Haemoglobinopathy refers to a disease
state (opathy) involving the haemoglobin
Sickle cell syndrome is a type of
qualitative haemoglobinopathy, occuring
due to point mutation in β-like gene,
leading to structural alteration in β-chain,
of globin part of Hb and affecting the
functional capacity of RBCs.
Sickle-cell disease (SCD), or sickle-cell
anaemia or drepanocytosis, is an autosomal
co-dominant genetic blood disorder
characterized by red blood cell that assume
an abnormal, rigid, sickle shape.
+Recurrent episodes of painful crises, and
progressive end-organ damage
• Sickle cell anaemia was
observed by a Chicago
physician, James Herrick
in 1910 in a West indian
student with severe
• In 1927, Hahn and
Gillespie described the
pathologic basis of the
disorder and its
relationship to the
In 1946, Beet reported that malarial
parasites were present less frequently in
blood smears from patients with SCD
compared with normal individuals.
It was determined that sickle cell trait
confers resistance against infection with
plasmodium falciparum occuring early in
childhood between the time, that
passively acquired immunity passes and
active immunity develops.
Pauling and Co-workers defined the
genetics of the disorder and clearly
distinguished heterozygous sickle trait
(Hb AS)from the homozygous state (Hb
The highest frequency of sickle cell trait
is in Africa where the frequency is 20-
40%,the high prevalence can be
explained by the selective survival
advantage it confers in areas where
Falciparum malaria is endemic.
In the United states, approximately 12%
of african Americans have a
It has also been found in individuals from
the middle east, India, and the
Also from regions of caribbean and
central & South America.
Sickle cell is becoming more prominent in
southern India, particularly in certain
Incidence with Malaria
The sickle gene occurs with greatest
frequency in central africa ,the near
East, the region around the
mediterranian,and parts of India.
The frequency of gene parallels the
incidence of P. falciparum and seems
to offer some protection in young
patients with cerebral falciparum
Basic molecular lesion:
In HbS, basic genetic defect is Single
point mutation in one amino acid out of
146 in haemoglobin molecule.
There is substitution of a Valine for
Glutamic acid, at 6th residue position
of β-Globin, producing Hb α₂ β₂ S
Glutamic acid has a net charge of -1,
whereas Valine as a net charge of +0.
This amino acid substitution results in
charge of +1, resulting a structural
change in the Hb molecule.
Molecular pathology of SCD
The sickle mutation
The s Mutation
6th Codon of -Globin Gene
In Sickle Cell Disease
Gower 1: 2 2
Gower 2: 2 2
Portland: 2 2
F: 2 2
A2: 2 2
Hemoglobins in SS by age > 1 yr
Mechanism of Sickling.
During deoxygenation the red cells
containing Hb S change from biconcave
disc shape to an elongated Cresent
shape, this process is ‘Sickling’.
The Molecule of Hb under
deoxygenated condition polymerize to
form Pseudocrystalloid structures
known as ‘Tactoids’.
These aggregate to form elongated rod
These elongated fibres align and distord
the red cells to classic Sickle cell.
These polymerised deoxy-Hb S activates a
membrane channel called Psickle that is
otherwise inactive in normal RBCs.
These membrane channels open when the blood
Po2 decreases to less than 50mm Hg.
Open Psickle channels allow the influx of Ca, raisin
the intracellular Ca levels & activating a second
membrane channel called the gardos channel.
An activated gardos channel causes the efflux of K
that stimulates the efflux of Cl through another
membrane channel to maintain charge equilibrium
across the RBC membrane.
The efflux of these ions leads to
dehydration, effectively increasing the
intracellular concentration of Hb S &
The oxygen dependent process is
However the damage to red cell
membrane leads to the formation of
irreversible sickled cell even after they
are exposed to normal oxygen tension.
Factors determining the rate of
Presence of non-Hb S
haemoglobins, Hb F.
Intra cellular concentration of Hb S.
Total haemoglobin concentrations.
Extent of deoxygenation.
Acidosis and Dehydration.
Increased concentration of 2,3-BPG in
the red cells.
↑SCD in malarial endemic regions:
Malarial parasite within RBC use the
oxygen within the cell
Reduce oxygen tension
RBC Sickling, injury to cells
Injured Cells get trapped in bleeding
Easily phagocytosed by
Selective destruction of Infected RBC’s
↓↓ Number of Malarial organisms
↑↑ in time for Immunity to develop.
It occurs in 3 different forms:
1. Heterozygous state for Hb S: Sickle
2. Homozygous state for Hb S : Sickle
3. Double heterozygous states
eg: Sickle β-thalassemia
Sickle C disease
Sickle SC disease
Sickle Cell Trait
Sickle haemoglobin (S) + Normal haemoglobin (A) in RBC
• Adequate amount of normal Hb (A) in red blood cells
• RBC remain flexible
• Do Not have the symptoms of the sickle cell disorders,
• with exceptions:
• Pain when Less Oxygen than usual (activities at high
altitude (12,000ft), under general anaesthesia)
• Minute kidney problems*
Is the most common non sickling
Here lysine is substituted for glutamic
acid in 6th position of β globin chain.
Is inherited in same as HB S but manifest
as a milder disease.
Similar to Hb S, Hb C polymerises under
low oxygen tension, but the structure of
the polymers differs.
Hb polymers are long and thin
whereas the polymers in Hb C form a
short, thick crystal within the RBC.
The shorter Hb C crystal does not
alter RBC shape to the extent of Hb S,
resulting in diminished splenic
sequestration and hemolysis.
Is the most common double
At the 6th position, glutamic acid is
replaced by valine(Hb S) on one β-
globin chain & lysine(Hb C) on other β-
Hb SC disease resembles a mild SCD.
Growth & development are delayed
compared with normal children.
In contrast to SCD, significant
symptoms here do not occur until
May cause all the vaso-occlusive
complications of sickle cell
anemia, but the episodes are less
frequent, and damage is less
Double heterozygosity for Hb S & β-
thalassemia is the most common cause of
sickle cell syndrome in patients of
It causes a clinical syndrome resembling
that of mild or moderate sickle cell
The severity of this double heterozygous
condition depends on β-chain production
of the affected thalassemia β-genes.
If there is no globin chain production
from the β-thalessaemia globin gene (S-β0-
thal), the clinical course is similar to that of
homozygous sickle cell anaemia
If there is production 0f β globin (S-β+-thal),
patients tend to have a milder condition than
patients with Hb SC.
These patients can be distinguished from
individuals with Sickle cell trait
-greater amount of Hb S than Hb A
-↑↑ levels of Hb A2 and Hb F.
-microcytosis from thalassaemia
-abnormal blood morphology.
Sickle cell anemia is an autosomal co
dominent genetic disorder. For the
disease to be expressed, a person
must inherit either two copies of Hb S
variant(Sickle Cell Disease) or one
copy of Hb S and one copy of another
variant(Sickle Cell Trait)
Inheritance of Sickle Cell Anemia
If both parents have sickle
cell trait (HbAS) there is a one
in four (25%) chance that any
given child could be born with
sickle cell anemia.
There is also a one in four
chance that any given child
could be completely
There is a one in two (50%)
chance that any given child
will get the sickle cell trait
If one parent has sickle cell
anaemia (HbSS) and the
other is completely unaffected
(HbAA) then all the children
will have sickle cell trait.
None will have sickle cell
The parent who has sickle cell
anemia (HbSS) can only pass
the sickle hemoglobin gene to
each of their children.
• If one parent has sickle
cell trait (HbAS) and the
other has sickle cell
anaemia (HbSS) there is a
one in two (50%) chance
that any given child will get
sickle cell trait and a one in
two (50%) chance that any
given child will get sickle cell
• No children will be completely
• If one parent has sickle cell
trait (HbAS) and the other
does not carry the sickle
hemoglobin at all (HbAA)
then none of the children will
have sickle cell anemia.
• There is a one in two (50%)
chance that any given child will
get one copy of the HbAS gene
and therefore have the sickle
• It is equally likely that any given
child will get two HbAA genes
and be completely unaffected.
The clinical manifestations of the sickle
cell syndrome can vary from
asymptomatic to a potentially lethal
state as characterized by Sickle cell
Individuals affected with Sickle cell
disease are characteristically
asymptomatic until the the second half
of the first year of life owing to the
protective effect of Hb F.
During the first 6 months of life, mutated
β chains are produced to gradually
replace normal ᴕchains, causing Hb S
levels to increase as Hb F levels
Erythrocytes containing Hb S become
susceptible to hemolysis, and a
progressive hemolytic anaemia and
slenomegaly may become evident.
Typical course of sickle cell patient is, the
period of relatively normal functioning,
despite chronic anaemia, punctuated by
periods of either pain in various anatomical
sites, or other manifestations termed as
It is acute in onset
These have been classified as
-vaso occlusive painful crisis
Is the hallmark feature of SCD, accounting for
most hospital & emergency dept visits.
It results from complex interplay between
sickled red cells, neutrophils, endothelium, &
End result is that of tissue hypoxia leading to
tissue death & accompanying pain.
Fever is often present even in the absense of
This acute painful aspect of SCD can be
They manifest most often in the bones,
lungs, liver, spleen, eyes, penis, CNS &
The frequency of pain varies from none to
six per year
On average each episode persists for 4 to
5 days, although protracted episodes may
last for weeks.
Young children: mostly extremities
Older patients: abdomen, back, chest
Associated with intercurrent illness and
other Vaso-occlusive event
It’s a term used to
swelling of digits of
hands and feet(Hand-
Occurs early in infancy
marrow is present in
these bones at this
Most episodes resolve within 2 weeks.
Epiphyseal infarction can result in joint
pain and swelling mimicking septic
Impaired cellular and
together with infarction of
bone contribute to this
Non-typical serotypes of
are principle infection
Acute chest syndrome
Is due to pulmonary infarction from
sickling in microvasculature, infection or
Also bone marrow infarction results in
fat emboli to the lungs, being other
Is characterized by fever, acute chest
pain & presence of pulmonary infiltrates
on the Chest X ray.
In Children, acute chest syndrome
generally is precipitated by infection
characterized by Fever, cough, and
In adults, this organ failure is the most
common cause of Death.
Is usually seen under the age of 2 years,
in infants and young children.
The spleen rapidly enlarges (within hours)
& most of the circulating red cell mass
Is characterized by a sudden trapping of
Blood in the spleen, resulting in rapid
decline in Hb, often to less than 6g/dl,
result in hypovolemic shock &
Characterised by rapid enlarging
spleen, pain, hypoxemia and
These may be associated with fever,
pain and respiratory symtoms.
Circulatory collapse and death can
occur in 30 min.
Multiple episodes of splenic sequestration
leading to gradual loss of function(by the
age of 6-8 yrs) termed as Auto-
It confers a Non-functioning spleen, which
is reduced to a shrunken, fibrosed
Hence patients are prone to microbial
infections, especially encapsulated, such
as -S. pneumoniae.
Chronic liver abnormality in SCD are
frequent and are reflective of different
etiologies of liver dysfunction that include
Pigment gall stones, with bile duct
Acute or chronic cholecystitis,
Viral Hepatitis and
Too much bilirubin from break
down of Hb leads to gallstone
Nausea, vomitting, fever, sweating
, chills, clay coloured
Is the painful erection of penis
caused by sicklin red cells.
This complication usually occurs in
children and adolescents with SS or
SC with an onset at age 5 to 35.
It occurs as a severe episode
requiring hospitalization following
multiple episodes of short duration
, termed stuttering.
Onset in early morning, waking the
patient is common.
Impotence with severe disease or
Microvascular obstruction occurs
followed by neovascularization and
arterio venous aneurysm.
Haemorrhage, scarring and retinal
detachment leading to blindness are
7.CENTRAL NERVOUS SYSTEM:
25% of patients are affected with CNS
These include Transcient Ischaemic Attack,
Strokes and Cerebral haemorrhage.
-in SCD is a macrovascular phenomenon, that
affects approx. 11% of patients younger than 20
Is highest in first decade of life.
Ischaemic stroke is most common in children &
older adults, whereas haemorrhagic stroke in
third decade of life.
Cerebral blood flow is significantly
increased in SCD because of chronic
anaemia & hypoxaemia.
Cerebral vasculature is unable to
vasodilate further in response to
increased hypoxic stress thereby
-Ischaemic stroke: TIA, recent or
recurrent acute chest syndrome and
-Haemorrrhagic stroke: Anaemia &
Incidence varies between 4-20%
The acidic, hypoxic and hypertonic environment
of the renal medulla promotes sickling of Hb SS
RBCs leading to ischaemia of the renal
microcirculation, loss of medullary function &
renal papillary necrosis.
Usually painless, can result from papillary
necrosis, rupture of collateral vessels, & rarely
40% of SCD patients with nephrotic
syndrome develop end-stage renal
Occurs in ~ 20% of all patients
Occurs in 4.5% of all pediatric patients
- increased in Hemoglobin SS to 6.5%
- Increased incidence with age.
- Increased with anaemia, increased MCV,
and increased leukocyte count.
It occurs in 2-40% cases of Sickle cell
Most common in patients older than 10
years of age.
Typically ocurrs in lower extremities,
especially on malleoli and cause
chronic pain and disability.
Venous stasis is the predisposing factor.
II. BACTERIAL INFECTIONS
These patients have increased
susceptibility to life threatening infections
St. pneumonia and
Acute infections are common causes of
hospitalizations and have been the most
frequent cause of death, especially in the
first 3 years of life.
These are exacerbated by auto-
splenectomy effect as its ability to
function as a secondary lymphoid tissue
to clear organisms effectively from the
blood is diminished, or lost.
Pnemonia and Osteomyelitis.
III. HEMATOLOGICAL DEFECTS:
Essentially a hemolytic process, can be
correlated with intra-cellular polymer
Characterised by generalised weakness,
fatigue, shortness of breath on exertion,
Describes the occurnence of episodesof
accelerated haemolysis characterised by
decreased blood Hb, increased
reticulocytes and other markers of
Episodes of haemolysis occur in
-resolutive phase of Vaso-occlusive
-delayed haemolytic transfusion
This results from sudden arrest of
erythropoiesis due to folate deficiency.
FA requirement is higher in haemolytic
anaemia and this factor is responsible
for severe anaemia in patients who are
Aplastic episodes (bone marrow failure)
are the most common life threatening
haemotological complications, and
usually are associated with infection,
particularly with Parvo viruses 19
resulting in a severe but self limiting red
SCD patients usual can compensate for
the decrease in RBC survival by
increasing bone marrow output.
But when bone marrow is suppressed
temporarily by bacterial or viral infections
however the haematocrit decreases
substantially with no reticulocyte
This produces a very low Hb which may
cause heart failure.
IV. CARDIAC DEFECTS:
Enlarged heart: the hemodynamic
burden of anaemia results in elevated
cardiac output and hence ventricular
-Forceful precordial apical impulse
-Systolic & Diastolic flow murmers, as
manifestation of hyperdynamic
2. Chest pain
3. Shortness of
Danger Signs of a Crisis
7. Any sudden weakness
or loss of feeling
8. Pain that will not go
away with home
9. Priapism (painful
erection that will not go
10.Sudden vision change
V. OTHER FEATURES:
A vast majority of children with SCD
will show decline in growth compared
to normal peers.
Puberty is delayed on an average by
12 to 24 months, as is skeletal age.
High risk pregnancy
One third of patients will have
adverse obstretic outcomes as
defined by Miscarriages, StillBirths
or Ectopic implantation.
Preterm delivery occurs in 30-50%
of pregnancy in sickle cell disease
patients and 20% of infants have
low birth weight.
A five fold increase in risk for
Thromboembolism is present during
Other significant findings include
-higher rates of Caeserian section
-Pre-eclampsia or Eclampsia