Haemoglobin molecule and thalassaemia

Question 1

What does haemoglobin consist of?

Answer 1

Four haem groups and four globin chains

Question 2

What is each haem group bound to?

Answer 2

Fe2+

Question 3

How many oxygen molecules can each haemoglobin molecule bind?

Answer 3

4

Question 4

What are the four types of globin proteins?

Answer 4

Alpha
Beta
Gamma
Delta

Question 5

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

Answer 5

HbA= alpha2 beta2

Question 6

What is HbA2 comprised of?

Answer 6

Alpha2 delta2 (1-3.5%)

Question 7

What is HbF comprised of?

Answer 7

Alpha2 gamma2 (trace)

Question 8

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

Answer 8

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

Question 9

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

Answer 9

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

Question 10

How does the high affinity of oxyhaemoglobin have an effect?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

What is the shape of the oxygen dissociation curve?

Answer 12

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

Question 13

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

Answer 13

To the right

Question 14

Which three things shift the curve to the right?

Answer 14

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

Question 15

How many alpha globin genes are there from each parent?

Answer 15

2

Question 16

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

Answer 16

Alpha 2

Question 17

When is the expression of embryonic haemoglobin switched off?

Answer 17

After about 3 months gestation

Question 18

What is embryonic haemoglobin replaced by?

Answer 18

Foetal haemoglobin- consists of alpha and gamma globins

Question 19

When is foetal haemoglobin switched off?

Answer 19

Gradually upto birth and in first year of life

Question 20

What is foetal haemoglobin replaced reciprocally by?

Answer 20

Increase in beta globin gene expression

Question 21

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

Answer 21

One year of life

Question 22

Where are the two alpha genes found?

Answer 22

Chromosome 16

Question 23

Where are beta, gamma and delta genes found?

Answer 23

Chromosome 11

Question 24

How are these genes found?

Answer 24

In clusters in the order that they are expressed

Question 25

What are thalassemias?

Answer 25

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

Question 26

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

Answer 26

5%

Question 27

What is thalassemia major?

Answer 27

When the patient is transfusion dependent

Question 28

What is thalassemia trait?

Answer 28

Common variant with no clinical significance

Question 29

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

Answer 29

Alpha because it is needed in foetal life to produce HbF

Question 30

What is severe alpha thalassemia?

Answer 30

Severe defect in three or four alpha genes

Question 31

What is haemoglobin called with three alphas missing?

Answer 31

Haemoglobin H- needs lifelong transfusions

Question 32

What is haemoglobin called with four alphas missing?

Answer 32

Haemoglobin Barts- fatal

Question 33

What is beta thalassemia major?

Answer 33

Severe defect in both beta chains

Question 34

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

Answer 34

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

Question 35

What is someone with thalassemia trait like?

Answer 35

Carrier state- mildly anaemic but can be normal | Low MCV and low MCH

Question 36

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

Answer 36

A rise in HbA2 relative to HbA

Question 37

How can you differentiate between different types of thalassemia trait?

Answer 37

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

Question 38

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

Answer 38

No transcription

Question 39

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

Answer 39

No translation

Question 40

What gene mutation generally causes alpha thalassemia?

Answer 40

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

Question 41

What gene mutation generally causes beta thalassemia?

Answer 41

Point mutations

Question 42

When is alpha thalassemia clinically significant?

Answer 42

If 3 or 4 of the alpha genes are not functioning

Question 43

What does alpha+ thalassemia refer to?

Answer 43

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

Question 44

What does alpha 0 thalassemia refer to?

Answer 44

Both alpha globin genes on a chromosome are deleted | Only mild anaemia

Question 45

How can you differentiate between alpha+ and alpha 0?

Answer 45

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

Question 46

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

Answer 46

Risk of child with Haemoglobin Barts

Question 47

When is antenatal screening provided?

Answer 47

When the pregnant lady has two alphas missing

Question 48

What ethnicities is alpha 0 thalassemia common in?

Answer 48

``` Chinese South-east asian Greek Turkish Cypriot ```

Question 49

What is the pathophysiology of beta thalassemia mainly due to?

Answer 49

Surplus of alpha globin chains that form tetramers

Question 50

What do the alpha globin tetramers do?

Answer 50

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

Question 51

How does someone with beta thalassemia trait present?

Answer 51

``` Haemoglobin normal MCV low MCH low Red cell count increased HbA2 increased- electrophoresis ```

Question 52

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

Answer 52

Profound anaemia Fail to thrive Malaise Splenomegaly

Question 53

What is the pathogenesis of beta thalassemia?

Answer 53

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

Question 54

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

Answer 54

Iron overload (and viral transmission)

Question 55

What is the effect of iron overload?

Answer 55

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

Question 56

How do you manage iron overload?

Answer 56

Remove with desferrioxamine- an iron chelator

Question 57

What are the problems with desferrioxamine?

Answer 57

Not orally active and requires subcutaneous injection | Expensive

Question 58

What examples of oral iron chelators are there?

Answer 58

Deferipone and deferasirox

Question 59

How does deferipone get rid of iron?

Answer 59

Urinary excretion

Question 60

What are the problems with deferipone?

Answer 60

Risk of agranulocytosis | Life threatening sepsis

Question 61

How does deferasirox get rid of iron?

Answer 61

Faecal excretion

Question 62

What are the key indicators of iron overload?

Answer 62

Serum ferritin Liver iron Reduced cardiac iron

Question 63

What else is available as treatment for thalassemia major?

Answer 63

Stem cell transplantation

Question 64

What are the positives for stem cell transplantation?

Answer 64

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

Question 65

What are the negatives for stem cell transplantation?

Answer 65

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