The Haemoglobin Molecule and Thalassemia Flashcards
What are the different types of globin proteins?
Alpha, Beta, Gamma, Delta (and embryonic)
State the three different haemoglobins that are present in the human body.
HbA – alpha + beta = 95%
HbA2 – alpha + delta = 1-3.5%
HbF – alpha + gamma = trace
Describe how affinity of haemoglobin changes with oxygen binding and how this helps its role of oxygen transport.
The more oxygen binds, the greater the affinity of the haemoglobin for oxygen.
This is good because if deoxyhaemoglobin has a low affinity for oxygen(as no oxygen is already bound), it will only pick up oxygen if the oxygen saturation is very high (i.e. in the lungs) so it will not take up oxygen in the metabolically active tissues where the oxygen saturation is low and where the tissues need oxygen.
Similarly, oxyhaemoglobin has a high affinity for oxygen so it will only give up oxygen in environments where the oxygen saturation is very low (i.e. respiring tissues that need oxygen)
What effect does 2,3-DPG have on oxygen delivery?
It facilitates oxygen delivery by making the haemoglobin molecule less flexible and pushing out the oxygen.
State 3 factors that can shift the oxygen dissociation curve to the right.
Increase in 2,3-DPG
Increase in [H+]
CO2
What effect do HbS and HbF have on the oxygen dissociation curve?
HbS has a lower affinity for oxygen than HbA so it shifts the ODC to the right
HbF has a higher affinity for oxygen than HbA so it shifts the ODC to the left
What is special about alpha globin genes?
There are TWO alpha globin genes from each parent so there are FOUR alpha globin genes in total.
Which globin chains are present in early embryonic life but are switched off after about 3 months gestation?
Zeta and epsilon
Which globins are present in foetal haemoglobin?
Alpha
Gamma
When are the genes coding for the globin in foetal haemoglobin switched off?
It is decreased towards birth and in the first year after birth.
After 1 year of life, the normal adult pattern of haemoglobin synthesis would have been established.
Which globin chains are present in HbA2?
Alpha
Delta
On which chromosomes are the two globin gene clusters and which genes are present in each cluster?
Chromosome 16 – ALPHA cluster TWO alpha genes Zeta gene Chromosome 11 – BETA cluster Beta gene Gamma gene Delta gene Epsilon gene
What is thalassemia?
Disorders in which there is a reduced production of one of the two types of globin chains in haemoglobin leading to imbalanced globin chain synthesis
What are the two clinical variations of thalassemia?
Thalassemia trait = common variant with little clinical significance
Transfusion dependent – Thalassemia Major = fatal without transfusion
What is the outcome of alpha thalassemia major?
Fatal in utero because alpha globin is needed to make HbF (alpha + gamma)
What is the outcome of beta thalassemia major?
Diagnosed and treated in early infancy with regular transfusions
What is the name given to the loss of function of three alpha globin genes?
Haemoglobin H
Need life-long transfusions
What is the name given to the loss of function of four alpha globin genes?
Haemoglobin barts
Fatal in utero because alpha globin is needed to make HbF
What is beta thalassemia major? Describe how the disease progresses.
Severe defect in both beta globin chains
The foetus will have no problem in utero because they have normal functioning HbF (which doesn’t need beta globin)
At around 2-3 month after birth, you get a transition from HbF to HbA
At this time the baby will become profoundly anaemic.
They will need life-long transfusions from this point onwards.
State some features of thalassemia trait.
This the carrier state of thalassemia.
They may be mildly anaemic but they can also be normal.
Usually have a LOW MCH and LOW MCV
What can be used to distinguish between alpha thalassemia trait and beta thalassemia trait?
Haemoglobin electrophoresis can be used to measure the relative proportions of HbA2
Beta Thalassemia = raised HbA2 (> 3.5%)
Alpha Thalassemia = normal/low HbA2
What types of mutation cause alpha thalassemia and beta thalassemia?
Alpha thalassemia – deletion
Beta thalassemia – point mutation
What is alpha + thalassemia?
The situation in which one of the two globin genes on a chromosome are deleted (this can happen on one or both chromosomes)
Someone who is heterozygous for alpha+ thalassemia will still have 3 functioning alpha globin genes so they will only be mildly anaemic
What is alpha 0 thalassemia?
The situation in which both of the two globin genes on a chromosome are deleted (this can happen in one or both chromosomes)
In the heterozygous state there are still 2 functioning alpha globin genes so they will also only experience mild anaemia
How can you distinguish between alpha + and alpha 0 thalassemia?
Most people with alpha 0 thalassemia have a MCH < 25 pg
What could be the potentially devastating consequences for someone with mild anaemia caused by alpha 0 thalassemia?
Someone with alpha 0 thalassemia may not experience any symptoms themselves, but if they try and have a child with someone who also has alpha 0 thalassemia then there is a chance that their child may not have any functioning alpha genes (haemoglobin barts).
Which ethnic groups have a high prevalence of thalassemia?
Chinese South-east Asian Greek Turkish Cypriot
What is beta + thalassemia?
There is a reduction in beta globin output but there is still some residual beta globin gene expression
What is beta 0 thalassemia?
There is NO output of beta globin
What is the main cause of the pathophysiology of beta thalassemia?
The surplus of alpha globin chains form tetramers.
These alpha globin tetramers precipitate in the bone marrow, which leads to ineffective erythropoiesis and haemolysis in the peripheralcirculation.
What are the features of beta thalassemia trait?
Haemoglobin may be normal LOW MCV
LOW MCH
HIGH RBC
HbA2 INCREASED
What are the symptoms of beta thalassemia major that are present in the first year of life?
Profound anaemia
Failure to thrive
Malaise
Splenomegaly
Describe the pathogenesis of beta thalassemia.
There is death of red cells in the marrow because of ineffective erythropoiesis
The removal of red cells by the spleen causes:
Large spleen
Anaemia
Increased EPO
Expansion of bone marrow
What are the consequences of regular blood transfusions used to treat beta thalassemia major?
Iron Overload
Iron can accumulate in the liver (cirrhosis), heart (cardiac failure), endocrine organs (hypopituitarism, hypothyroidism, diabetes) etc.
Potential viral transmission
Name three drugs that can be used to treat iron overload. List anynegative aspects of these drugs.
Desferrioxamine (DFO)
Not orally active – must be given via subcutaneous infusion
Expensive
Deferiprone
Urinary excretion
Risk of agranulocytosis (which can lead to life-threatening sepsis)
Patients need to be monitored closely for neutropenia
Deferasirox
Faecal excretion
What are the key indicators of iron overload?
Serum ferritin
Liver iron
What are the good aspects of stem cell transplantation?
No transfusions
No chelation
Growth is normal
Curative treatment
What are the bad aspects of stem cell transplantation?
Transplant associated mortality is high over the age of 17 (30%)
Relatively few transplants done in adults
Infertility due to stem cell transplant
If the patient is iron overloaded at the time of transplantation there is a massively increased risk
