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Haematology > haemoglobinopathies and thalassaemia > Flashcards

haemoglobinopathies and thalassaemia Flashcards

1
Q

what are the 3 types of haemoglobin?

A

HbA (α2 β2)
HbA2 (α2 δ2)
HbF (α2 γ2 ) - foetal Hb

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2
Q

where is the α globin gene found?

A

The α globin gene is carried on chromosome 16

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3
Q

how many copies of the α globin gene found on each chromosome?

A

each chromosome has 2 copies of the alpha globin gene

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4
Q

what is found on chromosome 11?

A

β, δ and γ globin genes

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5
Q

how many copies of the β, δ and γ globin genes are there?

A

2 copies

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6
Q

when does foetal Hb (HbF α2 γ2 )

change to HbA?

A

3-6 months after birth

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7
Q

how does the switch from foetal haemoglobin occur?

A

γ chain production is replaced by β chain production

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8
Q

what are haemoglobinopathies?

A

A mutation in the globin genes that give rise to different types and amounts of haemoglobin

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9
Q

what are the 2 types of haemoglobinopathies?

A

structural variants

thalassaemia

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10
Q

what causes the structural variants in haemoglobinopathies?

A

Mutation of globin gene which produces functionally abnormal haemoglobin

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11
Q

what causes thalassaemia?

A

Mutation of globin gene which results in reduced or no globin chain synthesis

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12
Q

which of the haemoglobinopathies is a qualitative defect?

A

structural variants

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13
Q

which of the haemoglobinopathies is a quantitative defect?

A

thalassaemia

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14
Q

what are the structural variants characterised by?

A

the synthesis of structurally abnormal globin chains

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15
Q

how many structural variants have been described?

A

> 1000 different structural variants have been described

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16
Q

what are the 4 most common examples of structural variants?

A

Hb S
Hb C
Hb D
Hb E

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17
Q

what are some of the genetic reasoning of structural variants?

A

Usually a point mutation within the globin genes
Usually single amino acid substitutions on a globin gene
Alter the function of the haemoglobin

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18
Q

what is the most frequent structural variant?

A

sickle cell

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19
Q

what gave sickle cell its name?

A

its characteristic sickle shaped red cells

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20
Q

what is Haemoglobin S made up of?

A

2 α chains

2 β chains

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21
Q

what happens to the structure of Hb S during sickle cell?

A

An amino acid substitution one or both of the β genes

Glutamic acid in position 6 is replaced by valine

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22
Q

what does the structural variant in sickle cell lead to?

A

Leads to the production of functionally abnormal Haemoglobin S

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23
Q

what is the difference in solubility of deoxygenated HbS and deoxygenated HbA?

A

Deoxygenated HbS is 50 times less soluble than deoxygenated HbA

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24
Q

what is the role of deoxygenated HbS in the formation sickle cell?

A

Deoxygenated HbS lose solubility and polymerise into long rigid chains which deform the red cell into sickle shapes

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25
Q

when if HbS soluble?

A

when it is fully oxygenated

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26
Q

what are the conditions that predispose cells to sickling?

A

Hypoxia-insufficient levels of oxygen in the blood
Acidosis-Increased levels of acid in blood
Increased body temperature

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27
Q

how can sickling be reversed?

A

after re-oxygenation

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28
Q

what are the 2 types of inheritance which lead to sickle cell?

A
  • Homozygous (Hb S+S) both β globin genes affected

- Heterozygous (HB A+S) only one β globin gene affected

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29
Q

what are the features of sickle cell trait (5)?

A 
Normal haemoglobin level
Normal red cells in blood film
Usually asymptomatic
HbA and HbS present
Care must be taken when an individual is exposed to reduced oxygen concentration (<40%)
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30
Q

what are some symptoms of sickle cell trait?

A

Haematuria

Renal papillary necrosis

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31
Q

what are the features of Sickle cell Disease/Sickle Cell Anaemia?

A

Only HbS produced (HbS+S)
Severe haemolytic anaemia
Punctuated by crises
Jaundice

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32
Q

what are the clinical expressions of Sickle cell disease/Sickle cell anaemia?

A

Normal life
Severe crises
Shortened lifespan

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33
Q

what are the clinical features of Sickle cell anaemia (11)?

A 
Ulcers of lower leg
Dactylitis
Susceptibility to infection
Enlarged spleen
Pulmonary hypertension
Retinopathy
Priapism
Liver damage
Gallstones
Kidney infections
Severe crises
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34
Q

what are the types of crises?

A

Vaso-occlusive crises
Visceral sequestration crises
Aplastic crises
Haemolytic crises

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35
Q

which is the most frequent type of crisis?

A

Vaso-occlusive crises

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36
Q

in vaso-occlusive crises where do infarctions occur?

A

Bones
Lungs
Spleen
Brain

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37
Q

what causes sequestration crises?

A

Caused by sickling within organs and pooling of blood

Exacerbation of anaemia

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38
Q

when is splenic sequestration seen?

A

typically in infants

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39
Q

what are examples of sequestration crises?

A

sickle chest syndrome
splenic sequestration
hepatic sequestration
girdle sequestration

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40
Q

when do aplastic crises occur?

A

as a result of infection - Parvo virus

Folic acid deficiency

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41
Q

what are aplastic crises characterised by?

A

Sudden drop in Hb
Fall in reticulocytes
Transfusion support

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42
Q

what are haemolytic crises characterised by?

A

Increased rate of haemolysis
Fall in Hb
Rise in reticulocytes
Pain

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43
Q

what are the screening tests for sickle syndromes?

A

positive sickle solubility test

haemoglobin electrophoresis

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44
Q

what is a disadvantage of the positive sickle solubility test?

A

Does not differentiate between homozygous and heterozygous inheritance

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45
Q

what are the results of haemoglobin electrophoresis in homozygous inheritance?

A

shows the presence of a single major moving band in the position of HbS

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46
Q

what are the results of haemoglobin electrophoresis in heterozygous inheritance?

A

HbA and HbS bands-heterozygous inheritance

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47
Q

what are the prophylactic treatments for crises?

A

Folic acid
Good nutrition and hygiene
Vaccination
Antibiotics to reduce infection risk

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48
Q

how are crises treated?

A

Rest
Rehydration
Warmth
Pain relief

49
Q

what are other treatment options (sickle cell)?

A 
Pregnancy support and monitoring
Monitor HbS levels
Transfusion support
Hydroxyurea
Transplantation
50
Q

what is the prognosis for Sickle cell disease (HbS+S)?

A
  • High mortality rate

- Median survival rate 50 years

51
Q

why has the survival rate for sickle cell disease increased?

A

Increased with introduction of vaccination programme

Awareness of acute splenic sequestration syndrome

52
Q

why are neonatal screening programmes beneficial?

A

Identifies all those potentially affected
Ensures early treatment
Reduces mortality and morbidity rates.

53
Q

what are some of the screening services for Sickle cell disease (7)?

A 
Testing partners of affected mother
Genetic counselling for high risk parents
Antenatal diagnosis
Testing of newborn
Identification of “at risk” infant
Begin vaccination programme
Begin antibiotic treatment
54
Q

what are other clinically significant haemoglobinopathies?

A

HbC-West Africa
HbD-Indian sub-continent
HbE- South East Asia

55
Q

what happen in HbC haemoglobinopathy (4)?

A

Glutamic acid is replaced by lysine at position 6
Enlarged spleen
Mild haemolytic anemia
Target cells

56
Q

what happens in HbD haemoglobinopathy (3)?

A

Glutamic acid is replaced by glutamine at position 121
Homozygotes have mild haemolytic anaemia
Target cells

57
Q

what happens in HbE haemoglobinopathy?

A

Glutamic acid is replaced with Lysine at position 26

Mild microcytic hypochromic anaemia

58
Q

what are the combinations of HbS with other genetic defects of haemoglobin?

A

HbS/HbC

HbS/β-thalassaemia

59
Q

how are the combinations of HbS diagnosed?

A

Diagnosis by Hb electrophoresis and family studies

60
Q

what are thalassaemias?

A

Genetic disorders that result from a reduced or absent synthesis of α or β haemoglobin chains

61
Q

what are the 3 criteria for thalassaemia classification?

A
  • the affected globin gene
  • reduction rate of synthesis of globin
  • genotype
62
Q

what are the options for the affected globin gene in thalassaemia?

A

α globin chains

β globin chains

63
Q

what are the options for reduction in rate of synthesis of globin in thalassaemia?

A

Total reduction

Partial reduction

64
Q

what are the genotype options for thalassaemia?

A

Heterozygous

Homozygous

65
Q

how common is thalassaemia?

A

Among the most common single gene disorders in the world

66
Q

where is β thalassaemia common?

A

Mediterranean
Africa
India
Greece

67
Q

where is α thalassaemia common?

A

Indonesia
South-east Asia
Southern China

68
Q

how many α globin genes?

A

4 - 2 pairs

69
Q

where are α globin genes found?

A

chromosome 16

70
Q

what do 95% of thalassaemias result from?

A

95% thalassaemias result from a deletion on one or both pairs of globin genes

71
Q

what are the 6 possible genotypes for α thalassaemia?

A 
normal 
α+ heterozygote
α+ homozygote
αo heterozygote
αo homozygote - Barts hydrops foetalis
αo homozygote - Barts hydrops foetalis
αo α+ double heterozygote - Hb H disease
72
Q

what genotype is known as α+ heterozygote?

A

α-/αα

73
Q

what is the genotype known as α+ homozygote?

A

α-/α-

74
Q

what is the genotype that is known as αo heterozygote?

A

αα/–

75
Q

what is the αo homozygote - Barts hydrops foetalis

genotype?

A

–/–

76
Q

what is the αo α+ double heterozygote - Hb H disease genotype?

A

–/α-

77
Q

what is the normal alpha genotype?

A

αα/αα

78
Q

what does the clinical severity of α Thalassaemia syndromes depend on?

A

Varies according to how many missing or inactive genes

79
Q

which are the silent carriers of α Thalassaemia syndromes?

A

α+ heterozygote α-/αα

80
Q

what are the characteristics of α+ heterozygote α-/αα?

A
  • Deletion in one single globin gene
  • No haematological abnormality
  • Can only be defined with complete and reliable DNA analysis
81
Q

which genotype is the α thalassaemia trait?

A

α+ homozygote α-/α- or αo heterozygote αα/–

82
Q

what are the characteristics of thalassaemia trait?

A
  • Clinically indistinguishable
  • Identical laboratory profiles
  • Normal haemoglobin electrophoresis
  • Only DNA analysis will differentiate
83
Q

what are the clinical features of α thalassaemia trait?

A

Mild microcytic, hypochromic anaemia
No significant symptoms of disease
MCH lower in αo than α+

84
Q

what are the characteristics of Haemoglobin H disease –/α-?

A 
Deletion within 3 α globin genes
Moderate to severe anaemia and hepatosplenomegaly
Hb 80g/l
Transfusion support often unnecessary
Adult blood contains 5-35% Hb H ( β4)
85
Q

what is visible on a blood film of a patient with Haemoglobin H disease?

A

Microcytosis and hypochromasia
Poikilocytosis
Target cells
Polychromasia

Hb H inclusion bodies

86
Q

what is the main cause of haemolytic anaemia in Haemoglobin H disease?

A

Hb H inclusion bodies

87
Q

which is the most severe form α thalassaemia?

A

Haemoglobin Barts Hydrops Foetalis –/–

88
Q

what happens to the α globin genes in Haemoglobin Barts Hydrops Foetalis –/–

A

all 4 α globin genes are deleted

89
Q

what form of haemoglobin is formed in Haemoglobin Barts Hydrops Foetalis?

A

No functionally normal haemoglobin formed

Functionally useless Hb Barts (γ4) and HBH ( β4) formed

90
Q

what is the concentration of haemoglobin in patients of Haemoglobin Barts Hydrops Foetalis ?

A

at delivery 60 g/l

91
Q

what usually happens in the pregnancy of a foetus with Haemoglobin Barts Hydrops Foetalis?

A

pregnancy usually terminates in the third trimester

92
Q

what do β Thalassaemia syndromes result from?

A

Usually results from point mutations within the β globin gene

93
Q

how are β Thalassaemia syndromes classified?

A

Individuals grouped according to severity of their symptoms

94
Q

what are the 3 groups of β Thalassaemia syndromes?

A
  • β thalassaemia trait
  • β thalasaemia major
  • β thalassaemia intermedia
95
Q

what is the mildest form of β Thalassaemia syndromes?

A

β thalassaemia trait -heterozygous

96
Q

what causes β thalassaemia trait -heterozygous?

A

One abnormal β globin gene

97
Q

what is found in the lab investigations of β thalassaemia trait?

A 
Mild microcytic hypochromic anaemia
Target cells
Raised red cell count
Nucleated red cells
Tear drop cells
Microspherocytes
98
Q

what would be seen in a HPLC showing β thalassaemia trait?

A
  • Raised Hb F
  • Raised Hb A2
  • Important to differentiate thalassaemia from Iron deficiency
99
Q

what causes β thalassaemia major-Homozygous?

A

Inherit two abnormal β globin genes

100
Q

what are the skeletal deformities in β thalassaemia major caused by?

A

Erythroid hyperplasia

Expansion of bone marrow volume

101
Q

what are signs of β thalassaemia major?

A

Severe anaemia
Gross hepatosplenamegaly
Failure to thrive
skeletal deformities

102
Q

what would be seen in a bone marrow investigation for β thalassaemia major?

A
  • extreme erythroid hyperplasia
  • masked ineffective erythropoiesis
  • aggregates of excess α globin chains promotes intramedullary death of developing erythroblasts
  • Reduced lifespan of circulating red cells
103
Q

what causes the Extreme erythroid hyperplasia?

A

excessive growth of immature red blood cells

104
Q

why is marked ineffective erythropoiesis important?

A

does not result in the functional release of new erythrocytes

105
Q

what does Hb electrophoresis show in β thalassaemia major?

A

Marked increase in HbF (up to 98%)

No HbA

106
Q

what are other tests to diagnose thalassaemia?

A 
Hb Electrophoresis
Quantification of HbF
Column chromatography
Immunoassay
HPLC
Isoelectric focusing
DNA analysis
107
Q

what is the treatment for thalassaemia?

A

Regular blood transfusions
Maintain Hb at 100-120 g/l
Chelation therapy

108
Q

why is it important to maintain Hb at 100-120 g/l in the treatment of thalassaemia?

A

Suppresses erythropoiesis

Prevents skeletal changes

109
Q

what is a side effect of lifelong transfusion?

A

leads to accumulation of large amounts of iron within the body
Iron is toxic
Damages heart and liver

110
Q

what are some more treatments for thalassaemia?

A 
Vitamin C
Splenectomy
Immunisation
Antibiotic therapy
Folic acid
Bone marrow transplant
111
Q

what is the prognosis for thalassaemia without treatment?

A

5 years

112
Q

what is the prognosis for thalassaemia with treatment?

A

Without chelation 20-30 years

With chelation 50 years+

113
Q

when is a bone marrow transplant successful?

A

Without chelation 20-30 years

With chelation 50 years+

114
Q

true or false Not all cases of homozygous β thalassaemia have severe disease?

A

true

115
Q

true or false there are only a few varieties of β thalassaemic mutations?

A

false - Wide diversity of β thalassaemic mutations

116
Q

what is β thalassaemia intermedia?

A

Encompasses all cases of β thalassaemia with significant symptoms of disease which do not need regular blood transfusion to maintain Hb above 70g/l

117
Q

what does thalassaemia intermedia arises from?

A

Inheritance of “mild” β thal mutations
Co-inheritance with a gene that increase the rate of γ globin synthesis
Co-inheritance with α thalassaemia

118
Q

what are the laboratory and clinical findings of thalassaemia intermedia?

A

Bone changes
Bones break more easily
Hypersplenism

119
Q

is there iron overload in thalassaemia intermedia?

A

yes - due to morbidity-excessive absorption of dietary iron

Haematology (7 decks)

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