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TAS Haematology > Haemoglobinopathies ✅ > Flashcards

Haemoglobinopathies ✅ Flashcards

1
Q

What are haemoglobinopathies?

A

A group of disorders that arise from abnormal haemoglobin production

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2
Q

What can abnormal haemoglobin production result from in haemoglobinopathies?

A
  • Inadequate globin chain production

- Production of abnormal global chain

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3
Q

Give 2 examples of conditions where there is inadequate globin chain production?

A
  • Alpha-thalassaemia

- Beta-thalassaemia

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4
Q

Give an example of a condition where there is production of an abnormal globin chain?

A

Sickle cell anaemia

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5
Q

What are haemoglobinopathies characterised by?

A

Chronic haemolytic anaemia

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6
Q

What do thalassaemias occur due to?

A

Genetic defects that result in reduced rate of synthesis of either alpha-globin or beta-globin chains

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7
Q

What is the genetic defect in alpha-thalassaemia?

A

Usually alpha-globin gene deletion

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8
Q

What is the genetic defect in beta-thalassaemia?

A

Mainly point mutations in beta-globin gene

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9
Q

Where is the alpha-globin gene found?

A

Chromosome 16

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10
Q

How many copies of the alpha-globin gene are present on chromosome 16?

A

2

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11
Q

How many alpha-globin genes do normal individuals have?

A

4

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12
Q

What are the forms of alpha-thalssaemia?

A
  • Alpha-thalassaemia trait
  • Alpha-thalssaemia major
  • HbH disease
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13
Q

What produces alpha-thalassaemia trait?

A

Deletion of one or two copies of the alpha-globin gene

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14
Q

How does alpha-thalassaemia present clinically?

A

Generally asymptomatic

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15
Q

What produces alpha-thalassaemia major?

A

Loss of all 4 alpha-globin genes

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16
Q

How does alpha-thalassaemia major present?

A

Death in utero or during first few hours of life

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17
Q

What causes death in alpha-thalassaemia major?

A

Hydrops fetalis

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18
Q

What produces HbH disease?

A

Deletion of 3 alpha-globin genes

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19
Q

How does HbH disease present?

A
  • Anaemia

- Splenomegaly

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20
Q

What are the features of anaemia in HbH disease?

A
  • Microcytic

- Hypochromic

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21
Q

What is formed in HbH disease?

A

An abnormal haemoglobin called HbH

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22
Q

How is HbH formed?

A

The excess of beta-globin chains forms HbH

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23
Q

What does HbH haemoglobin consist of?

A

Only beta chains

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24
Q

How can HbH haemoglobin be detected?

A
  • High performance liquid chromatography (HPLC)

- Blood film using brilliant cresol blue stain

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25
Q

How can alpha-thalassaemia trait be detected?

A

Genetic testing to identify alpha-globin gene deletions

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26
Q

Does alpha-thalassaemia trait produce any abnormalities on HPLC?

A

No

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27
Q

Where is the beta-globin gene located?

A

Chromosome 11

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28
Q

What genetic abnormality causes beta-thalassaemia major?

A

Mutations in both copies of beta-globin gene on chromosome 11

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29
Q

What is the result of deletion of both copies of the beta-globin gene on haemoglobin production?

A

Complete absence or severe reduction of beta-globin production, and an excess of alpha-globin chains

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30
Q

What does anaemia result from in beta-thalassaemia major?

A
  • Ineffective erythropoiesis

- Haemolysis

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31
Q

What causes haemolysis in beta-thalassaemia major?

A

There is an excess of alpha-globin chain, and the free alpha-globin chains are highly unstable and precipitate in erythrocytes, which causes haemolysis

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32
Q

What does the anaemia trigger in beta-thalassaemia major?

A

An increase in erythropoietin production

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33
Q

What does the increased erythropoietin production in beta-thalassaemia major drive?

A

Extramedullary haematopoiesis

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34
Q

What are the features of anaemia in beta-thalassaemia major?

A
  • Severe
  • Microcytic
  • Hypochromic
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35
Q

What are the typical blood film changes in beta-thalassaemia major?

A
  • Target cells
  • Nucleated red blood cells
  • Basophilic stippling
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36
Q

How is a diagnosis of beta-thalassaemia major confirmed?

A

Haemoglobin HPLC

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37
Q

What is found on haemoglobin HPLC in beta-thalassaemia major?

A

Absence of HbA

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38
Q

What is the purpose of genetic testing in beta-thalassaemia?

A

Can identify mutations

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39
Q

What are the mutations in beta-thalassaemia classed as?

A

Either β0 or ß+

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40
Q

What does ß0 mean?

A

No production of beta globin

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41
Q

What does ß+ mean?

A

Reduced production of beta-globin

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42
Q

What is the significance of the finding of ß+ globin?

A

May show milder phenotype

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43
Q

What is the milder phenotype of beta-thalassaemia known as?

A

Beta-thalassaemia intermedia

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44
Q

What is HPLC?

A

A laboratory technique that can identify and measure the different types of Hb present in a blood sample

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45
Q

What can the use of identification of patterns of Hb variants by HPLC be used for?

A

Diagnosis of most haemoglobinopathies

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46
Q

When does beta-thalassasemia present?

A

3-6 months of age

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47
Q

Why does beta-thalassaemia present at 3-6 months of age?

A

Hb production switches from HbF to HbA during the first 3-6 months of life - HbF does not use beta-globin, but HbA does

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48
Q

What does HbF consist of?

A

Alpha-globin and gamma-globin chains

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49
Q

What does HbA consist of?

A

Alpha-globin and beta-globin chains

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50
Q

What % of Hb is HbA in a healthy 6 month old infant?

A

95%

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51
Q

How is beta-thalassaemia major treated?

A

Regular blood transfusions

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52
Q

How often are blood transfusions required in beta-thalassaemia major?

A

3-6 weekly

53
Q

What is the purpose of blood transfusion in beta-thalassaemia major?

A
  • Raises Hb

- Suppresses erythropoietic production

54
Q

What are the complications of lifelong transfusions for beta-thalassaemia major?

A
  • Progressive iron overload
  • Transfusion related viral infection
  • Development of red cell abnormalities
55
Q

How is the extent of iron overload caused by transfusion in beta-thalassaemia major measured?

A

Monitoring serum ferritin levels

56
Q

How is iron overload treated?

A

Iron chelation therapy

57
Q

When is iron chelation therapy used for overload caused by blood transfusion in beta-thalassaemia major?

A

Once 10-15 red cell transfusions has been given, and/or the serum ferritin increases above 1000ng/mL

58
Q

How was iron chelation therapy traditionally given?

A

Subcutaneous infusions of desferrioxamine

59
Q

How is iron chelation therapy now given?

A

Oral preparations of desferrioxamine

60
Q

How are iron levels monitored in children receiving transfusion for beta-thalassaemia?

A
  • Serum ferritin

- Assessment of potential sites of iron deposition

61
Q

How often should serum ferritin be monitored in children with beta-thalassaemia being treated with transfusions?

A

3 monthly

62
Q

How often should children receiving transfusions for beta-thalassaemia major have potential sites of iron deposition assessed?

A

1-2 year intervals

63
Q

Where should be assessed for potential iron deposition in children with beta-thalassaemia major being treated with blood transfusion?

A
  • Heart

- Liver

64
Q

How is iron deposition tested in children with beta-thalassaemia major being treated with blood transfusions?

A

MRI scans

65
Q

What is the advantage of using MRI to assess potential sites of iron deposition in children with beta-thalassaemia major being treated with blood transfusion?

A

Avoids the need for invasive biopsies

66
Q

How is beta-thalassaemia major cured?

A

Haemopoietic stem cell transplant

67
Q

What is the limitation of haemopoietic stem cell transplant as a treatment for beta-thalassaemia major?

A

It carries significant risks

68
Q

How is maternal screening for haemoglobinopathies carried out?

A
  • FBC

- HPLC

69
Q

When is maternal screening for haemoglobinopathies part of routine antenatal testing?

A

In areas where there is a high prevalence of carriers

70
Q

In low prevalence areas, who is targeted antenatal screening for haemoglobinopathies done in?

A

Women from ethnic groups at highest risk

71
Q

Which ethnic groups are at highest risk of haemoglobinopathies?

A
  • African
  • Caribbean
  • Indian subcontinent
  • Mediterranean
72
Q

Is newborn haemogloblinopathy screening performed in the UK?

A

Yes

73
Q

What is the purpose of newborn screening for haemoglobinopathies?

A

Primarily aimed at detecting cases of sickle cell disease, but will also identify most cases of beta-thalassaemia major

74
Q

What recently development has allowed for the prevention of haemoglobinopathies?

A

Pre-implantation g genetic diagnosis

75
Q

How does pre-implantation genetic diagnosis prevent haemoglobinopathies?

A

IVF is used in combination with molecular testing for globin mutations/deletions to allow unaffected embryos to be selected from embryo transfer

76
Q

What is the limitation of pre-implantation genetic diagnosis to prevent haemoglobinopathies?

A

It is a very specialised and expensive technique and is not yet widely available

77
Q

What ethnicities does sickle cell disease predominantly affected?

A
  • African
  • Caribbean
  • Middle Eastern
  • Indian
78
Q

What is the genetic abnormality in sickle cell disease?

A

Point mutation in beta-globin gene

79
Q

What is the mutated beta-globin gene in sickle cell disease known as?

A

ßs-globin

80
Q

What does the point mutation in the beta-globin gene in sickle cell disease result in?

A

A single amino acid change in the beta-globin protein

81
Q

What is the amino acid change in sickle cell disease?

A

Valine for glutamine

82
Q

What is the haemoglobin chain produced in sickle cell known as?

A

HbS

83
Q

How does HbS cause problems?

A
  • Relatively insoluble

- Polymerises when exposed to low oxygen tension

84
Q

What does the polymerisation of HbS at low oxygen tension lead to?

A

The formation of characteristic sickle cells

85
Q

How do sickle cells differ from normal haemoglobin cells?

A

They are dehydrated, rigid, and less deformable than normal red cells

86
Q

What is the result of sickle cells being rigid and less deformable?

A

They can obstruct blood flow in the microcirculation

87
Q

What predisposes to sickle cell crises?

A

Any factor which increases the risk of polymerisation

88
Q

What factors are protective against sickle cell crises?

A
  • Optimal hydration
  • Oxygenation
  • Increased quantities of HbF
89
Q

What do all forms of sickle cell disease have in common?

A

All have the presence of one or more copies of a beta-globin gene mutation

90
Q

What are the most common types of SCD?

A
  • Sickle cell anaemia
  • HbSC diseaes
  • S ß-thalassaemia
91
Q

What is the genetic abnormality in sickle cell anaemia?

A

Homozygous for beta-globin mutation (HbSS)

92
Q

What is the genetic abnormality in HbSC disease?

A

Single beta-globin mutation in combination with HbC mutation (HbSC)

93
Q

What is the genetic abnormality in S ß-thalassaemia?

A

People with ß-thalassaemia mutation in combination with ßS-globin

94
Q

How do the clinical features of all types of sickle cell disease compare with each other?

A

The clinical features are similar, but vary in severity

95
Q

Which of the sickle cell diseases are most severe?

A

Sickle cell anaemia

96
Q

Which of the sickle cell disease are least severe?

A

HbSC disease

97
Q

What are the clinical features of all forms of sickle cell diseases?

A
  • Chronic haemolytic anaemia

- Prone to recurrent sickle cell crises

98
Q

How might sickle cell crises present?

A
  • Veno-occlusive (painful) crisis
  • Sickle chest crisis
  • Splenic/hepatic sequesteration
  • Aplastic crisis
  • Cerebral infarction
99
Q

What causes aplastic crises in sickle cell disease?

A

Parvovirus B19 infection

100
Q

What is the incidence of cerebral infarction in sickle cell disease?

A

11%

101
Q

How is the incidence of cerebral infarction in sickle cell disease reduced?

A

Regular screening

102
Q

What is the incidence of cerebral infarction in children with sickle cell disease who undergo regular screening?

A

<5%

103
Q

How is sickle cell disease diagnosed?

A

HPLC

104
Q

Can patients with sickle cell anaemia produce HbA?

A

No

105
Q

What globins to patients with sickle cell anaemia rely on?

A

HbS and small amounts of HbF

106
Q

What is the management of sickle cell disease aimed at?

A
  • Preventing complications

- Symptomatic treatment of painful sickle crises

107
Q

What are the most important aspects of prevention of complications in sickle cell disease?

A
  • Avoidance of factors that may precipitate a crisis
  • Prevention of infection
  • Folic acid
108
Q

What factors may precipitate a sickle cell crisis?

A
  • Cold
  • Dehydration
  • Over-strenuous exercise
109
Q

What kind of organisms need to be prevented against in sickle cell disease?

A

Encapsulated organisms

110
Q

Give 2 examples of encapsulated organisms?

A
  • Pneumococcus

- Meningococcus

111
Q

How is infection with encapsulated organisms prevented in sickle cell disease?

A
  • Twice daily penicillin prophylaxis

- Vaccination

112
Q

Why are infections with encapsulated organisms more common in sickle cell disease?

A

Because most patients develop auto-infarction of the spleen before the age of 4 years

113
Q

Why is folic acid supplementation required in sickle cell disease?

A

Because of increased folate need due to chronic haemolysis

114
Q

Is the severity of SCID variable?

A

Yes, very

115
Q

What is the aim of treatments in SCID?

A

To modify the severity and natural history of the disease

116
Q

What treatments are available for SCID?

A
  • Hydoxycarbamide
  • Regular blood transfusion
  • Haematopoietic stem cell transplantation (HSCT)
117
Q

What is the effect of hydroxycarbamide in sickle cell disease?

A

It reduces the occurrence of crises

118
Q

How does hydroxycarbamide reduce the occurrence of crises in sickle cell?

A

It inhibits ribonucleotide reductase, which increases HbF

119
Q

What is the purpose of regular blood transfusion in sickle cell disease?

A
  • Prevent stroke

- Reduce sickle chest crises

120
Q

How often are blood transfusions given when used in sickle cell disease?

A

Monthly

121
Q

When are regular blood transfusions used for the prevention of sickle chest crises in sickle cell disease?

A

When hydroxycarbamide has been ineffective

122
Q

What is required when regular blood transfusions are used for more than a year in sickle cell disease?

A

Iron chelation therapy

123
Q

When is HSCT used in sickle cell disease?

A
  • CNS disease
  • Recurrent chest crises
  • Painful crises despite hydroxycarbamide treatment
124
Q

What is the pathogenesis of stroke in children with sickle cell disease?

A

Cerebral vasculopathy

125
Q

What vessel is particularly affected by cerebral vasculopathy in sickle cell disease leading to stroke?

A

Middle cerebral artery

126
Q

What investigation finding correlates with the presence of cerebral vasculopathy in sickle cell disease?

A

Increased MCA blood flow on transcranial doppler scanning

127
Q

What is the presumed mechanism of cerebral vasculopathy in sickle cell disease?

A

Chronic intravascular haemolysis

128
Q

What is the best known method for reducing intravascular haemolysis in sickle cell disease?

A

Regular red cell transfusion

TAS Haematology (7 decks)

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