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Haematology > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

Describe the structure of haemoglobin 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

What are the major forms of haemoglobin, and what globin chains do they contain?
What proportion are they present in adult blood?

A

HbA (2 alpha and 2 beta chains) - 97%
HbA2 (2 alpha and 2 delta chains) - 2.5%
HbF (2 alpha and 2 gamma chains) - 0.5%

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3
Q

What chromosome has the genes for alpha like chains? How many genes are there?

A

Chromosome 16

There are 2 genes per chromosome (i.e. 4 genes per cell)

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4
Q

What chromosome carries the genes for beta like chains?

How many genes are there?

A

Chromosome 11

1 gene per chromosome, 2 genes per cell.

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5
Q

What are the embryonic Hbs?

A

Gower 1
Portland
Gower 2

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6
Q

What chromosome carries the genes for gamma and delta globin chains?

A

Chromosome 11

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7
Q

By what age are adult levels of Hb reached?

A

6-12 months

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8
Q

What are the haemoglobinopathies?

A

Hereditary conditions affecting haemoglobin synthesis

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9
Q

What are the main groups of haemoglobinopathies?

A

Thalassaemias and structural haemoglobin variants

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10
Q

What are the thalassaemias?

A

Hereditary disorders of globin chain synthesis resulting in impaired haemoglobin production
(decreased rate of haemoglobin production)

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11
Q

What are structural haemoglobin variants?

A

Conditions in which there is normal rate of production of structurally abnormal globin chains leading to variant haemoglobin production (e.g. HbS)

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12
Q

What are the two main groups of thalassaemias?

A

Alpha and beta

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13
Q

What type of anaemia does thalassaemia cause?

A

Microcytic hypochromic anaemia

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14
Q

Why is there ineffective erythropoiesis in thalassaemia?

What else happens?

A

Because there is unbalanced accumulation of globin chains, leading to precipitations of globin chains in red cell precursors.
Precipitations of globin chains in mature red cells leads to haemolysis.

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15
Q

Why are thalassaemias increasingly prevalent in the UK?

A

Due to changing population demographics

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16
Q

Why have the mutations causing thalassaemias flourished in certain parts of the world?

A

Due to selective pressure in malaria endemic areas.

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17
Q

What causes alpha thalassaemia?

A

Deletions of one or both alpha genes from chromosome 16.

Point mutations are rare and cause non-deletional alpha thalassaemia.

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18
Q

What types of haemoglobin are affected by alpha thalassaemia?

A

All adult types - HbA, HbA2, HbF

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19
Q

What disease and genome does a patient who is missing one alpha gene have?

A

silent alpha thalassaemia trait

-a/aa

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20
Q

What disease and genome does a patient who is missing 2 alpha genes have?

A

alpha thalassaemia trait

-a/-a or –/aa

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21
Q

What disease and genome does a patient who is missing 3 alpha genes have?

A

HbH disease

–/-a

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22
Q

What disease and genome does a patient who has no functional alpha genes have?

A

Hb Barts hydrops fetalis

–/–

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23
Q

What are the symptoms and treatment of alpha thalassaemia trait?

A

It is clinically asymptomatic - no treatment needed

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24
Q

What are the findings on blood film of alpha thalassaemia trait?

A

Microcytic hypochromic red cells

Red cell inclusions (HbH bodies) can sometimes be seen with special staining

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25
Q

What is the Hb, ferritin and red cell count in alpha thalassaemia?

A

Mild anaemia
Normal ferritin
Raised red cell count

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26
Q

What proportion of alpha chain production is there in HbH disease in comparison to normal circumstances?

A
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27
Q

What are the Hb, MCV and MCH findings in HbH disease?

A

Low Hb, Low MCH, Low MCV

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28
Q

What is HbH?

A

Haemoglobin formed by four beta chains, which happens due to the presence of excess beta chains in HbH disease. HbH cannot carry oxygen.

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29
Q

Where is HbH disease commonest geographically?

A

SE Asia, Middle East, Mediterannean

30
Q

How does HbH disease behave in terms of its inheritance/

A

It behaves like an autosomal recessive condition

31
Q

What are the clinical features of HbH disease?

A 
There is wide variation - nearly asymptomatic to transfusion dependent.
Splenomegaly
Jaundice
Gallstones
Growth retardation
Iron overload
32
Q

What is the management of mild HbH disease?

A

Transfusion only needed at times of intercurrent illness

Folic acid supplementation due to increased RBC turnover

33
Q

What is the management of severe HbH disease?

A

Transfusions
Folic acid supplementation
Splenectomy may reduce transfusion need

34
Q

What is the severest form of alpha thalassaemia?

A

Hb Bart’s hydrops fetalis syndrome

35
Q

What forms of Hb are present at birth in Hb Bart’s hydrops fetalis syndrome?

A

Hb Bart’s (gamma4) and HbH (beta4)

Small amounts of embyronic Hb also present

36
Q

What are the clinical features of Hb Bart’s hydrops fetalis?

A 
Pallor
Oedema
Cardiac failure
Growth retardation
Skeletal and cardiovascular abnormalities
Severe hepatosplenomegaly
Most die in utero
Some survive to term but die shortly after birth
37
Q

What does the blood film show in Hb Bart’s hydrops fetalis?

A

Numerous nucleated RBCs in peripheral blood

38
Q

What does the blood film show in alpha thalassaemia?

A

Target cells

anisopoikilocytosis

39
Q

How is alpha thalassaemia diagnosed?

A

Suspected from ethnic origin and red cell indices (exclude iron deficiency)
Blood film
High performance liquid chromatography or Hb electrophoresis

40
Q

How is a thal trait confirmed, and the mutation involved determined?

A

Molecular testing

41
Q

If parents are at risk for alpha thalassaemia trait because of their ethnic background, what is used to screen for common mutations?

A

PCR

42
Q

What type of haemoglobin is affected in beta thalassaemia?

A

HbA

43
Q

What causes beta thalassaemia?

A

Usually point mutations

44
Q

How is beta thalassaemia inherited?

A

It is autosomal recessive

45
Q

How is beta thalassaemia classified?

A

Based on clinical severity as beta thalassaemia trait, beta thalassaemia intermedia and beta thalassaemia major.

46
Q

What are the features of beta thalassaemia trait and how is it diagnosed?

A

Asymptomatic
Low MCV/MCH
Raised HbA2 is diagnostic

47
Q

What is the treatment of beta thalassaemia major?

A

Lifelong transfusion dependency

48
Q

What are the clinical features of beta thalassaemia major/

A

Presents 6-24 months
Failure to thrive
Pallor
Extramedullary haemopoiesis causing hepatosplenomegaly, skeletal changes, organ damage.
Similar features to HbH disease but more severe

49
Q

What are the lab features of beta thal major?

A

Moderate to severe anaemia (Hb 30-90g/L)
Very low MCV and MCH
Reticulocytosis
Blood film shows target cells and anisopoikilocytosis
HPLC shows mainly HbF present with small amounts of HbA and slightly elevated HbA2.

50
Q

What is the management of beta thal major?

A

Regular transfusion programme to maintain Hb 95-105g/L

Bone marrow transplant may be an option if carried out before complications develop

51
Q

If treated effectively, what is the main cause of morbidity in beta thalassaemia?

A

Iron overload from repeated transfusions

52
Q

What are the complications of iron overload?

A 
Endocrine dysfunction (impaired growth and pubertal development, diabetes, osteoporosis)
Cardiac disease (arrhythmias, cardiomyopathy)
Liver disease (cirrhosis, hepatocellular carcinoma)
53
Q

How is iron overload managed?

A

Iron chelating drugs e.g. desferrioxamine, deferiprone, deferasirox

54
Q

How much iron is in a unit of red cells?

A

250mg

55
Q

How is iron excreted naturally?

A

There is no natural mechanism for iron excretion.

56
Q

What populations are primarily affected by the sickle cell syndromes?

A

Afro-caribbean populations

57
Q

What is the common feature of the sickle cell syndromes?

A

Inheritance of abnormal Hb beta-chain gene (BetaS)

58
Q

How many abnormal beta chains are inherited in a)sickle cell anaemia and b) sickle cell trait?

A

a) 2

b) 1

59
Q

What is HbS?

A

α2βs2

Structurally altered Hb, caused by inheritance of the betaS gene

60
Q

What is different about the beta chains produced by expression of the betaS gene to the normal beta chain gene?

A

There is a point mutation in codon 6 of the gene

This causes the amino acid in position 6 to be changed from glutamine to valine

61
Q

What parasite does HbS give some protection against?

A

Falciparum malaria

62
Q

Describe what happens to HbS (and the red cells that contain it) at low oxygen concentrations.

A

Deoxygenated HbS undergoes conformational change (i.e. if exposed to low oxygen levels for a prolonged period of time).
The abnormal HbS forms tetramers which aggregate to form large polymers leading to a loss of deformability of the red cell, which becomes sickle shaped.
The membrane becomes damaged and the cell becomes more rigid.

63
Q

What sort of anaemia does sickle cell anaemia cause?

How?

A

Haemolytic anaemia

Due to sequestration of red cells in the reticuloendothelial system.

64
Q

Why are the symptoms of anaemia in sickle cell anaemia often surprisingly mild?

A

Because HbS released oxygen more readily than HbA.

65
Q

How is sickle cell anaemia inherited?

A

It is autosomal recessive

66
Q

What types of Hb are present in the blood in sickle cell anaemia?

A

HbS (>80%)
No HbA
Variable amounts of HbF

67
Q

Name 5 precipitants of sickle cell crises.

A 
Hypoxia
Infection
Cold exposure
Stress/fatigue
Dehydration
68
Q

What areas are most commonly affected by vaso-occlusive crises?

A

Hips
Vertebrae
Shoulders

69
Q

What must bone infarction due to a vaso-occlusive crisis be differentiated from?

A

Salmonella osteomyelitis

70
Q

Describe the management of sickle cell crises

A 
Opiate analgesia
Hydration
Oxygen
Rest
Antibiotics if evidence of infection
Red cell exchange transfusion in severe crises or if neurological symptoms present.
71
Q

What is the longterm treatment of sickle cell anaemia?

A

Education/lifestyle measures to avoid precipitants
Folic acid supplementation
Prophylactic penicillin
Vaccination (pneumococcus, meningococcus, haemophilus)
Hydroxycarbamide can reduce disease severity by inducing HbF production

72
Q

How is sickle cell anaemia diagnosed?

A

Blood film
Screening test for sickling (blood sample deoxygenated to induce sickling)
Hb electrophoresis - no HbA detectable

Haematology (7 decks)

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