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Haematology > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

What is haemoglobin?

A

Tetramer made up of 2 alpha-like globin and 2 beta-like globin chains

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2
Q

How many haem groups attach to each globin chain?

A

One haem group per chain = 4 per haemoglobin molecule

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3
Q

What are the major forms of haemoglobin?

A 
HbA = major form present in adults, 2 alpha and 2 beta chains 
HbA2 = 2 alpha and 2 delta chains 
HbF = 2 alpha and 2 gamma chains
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4
Q

Where are alpha like genes located?

A

Chromosome 16 = two alpha genes per chromosome so 4 per cell

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5
Q

Where are beta like genes located?

A

Chromosome 11 = one beta gene per chromosome so 2 per cell

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6
Q

Is the expression of globin genes constant throughout life?

A

No = changes during embryonic life and childhood

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7
Q

What are haemoglobinopathies?

A

Autosomal recessive hereditary conditions affecting globin chain synthesis

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8
Q

What are the two main groups of haemoglobinopathies?

A

Thalassaemias and structural haemoglobin variants

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9
Q

What occurs in structural haemoglobin variants?

A

Normal production of abnormal globin chain causing variant haemoglobin

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10
Q

Are haemoglobinopathies common?

A

Relatively = most common monogenic disorders and major cause of morbidity worldwide

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11
Q

What occurs in thalassaemias?

A

Reduced globin chain synthesis resulting in impaired haemoglobin production

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12
Q

What are the type of thalassaemias?

A 
Alpha = affects alpha chains
Beta = affects beta chains
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13
Q

What is the consequence of thalassaemias?

A

Inadequate Hb production causing microcytic hypochromatic anaemia

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14
Q

What can occur if thalassaemias are severe?

A

Unbalanced accumulation of globin chain

Haemolysis and ineffective erythropoiesis

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15
Q

What areas are thalassaemias more common in?

A

Areas with endemic malaria

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16
Q

How many alpha genes do unaffected alpha thalassaemia sufferers have?

A

4 normal alpha genes

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17
Q

What causes alpha thalassaemia?

A

Deletion of one a+ or both a0 alpha genes from chromosome 16 = causes reduced a+ or absent a0 alpha chain synthesis from that gene

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18
Q

What types of haemoglobin can be affected by alpha thalassaemia?

A

HbA, HbA2 and HbF

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19
Q

How is alpha thalassaemia classified?

A

By the number of alpha genes

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20
Q

What are the different classes of alpha thalassaemia?

A

Unaffected = 4 normal alpha genes
Alpha thalassaemia trait = one or two alpha genes absent
HbH disease = only one alpha gene left
Hb Barts hydrops foetalis = no functional alpha genes

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21
Q

What kind of state is alpha thalassaemia state?

A

Asymptomatic thalassaemia trait = no treatment needed

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22
Q

What are the features of alpha thalassaemia trait?

A

Microcytic and hypochromatic red cells with mild anaemia

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23
Q

How is alpha thalassaemia distinguished from iron deficiency?

A

Ferritin is normal in alpha thalassaemia

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24
Q

What is HbH disease?

A

More severe form of alpha thalassaemia = only one working alpha gene per cell

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25
Q

What are the features of HbH disease?

A

Anaemia with very low MCV and MCH
Excess beta chains form tetramers called HbH
Causes jaundice and splenomegaly

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26
Q

What can be seen on stains of patients with HbH disease?

A

Red cell inclusions of HbH can be seen with special stains

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27
Q

Where is HbH disease common?

A

SE Asia

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28
Q

How can HbH disease be treated?

A

May need transfusion

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29
Q

What is Hb Barts hydrops foetalis?

A

Severest form of alpha thalassaemia = no alpha genes inherited from either parent

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30
Q

What are the consequences of Hb Barts hydrops foetalis?

A

Minimal or no alpha chain production so HbF and HbA can’t be made = tetramers Hb Barts and HbH produced as no alpha chains to bind

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31
Q

Why is there antenatal screening for Hb Barts hydrops foetalis when both parents are from SE Asia?

A

Possible risk of developing disease as a0 thalassaemia trait is prevalent in this area

32
Q

What are the features of Hb Barts hydrops foetalis?

A

Profound anaemia, cardiac failure, growth retardation, severe hepatosplenomegaly, skeletal and CV abnormalities

33
Q

What is the prognosis of Hb Barts hydrops foetalis?

A

Poor = most die in utero

34
Q

What kind of mutations tend to cause beta thalassaemias?

A

Point mutations = causes reduced (b+) or absent (b0) beta chain production depending on mutation

35
Q

What type of haemoglobin is affected by beta thalassaemia?

A

HbA

36
Q

How are beta thalassaemias classed?

A

By severity

37
Q

What are the different classes of beta thalassaemia?

A

Beta thalassaemia trait = b+/b or b0/b
Beta thalassaemia intermedia = b+/b+ or b+/b0
Beta thalassaemia major = b0/b0

38
Q

What are the severity of the different beta thalassaemias?

A

Beta thalassaemia trait = asymptomatic, no/mild anaemia
Beta thalassaemia intermedia = moderate severity
Beta thalassaemia major = severe

39
Q

What are the features of beta thalassaemia trait?

A

Low MCV and MCH

Raised HbA2 is diagnostic

40
Q

What types of beta thalassaemia need transfusion?

A

Beta thalassaemia intermedia = may need occasional transfusion
Beta thalassaemia major = lifelong transfusion dependency

41
Q

When does beta thalassaemia major present?

A

Age 6-24 months = presents as Hbf falls

42
Q

How does beta thalassaemia major present?

A

Pallor and failure to thrive

43
Q

What occurs in beta thalassaemia major?

A

Extramedullary haematopoiesis = causes hepatosplenomegaly, skeletal changes, organ damage and spinal compression

44
Q

What does haemoglobin analysis of beta thalassaemia major show?

A

Mainly HbF and no HbA

45
Q

How is beta thalassaemia major treated?

A

Regular transfusions to maintain Hb at 95-105g/l

Bone marrow transfusion = only if carried out before complications develop

46
Q

What are the benefits of transfusion in beta thalassaemia major?

A

Suppresses ineffective erythropoiesis
Inhibits over-absorption of iron
Allows for normal growth and development

47
Q

What is a potential complication of transfusions to treat beta thalassaemia major?

A

Iron overload

48
Q

What are the consequences of iron overload?

A

Endocrine dysfunction = impaired growth and pubertal development, diabetes, osteoporosis
Cardiac disease = cardiomyopathy, arrhythmias
Liver disease = cirrhosis, hepatocellular cancer

49
Q

How much iron is there per unit of packed red cells?

A

250mg

50
Q

What affect does chronic anaemia have on iron metabolism?

A

Drives increased iron absorption

51
Q

Why is venesection not feasible as a treatment for iron overload?

A

Patient already anaemic

52
Q

How is iron overload treated?

A

Iron chelating drugs (e.g desferrioxamine) = bind to iron which is then excreted

53
Q

What are some complications of iron overload related to transfusion?

A

Viral infection (HIV, Hep B/C), alloantibodies, transfusion reactions

54
Q

Why are patients with iron overload more at risk of infections?

A

Bacteria like iron

55
Q

What causes sicking disorders?

A

Point mutations in codon 6 of beta globin gene that substitutes glutamine to valine producing bS

56
Q

What effect does the production of bS have on haemoglobin?

A

Alters the structure causing the formation of HbS

57
Q

What happens to HbS when it is exposed to low oxygen levels for a prolonged period?

A

HbS polymerises distorting the red cell and damaging the cell membrane

58
Q

What causes sickle cell trait?

A

One normal and one abnormal b gene

59
Q

What are the features of sickle cell trait?

A

Asymptomatic carrier state = few clinical features as HbS level too low to polymerise
Normal blood film = mainly HbA with <50% HbS

60
Q

What causes sickle cell anaemia?

A

Two abnormal b genes

61
Q

What effect does sickle cell anaemia have on red cells?

A

HbS >80% with no HbA

Chronic haemolysis causes shortened red cell lifespan

62
Q

Why does hyposlenism occur in sickle cell anaemia?

A

Sickled red cells sequestered in liver and spleen causing repeated splenic infarcts

63
Q

What are the episodes of tissue infarction due to vascular occlusion causing severe pain?

A

Sickle crisis

64
Q

What causes sickle cell disease?

A

Compound heterozygosity for HbS and another b chain mutation like beta thalassaemia or HbSC disease

65
Q

What are the features of HbSC disease?

A

Milder than sickle cell disease but increased risk of thrombosis

66
Q

What causes sickle crisis?

A

Sickle vaso-occlusion causing tissue ischaemia and pain

67
Q

What are the precipitants of sickle crisis?

A

Hypoxia, dehydration, infection, cold exposure, stress/fatigue

68
Q

How is sickle crisis treated?

A

Opiate analgesia and hydration plus rest and oxygen
Antibiotics if evidence of infection
Red cell exchange transfusion in severe crisis

69
Q

What is the long term management of sickle cell disease?

A

Prophylactic penicillin and vaccination
Folic acid supplementation
Hydroxycarbamide
Regular transfusion in some to prevent stroke

70
Q

Why do patients with sickle cell disease need prophylactic antibiotics?

A

To reduce risk of infection due to hyposplenism

Vaccinate against pneumococcus, meningococcus and haemophilus

71
Q

Why do sickle cell patients need folic acid supplementation?

A

Increased cell turnover so increased demand

72
Q

How does hydroxycarbamide reduce sickle cell disease severity?

A

Induces HbF production

73
Q

How are haemoglobinopathies diagnosed?

A

FBC = Hb, red cell indices
Blood film and ethnic origin
High performance liquid chromatography or electrophoresis = identifies abnormal haemoglobins

74
Q

What would high performance liquid chromatography of beta thalassaemia trait show?

A

Raised HbA2 is diagnostic

75
Q

How are haemoglobinopathies screened for antenatally?

A

Family origin questionnaire and FBC

Further testing if from high risk area or abnormal red cell indices

Haematology (24 decks)

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