Haemoglobin molecule and thalassaemia Flashcards
What does haemoglobin consist of?
Four haem groups and four globin chains
What is each haem group bound to?
Fe2+
How many oxygen molecules can each haemoglobin molecule bind?
4
What are the four types of globin proteins?
Alpha
Beta
Gamma
Delta
What is the most common for of haemoglobin (95) and what is it comprised of?
HbA= alpha2 beta2
What is HbA2 comprised of?
Alpha2 delta2 (1-3.5%)
What is HbF comprised of?
Alpha2 gamma2 (trace)
How would affinity differ between a haemoglobin molecule with 3 oxygens and a haemoglobin molecule with 1 oxygen?
The one with 3 is in a relaxed form so would have a higher affinity
What does it mean that a haemoglobin molecule with no oxygen has a low affinity?
It will only take up oxygen if the saturation is very high (lungs) and not in metabolically active tissues
How does the high affinity of oxyhaemoglobin have an effect?
It will not release oxygen easily, only in tissues when there is no oxygen around
What happens when you are in the tight configuration (deoxyhaemoglobin)?
You have a molecule called 2,3-DPG which forms extra bond and makes the molecules less flexible
What is the shape of the oxygen dissociation curve?
Sigmoid- low affinity when oxygen is low and high affinity when high pressure
In which direction do things that stabilise the deoxyhaemoglobin molecule and decrease its affinity shift the curve?
To the right
Which three things shift the curve to the right?
H+ ions
2,3-DPG
CO2 (Bohr effect)
How many alpha globin genes are there from each parent?
2
What type of alpha gene is expressed more than the other?
Alpha 2
When is the expression of embryonic haemoglobin switched off?
After about 3 months gestation
What is embryonic haemoglobin replaced by?
Foetal haemoglobin- consists of alpha and gamma globins
When is foetal haemoglobin switched off?
Gradually upto birth and in first year of life
What is foetal haemoglobin replaced reciprocally by?
Increase in beta globin gene expression
When is the normal adult pattern of haemoglobin synthesis normally established?
One year of life
Where are the two alpha genes found?
Chromosome 16
Where are beta, gamma and delta genes found?
Chromosome 11
How are these genes found?
In clusters in the order that they are expressed
What are thalassemias?
Disorders in which there is reduced production of one of the two types of globin chains in haemoglobin leaving to imbalanced globin chain synthesis
What percentage of the world population is expected to be carriers for thalassemia?
5%
What is thalassemia major?
When the patient is transfusion dependent
What is thalassemia trait?
Common variant with no clinical significance
What type of thalassemia major is fatal in utero and why?
Alpha because it is needed in foetal life to produce HbF
What is severe alpha thalassemia?
Severe defect in three or four alpha genes
What is haemoglobin called with three alphas missing?
Haemoglobin H- needs lifelong transfusions
What is haemoglobin called with four alphas missing?
Haemoglobin Barts- fatal
What is beta thalassemia major?
Severe defect in both beta chains
When do you first notice anaemia due to beta thalassemia major?
At 2-3 months when there is a transition from HbF to HbA, the baby will become profoundly anaemic
What is someone with thalassemia trait like?
Carrier state- mildly anaemic but can be normal
Low MCV and low MCH
What will haemoglobin electrophoresis show in someone with beta thalassemia trait?
A rise in HbA2 relative to HbA
How can you differentiate between different types of thalassemia trait?
HbA2
Alpha thalassemia trait= normal or low HbA2
Beta thalassemia trait= high HbA2
What happens if you have a gene abnormality resulting in loss of start signal?
No transcription
What happens if you have a gene abnormality resulting in mRNA becoming unstable?
No translation
What gene mutation generally causes alpha thalassemia?
Deletion of one or more of the alpha globin genes on a chromosome
What gene mutation generally causes beta thalassemia?
Point mutations
When is alpha thalassemia clinically significant?
If 3 or 4 of the alpha genes are not functioning
What does alpha+ thalassemia refer to?
The situation in which one of the two genes on a chromosome is deleted
Only experience mild anaemia
What does alpha 0 thalassemia refer to?
Both alpha globin genes on a chromosome are deleted
Only mild anaemia
How can you differentiate between alpha+ and alpha 0?
Vast number of carriers of alpha 0 thalassemia have an MCH < 25
Why can a couple who both have alpha 0 thalassemia have potentially devastating consequences?
Risk of child with Haemoglobin Barts
When is antenatal screening provided?
When the pregnant lady has two alphas missing
What ethnicities is alpha 0 thalassemia common in?
Chinese South-east asian Greek Turkish Cypriot
What is the pathophysiology of beta thalassemia mainly due to?
Surplus of alpha globin chains that form tetramers
What do the alpha globin tetramers do?
They precipitate in the bone marrow which leads to ineffective erythropoiesis and haemolysis in the peripheral circulation
How does someone with beta thalassemia trait present?
Haemoglobin normal MCV low MCH low Red cell count increased HbA2 increased- electrophoresis
What symptoms are present in first year of life with thalassemia major (beta)?
Profound anaemia
Fail to thrive
Malaise
Splenomegaly
What is the pathogenesis of beta thalassemia?
Death of red cells in marrow Ineffective erythropoiesis Removal of red cells by the spleen Large spleen Anaemia Increased erythropoietin Expansion of bone marrow
Blood transfusions are vital for patients with thalassemia major but what is a serious complication?
Iron overload (and viral transmission)
What is the effect of iron overload?
It accumulates in the liver causing cirrhosis and in the endocrine glands causing:
Diabetes (pancreas)
Hypogonadism (pituitary)
Hypothyroidism (thyroid)
How do you manage iron overload?
Remove with desferrioxamine- an iron chelator
What are the problems with desferrioxamine?
Not orally active and requires subcutaneous injection
Expensive
What examples of oral iron chelators are there?
Deferipone and deferasirox
How does deferipone get rid of iron?
Urinary excretion
What are the problems with deferipone?
Risk of agranulocytosis
Life threatening sepsis
How does deferasirox get rid of iron?
Faecal excretion
What are the key indicators of iron overload?
Serum ferritin
Liver iron
Reduced cardiac iron
What else is available as treatment for thalassemia major?
Stem cell transplantation
What are the positives for stem cell transplantation?
No transfusions
No desferrioxamine (chelator)
Growth is normal
This is a curative treatment
What are the negatives for stem cell transplantation?
Transplant associated mortality
Relatively few transplants are done
Infertility due to stem cell transplant
