Download MBBS Pathology PPT 10 Hemolytic Anemia Thalassemia Lecture Notes

THALASSEMIA

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Pre -Lecture Feedback Questionnaire

Q 1. Have you ever heard about a disease

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cal ed thalassemia?
a. I know it from TV
b. I heard on the radio
c. I read in the newspaper

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d. I heard at school
e. I have a relative with this disease

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f. I know someone with this disease
g. I have a relative who is a thalassemia carrier
h. I have never heard
i. I learned from another source

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Q 2. If you have heard about thalassemia,

write what you know in a few sentences.
Q 3. Is this disease is inherited?
Yes, inherited

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No
No idea

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Q 4. Do you know the importance of being a

carrier of these diseases?
a. I don't know

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b. If you know, explain in few words
Q 5. Do you know if you are a carrier for

Thalassemia?
a. I don't know

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b. Yes I am a carrier for Thalassemia
c. I am not a carrier for Thalassemia

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Q 6. Is it possible to identify carriers?

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What is the position of the

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disease in India?

? India is the thalassemia capital of the world with 40

mil ion carriers and over 1, 00,000 patients.

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? There is no prevention and control programme at the

national level.

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? With preventive health checks not being the norm in

India, people suffering from thalassemia are

unknowingly passing on this genetic disorder to their

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children.

? Over 1, 00,000 patients across the country die before

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they turn 20 due to lack of access to treatment.

Ref: The Hindu report on Thalassemia in India
? Every year approximately 100,000 children

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with Thalassemia Major are born world over,

of which 10,000 are born in India.

? It is estimated that there are about 65,000-

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67,000 -thalassemia patients in our country

with around 9,000-10,000 cases being added

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every year

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Ref: Indian Pediatr. 2007 Sep;44(9):647-8

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Learning objectives

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? What is thalassemia?
? Molecular Pathology of thalassemia
? Pathophysiology of Thalassemia
? Classification of Thalassemia
? Clinical Presentation of Thalassemia

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? Peripheral smear findings in Thalassemia
? How to diagnose a suspected case of

thalassemia

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THALASSEMIA

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SYNDROME

Definition :Heterogenous group of inherited

disorders caused by genetic lesions leading

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to decreased synthesis of either or ?

globin chain of Hb A

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Deficient synthesis of ? chain- ? Thalassemia

Deficient synthesis of chain- Thalassemia
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GLOBIN SYNTHESIS:

Globin synthesis depends on two gene

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clusters situated on

Chromosome -11 for ? globin chain

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Chromosome -16 for globin chain

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MOLECULAR PATHOGENESIS

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? ? Thassemia
? 1) ?0 ?Thalassemia, Total absence of ?

globin chain in homozygous state

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? 2) ?+- Thassemia, Reduced ? globin

synthesis in homozygous state

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Promoter region mutations

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Chain Terminator Mutations

Splicing Mutations

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5'

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3'

Promoter

Exon 1

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Exon 2

Exon 3

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sequence

?+ Thal

?0 Thal

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?+ Thal

Transcription defect
RNA splicing defect

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Translation defect

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PATHOPHYSIOLOGY OF

THALASSEMIAS

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? - Thalassemia is due to an m-RNA

abnormality this mutation reduces or

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inhibit the production of - globin

chains.

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?Point mutation in or near the - globin

gene (Most Common) ?

i) Defective splicing (splice do not occur

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or occur at wrong site)

ii) Stop codon ? non sense lesions

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(chain terminate prematurely)



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? Frame shift mutation (insertion or

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deletion of a single nucleotide,

resulting in lengthening or shortening

of DNA molecules)

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Patho - Physiology of

Thalassemia

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2

2

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Precipitation

Hb F

Selective survival of Hb F containing

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Extravascular

cells

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# of RBCs Precursors

Hemolysis

within marrow

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Splenomegaly

High O2 affinity of RBCs

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Ineffective

Erythropoiesis

Tissue Hypoxia

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Anemia

Erythropoietin

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Anemia

Tissue Hypoxia

erythropoietin

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Blood

Transfusion

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Marrow Expansion

Bone Deformity

Iron absorption

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Metabolic Rate

Iron Loading

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Gout
Folate Deficiency

Endocrine Deficiencies
Cirrhosis

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Cardiac Failure
Death

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Clinical & Genetics Classification of

Thalassemias

Clinical

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Genotype

Disease

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Nomenclature

Thalassemia Homozygous thal

Severe

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Major

(0/ 0)

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+/ +

Thalassemia +/ + +/ 0 0/ Severe but doesn't

Intermedia

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+/

require regular BT

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Thal minor

0/ , +/

Asymptomatic

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Alpha Thalassemia

Clinical

Genotype

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Disease

Nomenclature

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a) Silent Carrier

- /

Asymptomatic

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b) ? Thal trait

--/

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Asymptomatic (like

Thal minor)

c) Hb. H disease

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--/-

Severe

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d) Hydrops fetalis

--/--

Lethal in uterus

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Clinical Presentation

? Children with thalassemia remains

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asymptomatic till the age of 6 months.

? Mostly having symptoms related to anaemia
like Jaundice
Fatigue

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Pallor
Shortness of breath
Delayed growth/puberty
Skeletal deformities

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Clinical Presentation contd..

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? Organomegaly ? Hepatomegaly
Splenomegaly
Lymphodenopathy

Skull X-Ray: New bone formation on the

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outer table producing perpendicular

radiations resembling a crew-cut

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appearance.

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Peripheral smear findings

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marked poikilocytosis, anisocytosis, and

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polychromatophilia

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The signs of active normoblasts in erythropoiesis are in

3evidence:

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Howell-Jolly bodies, polychromatophilia, and 33

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nucleated RBCs.

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nucleated RBC & Target cells

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basophilic strippling.

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acant

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022

es, spherocytes, target cell,and schistocytes.

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leptocyte and target cell.

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Reticulocytosis - demonstrated by new

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methylene blue stain

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? RBCs: marked poikilocytosis,

anisocytosis, and polychromatophilia.

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? The predominant poikilocyte is the target

cell.

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? The poikilocytes of hemolysis are also

seen: acanthocytes,

spherocytes,

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burr cells, and schistocytes.

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? Moderate to marked basophilic stippling is

seen in both the nucleated and non-

nucleated forms of erythrocytes.

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lNucleated RBCs which are almost invariably

present are often numerous and may

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outnumber the leukocytes.

lThe last two nucleated RBC stages, the

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polychromic normoblast and orthochromic

normoblasts, are the predominant forms seen.

l Reticulocytosis is usually present and may

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be quite high, e.g., 20% or greater.

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The signs of active erythopoiesis:

Howel -Jol y bodies,

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polychromatophilia,

and nucleated RBCs.

? Leukocyte: Leukocyte counts range from

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10,000-25,000/mm3, and occasionally present

immature form.

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METHODS FOR INVESTIGATION

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OF THALASSEMIA

? Complete Blood Count (Rule of 3)
? HbA2 and Hb F, measurement by HPLC

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? Molecular methods e.g, PCR for

mutational analysis.

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Management

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? Haematopoietic stem cell transplantation
? Blood transfusion
? Chelation Therapy(Deforaxmine,Defriporone)
? Hydroxyurea

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Post-Lecture Feedback

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Questionnaire

What are the main characteristics of

thalassemia?

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What are the complaints of the patients?
What is the treatment?

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Q 2. Are the disease inherited?

a. Yes, inherited

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b. No
c. I have no idea

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Q3. What is the impact of consanguineous

marriages on these diseases?

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Q4. What is the impact of being a carrier of

these diseases?
Q5. Do you want to have a blood test to

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learn if you are a hemoglobinopathy carrier?
a.Yes
b.No

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Q6. What is your opinion about the study?

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QN 1.Which ONE of the following is NOT a

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feature of thalassaemia intermedia?

A) It may be due to homozygous
o thalassaemia
B) It may be associated with extramedullary

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haemopoiesis
C) It is usually associated with splenomegaly
D) It may cause iron overload

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QN2. Which ONE of these statements is

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TRUE about thalassaemia major?

? A. The major cause of death is liver failure
? B. It requires iron chelation at diagnosis
? C. It is usually caused by deletion of

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globin genes
? D. It may be diagnosed antenatally

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QN3. Which ONE of the following

statements is TRUE about thalassaemia

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trait?

A. It is associated with a raised haemoglobin

A2 level

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B. It is associated with iron overload
C. It is associated with a reticulocytosis
D. It is associated with splenomegaly

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Points to be remember

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? Most common cause of + Thalassemia
? Most common cause of 0 Thalassemia
? Thalassemia :MC type of mutation seen
? Thalassemia : MC type of mutation seen

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? Role of Hydroxy urea in Thalassemia
? D/D of MCHC anemia
? Lab diagnosis of thalassemia

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