Haematology-heamoglobin abnormality

1. Sickle cell
Anaemia
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2. ABNORMAL HEMOGLOBINS AND THE
HEMOGLOBINOPATHIES
• Abnormal hemoglobins arise from mutation affecting the gene directing the
structure of a particular pair of polypeptide chains.
• They are classified as α, β, γ, δ chain variants depending on the chains involved.
• The majority of abnormal hemoglobins differ from the corresponding normal
hemoglobin by the substitution of a single amino acid in one of their pairs of
polypeptide chains.
• A small number of abnormal hemoglobins have double amino-acid substitutions
and others have deletions of amino acids. Abnormal hemoglobins are inherited as
autosomal co-determinants.
• The subjects who inherit one normal and one abnormal gene are heterozygotes,
and those who have two identical abnormal genes are homozygotes. The
homozygous state is usually referred to as the 'disease' and the heterozygous
state as the 'trait',
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3. The Sickle Hemoglobinopathies
• These are hereditary disorders in which the red cells contain Hb-S,
which differs from Hb-A in the substitution of valine for glutamic acid
in the sixth position from the N-terminal end of the β -chain.
• The sickle hemoglobinopathies include the heterozygous (sickle-cell
trait) and the homozygous (SS disease) states for Hb-S in addition to
conditions in which Hb-S combines with other hemoglobin structural
variants or thalassemia.
• In the deoxygenated state, the solubility of Hb-S is ten percent of that
of Hb-A. The conformational changes induced by deoxygenation in
Hb-S cause the cells to become rigid and deformed, assuming a sickle
or crescent shape.
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4. Autosomal Recessive Disorder
• Autosomal recessive is one of several ways that a trait, disorder, or disease can be
passed down through families.
• An autosomal recessive disorder means two copies of an abnormal gene must be
present in order for the disease or trait to develop.
• An affected person usually has unaffected parents, each carrying a single copy of
the mutated gene i.e. carriers (heterozygotes)
• To have an autosomal recessive disorder, you inherit two mutated genes, one
from each parent. These disorders are usually passed on by two carriers.
• Two mutated copies of the gene are present in each cell when a person has an
autosomal recessive disorder
• A mutation is a change to the structure of a gene. It occurs when a gene is
damaged or changed, altering the genetic information carried by that gene
• Autosomal recessive disorders are typically not seen in every generation of an
affected family
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5. What is Sickle cell disease
• Sickle cell disease (SCD) is a life
threatening autosomal recessive
genetic disorder resulting from
inheritance of abnormal genes from
both parents.
• Normal red blood cells (RBCs) are
biconcave disc shaped and move
smoothly through the blood
capillaries.
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8. Sickle cell disease is caused by a point
mutation in the sixth codon of β-globin
that leads to the replacement of a
glutamate residue with a valine residue.
The abnormal physiochemical properties
of the resulting sickle hemoglobin (HbS)
are responsible for the disease.
The life span of RBCs in SCD patients is only
about 10 to 20 days and the bone marrow
can't replace them fast enough.
As a result there is decrease in number of
RBCs in the body and the RBCs don’t
contain sufficient amount of hemoglobin.
 In SCD the RBCs become sickle or crescent
shaped which are stiff &sticky and tend to
block the blood flow in small capillaries.
Blocked blood flow causes ischemia leading
to severe pain and gradual damage to
organs
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9. • The sickling of red cells in the Circulating blood has following two
major pathological effects:
1. The rigid and distorted cells block small blood vessels. This leads
to blockage of small blood vessels causing ischemia and infarction.
2. Due to repeated formation of sickle and non-sickle formation,
there is loss of fragments of red cell membrane and with the
result, the cell becomes spherocytic and fragile.
• These cells are removed prematurely by the Reticuloendothelial
system and to some extent are also destroyed in the circulation,
resulting in both extravascular and intravascular hemolysis
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11. Who is at Risk?
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18. Pathogenesis
• Hb S molecules undergo polymerization when deoxygenated.
• Initially the red cell cytosol converts from a freely flowing liquid to a
viscous gel as Hb S aggregates form.
• With continued deoxygenation aggregated Hb S molecules assemble into
long needle- like fibers within red cells, producing a distorted sickle or
holly-leaf shape.
• In heterozygotes with sickle cell trait, about 40% of the hemoglobin is HbS
and the rest is Hb A, which interferes with Hb S polymerization.
• As a result, red cells in heterozygous individuals do not sickle except under
conditions of profound hypoxia.
• Hb F inhibits the polymerization of Hb S even more than Hb A; hence,
infants do not become symptomatic until they reach 5 or 6 months of age,
when the level of Hb F normally falls.
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19. Sickle-cell Trait
• Sickle cell trait is the heterozygous state for the Hb-S gene.
• Hb-S comprises 35-95 per cent of the total hemoglobin.
The other hemoglobins present are Hb-A, Hb-A2, and HbF.
• The red cell life span is normal since cell do not contain
sufficient Hb S to undergo sickling at deoxygenated state.
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20.  Blood picture:
• In the stained blood film, usually
sickle cells are not present ..
• MCV and MCH are normal
• Normal red cell morphology with
occasional target cells
• Normal reticulocytes
• Positive sickle cell test and
presence of Hb S by
• Hemoglobin electrophoresis
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22. • Sickle cell trait does not cause anemia and in general is
asymptomatic.
• Sickling can be demonstrated by the sickle test
• Sickle cell trait occurs in about eight per cent of American Blacks. In
Africa its prevalence rate in many populations is over 20 per cent and
about so per cent in some tribes
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23. Homozygous Sickle cell Disease
• In homozygous Sickle-ceil disease, the patient receives one Hb-S gene
from each parent, both of whom show sickle-cell trait.
• The red cells of the patient contain sufficient Hb-S for sickling. Nearly
all patients are anemic and sickle-cell crises are a characteristic
feature of the disease.
• Sickle cell crisis may be vasa-occlusive, aplastic or sometimes
hemolytic. Vaso-occlusive crisis consist of sudden attacks of bone or
abdominal pain.
• Bacterial infection is the most common cause of the early morbidity
and mortality.
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24. • The laboratory findings are as follows:
• Normocytic, normochromic red cells
• Normal MCV and MCH
• Presence of sickle cells, Howell-Jolly bodies and
• nucleated red blood cells
• Increased reticulocytes
• Increased platelets
• Decrease in osmotic fragility of red cells
• Hemoglobin electrophoresis show 'S' band (which
migrates more slowly than Hb A
• Positive sickle cell test using sodium metabisulfite
• The stained blood film shows moderate anisocytosis
and varying degrees of poikilocytosis. Oval cells,
occasional target cells and Howell-Jolly bodies are
present. Reticulocytes and nucleated red blood cells
are increased
• There is increase in indirect bilirubin. Even with
marked anemia, erythrocyte sedimentation rate is
slow, since the abnormal shape of sickle cells prevents
rouleaux formation.
Howell-Jolly bodies
Reticulocyte
Nucleated RBC
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25. Sickle-cell Hb C Disease
• Sickle-cell Hb C disease results from the inheritance of the Hb S gene
from one parent and the Hb C gene from the other.
• Clinically it is less severe than homozygous sickle-cell disease.
• The patients are usually only mild anemic or may have normal
hemoglobin level. Blood film shows numerous target cells but
irreversibly sickled cells are often not seen.
• MCV and MCH are mildly reduced and the reticulocyte count is mildly
elevated.
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26. • Hemoglobin D: It results from the replacement of beta 121
glutamic acid by glutamine. It does not produce sickling.
HbD Punjab is the commonest Hb variant seen in Punjabi
population.
• Hemoglobin E: It results from replacement of beta 26
glutamic acid by lysine. Heterozygotes are completely
asymptomatic and homozygotes show a slight decrease in
hemoglobin level. It is primarily seen in orientals of South-
East Asia and the variant is very prevalent in West Bengal in
India.
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