.
• Patients with AS develop no significant clinical
problems except when they become severely
hypoxic and may develop sickle cell crises.
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2. Homozygous State:Sickle Cell Anaemia (SS)
• Sickle cell anaemia (SS) is a homozygous state of HbS
in the red cells in which an abnormal gene is
inherited from each parent.
• SS is a severe disorder associated with protean
clinical manifestations and decreased life
expectancy.
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PATHOGENESIS
• Following abnormalities are observed:
1. Basic Molecular Lesion
2. Mechanism of Sickling
3. Reversible-irreversible Sickling
4. Factors Determining Rate of Sickling
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1. Basic Molecular Lesion
➢ In HbS, basic genetic defect is the single point
mutation in one amino acid out of 146 in
haemoglobin molecule— there is substitution of
valine for glutamic acid at 6-residue position of
the Beta-globin.
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2. Mechanism of Sickling:
➢ During deoxygenation, the red cells containing HbS change
from biconcave disc shape to an elongated crescent-shaped
or sickle-shaped cell.
➢ This process termed sickling occurs both within the intact
red cells and in vitro in free solution.
➢ The mechanism responsible for sickling upon deoxygenation
of HbS-containing red cells is the polymerisation of
deoxygenated HbS which aggregates to form elongated rod-
like polymers.
➢ These elongated fibres align and distort the red cell into
classic sickle shape.
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3. Reversible-irreversible Sickling
➢The oxygen-dependent sickling process is usually
reversible.
➢However, damage to red cell membrane leads to
formation of irreversibly sickled red cells even
after they are exposed to normal oxygen tension.
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4. Factors Determining Rate of Sickling
➢ Following factors determine the rate at which the polymerisation of HbS
and consequent sickling take place:
i) Presence of non-HbS haemoglobins: The red cells in patients of SS
have predominance of HbS and a small part consists of non-HbS
haemoglobins, chiefly HbF (2-20% of the total haemoglobin). HbF-
containing red cells are protected from sickling while HbA-containing
red cells participate readily in co-polymerisation with HbS.
ii) Intracellular concentration of HbS.
iii) Total haemoglobin concentration.
iv) Extent of deoxygenation.
v) Acidosis and dehydration.
vi) Increased concentration of 2, 3-BPG (bis-phospho-glycerate) in the
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red cells.
CLINICAL FEATURES
• The clinical manifestations of homozygous sickle cell
disease are widespread.
• The symptoms begin to appear after 6th month of life
when most of the HbF is replaced by HbS.
• Infection and folic acid deficiency result in more severe
clinical manifestations.
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• The features are as under:
1. Anaemia: There is usually severe chronic haemolytic anaemia
(primarily extravascular) with onset of aplastic crisis in between.
The symptoms of anaemia are generally mild since HbS gives up
oxygen more readily than HbA to the tissues.
2. Vaso-occlusive phenomena: Patients of SS develop recurrent
vaso-occlusive episodes throughout their lives due to obstruction
to capillary blood flow by sickled red cells upon deoxygenation or
dehydration. Vaso-obstruction affecting different organs and
tissues results in infarcts which may be of 2 types:
i) Microinfarcts
ii) Macroinfarcts
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i) Microinfarcts affecting particularly the abdomen, chest, back
and joints and are the cause of recurrent painful crises in SS.
ii) Macroinfarcts involving most commonly
➢ Spleen (splenic sequestration, autosplenectomy),
➢ Bone marrow (pains)
➢ Bones (aseptic necrosis, osteomyelitis)
➢ Lungs (pulmonary infections)
➢ Kidneys (renal cortical necrosis)
➢ CNS (stroke)
➢ Retina (damage) and
➢ Skin (ulcers)
Result in anatomic and functional damage to these organs.
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3. Constitutional symptoms: In addition to the features of
anaemia and infarction, patients with SS have impaired
growth and development and increased susceptibility to
infection due to markedly impaired splenic function.
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3. Double Heterozygous States:
• Double heterozygous conditions involving combination
of HbS with other haemoglobinopathies may occur.
• Most common among these are sickle-β-thalassaemia
(βSβthal), sickle C disease (SC), and sickle D disease (SD).
All these disorders behave like mild form of sickle cell
disease.
• Their diagnosis is made by haemoglobin electrophoresis
and separating the different haemoglobins.