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• 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. 2


• Sickle syndromes occur in 3 different forms:

1. As heterozygous state for HbS: sickle cell trait


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). 3


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. 4


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. 5



• Following abnormalities are observed:

1. Basic Molecular Lesion

2. Mechanism of Sickling

3. Reversible-irreversible Sickling

4. Factors Determining Rate of Sickling 6 7


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. 8


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. 9


3. Reversible-irreversible Sickling

➢The oxygen-dependent sickling process is usually


➢However, damage to red cell membrane leads to

formation of irreversibly sickled red cells even

after they are exposed to normal oxygen tension. 10


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 11

red cells.



• 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. 12


• 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 13


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. 14


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. 15


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


• Their diagnosis is made by haemoglobin electrophoresis

and separating the different haemoglobins.