29. Haemoglobinopathies

Question 1

Describe the structure of haemoglobin

Answer 1

Tetrama i.e. four subunits - all fit together to hold one atom of ferrous iron each (haem groups)

Question 2

Why is the structure of haemoglobin so important that it is like this?

Answer 2

The holding of the four ferrous irons (haem groups) in this way means that oxygen can get close to the iron and be moved around the blood but is not close enough to react with and oxidise the iron

Question 3

How is oxygen released from the haemoglobin?

Answer 3

The low pH of tissues will cause the subunits of the haemoglobin to squeeze together an an O2 will pop off

Question 4

What are the haemoglobin subunits present in adults?

Answer 4

Two alpha globin
Two beta globin
a2B2

Question 5

Describe the genes that encode these subunits and their relevance

Answer 5

There are multiple gene for each subunits i.e. two genes for the alpha subunit on chromosome 16 and fve genes for the beta subunit on chromosome 11

A different mix of these genes will produce different forms of haemoglobin

Question 6

What is the first form of haemoglobin that is produced in humans and why?

Answer 6

Zeta Hb. is first produced in the first six weeks of gestation - contains two zeta subunits and two elipson subunits

This has a very high affinity for O2 and is confined to the yolk sac

Question 7

What is the main haemoglobin produced in the foetus?

Answer 7

Foetal haemoglobin replaces zeta haemoglobin - is produced in the liver and the spleen until 3-6 months following birth

Two alpha subunits and two gamma subunits

Question 8

When is adult haemoglobin produced and what is it’s structure?

Answer 8

Following the first 3-6 months of birth

Two alpha subunits and two beta subunits

Question 9

What are the different forms of haemoglobin that are present within an adult?

Answer 9

Adult haemoglobin - to functionally carry oxygen around to the respiring tissues
Small amounts of foetal haemoglobin
Small level of HBA2 in the blood too but unsure as to why or it’s function

Question 10

What is the structure of HBA2?

Answer 10

Two alpha subunits and two delta subunits

Question 11

What is Thalassaemia?

Answer 11

Genetic problem of the blood caused by inadequate quantities of one or other of the subunits making up haemoglobin

Question 12

What are the different types of thalassaemia?

Answer 12

Alpha thalassaemia

Beta thalassaemia

Question 13

Describe alpha thalassaemia and how it is caused

Answer 13

Can be minima, minor or major
Generally due to a deletion mutation
Mutation occurs to the genes coding for the alpha subunit on chromosome 16
The severity of this (minima, minor or major) is dependant on how many of the genes (4) are mutated)
If all four genes are mutated then life cannot be sustained - either stillborn or child will die very soon after birth

Question 14

What are the symptoms and presenting features of the different types of alpha thalassaemia?

Answer 14

One gene defective - no clinical signs or symptoms
Two genes defective - generaly asymptomatic but symptoms of iron deficiency anaemia are present
Three genes defective - presents as severe anaemia - patient has pallor and is fatigued
Four genes defective - cannot sustain life

Question 15

Describe beta thalassaemia and how it is caused

Answer 15

Due to mutated beta genes on chromosome 11
Generally due to a point mutation

Can be heterozygous - inherit only one mutated HbB gene and one functioning HbB gene or can be homozygous (beta thalassaemia major) where you inherit two copies of the mutated gene

Question 16

What is the effect of beta thalassaemia on HbA production and what does this result in?

Answer 16

Lack of production of HbB results in a lack of production of HbA
SO the patient will have microcytic anaemia

Question 17

What is the pathophysiological effect of beta thalassaemia?

Answer 17

There is a loss of synthesis of beta globins SO alpha tetramas form instead (four alpha globin structure)
These alpha tetramas are very unstable and less effective at carrying O2 - easily fall apart and stick to the inside of the erythrocyte membrane - often occurs within normoblasts in the liver
SO there is not just poor oxygen carrying capacity but also damage to the bone marrow production mechanism as dead cells multiply in the bone marrow and not enough O2 enters - erythropoiesis is reduced
The low HbA means that the patient also retains more HbF and HbA2

Question 18

What are the clinical effects of untreated beta thalassaemia?

Answer 18

Hypochromic, microcytic anaemia
Bone marrow expansion and splenomegaly due to intense marrow hyperplasia and haemopoiesis
Bone deformity and extramedullary erythropoetic masses (sticking of the ertythrocytes to the blood vessel wall)
Failure to thrive - failure of switching from foetal Hb. to adult Hb.
Heart failure and death by age 3/4

Question 19

What is the treatment for thalassaemia major? (alpha and beta)

Answer 19

Regular transfusions 
Iron chelation therapy - binds iron in the same way that ferritin does to prevent free iron 
Splenectomy 
Allogenic bone marrow transplant 
Possibly gene therapy in the future

Question 20

What is the risk of a patient having regular transfusions?

Answer 20

Can cause an iron overload - will lead to free iron in the blood and this can trigger unwanted reactions

Question 21

What is the main difference in the blood test/blood film between iron deficiency anaemia and thalassaemia?

Answer 21

Microcytic anaemia is more severe in thalassaemia - the erythrocyte MCV will be around 20 rather than 70

Question 22

What causes sickle cell disease?

Answer 22

Mutation of one of the beta haemoglobin genes causing erythrocytes to become sickle shaped
Mutation of glutamic acid to valine (GAG to GTG) and HbS is formed - 2 x a globin and 2 x Bs globin

Question 23

Describe the erythrocytes in sickle cell anaemia

Answer 23

Cells are sickle shaped - they precipitate and crystallise, causing the shape change
Cells are brittle and cannot pass through the capillaries smoothly - can clump within the capillary or can break open
Cells have a decreased survival time - leads to ischaemia of downstream organs

Question 24

What is haemolytic anaemia and why is it common in SCA?

Answer 24

Form of anaemia due to haemolysis - breakdown of erythrocytes
Because the cells do not bend as they go through the capillary as they should do and so they break

Question 25

Why does SCA commonly cause ischaemia?

Answer 25

They stick to the walls of the endothelium

This makes it harder for blood to pass through the capillaries

Question 26

What are the clinical consequences of SCA?

Answer 26

Anaemia
Increased rate of infection
Necrosis due to ischaemia
Retinopathy - the eye requires very high levels of blood

Question 27

How is SCA managed?

Answer 27

Infection prophylaxis
Transfusions for acute and chronic complications
Hydroxyurea increases HbF to overtake HbS and so reduces painful crises
Bone marrow transplantation

Question 28

What is the significance of having HbC?

Answer 28

This is a minor form of sickle cell anaemia

Question 29

What is the significance of having HbE?

Answer 29

A mutation in the beta chain - have mild beta thalassaemia