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Haematology > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

Describe the structure of haemoglobin (adult).

A

A tetramer made up of 2 alpha globin like chains and 2 beta globin like chains
+
One haem group attached to each globin chain

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2
Q

Globin chains keep haem _______, and protect it from _________

A
  1. Soluble

2. Oxidation

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3
Q

What are the 3 major forms of haemoglobin and what chains are these composed of?

A
  • HbA = 2 alpha chains and 2 beta chains; α2β2.
  • HbA2 = 2 alpha and 2 delta; α2δ2.
  • HbF = 2 alpha and 2 gamma; α2γ2.
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4
Q

In adults, what proportion of the haemoglobin is made up of each of the above types?

A

HbA - 97%.
HbA2 - 2.5%.
Hbf - 0.5%.

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5
Q

What chromosome are alpha like genes on?

A

16

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6
Q

How many alpha genes are there per i) chromosome? ii) cell?

A

i) 2.

ii) 4.

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7
Q

What chromosome are beta like genes on?

A

11

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8
Q

How many beta genes are there per i) chromosome? ii) cell?

A

i) 1.

ii) 2.

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9
Q

When does the expression of globin genes change?

A

During embryonic life and childhood.

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10
Q

At what age are alpha Hb levels reached?

A

6-12 months

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11
Q

What are genes arranged in order of?

A

Expression

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12
Q

What are haemoglobinopathies?

A

Hereditary conditions affecting globin chain synthesis

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13
Q

What is the mode of hesitance of haemoglobinopathies?

A

Autosomal recessive

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14
Q

What are the 2 main groups of haemoglobinopathies?

A
  • Thalassaemias

* Structural haemoglobin variants

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15
Q

What are thalassaemias?

A

Conditions where there is a decreased rate of globin chain synthesis

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16
Q

‘Conditions where there is a decreased rate of globin chain synthesis’ - name the condition.

A

Thalassaemia

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17
Q

What are structural haemoglobin variants?

A

Conditions where there is normal production of structurally abnormal globin chains - variant haemoglobin e.g. HbS.

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18
Q

What is a thalassaemia?

A

Reduced globin chain synthesis, resulting in impaired haemoglobin production

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19
Q

What are the 2 main groups of thalassaemias?

A
  • Alpha thalassaemia; α chains affected.

* Beta thalassaemia; β chains affected.

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20
Q

What does the inadequate Hb production in thalassaemias result in?

A

Microcytic Hypochromic Anaemia.

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21
Q

Thalassaemias can be toxic. Explain why.

A

There is unbalanced accumulation of globin chains and this results in:

  • Ineffective erythropoiesis
  • Haemolysis.
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22
Q

Why are thalassaemias imprortant?

A

They are the commonest myogenic disorder

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23
Q

What do the mutations in alpha thalassaemias affect?

A

α globin chain synthesis

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24
Q

How many alpha genes do unaffected individuals have?

A

4 - αα/αα.

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25
Q

What happens to alpha chains in alpha thalassaemia?

A

There is reduced α+ or absent α0 synthesis of α chains

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26
Q

What does an absent a chain result from?

A

Deletion of one α+ (-α) or both α0 (–) alpha genes from chromosome 16.

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27
Q

What type of Hb is affected in alpha thalassaemias?

A

HbA, HbA2 and HbF are all affected

Because alpha genes are present in all adult forms of Hb

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28
Q

What would the genes of someone without an alpha thalassaemia look like?

A

4 normal α genes (αα/αα).

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29
Q

What is an alpha thalassaemia trait?

A

Where there are one or two genes missing

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30
Q

Outline the different options of an alpha thalassaemia trait.

A

α+/α (-α/αα)
α0/ α (–/αα)
α+/α+(-α/-α)

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31
Q

What is HbH disease?

A

Where there is only one alpha gene left α0/α+(–/-α )

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32
Q

What is it called when there are no functional α genes α0/α0 (–/–)?

A

Hb Barts hydrops fetalis

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33
Q

What is Hb Barts hydrops fetalis?

A

When there are no functional α genes α0/α0 (–/–)

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34
Q

What are the genetics of an alpha thalassaemia trait?

A

α+/α (-α/αα) or α0/α (–/αα)

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35
Q

Look at the different alpha traits below, would any of them cause a problem?

i) α+/α (-α/αα)
ii) α0/α (–/αα)

A

NO - these will both be asymptomatic and cause no problems

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36
Q

On investigation, what will the clinical picture be with someone with…

i) α+/α (-α/αα)
ii) α0/α (–/αα)

A

Microcytic, hypochromic red cells with mild anaemia

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37
Q

What is Microcytic, hypochromic red cells with mild anaemia important to distinguish from?

A

Iron deficiency.

  • Ferritin will be normal and red blood cell count raised
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38
Q

What, essentially, is alpha thalassaemia trait?

A

Not a disease but a mild anaemia

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39
Q

What is HbH disease?

A

A severe form of alpha thalassaemia in which there is only 1 alpha globin chain

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40
Q

What is the genetics for HbH?

A

There is only one α gene per cell α0/α+(–/-α )

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41
Q

What do the blood tests of HbH disease show?

A

Anaemia with very low MCV and MCH

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42
Q

What does the HbH in HbH disease refer to?

A

Excess β chains form tetramers (β4) called HbH which can’t carry oxygen

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43
Q

What can be seen with special stains in HbH?

A

Red cell inclusions of HbH

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44
Q

Outline the clinical features of HbH disease?

A
  • Moderate anaemia to transfusion dependant
  • Splenomegaly
  • Extramedullary haematopoiesis
  • Jaundice
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45
Q

What might severe cases of HbH disease require?

A

Splenectomy +/- transfusion

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46
Q

In what ethnic groups in HbH common? Why?

A

S.E Asian, Middle Eastern and Mediterranean.

  • α0 is prevalent there
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47
Q

How is HbH disease inherited?

A

If get no alpha globulin genes from one parent, and one alpha globulin gene from the other

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48
Q

What is Hb Barts hydrops fetalis syndrome?

A

The severest form of alpha thalassaemia

49
Q

What are the genetics of Hb Barts hydrops fetalis syndrome?

A

No α genes inherited from either parent α0/α0(–/–).

50
Q

What is the result of no alpha genes being inherited in Hb Barts?

A

There is minimal or no α chain production, meaning HbA can’t be made

51
Q

What comprise the majority of Hb at birth in Hb Barts?

A

Hb Barts (γ4) and HbH (β4).

52
Q

List the main clinical features of Hb Barts.

A
  • Severe anaemia.
  • Cardiac failure.
  • Growth retardation.
  • Severe hepatosplenomegaly.
  • Skeletal and cardiovascular abnormalities.
  • Almost all die in utero.
53
Q

What are beta thalassaemias?

A

A disorder of beta chain synthesis

54
Q

What are beta thalassaemias usually caused by?

A

Point mutations.

Over 200 mutations identified so far

55
Q

What does a point mutation (in b thalassaemia) result in?

A

Reduced (β+), or absent (β0) beta chain production

56
Q

What type of Hb does beta thalassaemias affect?

A

Only HbA (α2β2) because only beta chains are affected.

57
Q

What is classification of beta thalassaemia based on?

A

Severity

58
Q

Outline the 3 different classifications of beta thalassaemias.

A

β thalassaemia trait (β+ /β or β0/ β)

  • Asymptomatic
  • No/mild anaemia, low MCV/MCH, raised HbA2

β thalassaemia intermedia (β+ /β+ or β0 /β+)
* Moderate severity requiring occasional transfusion

β thalassaemia major (β0 /β0)
* Severe, lifelong transfusion dependency

59
Q

When does beta thalassaemia major present?

A

Aged 6-24months as HbF falls offAged 6-24months as HbF falls off

60
Q

What does beta thalassaemia major present with?

A

With pallor and failure to thrive
+
Extramedullary haematopoiesis

61
Q

What process occurs to try and compensate for the anaemia in beta thalassaemia major? What are the clinical manifestations of this?

A

Extramedullary haematopoiesis.

This causes: hepatosplenomegaly, skeletal changes, organ damage.

62
Q

On Hb analysis of someone with beta thalassaemia, what is found?

A

Mainly HbF, with minimal HbA.

63
Q

What is the mainstay treatment of beta thalassaemia major?

A

Regular transfusion to maintain Hb at 95-105g/l.

64
Q

What are the effects of regular transfusion in beta thalassaemia major?

A
  • Suppression of ineffective erythropoiesis
  • Inhibition of over-absorption of iron

… allowing for relatively normal growth and development

65
Q

In beta thalassaemia major the main tx is regular transfusion. Before this the patient is at risk of dying. Once you start tx, what becomes the biggest risk of dying?

A

Iron overload from transfusion

66
Q

If regular transfusion is not working in beta thalassaemia, what can be done?

A

Bone marrow transplant – if carried out before complications develop

67
Q

Outline the different consequences of iron overload.

A
  • Endocrine dysfunction:
  • impaired growth and pubertal development.
  • diabetes.
  • osteoporosis.
  • Cardiac disease:
  • cardiomyopathy.
  • arrhythmias.
  • Liver disease:
  • cirrhosis.
  • hepatocellular cancer.
68
Q

How much iron is in each unit of red cells?

A

250mg. (because 500ml blood / 2 = 250mg)

69
Q

Why is iron overload such a problem?

A

Chronic anaemia drives increased iron absorption

70
Q

What is the treatment for iron overload?

A

Venesection

71
Q

Why can venesection not be used to treat patients with iron overload in beta thalassaemia major (who are receiving regular transfusions)?

A

Not done because pt is already anaemic

72
Q

What is used to treat iron overload in patients with beta thalassaemia major (who are receiving regular transfusions)?

A

Iron chelating drugs, such as desferrioxamine.

73
Q

What is used to treat iron overload in patients with beta thalassaemia major (who are receiving regular transfusions)?

A

Desferrioxamine

Iron chelating drugs, such as desferrioxamine.

74
Q

How does Desferrioxamine work?

A

Chelators bind to iron, and complexes formed are excreted in urine or stool

75
Q

List some transfusion related complications in beta thalassaemia.

A
  • Viral infections – HIV, hep B and C.
  • Alloantibodies – hard to crossmatch suitable blood.
  • Transfusion reactions.
76
Q

Why are people with beta thalassaemia, receiving regular transfusions, at increased risk of sepsis?

A

Bacteria likes iron

These patients are in iron overload

77
Q

Describe (from genes to pathology) the pathophysiology of sickling disorders.

A
  • Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine producing bS
  • This alters the structure of the resulting Hb→ HbS (α2βs2)
  • HbS polymerises if exposed to low oxygen levels for a prolonged period
  • This distorts the red cell, damaging the RBC membrane
78
Q

What are sickling disorders?

A

There is abnormal haemoglobin called haemoglobin S with an unusual sickle or crescent shape, meaning they are not as good at transporting oxygen

79
Q

What does the point mutation in codon 6 of the beta globin gene do?

A

Substitutes glutamine to valine, producing bS

80
Q

What does the substitution of glutamine to valine do?

A

The structure of Hb is altered to HbS (α2βs2).

81
Q

What is the problem when Hb changes to HbS?

A

HbS POLYMERISES if exposed to low oxygen levels for a prolonged period.

This distorts the red cell, damaging the RBC membrane

82
Q

In terms of genetics, what causes sickle cell trait?

A

One normal and one abnormal β gene (β/βs).

83
Q

Is sickle trait problematic?

A

NO - millions have it and are asymptomatic

84
Q

Why in sickle trait are there little clinical features?

A

HbS level is too low for polymerisation to occur

85
Q

When may cells sickle in sickle trait?

A

In severe hypoxia e.g. high altitude, under anaesthesia.

86
Q

What is the blood film like in someone with sickle trait?

A

Normal

87
Q

What is the main form of Hb in sickle trait?

A

HbA!

  • HbS <50%.
88
Q

In terms of genetics and inheritance, what is sickle cell anaemia caused by?

A

Two abnormal β genes (βs/βs), autosomal recessive

89
Q

Describe the Hb composition in sickle cell anaemia.

A

HbS >80%, no HbA

90
Q

What is the effects of sickle cell anaemia on the body.

A

Sickle crisis

91
Q

In terms of HbS, what is the difference between …

I) Sickle cell trait
ii) Sickle cell anaemia

A

i) <50% of HbS

II) >80% HbS

92
Q

What is sickle crisis?

A

Episodes of tissue infarction due to vascular occlusion

93
Q

What do symptoms in sickle crisis depend on?

A

Site and severity

94
Q

What may sickle crisis affect?

A

Digits (dactylitis), bone marrow, lung, spleen, CNS.

95
Q

What symptom may be extremely severe in sickle crisis?

A

Pain

96
Q

What 3 major things can happen to the body in sickle cell anaemia?

A
  • Sickle crisis
  • Chronic haemolysis
  • Hyposplenism
97
Q

Why does chronic haemolysis occur in sickle cell anaemia?

A

Due to shortened RBC life span

SEQUESTRATION OF SICKLED RBC’s IN LIVER AND SPLEEN.

98
Q

Why does hyposplenism occur in sickle cell anaemia?

A

Due to repeated splenic infarcts

99
Q

When do other sickling disorders occur?

A

Where there is compound heterozygosity for HbS and another β chain mutation.

100
Q

Give examples of other sickling disorders.

A
  • HbS/β thalassaemia; mild if β+, severe if β0

* HbSC disease; milder, but increased risk of thrombosis.

101
Q

What are the consequences of sickle cell vast-occlusion?

A

Tissue ischaemia and severe pain.

102
Q

What are the precipitants of a sickle crisis?

A
  • Hypoxia.
  • Dehydration.
  • Infection.
  • Cold exposure.
  • Stress/fatigue.
103
Q

What can help reduce the risk of a sickle crisis?

A

Education !!!

104
Q

Outline the treatment of a painful crisis.

A
  • Opiate analgesia.
  • Hydration.
  • Rest.
  • Oxygen.
  • Antibiotics if evidence of infection.
105
Q

What constitutes for a severe sickle crisis?

A

Chest or neuro crisis

106
Q

What is the treatment of a severe sickle crisis?

A

Red cell exchange transfusion.

107
Q

How does a red cell exchange transfusion work in the treatment of a severe sickle crisis?

A

It decreases the concentration of HbS and improves tissue function

108
Q

What are the long term effects of a sickle crisis?

A
  • Impaired growth.
* Risk of end-organ damage:
 pulmonary hypertension. 
 renal disease. 
 avascular necrosis. 
 leg ulcers. 
 stroke.
109
Q

Outline the key factors to be addressed in the long-term management of sickle cell disease.

A
  • Hyposplenism

* Folic acid supplementation

110
Q

How is hyposplenism managed long term?

A
  1. Prophylactic penicillin.

2. Vaccination: pneumococcus, meningococcus, haemophilus.

111
Q

Why is folic acid supplementation needed long term in sickle crisis?

A

There is increased demand due to increased RBC turnover.

112
Q

What can reduce the severity of sickle crisis long term?

A

Hydroxycarbamide – by inducing HbF production

113
Q

Outline the key areas addressed in reaching a haemoglobinopathy diagnosis.

A
  • FBC; Hb, red cell indices.
  • Blood film.
  • Ethnic origin.
  • High performance liquid chromatography (HPLC) or gel electrophoresis
114
Q

What does HPCL do?

A

Quantifies haemoglobins present, and identifies abnormal haemoglobins e.g. HbS in sickle cell disease

115
Q

What is the diagnostic test of beta thalassaemia trait?

A

Raised HbA2

116
Q

What is HPLC (high performance liquid chromatography) like in alpha thal trait?

A

Normal

117
Q

How is a diagnosis of alpha thalassaemia trait diagnosed if HPLC is normal in this condition?

A

DNA testing

118
Q

Antenatal screening to identify carrier parents for thalassaemis is now standard in the UK. Describe this.

A
  • Family origin questionnaire and FBC.

* Further testing if from high-risk area or abnormal RBC indices.

Haematology (26 decks)

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