understanding sickle cell anemia

1. SICKLE CELL ANEMIA
(Hemoglobin Disorder)
Prepared by Lalruatdiki
Roll no-3, M.Sc 2nd Sem
Department of Biotechnology

2. History
•
In 1904, an African-American patient of Dr. James Herrick was
suffering from dizzy spells, open sores on his legs, and weakness. A
blood sample was taken of the patient and studied under the
microscope. Dr. Herrick noticed a problem with his patient's red blood
cells. The red blood cells were bent and twisted into crescent shapes
that reminded the doctor of a sickle, a tool that was used by farmers to
cut grain before modern-day farm equipment. In fact, this is where the
disease got its name. Dr. Herrick is given credit for the discovery of
this disease and the name by which we know it today--sickle-cell
anemia. He was the first to say that the sickle shape of his patient's red
blood cells was causing the weakness, dizzy spells, and sores on his
patient's legs.

3. DEFINITION
• Sickle cell disease(SCD):is a hereditary blood disorder, characterized by an
abnormality in the oxygen-carrying haemoglobin molecule in red blood cells.
• This leads to a propensity for the cells to assume an abnormal, rigid, sickle-
like shape under certain circumstances.
• Sickle-cell disease is associated with a number of acute and chronic health
problems, such as severe infections, attacks of severe pain ("sickle-cell
crisis"), and stroke, and there is an increased risk of death.
• more common in the US among the African American population, and around
the world, it usually happens among populations originating in tropical areas.
 Red bood cells contain an iron rich protein called hemoglobin that carries oxygen
from lungs to the rest of the body. Normal cells are disc shaped, flexible and look
like donuts without holes in the center which enables them to travel through small
blood vessels to deliver oxygen to all parts of the body.

4. Structure of hemoglobin

6. What causes sickle cell anemia?
• Caused by abnormal hemoglobin called sickle hemoglobin or
hemoglobin S as a result of genetic mutation (missense mutation)
in the gene for hemoglobin, which results in the production of
sickle hemoglobin.
• Causes red blood cells to develop a sickle, or crescent shape.

7. Molecular Basis of Disease
• Normally, humans have hemoglobin A,
alpha chain=141 amino acids long.
beta chain=146 amino acids long.
• The sickle-cell disease occurs when the 6th amino acid, glutamic acid (hydof
the beta chain, is replaced by valine to change its structure and function.
• Mutation is a single nucleotide substitution on chromosome 11.
• GAG  GTG results in substitution of valine (negatively charged) for
glutamate (non polar)
• Mutant hemoglobin polymerizes under low oxygen conditions, it sticks
together and form bundles of long rods that distort red cells into the classic
sickle shape.
• Sickle cells are stiff and sticky. They tend to block blood flow in the blood
vessels of the limbs and organs. And therefore can cause pain and organ
damage.

8. Mutation on chromosome No 11
Mutation

9. • The sickle-shaped red blood cells break apart easily causing anemia.
• Hemoglobin S with this mutation is referred to as HbS as opposed to the normal
adult HbA.
Effects at the DNA level

11. Oxygen’s functional imbalance and the changes in the
RBC membrane
• Under deoxygenation condition, hemoglobin S polymerized to form
sickle cell.
• Prevents the use of oxygen by hemoglobin S.
• Free oxygen combine to form molecular oxygen.
• Free electrons are incorporated by the oxygen molecule.
• Activated species of oxygen superoxide anions.
• Superoxide anions attack the membrane. Destruction of fat acids by the
superoxide anions and formed membrane lesions.
• The activated oxygen also oxidizes the hemoglobin S molecule turning
it into meta HbS.
• The meta HbS get together forming Heinz Bodies towards the
membrane, alters the Band 3 protein and the phosphatidylserine
arrangement in the membrane leading to exposition of membrane.

12. Sickling consequences
The sickled red cells with membrane alterations impair blood flow
causing vascular occlusion.
It causes tissue swelling and pain in the hands and feet.
It also causes hemolysis. Sickle RBC live for 10-20 days instead of the
normal 120 days. So people with this disorder often have low red blood
cell counts (anemia), which is why this disease is commonly referred to
as sickle cell anemia.
The sickled red cells are phagocytised by macrophage. Macrophage
activated by phagocytosis, released cytokines and diffuse to the
microvessels of the central nervous system sending signals that cause
vaso constriction i.e increase heart rate and blood pressure, metabolic
disturbances, fever, pain.

13. Pathophysiology
Deoxygenation
polymerization of
hemoglobin
sickling of red cells
endothelial
damage/activation
RBC and leukocyte adhesion
to endothelium,
vasoconstriction
vascular occlusion, organ
ischemia and end-organ
damage

14. Genetic cross
• Children are born with sickle cell disease; it is not
contagious.
• Occurs when a person inherits two abnormal copies of the
hemoglobin gene , one from each parent.
• A person with a single abnormal copy does not experience
symptoms and is said to have sickle cell trait. Such people
are referred to as carriers.

15. • If one parent has sickle-cell anemia and the other has sickle cell
trait, then the child has a 50% chance of having sickle cell disease
and 50% chance of having sickle-cell trait.

16. • When both parents have sickle-cell trait, a child has a 25% chance of sickle-
cell disease, 25% do not carry any sickle-cell alleles, and 50% have the
heterozygous condition.

17. Effects at the protein level
Normal hemoglobin (left) and hemoglobin
in sickled red blood cells (right) look
different; the mutation in the DNA slightly
changes the shape of the hemoglobin
molecule, allowing it to clump together.

18. • There are effects at the cellular level: when red blood cells carrying
mutant hemoglobin are deprived of oxygen, acidosis, dehydration,
hypoxia, they become sickle-shaped instead of the usual round shape.
This shape can sometimes interrupt blood flow.
• There are negative effects at the whole organism level: under
conditions such as high elevation and intense exercise, a carrier of the
sickle cell allele may occasionally show symptoms such as pain and
fatique.
• There are positive effects at the whole organism level: Carriers of the
sickle cell allele are resistant to malaria, The reason is that in tropical
areas there is also a high incidence of malaria, a parasitic disease
caused by the bug Plasmodium falciparium, which is carried by the
Anopheles mosquitoe. In one of the stages of the life of the parasite, it
depends on the red cell (actually, on hemoglobin) to survive.

19. References
1. Biotechnology, a problem approach by
Pranav Kumar, Usha Mina.
2. Theoretical genetics, stephen taylor.
3. Hemoglobin and its defects, Info Biochemistry
4. Understanding evolution; “a case study on
sickle cell anemia”.