SMC, JSMU, MBBS, Blood module

1. ENZYMES
A protein with catalytic properties
due to its power of specific
activation
© 2007 Paul Billiet ODWS

2. The Thalassemias

3. Objectives
By the end of this lecture the student should be able to:
Understand the normal stucture of Haemoglobin
• Know the Diverse group of disorders which manifest
as anemia of varying degrees.
• Know the defective production of globin portion of
hemoglobin molecule.
• Know the Distribution of disease worldwide.
• Describe the disease either homozygous or
heterozygous defect.
• Know the Defect results from abnormal rate of
synthesis in one of the globin chains.

4. Hemoglobin Review
• Each complex consists of :
– Four polypeptide chains, non-covalently bound
– Four heme complexes with iron bound
– Four O2 binding sites

6. Globin Chains
• Alpha Globin
– 141 amino acids
– Coded for on Chromosome 16
– Found in normal adult hemoglobin, A1 and A2
• Beta Globin
– 146 amino acids
– Coded for on Chromosome 11, found in Hgb A1
• Delta Globin
– Found in Hemoglobin A2--small amounts in all adults
• Gamma Globin
– Found in Fetal Hemoglobin
• Zeta Globin
– Found in embryonic hemoglobin

7. Normal Haemoglobin
• HbA - α2β2
• HbA2 - α2δ2
• HbF – α2γ2

8. Each goblin chain have separate genetic control
α –thalassaemia affect α-chain synthesis
β –thalassaemia affect β -chain synthesis

9. Thalassemia
►Diverse group of disorders which manifest
as anemia of varying degrees.
►Result of defective production of globin
portion of hemoglobin molecule.
►Distribution is worldwide.
►May be either homozygous defect or
heterozygous defect.
►Defect results from abnormal rate of
synthesis in one of the globin chains.
9

10. Thalassemia
►Results in overall decrease in amount of
hemoglobin produced and may induce
hemolysis.
►Two major types of thalassemia:
– Alpha (α) - Caused by defect in rate of
synthesis of alpha chains.
– Beta (β) - Caused by defect in rate of
synthesis in beta chains.
►May contribute protection against malaria.
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11. Genetics of Thalassemia
►Adult hemoglobin composed two
alpha and two beta chains.
►Alpha thalassemia usually caused by
gene deletion;
►Beta thalassemia usually caused by
mutation.
►Results in microcytic, hypochromic
anemias of varying severity. 11

12. GeneticTypes of Thalassaemia :
There are two basic groups of thalassaemia.
 Alpha ( α )Thalassaemia
 Beta ( β )Thalassaemia

13. Demographics: Thalassemia
• Found most
frequently in the
Mediterranean,
Africa, Western and
Southeast Asia, India
and Burma.

14. Beta
Thalassemia
14

15. β-Thalassaemia
An absence or deficiency of β-chain synthesis of adult HbA
β Chain synthesis
Hb-A
γ and δ chain
Hb-A = α2β2

16. On the basis of synthetic ability β-genes
are designated as
• β gene – can synthesize normal amount
of β-chain
• β+
gene – can synthesize reduced
amount of β-chain
• β0
gene – cannot synthesize β-chain

17. Pathophysiology of β-Thalassaemia
Various mutation in β-gene
Complete or partial absence of β-chain
Decreased adult HbA
α-chain synthesis remain normal
Free complementary α-chain – unstable and
precipitate within normoblasts as insoluble
inclusions
Cell membrane damage & impaired DNA synthesis
apoptosis i.e. ineffective erythropoeisis

18. 70-80% marrow normoblasts undergo apoptosis
Inclusion bearing red cells undergo
sequestration & destruction in spleen

19. Partial or lack of HbA synthesis ↓MCHC &
MCH Hypochromia & microcytosis
Norm
al
Thalassae
mia

20. ↑Haemolysis ↑demands of phagocytic
function  hyperplasia of phagocytes
Hepatosplenomegaly
To compensate anaemia extramedullary
haemopoiesis in liver, spleen & brain
Organomegaly

21. ↑Erythropoiesis marrow expansion & thinning
of cortex of skull bone Thalassaemia facies

22. Classification & Terminology
Beta Thalassemia
• Normal β/β
• Minor β/β0
β/β+
• Intermedia β0
/β+
β+
/β+
• Major β0
/β0
β+
/β+
β0
/β+

23. Classical Syndromes of Beta
Thalassemia
►Silent carrier state – the mildest form of beta
thalassemia.
►Beta thalassemia minor - heterozygous
disorder resulting in mild hypochromic,
microcytic hemolytic anemia.
►Beta thalassemia intermedia - Severity lies
between the minor and major.
►Beta thalassemia major - homozygous
disorder resulting in severe transfusion-
dependent hemolytic anemia.
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24. Silent Carrier State for β
Thalassemia
►Are various heterogenous beta mutations that
produce only small decrease in production of
beta chains.
►Patients have nearly normal beta/alpha chain
ratio and no hematologic abnormalities.
►Have normal levels of Hb A2.
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25. Beta Thalassemia Minor
►Caused by heterogenous mutations that affect beta
globin synthesis.
►Usually presents as mild, asymptomatic hemolytic
anemia unless patient in under stress such as pregnancy,
infection, or folic acid deficiency.
►Have one normal beta gene and one mutated beta gene.
►Hemoglobin level in 10-13 g/dL range with normal or
slightly elevated RBC count.
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26. Beta Thalassemia Minor
►Anemia usually hypochromic and microcytic with
slight aniso and poik, including target cells and
elliptocytes; May see basophilic stippling.
►Rarely see hepatomegaly or splenomegaly.
►Have high Hb A2 levels (3.5-8.0%) and normal to
slightly elevated Hb F levels.
►Are different variations of this form depending upon
which gene has mutated.
►Normally require no treatment.
►Make sure are not diagnosed with iron deficiency
anemia.
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27. Beta Thalassemia Intermedia
►Patients able to maintain minimum hemoglobin (7 g/dL
or greater) without transfusions.
►Expression of disorder falls between thalassemia minor
and thalassemia major. May be either heterozygous for
mutations causing mild decrease in beta chain
production, or may be homozygous causing a more
serious reduction in beta chain production.
►See increase in both Hb A2 production and Hb F
production.
►Peripheral blood smear picture similar to thalassemia
minor.
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28. Beta Thalassemia Intermedia
►Have varying symptoms of anemia, jaundice,
splenomegaly and hepatomegaly.
►Have significant increase in bilirubin levels.
►Anemia usually becomes worse with infections,
pregnancy, or folic acid deficiencies.
►May become transfusion dependent as adults.
►Tend to develop iron overloads as result of increased
gastrointestinal absorption.
►Usually survive into adulthood.
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29. Beta Thalassemia Major 1 of 3
►Characterized by severe microcytic, hypochromic
anemia.
►Detected early in childhood:
– Infants fail to thrive.
– Have pallor, variable degree of jaundice, abdominal
enlargement, and hepatosplenomegaly.
►Hemoglobin level between 4 and 8 gm/dL.
►Severe anemia causes marked bone changes due to
expansion of marrow space for increased
erythropoiesis.
►See characteristic changes in skull, long bones, and
hand bones. 29

30. Beta Thalassemia Major 2 of 3
►Have protrusion upper teeth and Mongoloid facial
features.
►Physical growth and development delayed.
►Peripheral blood shows markedly hypochromic,
microcytic erythrocytes with extreme poikilocytosis,
such as target cells, teardrop cells and elliptocytes. See
marked basophilic stippling and numerous NRBCs.
►MCV in range of 50 to 60 fL.
►Low retic count seen (2-8%).
►Most of hemoglobin present is Hb F with slight
increase in Hb A2.
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31. Beta Thalassemia Major 3 of 3
►Regular transfusions usually begin around one year of
age and continue throughout life.
►Excessive number of transfusions results in tranfusional
hemosiderosis; Without iron chelation, patient
develops cardiac disease.
►Danger in continuous tranfusion therapy:
– Development of iron overload.
– Development of alloimmunization (developing antibodies to
transfused RBCs).
– Risk of transfusion-transmitted diseases.
►Bone marrow transplants may be future treatment,
along with genetic engineering and new drug therapies.
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34. Alpha
Thalassemia
34

35. Classification & Terminology
Alpha Thalassemia
• Normal αα/αα
• Silent carrier - α/αα
• Minor -α/-α
--/αα
• Hb H disease --/-α
• Barts hydrops fetalis --/--

36. Alpha Thalassemias
• Result from gene deletions
• One deletion—Silent carrier; no clinical
significance
• Two deletions—α Thal trait; mild hypochromic
microcytic anemia
• Three deletions—Hgb H; variable severity, but
less severe than Beta Thal Major
• Four deletions—Bart’s Hgb; Hydrops Fetalis;
In Utero or early neonatal death

37. Alpha Thalassemia 2 of 2
►Predominant cause of alpha thalassemias is large
number of gene deletions in the alpha-globin gene.
►Are four clinical syndromes present in alpha
thalassemia:
– Silent Carrier State
– Alpha Thalassemia Trait (Alpha Thalassemia Minor)
– Hemoglobin H Disease
– Bart's Hydrops Fetalis Syndrome
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38. Silent Carrier State
►Deletion of one alpha gene, leaving
three functional alpha genes.
►Alpha/Beta chain ratio nearly normal.
►No hematologic abnormalities
present.
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39. Alpha Thalassemia Trait
(Alpha Thalassemia Minor)
►Also called Alpha Thalassemia Minor.
►Caused by two missing alpha genes. May be
homozygous (-a/-a) or heterozygous (--/aa).
►Exhibits mild microcytic, hypochromic anemia.
►May be confused with iron deficiency anemia.
►Although some Bart's hemoglobin (γ4) present at birth,
no Bart's hemoglobin present in adults.
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40. Hemoglobin H Disease 1 of 2
►Second most severe form alpha thalassemia.
►Usually caused by presence of only one gene producing
alpha chains (--/-a).
►Results in accumulation of excess unpaired gamma or
beta chains. Born with 10-40% Bart's hemoglobin (γ4).
Gradually replaced with Hemoglobin H (β4). In adult,
have about 30-50% Hb H.
γ4 β4
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41. Bart’s Hydrops Fetalis
Syndrome
►Most severe form. Incompatible with life. Have no functioning
alpha chain genes (--/--).
►Baby born with hydrops fetalis, which is edema and ascites
caused by accumulation serous fluid in fetal tissues as result of
severe anemia. Also see hepatosplenomegaly and cardiomegaly.
►Predominant hemoglobin is Hemoglobin Bart, along with
Hemoglobin Portland and traces of Hemoglobin H.
►Hemoglobin Bart's has high oxygen affinity so cannot carry
oxygen to tissues. Fetus dies in utero or shortly after birth. At
birth, see severe hypochromic, microcytic anemia with numerous
NRBCs.
►Pregnancies dangerous to mother. Increased risk of toxemia and
severe postpartum hemorrhage.
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45. Thanks