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 schoole. I have a relative with this disease
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2f. 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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NoNo idea
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4Q 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 wordsQ 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 Thalassemiac. I am not a carrier for Thalassemia
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5Q 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 inIndia, 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 year3/24/2022
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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SYNDROMEDefinition :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- ? ThalassemiaDeficient 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 chain3/24/2022
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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 defect3/24/2022
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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 - globingene (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)3/24/2022
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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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20Patho - Physiology of
Thalassemia
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2
2
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PrecipitationHb F
Selective survival of Hb F containing
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Extravascular
cells
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# of RBCs PrecursorsHemolysis
within marrow
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Splenomegaly
High O2 affinity of RBCs
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IneffectiveErythropoiesis
Tissue Hypoxia
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Anemia
Erythropoietin
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AnemiaTissue Hypoxia
erythropoietin
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Blood
Transfusion
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Marrow ExpansionBone Deformity
Iron absorption
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Metabolic Rate
Iron Loading
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GoutFolate Deficiency
Endocrine Deficiencies
Cirrhosis
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Cardiac FailureDeath
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Clinical & Genetics Classification ofThalassemias
Clinical
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Genotype
Disease
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NomenclatureThalassemia 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 minor0/ , +/
Asymptomatic
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Alpha ThalassemiaClinical
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 (likeThal 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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PallorShortness of breath
Delayed growth/puberty
Skeletal deformities
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Clinical Presentation contd..
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? Organomegaly ? HepatomegalySplenomegaly
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.3/24/2022
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Peripheral smear findings
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marked poikilocytosis, anisocytosis, and
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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.3/24/2022
nucleated RBC & Target cells
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3/24/2022basophilic strippling.
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acant
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022
es, spherocytes, target cell,and schistocytes.
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37leptocyte and target cell.
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Reticulocytosis - demonstrated by new
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methylene blue stain
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39? 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 alsoseen: acanthocytes,
spherocytes,
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burr cells, and schistocytes.3/24/2022
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? Moderate to marked basophilic stippling isseen in both the nucleated and non-
nucleated forms of erythrocytes.
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41lNucleated 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 orthochromicnormoblasts, 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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42The 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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QuestionnaireWhat 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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49Q 2. Are the disease inherited?
a. Yes, inherited
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b. Noc. I have no idea
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50Q3. What is the impact of consanguineous
marriages on these diseases?
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Q4. What is the impact of being a carrier ofthese 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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3/24/202252
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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haemopoiesisC) 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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54QN3. 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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