4: Hb and thalassaemia Flashcards
When is Hb synthesised
During development of RBC
Mostly during erythroblast stage
Where is haem + globin synthesised
Haem - in mitochondria
Globin - in ribosomes
How is haemoglobin synthesised
- Iron transported to cell by transferrin
- Endocytosed -> transported to mitochondria where haem synthesis occurs
- Alpha/beta globin chains synthesised by ribosomes
Describe the structure of haem
Protoporphyrin ring with central iron atom (ferroprotoporphyrin ring)
Central iron able to bind reversibly with oxygen
What enzyme regulates haem synthesis
ALA synthase
Describe the structure of globin
8 functional globin chains arranged into 2 clusters
alpha cluster (alpha globin) beta cluster (beta gamma delta globin)
Tertiary structure: Approximate sphere, hydrophilic surface, hydrophobic core, haem pockets
Explain defects in globin gene expression pre/post-natally
Alpha globin starts to be expressed very early in the embryo (first few weeks), so defect will lead to very early death
Beta globin starts being produced around 3-6 months after giving birth so defects can be identified and managed before it becomes fatal
What is the most abundant type of adult haemoglobin
HbA = 2 alpha + 2 beta globin chains
96-98% of all haemoglobins
What factors cause O2 disc. curve to shift to the left? What is the effect of this?
Low 2,3-DPG
High pH
Oxygen binds more avidly to haemoglobin, so LESS oxygen dissociation
What factors cause O2 disc. curve to shift to right?
What is the effect of this?
High 2,3-DPG (released by respiring tissues)
High H+
High CO2 (from respiring tissues)
HbS
Oxygen dissociates more readily from Hb into tissues
What is the geographical distribution of thalassaemia associated with?
Malaria
Hence higher prevalence in subsaharan africa, india, south east asia
Which chromosomes code for which globin chains?
Chromosome 16 = alpha 1 & 2 + zeta
Chromosome 11 = beta gamma delta
What is beta thalassaemia?
Autosomal RECESSIVE inherited blood disorder
Deletion or mutation in beta globin genes
Reduced/absent production of beta globins
Prevalence in mediterranean countries, africa, india, south-east asia
What is the lab diagnosis of beta thalassaemia?
Full blood count - Microcytic Hypochromic red cells, increased RBCs relative to Hb, Low MCV + MCH
Film - Target cells, poikilocytosis but no anisocytosis
Hb electrophoresis/HPLC - Raised HbA2 (2a2d)
DNA studies - Genetic analysis for mutations on beta globin genes
Beta thalassaemia major
2 copies of mutant beta globin gene
SEVERE anaemia
Can’t survive without regular blood transfusions
Clinical presentation around 4-6 months from birth
What features might you see on film of beta thalassaemia?
alpha chain precipitates Pappenheimer bodies (due to excess iron)
Clinical presentation of b thal major?
Severe anaemia after 4-6 months
Hepatosplenomegaly
Blood film shows gross hypochromia, poikilocytosis and nucleated RBCs
Hyperactive bone marrow (erythroid hyperplasia)
Extra-medullary haematopoiesis
Clinical features of b thal major?
Jaundice Chronic fatigue Splenomegaly Delay in growth/puberty Iron overload
Complications of b thal major?
Cholelithiasis and biliary sepsis
Cardiac failure
Endocrinopathies
Liver failure
Major cause of death in beta thal. patients?
Cardiac disease
Treatment for thal major
Regular blood transfusions
Iron chelation therapy
Possible splenectomy/bone marrow transplant
What are the properties of transfusion blood?
Phenotyped red cells (as similar to patient’s RBC as possible)
Pre-transfusion Hb 95-100g/L
2-4 weekly
Why are thalassaemia patients prone to infection? Give an example of a common infection
Some organisms thrive on iron, which will be in excess in thalassaemia patients
Yersinia is an example of this
When do you start iron chelation therapy?
After 10-12 transfusions
What iron chelators can we use? State some side effects
Deferasirox (oral) - more recent
SE: GI symptoms, hepatitis, renal impairment
Hence can’t use in some patients
DFO (sc infusion, iv in iron overload) - long-established
SE: retinopathy, sensorineural hearing loss
Deferiprone (oral) - effective for CARDIAC iron overload
SE: hepatic impairment
How do you monitor iron overload?
R2 MRI scan (Ferriscan) - non-invasive quantitation of liver iron conc.
Not affected by inflammation/cirrhosis
<3mg = normal
How is severity of alpha thalassaemia determined
Severity depends on number of alpha globin genes affected.
What would you see on HPLC of alpha thalassaemia
Tetramers and dimers of excess beta globin chains
Screening in the UK?
All women screened antenatally for haemoglobin disorders
