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MCD Haematology > Haemoglobin molecule and thalassaemia > Flashcards

Haemoglobin molecule and thalassaemia Flashcards

1
Q

What does haemoglobin consist of?

A

Four haem groups and four globin chains

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2
Q

What is each haem group bound to?

A

Fe2+

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3
Q

How many oxygen molecules can each haemoglobin molecule bind?

A

4

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4
Q

What are the four types of globin proteins?

A

Alpha
Beta
Gamma
Delta

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5
Q

What is the most common for of haemoglobin (95) and what is it comprised of?

A

HbA= alpha2 beta2

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6
Q

What is HbA2 comprised of?

A

Alpha2 delta2 (1-3.5%)

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7
Q

What is HbF comprised of?

A

Alpha2 gamma2 (trace)

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8
Q

How would affinity differ between a haemoglobin molecule with 3 oxygens and a haemoglobin molecule with 1 oxygen?

A

The one with 3 is in a relaxed form so would have a higher affinity

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9
Q

What does it mean that a haemoglobin molecule with no oxygen has a low affinity?

A

It will only take up oxygen if the saturation is very high (lungs) and not in metabolically active tissues

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10
Q

How does the high affinity of oxyhaemoglobin have an effect?

A

It will not release oxygen easily, only in tissues when there is no oxygen around

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11
Q

What happens when you are in the tight configuration (deoxyhaemoglobin)?

A

You have a molecule called 2,3-DPG which forms extra bond and makes the molecules less flexible

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12
Q

What is the shape of the oxygen dissociation curve?

A

Sigmoid- low affinity when oxygen is low and high affinity when high pressure

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13
Q

In which direction do things that stabilise the deoxyhaemoglobin molecule and decrease its affinity shift the curve?

A

To the right

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14
Q

Which three things shift the curve to the right?

A

H+ ions
2,3-DPG
CO2 (Bohr effect)

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15
Q

How many alpha globin genes are there from each parent?

A

2

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16
Q

What type of alpha gene is expressed more than the other?

A

Alpha 2

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17
Q

When is the expression of embryonic haemoglobin switched off?

A

After about 3 months gestation

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18
Q

What is embryonic haemoglobin replaced by?

A

Foetal haemoglobin- consists of alpha and gamma globins

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19
Q

When is foetal haemoglobin switched off?

A

Gradually upto birth and in first year of life

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20
Q

What is foetal haemoglobin replaced reciprocally by?

A

Increase in beta globin gene expression

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21
Q

When is the normal adult pattern of haemoglobin synthesis normally established?

A

One year of life

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22
Q

Where are the two alpha genes found?

A

Chromosome 16

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23
Q

Where are beta, gamma and delta genes found?

A

Chromosome 11

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24
Q

How are these genes found?

A

In clusters in the order that they are expressed

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25
Q

What are thalassemias?

A

Disorders in which there is reduced production of one of the two types of globin chains in haemoglobin leaving to imbalanced globin chain synthesis

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26
Q

What percentage of the world population is expected to be carriers for thalassemia?

A

5%

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27
Q

What is thalassemia major?

A

When the patient is transfusion dependent

28
Q

What is thalassemia trait?

A

Common variant with no clinical significance

29
Q

What type of thalassemia major is fatal in utero and why?

A

Alpha because it is needed in foetal life to produce HbF

30
Q

What is severe alpha thalassemia?

A

Severe defect in three or four alpha genes

31
Q

What is haemoglobin called with three alphas missing?

A

Haemoglobin H- needs lifelong transfusions

32
Q

What is haemoglobin called with four alphas missing?

A

Haemoglobin Barts- fatal

33
Q

What is beta thalassemia major?

A

Severe defect in both beta chains

34
Q

When do you first notice anaemia due to beta thalassemia major?

A

At 2-3 months when there is a transition from HbF to HbA, the baby will become profoundly anaemic

35
Q

What is someone with thalassemia trait like?

A

Carrier state- mildly anaemic but can be normal

Low MCV and low MCH

36
Q

What will haemoglobin electrophoresis show in someone with beta thalassemia trait?

A

A rise in HbA2 relative to HbA

37
Q

How can you differentiate between different types of thalassemia trait?

A

HbA2
Alpha thalassemia trait= normal or low HbA2
Beta thalassemia trait= high HbA2

38
Q

What happens if you have a gene abnormality resulting in loss of start signal?

A

No transcription

39
Q

What happens if you have a gene abnormality resulting in mRNA becoming unstable?

A

No translation

40
Q

What gene mutation generally causes alpha thalassemia?

A

Deletion of one or more of the alpha globin genes on a chromosome

41
Q

What gene mutation generally causes beta thalassemia?

A

Point mutations

42
Q

When is alpha thalassemia clinically significant?

A

If 3 or 4 of the alpha genes are not functioning

43
Q

What does alpha+ thalassemia refer to?

A

The situation in which one of the two genes on a chromosome is deleted
Only experience mild anaemia

44
Q

What does alpha 0 thalassemia refer to?

A

Both alpha globin genes on a chromosome are deleted

Only mild anaemia

45
Q

How can you differentiate between alpha+ and alpha 0?

A

Vast number of carriers of alpha 0 thalassemia have an MCH < 25

46
Q

Why can a couple who both have alpha 0 thalassemia have potentially devastating consequences?

A

Risk of child with Haemoglobin Barts

47
Q

When is antenatal screening provided?

A

When the pregnant lady has two alphas missing

48
Q

What ethnicities is alpha 0 thalassemia common in?

A 
Chinese
South-east asian
Greek
Turkish
Cypriot
49
Q

What is the pathophysiology of beta thalassemia mainly due to?

A

Surplus of alpha globin chains that form tetramers

50
Q

What do the alpha globin tetramers do?

A

They precipitate in the bone marrow which leads to ineffective erythropoiesis and haemolysis in the peripheral circulation

51
Q

How does someone with beta thalassemia trait present?

A 
Haemoglobin normal
MCV low
MCH low
Red cell count increased
HbA2 increased- electrophoresis
52
Q

What symptoms are present in first year of life with thalassemia major (beta)?

A

Profound anaemia
Fail to thrive
Malaise
Splenomegaly

53
Q

What is the pathogenesis of beta thalassemia?

A 
Death of red cells in marrow
Ineffective erythropoiesis
Removal of red cells by the spleen
Large spleen
Anaemia
Increased erythropoietin
Expansion of bone marrow
54
Q

Blood transfusions are vital for patients with thalassemia major but what is a serious complication?

A

Iron overload (and viral transmission)

55
Q

What is the effect of iron overload?

A

It accumulates in the liver causing cirrhosis and in the endocrine glands causing:
Diabetes (pancreas)
Hypogonadism (pituitary)
Hypothyroidism (thyroid)

56
Q

How do you manage iron overload?

A

Remove with desferrioxamine- an iron chelator

57
Q

What are the problems with desferrioxamine?

A

Not orally active and requires subcutaneous injection

Expensive

58
Q

What examples of oral iron chelators are there?

A

Deferipone and deferasirox

59
Q

How does deferipone get rid of iron?

A

Urinary excretion

60
Q

What are the problems with deferipone?

A

Risk of agranulocytosis

Life threatening sepsis

61
Q

How does deferasirox get rid of iron?

A

Faecal excretion

62
Q

What are the key indicators of iron overload?

A

Serum ferritin
Liver iron
Reduced cardiac iron

63
Q

What else is available as treatment for thalassemia major?

A

Stem cell transplantation

64
Q

What are the positives for stem cell transplantation?

A

No transfusions
No desferrioxamine (chelator)
Growth is normal
This is a curative treatment

65
Q

What are the negatives for stem cell transplantation?

A

Transplant associated mortality
Relatively few transplants are done
Infertility due to stem cell transplant

MCD Haematology (11 decks)

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