The Haemoglobin Molecule and Thalassaemia Flashcards
What is the role of red blood cells, what is it’s normal concentration and what does it contain
Carrys oxygen from lungs to tissue and CO2 from tissue to lungs
3.5-5 x 10^12/L
Contains haemoglobin
No nucleus
Where is haemoglobin found, what is its normal concentration and how much is produced/destroyed every day
Found only in RBCs
normal conc. = 120-165g/L
Approx 90mg/kg produced and destroyed in the body every day
Describe the structure of haemoglobin
4 polypeptide subunits of 2 alpha chains and 2 beta chains with a prosthetic haem group
4 haem+4 globin chains = 1 Hb molecule
Which organelles are involved in haemoglobin synthesis
haem - mitochondria
globin - ribosomes
Describe the structure of haem
Same in all types of Hb
Combination of protoporphyrin ring with central iron atom, usually in the ferrous form (Fe2+)
Able to reversibly bind to oxygen
Describe the synthesis of haem
Mainly in the mitochondria which contains the ALAS enzyme
more haem made = -ive feedback on enzyme activity
Iron is brought to the mitochondria (via transferrin) for haem synthesis
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.
Describe the global gene clusters
Eight functional globin chains, arranged in two clusters:
beta cluster (b, g, d and e globin genes) on the short arm of chromosome 11
alpha cluster (a x2 and z globin genes) on the short arm of chromosome 16
Describe the changes in location of RBC production in the foetus
Main site of RBC production at first is the yolk sac, then liver, then spleen
After birth, main production is the bone marrow
Describe the alteration of gene expression and globin production in the foetus
- zeta and epsilon globin chains immediately
- switch to alpha and gamma (3-6 months of life)
- Then alpha and beta
Little delta globin synthesis
How many alpha genes are there in total
There are 2 alpha globin genes from each parent so there are 4 alpha globin genes in total.
What makes up Hb A and what is the normal percentage
alpha2,beta2
96-98%
What makes up Hb A2 and what is the normal percentage
alpha2,delta2
1.5-3.2%
What makes up Hb F and what is the normal percentage
alpha2,g2
0.5-0.8%
Describe the secondary structure of globin
75% alpha and beta chains in helical arrangement
Structure varies with the no. of O2 molecules bound
With no or few O2 bound, Hb is in the ‘tight’ configuration and is stabilised by 2,3-BPG.
Describe the tertiary structure of globin
approx sphere
Hydrophilic surface (charged polar side chains) and a hydrophobic core
Haem pocket
Describe the oxygen-haemoglobin dissociation curve
Sigmoid shape
Binding of one molecule facilitate the second molecule binding (cooperativity)
What is P50 on the oxygen dissociation curve
Partial pressure of O2 at which Hb is half saturated with O2
26.6mmHg
What is the advantage of the cooperative binding of haemoglobin
Deoxyhaemoglobin (tight form) has a very low affinity for O2, so it will only pick it up when the pO2 is very high, like in the lungs, and it won’t take O2 away from metabolically active tissues that need it.
What does position of the Hb-oxygen dissociation curve depend on
Concentration of 2,3-DPG
H+ ion concentration (pH)
CO2 in red blood cells
Structure of Hb
What causes right shift on the oxygen-dissociation curve
High 2,3-DPG
High H+
High CO2
HbS
What causes left shift on the oxygen-dissociation curve
Low 2,3-DPG
Low H+
Low CO2
HbF
What are haemoglobinopathies
Structural variants of haemoglobin
or
Defects in globin chain synthesis (thalassaemia)
Define thalassaemia
Disorders in which there is a reduced production of one of the two types of globin chains in haemoglobin leading to an 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 most common type of mutation in alpha and beta thalassaemia
alpha - deletion
Beta - point mutation
Describe beta thalassaemia major
Severe defect in both β chains (beta0)
What are the clinical features of beta thalassaemia major in the first year of life and why may it be a problem in the first 2-3 months
Profound anemia
Failure to thrive
Malaise (general discomfort feeling)
Splenomegaly
Problem as there is a switch from HbF to HbA
Why does beta thalassaemia major cause splenomegaly
α chains form tetramers (α4), which precipitate in bone marrow causing ineffective erythropoiesis
If they do enter the circulation, the spleen removes them -> splenomegaly
Describe the inheritance of beta thalassaemia
Autosomal recessive
B0 = thal. major (both genes)
B+ = only one gene damaged
Carriers are aymsymptomatic but to have microcytic hypo chromic indicies
What investigations should be done for thalassaemia
FBC
Rilm
Hb EPS/HPLC
Globin chains synthesis/ DNA studies
What will show on the film for a beta thalassaemia major
Extreme hypochromia Microcytosis Poikilocytosis Tear drop cells + elliptical Howell jolly bodies
Which are the 2 major inclusion bodies seen in beta thalassaemia
Alpha globin precipitates Pappenheimer bodies (Perls stain - inky blue granules)
What are the clinical features of beta thalassaemia major
Splenomegaly Skeletal deformity (increased BM) Chronic fatigue Failure to thrive Jaundice Iron overload
What is the life expectancy of un-treated beta thalassaemia patients
Death at 7 years without transfusion
What is the life expectancy of treated (transfusion) beta thalassaemia patients and why
25
Iron overload -> liver cirrhosis, heart failure, diabetes, endocrine failure
potential viral transmission
What is the treatment for thalassaemia major
Regular blood transfusions Iron chelation therapy (Splenectomy Supportive medical care Hormone therapy Hydroxyurea to boost HbF Bone marrow transplant)
What are the types of iron chelation therapies
Deferasirox (Exjade)
Desferrioxamine (deferral)
Deferiprone (ferriprox)
What is the purpose of iron chelation therapy
Remove iron to prevent overload
Why is desferrioxamine not used as much as other iron chelation therapies
SC injected (not orally active)
Expensive
Compliance issues
Increased risk of Klebsiella and Yersinia infection
Describe Deferasirox (Exjade) (admin, dose)
Oral
Dose 20-40mg/kg
What are the unwanted effects of defarasirox
rash
GI symptoms
hepatitis
renal impairment
Describe deferiprone (admin and dose)
Oral
Dose 5-100 mg/kg/day
What is used to monitor iron overload
Serum ferritin
Liver iron
Hepatic and cardiac MRI
Describe HbE beta thalassaemia
Very common combo in south east Asia
Variable in expression - may be as severe as beta thalassaemia major
Describe beta thalassaemia trait
Little drop in Hb
May cause mild anaemia
high RBC, low MCV and MCH. In β-thalassaemia trait, haemoglobin electrophoresis will show a greater proportion of HbA2 (d chains not β).
Describe alpha thalassamia
Varying prognoses depending on how many chains are affected
2 or 3 - mild anaemia
1 - HnH formation + severe anaemia
0 - haemoglobin Barts - fatal in utero
What is the chance of HbBarts with 2 parents with only 2 alpha chains
25%
