DR SANNI EMMANUEL OLADIPO

 Sickle cell disease is an inheritable, genetic

and fatal disease causing red blood cells
disorders .

 It is the most common public health

problem in the African and Asian countries
of the world.

 The Haemoglobinopathies are the

commonest, life-threatening, monogenic
disorders in the world.
 About 7% of the world population are carriers &
300,000 - 400,000 affected children are born
every year with major Haemoglobinopathies (SCD
& Thalassaemias)

The majority of these abnormalities (70%) are due

to sickle cell disease.

 80%of this occurs in middle and low resource

countries like Nigeria
 Sickle cell disease (SCD) is a group of
haemoglobin disorders in which the sickle βeta -
globin gene is inherited.

The sickling disorders include;

 Heterozygous state for haemoglobin S as in

Sickle-cell trait (HbAS)

Homozygous state-Sickle cell anaemia (HbSS)

 Compound Heterozygous state -

Sickle-thalassaemia (HbSβthal, HbSC, HbSE etc

 SCD is a disease of public health
importance and hence its being celebrated
annually on June 19 as World Sickle Cell
Awareness Day.

 The date was chosen to commemorate the

day in which a resolution was officially
adopted by the General Assembly of the
United Nations recognizing SCD as a public
Health concern in 2008
 According to WHO,SCD is one of the main
cause of premature death amongst children
under the age of five in various African
countries.

 The date is set aside to increase public

knowledge and to raise awareness of Sickle
Cell Disease and the struggles the sufferers
and families go through.

 Also to help in removing stigma and myths

associated with Sickle Cell Disease.
Sickle cell disease was known to the scientific
community in 1910 when James Herrick
described an anemia characterized by bizarre,
sickle shaped RBCs” in the blood of black dental
student studying in Chicago named Walter
Clement Noel from the island of Grenada.

Although the disorder has been present in

Africa for at least five thousand years and has
been known `with different names in many
tribal languages.
 Symptoms related to sickle cell crises were
known by various names in Africa long
before they were recognized in the western
hemisphere.

 This disease and affected children were

called Ogbanje by Igbo & Abiku, Lakuegbe in
Yoruba land, Chwechweechwe in Ghana,
Adep in Cameroon.

 All because of severe mortality inflicted by

SCA and nearly 100% mortality in those
African settings.
Sickle cell disease is a pan-ethnic condition
with the highest prevalence among those of
African, Mediterranean, Middle Eastern,
Indian, Caribbean, and Central and South
American descent.

The trans-Atlantic slave route has make the

disease to be prevalent in Western world

More than two-third of people with SCD are

in sub Sahara Africa where malaria is
endemic
The mortality is quiet high as 50-80% of
infants born with SCD in Africa die before
the age of 5 years.

Its estimated that 240,000 children are

born annually in sub-Sahara Africa.

Nigeria has the highest number of

homozygous cases in the world with a
prevalence of sickle cell anaemia ranging
between 1.5-3.1% (Average 2%).
Trans-Atlantic Slave Routes

Frankel NA http://www.slaverysite.com/Body/maps.htm
WHO estimates the prevalence of SCA to be about
20 per 1000 live births annually, which translates
into more than 100,000 children born annually
with sickle-cell anaemia in Nigeria.

There are about 2-3 million homozygous cases

(HbSS) and up to 40 million sickle cell trait (HbAS).
The areas with high prevalence corresponds to
malaria endemic zone.

Sickle cell trait are more resistant to malaria than

those with two normal haemoglobin genes and
making the gene to persist
 Genetic studies by Kan and Dozy,1978 and
Antonarakis et al 1982 have finally
established the multicentre origin of the Sickle
cell disease in Africa, i.e Benin, Bantu, Senegal

There are different Haplotypes

 Senegal Haploytpe
 Benin Haplotype
 Cameroon haplotype
 CAR/Bantu Haplotype
 Saudi Arabia/India
Origin(s) of the Sickle Mutation
The widely accepted theory(balanced
polymorphism) is that HbS offers selective
protection against Falciparum malaria
probably because of induction of sickling
even at physiological oxygen tension by P.
falciparum.
Sickling results in sequestration of
parasitized red cells deep within reticulo-
endothelial system where microenvironment
is hostile for parasite growth.
This is more reason while the prevalence of
SCD is high in Malarial holoendemic region
 Sickle cell disease is inherited in a Mendelian
fashion, an autosomal recessive disorder which
occurs as a result of single nucleotide mutation
in a gene that code for β-globin gene.

In order for full disease symptoms to manifest

individual must carry 2 copies of the HbS genes.

Missense mutation in the B-globin gene is the

commonest.
SCD gene is located on Chromosome 11
There is a single base change in the DNA
coding for the amino acid in the 6th position
of the β-globin gene.

Adenine is replaced by thymine leading to

amino acid change from glutamic acid to
valine
Molecular basis of sickling
As red cell releases oxygen to the tissue,
there is a conformational change that
exposes a hydrophobic patch on the surface
of the βs-globin chain at the site of β6 valine.

Binding of this site to a complementary

hydrophobic site on a β-subunit of another
haemoglobin tetramer triggers the formation
of large polymers.
 The polymers consist of staggered
haemoglobin tetramers that aggregate into
21-nm-diameter helical fibres, with one
inner and six peripheral double strands.

 Ordinarily the haemogblobin molecules

exists as single isolated units in the red cell
whether they have oxygen bound or not.

 The normal red cell maintain a basic disc

shape whether they are transporting oxygen
or not.
 Hb S only exists as isolated units in the red
cell when they have oxygen bound.

 When Oxygen is released they tend to stick

together and form long chain or polymers.
These polymers are held together by weak
forces.

 The abnormal valine amino acid interact

with the adjacent one
Acidosis and elevated level of 2,3-
diphosphoglycerate (2,3-DPG) promote
polymer formation by reducing the oxygen
affinity of haemoglobin.

The presence of HbA within the red cells, as in

sickle trait, inhibits polymerization by diluting
HbS.

The inhibitory effect of HbF on polymerization

of HbS is more profound owing to the greater
amino acid disparity between the βs- and γ-
globin chains hence the reason for use of
Hydroxyurea.
• It block the interaction between the
deoxygenated HbS molecules

Effect on erythrocytes
Upon deoxygenation red cells acquire the sickle
shape as a result of intracellular
polymerization of HbS, this is reversible upon
reoxygenation.

The presence of HbS polymer reduces

deformability, with consequent increase in
blood viscosity. Repeated or prolonged sickling
progressively damages the red cell membrane.
 Damage to red cell membrane promotes many
of the complications of sickle cell disease.

Heme component of Hb tends to be released

from the protein with repeated episode of
polmerization .

Some of these free heme lodges in the red

cell membrane.

The iron in the centre of the heme promote

formation of very dangerous compounds,
called reactive oxygen species.
These molecules damage both the lipid and
protein components of the red cell
membrane-----membrane stiffness

Damage protein form abnormal clusters in

the red cell membrane leading to cell
destruction or haemolysis.
 Membrane damage causes movement of
potassium ions and water out of the cell by
the Gardos pathway and potassium–
chloride co-transport, leading to
dehydration of red cells.

The free haemoglobin also leads to

reduction in Nitric oxide in the plasma and
endothelial dysfunction and several
complications like pulmonary
hypertension.
The damage to the red cell membrane cause
alteration of the chemistry of the red cell
membrane.

Perturbation of lipid organization causes

negatively charged phosphatidylserine to appear
on the red cell surface instead of its normal
location in the inner monolayer.

In addition, the red cells become abnormally

adherent to the vascular endothelium through
vascular cell adhesion molecule 1 (VCAM-1),
thrombospondin and fibronectin.
Clinical symptoms of SCD vary tremendously
between patients. The disease is more severe in
patients with HbSS or HbS βo-thalassaemia than
in those with HbSβ+thalassaemia or HbSC.

Some patients with SCD leave a relatively normal

life, while others develop severe crises even as
infants and may die in early childhood or as
young adults
 Genetic modifiers
There are 3 main factors that modifier the clinical
presentation of SCD
1. Beta S-globin haplotype
2. HbF Level ≥ 20% mild disease
≥ 30% asymptomatic
3. Co-existing -thalassaemia

The mildest disease is associated with the

Arab/India (AI) and the Senegal (SEN) haplotypes
The most severe disease is associated with the

Central African Republic (CAR) haplotype

Benin (BEN) and Cameroon (CAM) are intermediate
Haplotype Nigerian (%) Kuwaiti (%)
Benin 93.0 12.0
Saudi Arabia/ 0 80.4
Indian
Bantu 1.0 6.5
Cameroon 3.4 0
Senegal 0.2 0
Atypical 2.4 0
 Anaemia
SCA is characterized by chronic intravascular
and extravascular haemolysis. Sickling induced
membrane fragmentation and complement –
mediated lysis cause intravascular destruction
of red cells.

Membrane damage also leads to extravascular

haemolysis. The red cell survival is 4-25 days
and resulting anaemia, although the symptoms
may be low compared with degree of anaemia
this is because HbS readily gives up oxygen in
the tissue.
 Acute Painful Episodes
This is the most frequent symptom for which
patient seek medical attention.
Pains are usually precipitated by infection,
acidosis, dehydration, or deoxygenation (altitude,
operations, obstetric delivery, stasis of
circulation, exposure to cold).
In infants the initial pain episode typically
presents as dactylitis or hand and foot syndrome
with swelling over the dorsal surface of the hand
and feet.

In older children and adults the site of pain are

the back, chest, extremities and abdomen.
 Infections
Early loss of splenic functions due to repeated
infarction and inability to produced specific
immunoglobulin G (IgG) antibodies to
polysaccharides antigens increase the risk of
fulminant sepsis.

Patients are prone to infections by encapsulated

bacteria. Pneumococcal infection is a serious
problem in the under 3 years and accounted for
85-90% of septicaemia in the western world.
Meningitis accomplying pneumococcal sepsis
gives mortality of 20-50%.
 Types of crises in SCD
 Painful vaso-occlussive crises

 Visceral sequestration crises

Aplastic crises

Haemolytic crises
 Painful vaso-occlusive crises
These are the most frequent and are
precipitated by infection, acidosis, dehydration
etc .Infarct may occur in any organs including
the bones, lung and spleen.
Most serious VOC is of the brain(Stroke occurs
in about 7% of all patients)and Spinal cord.

Visceral sequestration crises

These are caused by sickling within organs and
pooling of blood, often with a severe
exacerbation of anaemia.
Acute chest syndrome commoner in adult
 Aplastic crises
Often occur with infection especially parvovirus
and lead to temporary shut down of red cell
production. This organism affect BFUe, there is
a sudden fall in haemoglobin and there is
absolute reticulocytopaenia, usually results in
blood transfusion

Haemolytic crises
These are characterized by an increased rate of
haemolysis with a fall in haemoglobin but rise
in reticulocyte count and usually accompany a
painful crises
 VOE Pulmonary Hypertension
Infection/Sepsis
ACS Nephropathy
Splenic Sequestration
Gallstones AVN
Ischemic Stroke
Priapism Leg Ulcers
Dactylitis
Fe Overload Chronic Lung Disease
Aplastic Crisis Multi Organ Failure
Hemorrhagic Stroke
Pediatrics Adults
 Pregnancy
The steady-state haemoglobin level falls in
SCD during pregnancy, similar to the decline
in haemoglobin observed in normal pregnant
women.
Folate deficiency can exacerbate the anaemia.
Painful episodes become more common in the
last trimester.
The incidence of pre-eclampsia is higher than
normal in SCD patients.
Growth retardation and fetal death is common
in mothers with sickle cell disease (SCD)
 The haemoglobin is usually 6-9 g/dl-low in
comparison to symptoms of anaemia.
 Sickle cells and target cells occur in the blood

Features of splenic atrophy (e.g. Howell Jolly

bodies) may also be present.
 Screening tests for sickling are positive when

the blood is deoxygenated (e.g. with dithionate)

 Haemoglobin electrophoresis in which HbSS is

detected.
 The amount of Hb F is variable and is usually 5-

15%,
Sickling test
Sickling of red cells can be induced by sealing a
drop of blood under a coverslip to exclude
oxygen or by adding 2% sodium
metabisulphite.

Solubility test
The solubility test for HbS utilizes a reducing
agent such as sodium dithionite, which is
added to the haemolysate.
The deoxy-HbS is insoluble and renders the
solution turbid.
 A. - Hb
AA

B & C - Hb
SS

D.- Hb
SC

E. - Hb
AS
 The prenatal diagnosis (PD) for the disease gives
the opportunity for expectant couples to have an
accurate, rapid result about the genotype of their
fetus
 Invasive methods:This practice is usually carried
out using either chorionic villus sampling (CVS)
or amniocentesis. Both procedures are invasive
with CVS being done between the 10th and 12th
week of pregnancy while amniocentesis is usually
carried out later (between the 14th and 20th
week)
 Circulating fetal cells in maternal plasma
 Cell-free fetal DNA in maternal plasma
 Fetal cells represent the ideal source of fetal
genetic material for NIPD,
 Fetal nucleated cells that are present in the

maternal circulation have been explored as a

source of fetal genetic materials for NIPD
   Among fetal cell categories found in the

circulation are trophoblasts, fetal leukocytes,

and fetal nucleated erythroblasts (nucleated
red blood cells (NRBCs)). 
 Detecting the presence or absence of
paternally inherited alleles in maternal
plasma in inherited diseases such as SCD
would allow the diagnosis or the exclusion of
those diseases in the fetus, respectively
 Polymerase chain reaction (PCR) is commonly
in use as a traditional molecular method for
prenatal diagnosis of hemoglobinopathies.
The PCR-based technologies differ in
genotyping hemoglobin variants.
 Amplification refractory mutation system
(ARMS), denaturing gradient gel
electrophoresis (DGGE), restriction
endonuclease PCR (RE-PCR), sequencing
analysis (Sanger), microarrays,
pyrosequencing, real-time PCR, and high-
resolution melting analysis (HRM) can be
counted among these PCR-based detecting
methods
Sickle cell disorder is a multi-organ disease
and so management requires multi-displinary
approach.
The core team includes:
Haematologist General Practitioner
Paediatrician Specialty Nurse,
Social worker Nutritionist,
Psychologist Child life Therapist,
Homecare
Community/Patient Advocate,
- All factors known to precipitate crises should
be avoided e.g dehydration, infections,
anoxia
-Routine immunization against encapsulated

organisms
-All children should receive prophylactic
penicillin which may be stopped after the age
of 5 years in the absence of any episode of
pneumococcal sepsis or splenectomy.
- Folic acid supplementation (1 mg per day) is

recommended.
-Good general hygiene and balance Nutrition
CATERGORY INTERVENTION
Newborn screening screening
Comprehensive care
Infection Prophylaxis Penicillin
Immunization
Brain injury Screening with TCD,MRI,
prevention Neurocognitive testing
Phenotypically matched red
Transfusion safety cell
and Iron overload Erythrocytaphresis, Iron
prevention Chelation

Lung injury
Prevention Incentive Spirometry
Antibiotics Hydroxyurea,
Transfusion,ECHO
Catergory Intervention
Surger y /Anaesthesia Peroperative transfusion

Avascular necrosis of Hip joint replacement

the Hip
Priapism Adrenergic agonist
Antiandrogen therapy
Pain Liberal anagesic,NSAIDS

Renal ACE for proteinuria

Renal transplantation
Gall bladder disease Laparascopic
Cholecytectomy
Severe disease
Allogeneic bone marrow
transplantation
Chronc transfusion
- Transfusion therapy
 Blood transfusion in SCD is used to treat severe

anaemia or to reduce the amount of circulating

sickle haemoglobin.
 Chronic transfusion with aim of reducing HbF to

<30% is important in preventing stroke , ACS.

Pain management
 Prompt management of pain is essential, given

its frequent occurrence and potential adverse

psychological consequences.

 PCM,Df118 Opioids analgesic diamorphine

 Hydroxyurea
Hydroxyurea (HU) is a tremendously
important drug in the management of patients
with SCD who have severe clinical
manifestations.
HU inhibits ribonucleotide reductase, leading

to S-phase arrest of replicating cells, and is

used in SCD because of its ability to stimulate
production of HbF.
HU increases HbF as a result of stress

erythropoiesis induced by its myelosuppressive

effect
 Other ways of ameloriating complications
in patient with SCD on Hydroxyurea
include

 - Increase water content of RBC-hydration

 - Decrease WBC and Platelet count.

Neutrophil and reticulocyte promote vaso-

occlusion through vascular adhesion
 -Reduce adhesion of RBC to vascular

endothelium
 - HU contain NO moiety which can be

released directly = vasodilatation

 Hydroxyurea usage leads to reduction in
- - Pain crises
- - Hospitalization
- - Neurologic events
- - Blood transfusion frequency
- - Acute chest syndrome
- - Mortality
 Allogeneic bone
marrow
transplantation
(BMT) from
matched sibling
donor cures 85% of
children with SCD
less than 16 years
of age.
 Gene therapy
This mode of treatment is at experimental
stage in animals and involves correction of SCD
by insertion of a gene into repopulating
haemopoietic cells and regulated expression in
erythropoietic lineage

Herbal therapies in sickle cell disease

Different herbal agents are available in Nigeria for the
treatment of sickle cell disease. Agents tested include:
Fagara Zantholoides (orin ata), Green Tea Extract,
Gallic Extract, Niprisan or Nicosan, Jobelin, Ciklavit and
Garcinia Kola (Orogbo).
Some of these herbal concussions have some
antisickling properties but further evaluation is needed
to confirm their efficacy.
 Due to unpredictable course and recurrent
pain of this illness, the affected patient
have a higher risk of depression and poor
family relationship

 Drug addiction especially to narcotics is

commoner among them.

 In view of these, attention to the wellbeing

as well as educational and vocational are
very important components and should be
part of the care provided to patient with
SCD