‫الجامعة التقنية الجنوبية‬

‫كلية التقنيات الصحية والطبية‬

3rd Stage ‫قسم تقنيات التحليالت المرضية‬
Hematology

Lecture 9
Hereditary
Hemoglobinopathies (2)
THALASSEMIA
Dr. Hussam S. Aziz
MD, MSc. Medical Genetics
 Introduction
2

 Hereditary hemoglobinopathies are genetic diseases

that are transmitted from parents to offspring
 The defect in hemoglobinopathies can be:
 Synthesis of abnormal Hb (structural), e.g. sickle cell
anemia
 Reduction in the rate of production of Hb
(quantitative), e.g. thalassemia
 Types of Hb:
 Hb F (α₂,γ₂)

 Hb A (α₂,β₂)
 Hb A₂ (α₂,δ₂)
 Types of Hb Throughout Life
3

 During prenatal (fetal) life, the predominant type

is Hb F. Small amounts of Hb A also present
 In adult, blood consists of the following types of
Hb:
 Hb A: 95%

 Hb A₂: 2-3%

 Hb F: 1-2%

 Switching from Hb F to Hb A takes place

between the 3rd and 6th months after birth
 Genetics of Hb
4

 Normally, every person has:

 2 copies of β-globin gene
 2 copies of γ-globin gene
 4 copies of α-globin gene
 Genetics of Hb
5
 Thalassemia
6

 Thalassemia is a hereditary hemoglobinopathy

resulted from mutations in globin genes that
reduce or stop the production of globin chains
 Depending on the involved globin chain,
thalassemia is divided into:
 α-thalassemia

 β-thalassemia

 α-thalassemia is more common in the Far East

 β-thalassemia is more common the
Mediterranean countries
 Geographical Distribution
7
 β-Thalassemia
8

 Beta thalassemia results from mutations in β-globin

gene that reduce or stop the production of β-globin
chains
 To date, over 200 different mutations along β-globin
gene are identified; majority are point mutations
 Certain mutations are particularly frequent in some
communities
 According to their effects of globin chain synthesis, β-
globin mutations are classified into:
 β⁺-reduces the production of β-chain by 10-50%

 β°-stops the production of β-chain completely

 Pathogenesis
9

 Mutations in β globin gene reduction in β chain

synthesis  reduction in Hb tetramere production
rate in the developing erythroblasts

 This leads to reduction in the amount of Hb in the

RBCs RBCs hypochromia and microcytosis

 Reduction in β-globin production also creates

imbalance between α- & β- globin amounts in the
developing erythroblasts (excess α-chains)
 Pathogenesis (cont.)
10

 This leads to accumulation of insoluble, unpaired

excess α-chains, and formation of toxic inclusion
bodies in the developing erythroblasts
 Toxic inclusion bodies kill the erythroblasts in the
bone marrow reduction in RBCs production
(ineffective erythropoiesis)
 Survived RBCs that reach the peripheral blood
stream have inclusion bodies of excess α-chains
that are detected by the spleen removal of
RBCs from the blood stream (shortening of the
RBCs lifespan) with massive hemolytic anemia
 Clinical Features of β-Thalassemia
11

 Excess α-globin chains precipitate in the RBCs

causing hemolysis
 According to severity, β-Thalassemia is divided into:
 β-Thalassemia major: mutations in both β-globin
genes (homozygote) severe anemia
 β-Thalassemia minor (trait): mutation in one of the
β-globin genes (heterozygote) asymptomatic
 β-Thalassemia intermedia: varying degrees of
symptoms, between thalassemia major and minor
 β-Thalassemia Minor
12

 Common
 Mutation in one β-globin gene: (β⁺/β) or (β°/β)
 Usually asymptomatic
 Also called thalassemia trait or carrier state
 Lab investigations show:
 Mild anemia (Hb 10-12 g/dL)

 Microcytic, hypochromic

 MCV ↓

 MCH ↓

 RBC count ↑

 Hb A₂↑ (>3.5%)
 β-Thalassemia Major
13

 Severe anemia (Hb < 7 g/dL), Hb can reach 2-3g/dL

 Mutations in both β-globin genes:
 β⁺/β⁺

 β⁺/β°

 β°/β°

 Clinical features:
 Sever anemia appears at 3-6 months after birth when
Hb switches from γ-chain to β-chain
 Thalassemic facies

 Failure of growth

 Delayed or absent puberty

 β-Thalassemia Major
14
 β-Thalassemia Major
15

 Clinical features (continue):

 Enlargement of liver and spleen (hepatospleno-
megaly) as a result of excessive RBCs destruction
and extra-medullary erythropoiesis (outside
bone marrow). Large spleen increases blood
requirement due to RBC destruction sometimes
treated by splenectomy
 Expansion of bones caused by intense bone
marrow hyperplasia thalassemic facies, and
thinning of many bones with tendency to fractures
 Bossing of the skull with an hair-on-end
appearance by x-ray
 β-Thalassemia Major
16

 Clinical features (continue):

 Repeated blood transfusion iron overload skin
pigmentation, liver cirrhosis, diabetes mellitus, etc.
 Iron might damage the heart heart failure (most
common cause of death)
 Increase in bacterial and blood born viral infection
(HBV, HIV)
 β-Thalassemia Major
17
 β-Thalassemia Intermedia
18

 Clinical features in between thalassemia major

and minor
 Hb: 7-10 g/dL
 Hypochromic, microcytic anemia
 Laboratory Tests
19

 Complete blood count (CBC)

 Blood film
 Hb electrophoresis
 HPLC
 Genetic tests
 CBC Results
20

 Severe hypochromic, microcytic anemia

 Reticulocyte count ↑
 ↓
MCV
 MCH ↓

 Hb level ↓ (7-11 g/dL)

 RBC count normal or decreased
 Blood Film
21

 Microcytic
 Hypochromic
 Anisocytosis
 Poikilocytosis
 Target cells
 Tear drop cells
 Nucleated RBCs
 RBC fragments
 Inclusion bodies
 Blood Film
22
 Blood Film
23
 Blood Film
24
 Blood Film
25
 Blood Film
26
 Hb Electrophoresis
27

 Hb A ↓ or
absent
 Hb A₂ ↑

 Hb F ↑
 Other Tests
28

 DNA analysis (PCR or DNA sequencing) detect the

mutation, can be used prenatally
 Assessment of iron status (s. ferritin, s. iron, iron
binding capacity), serves 2 purposes:
 Differentiate between thalassemia and iron
deficiency anemia
 Assess iron level (iron overload) in the body

 Bone marrow biopsy

 Liver biopsy
 Liver and heart imaging (X-ray, C-T scan, MRI, etc.)
 Treatment
29

 Regular blood transfusion to maintain Hb>10 g/dL

(usually requires 2-3 times every 4-6 weeks)
 Regular folic acid supply (e.g. 5 mg/day)
 Iron chelation therapy to prevent iron overload.
Drug used is deferoxamine increases iron
excretion with urine and stool
 Vitamin C: increases iron excretion
 Hydroxyurea: can be given to increase Hb F level
 reduces the severity of clinical features and
frequency of blood transfusion
 Treatment (Cont.)
30

 Splenectomy done after age of 6. Reduces

blood transfusion requirement
 Endocrine treatment, e.g. growth hormone and
insulin
 Immunization against blood born viruses, e.g.
hepatitis C virus
 Bone marrow transplantation
 Iron Chelation Therapy
31
 Liver: Before and After Iron Chelation
32
Therapy
 Combination of β-Hemoglobinopathies
33

 Combination of different β-hemoglobinopathies

produces anemias of different severities.
Examples:
 HB S/β-thal (sickle thal) features of both,
sickle cell anemia and thalassemia
 HB βδ: high Hb F level
34 α-Thalassemia
 α-Thalassemia
35

 Less common than β-thalassemia

 More common in the far East Asian countries
 Normally, four α-globin genes present (αα/αα)
 Mutations are usually large deletions of part of
the genes
 Clinical severity depends on the number of
deleted (mutated) α-globin genes
 Mutations in one gene (αα/α-) or two genes (--
/αα) or (-α/-α), produces asymptomatic carrier
state (α-thalassemia trait)
 α-Thalassemia (Cont.)
36

 Deletion of three α-globin genes (α-/--) leads to

moderately sever anemia (Hb 7-11 g/dL), with
spleenomegaly and producing Hb H (β₄) (Hb H
disease) Heinz (inclusion) bodies in RBCs
 In fetal life, deletion of three α-globin genes (α-/--)
produces Hb Barts (γ₄)
 Deletion of four α-globin genes is incompatible
with life, produces hydrops fetalis, and the fetus
dies in utero
 Clinical features, laboratory results, and treatment
of α-thalassemia are similar to β-thalassemia
 Genetics of α-Thalassemia
37
 Genetics of α-Thalassemia
38
 α-Thalassemia: Blood Film
39

 Microcytic
 Hypochromic
 Anisocytosis
 Poikilocytosis
 Target cells
 Tear drop cells
 Nucleated RBC
 RBC fragments
 Tear drop cells
 α-Thalassemia: Blood Film
40
 α-Thalassemia: Blood Film
41
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