Download Thalassemia

Anwar Zaben
Arwa Maqboul
Eias Al-ashhab
Majd Barahmeh
Ra’ed Mashalah
• Qualitative
Sickle cell anemia
Hb C disease
Hb SC disease
• Qauntitative
 Thalassemias (α and )
Secondary Laboratory Investigation
Cellulose Acetate Hb Electrophoresis
Secondary Laboratory Investigation
Cellulose Acetate Hb Electrophoresis
Secondary Laboratory Investigation
Cellulose Acetate Hb Electrophoresis
Secondary Laboratory Investigation
Cellulose Acetate Hb Electrophoresis
• Sickle cell is an autosomal recessive
disease.
• Therefore, the child can only get
Sickle cell if both parents are
carriers, not if only one is and the
other is normal. They have a 25%
chance of getting it if both are
carriers
•This results when
both copies of the
hemoglobin beta
gene have an S
mutation.
Hemoglobin
Alpha
•All of this person’s
beta subunits are
replaced by beta S.
Alpha
Beta S
Beta S
symptoms
1-Sickle cell crises : pain episodes
[o2]
RBCs assume the sicklelike shape
They clog at the
capillaries and block
the blood flow
Tissue are not oxygenated
resulting in tissue injury or
tissue death
Those sickle-like
shape cant
squeeze like
normal RBCs
Pain episodes
crises
•Brain : could cause a stroke
•spleen and kidney : renal and splenic
dysfunction
•Muscle ,bone and joint
•Lungs : acute chest syndrome
2- hemolytic anemia :
Sickled RBCs have shorter lifetime
span ( 20 days instead of 120 days ) .
It causes to decrease the number of
RBCs
anemia
3-hyperbilirubinemia:
RBCs breakdown in spleen
Heme group breakdown produces
bilirubin
We can get rid of bilirubin by liver and
kidney
Elevated levels of bilirubin causes to
color the skin and eyes with yellow color
4- increased susceptibility to infections:
Blood blockage in splenic tissue
damages the tissue
making the patient more
susceptible to infections
Spleen is responsible for activating
immune respond
PO2
PCO2
[2,3-BPG]
dehydration
treatment
-Analgesics to reduce pain
-Antibiotics ( ex : penicillin) reduces
morbidity and mortality due to bacterial
infections
-Blood transfusion if the patient has chronic
anemia
Blood transfusion complications :
-blood borne infections
-hemosiderosis (accumulation of iron in
heart ,liver and endocrine organs )
1 of 500 newborn African
Americans have the homozygous
Hb S genes
1 of 12 newborn African American
have the trait sickle cell disease
The parasite causing malaria has
lifetime span as the normal RBC
but sickled RBCs have shorter
lifetime span
the
parasite dies before causing
malaria
Hemoglobinpathies
Over 800 different mutations of globin chains of human hemoglobin
have been discovered
Mutations are classified by the type of mutation.
Examples:
•
•
•
•
•
•
Insertion
Deletion
Base change
Base mismatch (translocation
Duplication
Inversion
These mutations can affect the structure of the
protein leading to a deformed protein with
malfunction
(e.g.: Mutation in alpha chain, and beta chain)
Hemoglobin C
Hemoglobin C (Hb C) is a beta globin chain
mutation, it is caused by the amino acid
substitution of lysine instead of glutamine at the
Beta-6 position, making the Hb C a less soluble
protein than Hb A which is the most abundant
hemoglobin protein in adults
(around 90% of total hemoglobin in adults.)
Since Hb C is a less soluble hemoglobin than Hb
A, this means that Hb C forms hexagonal crystals
in the infected blood cell
When Hemoglobin C is present in any of its
states (homozygous Hb C, heterozygous Hb SC,
and Hb AC) it induces red cell dehydration
Hemoglobin C disease
Some characteristics of homozygous
hemoglobin C disease (Hb CC) include:
• Cell dehydration
• Target cells
• Mild hemolysis with no significant anemia
(mild anemia)
While heterozygous Hemoglobin C patients are
phenotypically normal and the above symptoms
doesn’t apply
In homozygous hemoglobin C patients, the Hb C
amount in a blood cell is about 100%, while in
heterozygous hemoglobin C patients (Hb AC),
the percentage of the Hemoglobin C protein is
about 35-45% and the rest is normal
Hemoglobin (Hb A)
Cell dehydration
Dehydration is caused by abnormal cellular
Potassium loss by the K-Cl cotransport pathway
(Potassium – Chloride cotransporter) due to
interactions between the abnormally positive
charged hemoglobin protein and the cell
membrane causing an elevated K-Cl cotransport
activity
Hemoglobin SC disease
This disease is caused by having double
heterozygotes for Beta S and Beta C in patients.
In Hb SC disease, Hb C increases K-Cl cotransport
activity, this causes the high intraerythrocytic
concentration of Hb S to make polymers, giving the
red cell it’s sickled shape
In Hb SC disease, the cell contains 50% of Hb S and
50% of Hb C, no normal hemoglobin is present (Hb A)
Some Hb SC symptoms
Some of the Hb SC disease symptoms include:
• Retinopathy
• Ischemic necrosis of bone
• Mild painful crisis
• Possible asplenia (about 45% of patients older
than 25) leading to sepsis (lowering B.P,
dysfunction in kidneys, liver, lungs and CNS)
Methemoglobin
• Normal hemoglobin contains ferrous ions on
the center of the heme groups
• Methemoglobin is formed when ferrous
oxidized to ferric
• Our blood contains normally about 1% Hb M
Methemoglobinemia
Causes
• Drugs ( nitrates)
• Endogenous products (reactive o
intermediates)
• Inherited defects (mutations)
• Deficiency of NADH- Hb M reductase
Effects and Symptoms
• Functional Anemia
 Chocolate cyanosis
 Chocolate-cholored blood
• Tissue hypoxia → anxiety, headache , dyspnoea , weakness ,
lightheadache .
• Rare cases → coma , death.
Treatment
• Methylene
blue
Hemoglobin Synthesis
Adult hemoglobin - 96% HbA (α2β2)
α
α
β
β
Clinically significant variant hemoglobins usually β abnormalities
Thalassemia
 Absent or  Synthesis of Globin Chains
(Quantitative)
 Most Frequent in Mediterranean, African,
or Asian Populations
  - Thalassemia -   Chain Synthesis
(Gene Mutations)
  - Thalassemia -   Chain Synthesis (1-3
of 4 Genes Deleted) (SE Asians)
Global Distribution of Thalassemia
Carrier Frequencies for Common
Hemoglobin Disorders/WHO- percent
Region
 Thalassemia
α◦
thalassemia
α⁺
thalassemia
Americas
0-3
0-5
0-40
Easter Mediterranean
2-18
0-2
1-60
Europe
0-19
1-2
0-12
S Asia
0-11
1-30
3-40
Sub-Saharan Africa
0-12
0
10-50
W Pacific
0-13
0
2-60
 - Thalassemia's
• α⁺ thalassemia (common /milder form)→ mild
hypochromic anemia in homozygous
• α◦ thalassemia's → stillbirth, with toxemic and
postpartum complications
• α ⁺ + α◦ thalassemia's → Hb H , varies in
severity
Classification & Terminology
Alpha Thalassemia
•
Terminology
•
•
•
•
•
Silent carrier
Minima
Minor
Intermedia
Major
Symbolism
Alpha Thalassemia
•
Greek letter used to designate globin
chain:

Symbolism
Alpha Thalassemia
/ : Indicates division between genes
inherited from both parents:
/
•
Each chromosome 16 carries 2 genes. Therefore the
total complement of  genes in an individual is 4
Symbolism
Alpha Thalassemia
- : Indicates a gene deletion:
-/
Classification & Terminology
Alpha Thalassemia
• Normal
• Silent carrier
• Minor
• Hb H disease
• Barts hydrops fetalis
/
- /
-/-
--/
--/-
--/--
Silent Carrier of α- Thalassemia

are clinically and hematologically healthy

may have mild reductions in mean corpuscular
volume (MCV) and mean corpuscular
hemoglobin (MCH).

Normal Hb electrophoresis

Detected by gene analysis
α-thalassemia trait

minimal to no anemia and a low MCV and MCH.

Normal electrophoresis

May show microcytosis and target cells

Identified by gene analysis
Hb H disease / Hb (4)disease

marked variability in degree of anemia

patients may range from asymptomatic to
needing periodic transfusions to having severe
anemia with hepatomegaly and splenomegaly

Some patients may also suffer hydrops fetalis
syndrome in utero
electrophoresis
Hb H disease can be identified by
electrophoresis
Hydrops fetalis
(
erythroblastosis fetalis):
Swollen dead fetus

Usually these infants die in utero or shortly after
birth

An excess of Bart hemoglobin (γ4), which is
unable to carry oxygen effectively, is indicated

Infants born have massive total body edema
with high output congestive heart failure due to
the severe anemia

massive hepatomegaly due to heart failure and
extramedullary hematopoiesis
 - Thalassemia
Chromosome 16
 

Silent carrier
HbH

β4
disease
(severe anemia)
 


 - thalassemia trait
(+/- anemia)
Hb Bart
γ4
Hydrops fetalis
(lethal in utero)
Beta Thalassemia
•Inherited
disorder (handed to
children from parents equally)
•A gene from each parent
•Carrying beta thalassemia
HB
disorder (minor beta thalassemia)
•2 genes of Beta thalassemia
life
long disorder
(major beta
thalassemia)
Symbolism
Beta Thalassemia
•
Greek letter used to designate globin
chain:

Symbolism
Beta Thalassemia
+:
Indicates diminished, but some
production of globin chain by gene:
+
Symbolism
Beta Thalassemia
0
:Indicates no production of globin chain by
gene:
0
Classification & Terminology
Beta Thalassemia
• Normal
• Minor
• Intermedia
• Major
/
/0
/+
0/+
0/0
+/+
Beta Thalassemia
Minor
•
Carrying beta thalassemia
beta thalassemia gene + normal HB A gene
Testing
Measure RBC size (MCV).
•Analyse the types of HB.
•(A+A2)
•
Advantages
Protection from Malaria
•Protection from heart attacks
•But……………………?
•
Passing beta
thalassemia minor
The
child may carry beta tahassemia
The child may not carry any HB variant
Beta thalassemia major
2 defected Beta genes
no beta
chains synthesis
alpha chains
precipitate
premature death of
RBCs.
•Complications
•Enlargement…
•
Treatment
Regular Blood transfusion ……4
weeks.
•Blood testing
•Live through 20s ……remove iron
(desferrioxamine) pump
•
•Bone
marrow transplantation
•Disadvantages
Expensive , tiresome , not available
for every one
The need of the hour
(prevention)
•Screening
1.
2.
3.




and Counseling
Carrier testing
Inform carriers
Both carriers
counsellor
Prenatal diagnosis (unborn baby) if affected
terminate or continue with planning
Neonatal diagnosis (after birth) if early diagnosed
Save the child
Telling a partner to
have a blood test
When ?
•Before
marriage
•Before pregnancy
•As soon as the pregnancy started
•Easy…..
because ?
Passing Beta
thalassemia major
Child may carry beta thalassemia major
•Child may not carry any HB variant
•Child may carry beta thalassemia trait
•
Facts
•Beta
thalassemia major one of the
commonest inherited disorder
•1 of 50 human beings carry beta
thalassemia (100 million carriers)
•100000 children are born with beta
thalassemia major
•Carriers are particularly common among
people originate from Mediterranean , ME
and east of Asia and not common among
people from northern Europe.