The Haemoglobin Molecule and Thalassemia Flashcards
State the 3 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 O2 binds, the greater the affinity of the Hb for O2.
Beneficial because if deoxyHb has low affinity for O2 (as no O2 is already bound), it will only pick up O2 if O2 sat. is very high (i.e. lungs) so won’t take up O2 in metabolically active tissues where O2 sat. is low + where tissues need O2.
Similarly, oxyHb has a high affinity for O2 so will only give up O2 in environments where the O2 sat. is very low (i.e. respiring tissues that need O2)
State 2 factors that can shift the oxygen dissociation curve to the left and what this means
Gives up O2 less readily
Low 2,3-DPG
Increased pH
State 3 factors that can shift the oxygen dissociation curve to the right and what this means
Gives up O2 more readily
High 2,3-DPG
High [H+]
High CO2
What effect do HbS and HbF have on the oxygen dissociation curve?
HbS has a lower affinity for O2 than HbA so it shifts the ODC right
HbF has a higher affinity for O2 than HbA so it shifts the ODC left
Which globin chains are present in early embryonic life but are switched off after about 3 months gestation?
Zeta
Epsilon
Which globins are present in foetal haemoglobin?
Alpha
Gamma
When are the genes coding for the globin in foetal haemoglobin switched off?
Decreased towards birth + in 1st year after birth.
After 1 year of life, normal adult pattern of Hb synthesis is established.
On which chromosomes are the 2 globin gene clusters and which genes are present in each cluster?
Chromosome 16: ALPHA cluster 2 alpha genes Zeta gene Chromosome 11: BETA cluster Beta gene Gamma gene Delta gene Epsilon gene
What is thalassemia?
Genetic disorders characterised by a defect in globin chain synthesis (alpha or beta)
What are the 2 clinical variations of thalassemia?
Trait (minor)= carrier state, usually asymptomatic (Intermedia= spectrum of phenotypes) Transfusion dependent (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 + treated in early infancy with regular transfusions
What is the name given to the loss of function of 3 alpha globin genes?
Haemoglobin H
Need life-long transfusions
What is the name given to the loss of function of 4 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 (doesn’t need beta globin)
At 2-3 month after birth, there is transition from HbF to HbA
Here, baby becomes profoundly anaemic.
Need life-long transfusions from this point.
State the classic features of an FBC of a patient with thalassemia
Microcytic hypochromic blood picture in absence of iron deficiency
Increased RBCs relative to Hb
What can be used to distinguish between alpha thalassemia trait and beta thalassemia trait?
Haemoglobin electrophoresis can be used to measure relative proportions of HbA2
Beta = raised HbA2 (> 3.5%) + raised HbF
Alpha = normal HbA2 + normal HbF
Why does the distribution of thalassaemia correlate with M. falciparum distribution?
Thalassaemias offer protection against malaria
Make it harder for parasite to enter RBC
What is beta + thalassemia?
Reduction in beta globin output but there is still some residual beta globin gene expression
What is beta 0 thalassemia?
NO output of beta globin
What are the clinical presentations of beta thalassemia major that are present in the first year of life?
Profound anaemia
Hepatosplenomegaly (due to extra medullary haematopoiesis)
Blood film shows gross hypochromia, poikilocytosis + NRBC’s
Erythroid hyperplasia (BM trying to increase output)
List 7 clinical features of beta thalassemia.
Chronic fatigue Failure to thrive Jaundice Delay in growth Skeletal deformity Splenomegaly Iron overload
List 4 complications that arise in beta thalassemia major due to iron overload
Liver failure
Cardiac failure
Endocrinopathies
Cholelithiasis + biliary sepsis
Name 3 drugs that can be used as iron chelators. List any negative aspects of these drugs.
Desferrioxamine (DFO)
Must be given via subcutaneous infusion + Expensive
Deferiprone: Urinary excretion
Deferasirox: Faecal excretion
What are the 4 methods of monitoring iron overload?
Serum ferritin
Liver biopsy
T2 cardiac + hepatic MRI
Ferriscan- R2 MRI
What are 4 good aspects of stem cell transplantation?
No transfusions
No chelation
Growth is normal
Curative treatment
What are 4 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
When is haemoglobin synthesised?
65% erythroblast stage
35% reticulocyte stage
Where are the 2 components of Hb synthesised?
Haem= Mitochondria Globin= Ribosomes
Which enzyme is involved in the manufacture of Haem? How?
Delta-ALA
When excess haem is produced, it exerts a negative feedback on this enzyme + synthesis of haem is reduced
What is haem composed of?
Protoporphyrin ring with central iron atom
What technique can be used to separate different Haemaglobins based on their charge and molecular mass?
High performance liquid chromatography (HPLC)
Describe the primary, secondary and tertiary structure of globin
Primary: alpha= 141 AA’s, non-alpha= 146 AA’s
Secondary: 75% A + B chains helical arrangement
Tertiary: ~Sphere, hydrophilic surface, haem pocket
Describe the shape of the oxygen-haemoglobin dissociation curve. What is p50?
Sigmoid shape
P50= pO2 at which half Hb is saturated with O2 ~26.6mmHg
What are the 2 types of haemoglobinopathy?
Structural variants of Hb being produced e.g. HbS
Defects in globin chain synthesis (Thalassaemia)
What causes B thalassaemia?
Point mutation in B globin gene
Results in reduced or absent production of B globin chains
Describe 3 features on a blood film seen in thalassaemia
Hypochromia
Target cells
Poikilocytosis
What is the only reliable way of diagnosing alpha thalassaemias?
DNA analysis
List 7 treatment options for thalassaemia major
Regular blood transfusions Iron chelation therapy Splenectomy Supportive medical care Hormone therapy Hydroxyurea to boost HbF BM transplant
What is required in splenectomised patients? Why?
Prophylaxis (immunisation + antibiotics)
More susceptible to infection, particularly from encapsulated bacteria
List 4 side effects of deferasirox
Rash
GI symptoms
Hepatitis
Renal impairment
List 4 side effects of Desferrioxamine
Vertebral dysplasia
Pseudo-rickets
Retinopathy
High tone sensorineural loss
List 4 side effects of Deferiprone
GI disturbance
Hepatic impairment
Neutropenia
Agranulocytosis
What is the best way of prescribing iron chelators?
Combination therapy- reducing dose of individual drugs, thus reducing side effects
