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Haematology > Week 1- thalassamia, haemoglobinopathies and sickle cell > Flashcards

Week 1- thalassamia, haemoglobinopathies and sickle cell Flashcards

1
Q

What is the structure of haemoglobin?

A

2 alpha globin chains and two beta globin chains.

4 Haem groups made up of an iron centre and porphyrin ring.

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2
Q

What is the function of the globin chains?

A

They keep haemoglobin soluble and stop oxidative damage.

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3
Q

What are the major forms of haemoglobin?

A

HbA- this is the classic haemoglobin. Made up of 2 alpha chains and 2 beta chains.
HbA2- made up of 2 alpha chains and 2 delta chains
HbF- two alpha chains and two gamma chains

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4
Q

Describe the percentage of HbA, HbA2 and HbF in the population?

A

HbA- 97%
HbA2- 2.5%
HbF-0.5%

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5
Q

Where would you find the genes encoding for alpha chains? How many are there?

A

On chromosome 16.

There are two alpha genes per chromosome, therefore 4 per cell.

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6
Q

Where would you find the genes encoding for beta chains? How many are there?

A

Found on chromosome 11.

There is one beta gene per chromosome, therefore 2 per cell.

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7
Q

At birth, what changes occur in the haemoglobin molecule?

A

At birth, the gamma haemoglobin starts to decrease and the beta haemoglobin starts to increase. This shows the transfer from feotal haemoglobin to adult haemoglobin.

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8
Q

What is a haemoglobinopathy?

A

Hereditary conditions affecting globin chain synthesis.

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9
Q

How are haemoglobinopathies inherited?

A

Generally they behave as autosomal recessive conditions.

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10
Q

What are the two main groups of haemoglobinopathies?

A

Thalassaemia’s- decreased rate of Hb globin chain synthesis
or
Structural haemoglobin variants- normal production of abnormally structured globin chains

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11
Q

What does an alpha thalassaemia affect?

A

Alpha globin chains

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12
Q

What does a beta thalassaemia affect?

A

Beta globin chains

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13
Q

How will the morphological appearance of RBC’s be described in thalassaemia?

A

Microcytic hypo chromic cells-

This is because- you aren’t making enough globin chains therefore you are not making enough haemoglobin. This means the colour in the cells won’t be as red and they will be smaller due to lack of Hb.

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14
Q

What occurs if you have unbalanced accumulation of globin chains?
(Due to one type not being made enough but the other types are all fine)

A

The accumulation can be toxic and can result in ineffective erythropoiesis and haemolysis.

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15
Q

On a worldwide scale, where are thalassaemias common?

A

They are common in areas where malaria was prevalent- because it induced a selective pressure on the people.

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16
Q

What denotation is used for a reduced alpha gene expression?

A

alpha +

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17
Q

What denotation is used for absent alpha gene expression?

A

Alpha 0

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18
Q

If you have deletion of one alpha gene, what will this result in (alpha 0 or alpha +)?

A

Deletion in one will cause a+ (reduced expression) (a,-)

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19
Q

If you have deletion of two alpha genes, what will this result in (alpha 0 or alpha +)?

A

Alpha 0 (–)

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20
Q

Which types of haemoglobin will alpha thalassaemias affect?

A

All types- HbF, HbA2 and HbA

As alpha chains are present in all of them.

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21
Q

What would the genes of someone with alpha thalasaemia trait look like? (all the a’s are actually alphas)

A 
They have one or two deletions of an alpha gene. 
This could be:
a, a0 (aa,--),
a+,a+ (a-,a-),
a+, a (-a,aa)
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22
Q

What would the genes of someone with HbH disease look like?

A

They have only one alpha gene left. (a0, a+) (–,a-)

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23
Q

Describe the alpha genes of someone with Hb Barts hydrops fetalis?

A

They have no alpha genes remaining (–,–) (a0,a0)

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24
Q

Would you get symptoms with alpha thalassaemia trait?

A

You will only get mild symptoms.

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25
Q

What will the morphological appearance of the RBC’s be like in alpha thalassaemia trait?

A

You will get microcytic, hypo chromic red cells with mild anaemia.

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26
Q

How can you distinguish between alpha thalassaemia trait and iron deficiency anaemia?

A

Alpha thalassaemia trait will give you an increase in RBC’s. Because they are still carrying Hb, just less, therefore they increase the numbers of red cells to make up for it. Also serum ferritin will be normal.
Iron deficiency anaemia has iron as a limiting factor therefore RBC count will not be increased.

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27
Q

How will (on investigation) HbH disease present?

A

Anaemia with very low MCV (cell is very small) and MCH (low amounts of Hb in the cells).

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28
Q

What is the beta chains response in HbH disease?

A

The excess beta chains form tetramers (beta4) called HbH which can’t carry oxygen.
Blood stain will show golf ball cells (HbH)

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29
Q

What clinical features can be seen in HbH disease?

A

They could have moderate anaemia to transfusion dependency.
Red cell production starts to occur outwit the bone marrow (e.g. spleen, liver) causing splenomegaly. Called extra medullary haematopoeisis.
The patient may be jaundiced due to- haemolysis, ineffective erythropoesis.

30
Q

How would you treat HbH disease?

A

Severe cases will need splenectomy +/- transfusion.

31
Q

Where is HbH disease most common?

A

In south east Asia, Middle East and the Mediterranean (where a0 is most prevalent)

32
Q

How can HbH disease be inherited?

A

There is only one way to inherit HbH disease- have one parent with a0 (no copies on one gene) and have one parent with a+ (only one copy on one gene).

33
Q

What happens to HbA in Hb Barts hydrops fetalis?

A

There is no production of HbA because they can’t create alpha globin chains. At birth the foetus has been using either HbH (beta 4) or Hb Barts (gamma 4)

34
Q

What are the clinical features of Hb Barts hydrops fetalis?

A 
Severe anaemia 
Cardiac failure 
Growth retardation 
Severe hepatosplenomegaly 
Skeletal and cardiovascular abnormalities. 
Almost all die in utero
35
Q

What sort of mutation usually causes beta thalassaemia?

A

Point mutations.

36
Q

What is a reduced beta chain production denoted as?

A

Beta + (B+)

37
Q

What is an absent beta chain production denoted as?

A

Beta 0 (B0)

38
Q

Which haemoglobin is affected in beta thalassaemia?

A

HbA is the only one containing beta chains and is therefore the only one affected.

39
Q

How is beta thalassaemia classified?

A

Classified by severity.

Goes from mild (beta thalassaemia trait) to moderate (beta thalassaemia intermedia) to severe (beta thalassaemia major).

40
Q

Describe the genes in beta thalassaemia trait?

A

Have one copy of normal beta genes, and one abnormal copy, this could be B+ or beta 0.
(B+,B)-
(B0,B)

41
Q

How does beta thalassaemia trait present?

A

Asymptomatic.

No or mild anaemia, low MCV/MCH, raised HbA2.

42
Q

Describe the genes in beta thalassaemia intermedia?

A

Have reduced or absent in both genes. (both genes have to be affected to have this).
(B+, B+)
or (B0, B+)

43
Q

Will beta thalassamia intermedia need intervention?

A

Its of moderate severity so may need the occasional blood transfusion.

44
Q

Describe the genes in beta thalassaemia intermedia?

A

Both genes are affected. They have reduced or absent in both genes. (both genes have to be affected to have this).
(B+, B+)
or (B0, B+)

45
Q

Will beta thalassaemia major need intervention?

A

Severe, lifelong transfusion dependency.

46
Q

When does beta thalassaemia major present and why?

A

It presents at 6-24 months. This is because the HbF starts to fall and the beta chains are supposed to accommodate for this, obviously they can’t because the genes are absent.

47
Q

What are the symptoms of having beta thalassaemia major?

A

They will have pallor, failure to thrive.

Extramedullary haematopoeisis- causing hepatosplenomegaly, skeletal changes and organ damage.

48
Q

If you were to analyse the haemoglobin of someone with beta thalassaemia major, what would it comprise of?

A

Little HbA

Mostly HbF

49
Q

What are some complications of extra medullary haematopoeisis?

A

Can cause skeletal changes- spinal compression from marrow tissue pressing on nerves.

50
Q

How do you manage beta thalassaemia major?

A

Regular transfusion program to maintain Hb at 95-105g/l
This helps to suppress ineffective erythropoiesis and inhibit over absorption of iron.
Bone marrow transplant could be an option if carried out before complications occur.

51
Q

What is a common problem associated with regular transfusion?

A

Iron overload.

52
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

53
Q

Why do you get iron overload in regular transfusions?

A

Each unit of RBC’s contains 250mg of iron. Due to chronic anaemia, patients absorb more iron therefore iron overload is common.

54
Q

How do you manage iron overload?

A

Iron chelating drugs such as desferrioxamine

They bind to iron and complexes formed are excreted in the urine and stool.

55
Q

What other complications do patients with beta thalassaemia major treated with blood transfusions suffer from?

A

Increased risk of sepsis (bacteria like iron)

Transfusion related risks- viral infection, transfusion reactions.

56
Q

What mutation causes sickling disorders?

What is the consequence of this mutation?

A

A point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine producing Bs.
Alters the haemoglobin structure to HbS.

57
Q

What happens to HbS if it is exposed to low oxygen levels for a prolonged period of time?

A

It polymerises, changing the red cell shape by damaging the membrane. This exposes more reactive parts of the red cell.

58
Q

What is sickle trait?

A

When you have one normal and one abnormal version of the beta gene.

59
Q

Do you have symptoms with sickle trait?

A

No, its asymptomatic.

60
Q

Are there any conditions under which sickle trait patients will have their sickle cells polymerise?

A

Unlikely unless in extremes of hypoxia e.g. altitude. This is due to the HbS not being in high enough concentrations to cause any harm.

61
Q

What percentage of the patients blood with sickle cell trait will be HbS?

A

HbS<50%

HbA>50%

62
Q

How many abnormal genes does someone with sickle cell anaemia have?

A

Two abnormal beta genes (bs,bs)

63
Q

How is sickle cell anaemia inherited?

A

Autosomal recessively.

64
Q

What percentage of the patients blood will be HbS in sickle cell anaemia?

A

HbS>80%.

65
Q

What occurs during sickle cell anaemia that causes illness?

A

Because of the shape of the RBC’s, they can’t flow through blood vessels normally. This can cause tissue hypoxia and damage causing severe pain.
You can also get chronic haemolysis- the abnormal red cells don’t flow normally so have a shortened lifespan.
You also get hyposplenism (the spleen gets constantly infarcted (because it has tiny vessels), meaning it becomes small).

66
Q

What things precipitate a sickle cell crisis?

A 
Hypoxia
Dehydration
Infection
Cold exposure
Stress/fatigue
67
Q

How do you treat sickle cell crisis?

A 
Opiate analgesia (its very painful)
Hydration
Rest
Oxygen
Antibiotics- if evidence of infection
Red cell exchange transfusion in severe crisis.
68
Q

What are the long term effects of sickle cell disease?

A

Impaired growth

Risk of end organ damage- pulmonary hypertension, renal disease, avascular necrosis, leg ulcers, stroke

69
Q

What is the long term management of hyposplenism?

A

Need to reduce the risk of infection- with prophylactic penicillin and vaccinations.

70
Q

What is the long term management of sickle cell disease?

A

Manage hypospenism
Folic acid supplementation- to increase red cell turnover
Hydroxycarbamide- induces HbF production

71
Q

Which investigations would you use to look for haemoglobinopathies?

A

High performance liquid chromatography
Gel electrophoresis
These will allow you to look for abnormal haemoglobin e.g. HbS, presence of high quantities of HbA2 (diagnostic of beta thalassaemia trait), HPLC will be normal in alpha thalassaemia so need DNA analysis.

Haematology (26 decks)

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