4: Hb and thalassaemia

Question 1

When is Hb synthesised

Answer 1

During development of RBC

Mostly during erythroblast stage

Question 2

Where is haem + globin synthesised

Answer 2

Haem - in mitochondria

Globin - in ribosomes

Question 3

How is haemoglobin synthesised

Answer 3

• Iron transported to cell by transferrin
• Endocytosed -> transported to mitochondria where haem synthesis occurs
• Alpha/beta globin chains synthesised by ribosomes

Question 4

Describe the structure of haem

Answer 4

Protoporphyrin ring with central iron atom (ferroprotoporphyrin ring)
Central iron able to bind reversibly with oxygen

Question 5

What enzyme regulates haem synthesis

Answer 5

ALA synthase

Question 6

Describe the structure of globin

Answer 6

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

Question 7

Explain defects in globin gene expression pre/post-natally

Answer 7

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

Question 8

What is the most abundant type of adult haemoglobin

Answer 8

HbA = 2 alpha + 2 beta globin chains

96-98% of all haemoglobins

Question 9

What factors cause O2 disc. curve to shift to the left? What is the effect of this?

Answer 9

Low 2,3-DPG
High pH

Oxygen binds more avidly to haemoglobin, so LESS oxygen dissociation

Question 10

What factors cause O2 disc. curve to shift to right?

What is the effect of this?

Answer 10

High 2,3-DPG (released by respiring tissues)
High H+
High CO2 (from respiring tissues)
HbS

Oxygen dissociates more readily from Hb into tissues

Question 11

What is the geographical distribution of thalassaemia associated with?

Answer 11

Malaria

Hence higher prevalence in subsaharan africa, india, south east asia

Question 12

Which chromosomes code for which globin chains?

Answer 12

Chromosome 16 = alpha 1 & 2 + zeta

Chromosome 11 = beta gamma delta

Question 13

What is beta thalassaemia?

Answer 13

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

Question 14

What is the lab diagnosis of beta thalassaemia?

Answer 14

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

Question 15

Beta thalassaemia major

Answer 15

2 copies of mutant beta globin gene
SEVERE anaemia
Can’t survive without regular blood transfusions
Clinical presentation around 4-6 months from birth

Question 16

What features might you see on film of beta thalassaemia?

Answer 16

alpha chain precipitates
Pappenheimer bodies (due to excess iron)

Question 17

Clinical presentation of b thal major?

Answer 17

Severe anaemia after 4-6 months
Hepatosplenomegaly
Blood film shows gross hypochromia, poikilocytosis and nucleated RBCs
Hyperactive bone marrow (erythroid hyperplasia)
Extra-medullary haematopoiesis

Question 18

Clinical features of b thal major?

Answer 18

Jaundice
Chronic fatigue
Splenomegaly
Delay in growth/puberty
Iron overload

Question 19

Complications of b thal major?

Answer 19

Cholelithiasis and biliary sepsis
Cardiac failure
Endocrinopathies
Liver failure

Question 20

Major cause of death in beta thal. patients?

Answer 20

Cardiac disease

Question 21

Treatment for thal major

Answer 21

Regular blood transfusions
Iron chelation therapy
Possible splenectomy/bone marrow transplant

Question 22

What are the properties of transfusion blood?

Answer 22

Phenotyped red cells (as similar to patient’s RBC as possible)
Pre-transfusion Hb 95-100g/L
2-4 weekly

Question 23

Why are thalassaemia patients prone to infection? Give an example of a common infection

Answer 23

Some organisms thrive on iron, which will be in excess in thalassaemia patients

Yersinia is an example of this

Question 24

When do you start iron chelation therapy?

Answer 24

After 10-12 transfusions

Question 25

What iron chelators can we use? State some side effects

Answer 25

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

Question 26

How do you monitor iron overload?

Answer 26

R2 MRI scan (Ferriscan) - non-invasive quantitation of liver iron conc.
Not affected by inflammation/cirrhosis
<3mg = normal

Question 27

How is severity of alpha thalassaemia determined

Answer 27

Severity depends on number of alpha globin genes affected.

Question 28

What would you see on HPLC of alpha thalassaemia

Answer 28

Tetramers and dimers of excess beta globin chains

Question 29

Screening in the UK?

Answer 29

All women screened antenatally for haemoglobin disorders