Haemoglobinopathies

Question 1

What are the major forms of haemaglobin?

Answer 1

HbA (2 alpha and 2 beta)
HbA2 (2 alpha and 2 delta)
HbF (2 alpha and 2 gamma)

Question 2

What are the proportions of each form of haemaglobin in adults?

Answer 2

HbA = 97% 
HbA2 = 2.5% 
HbF = 0-0.5%

Question 3

What chromosome codes for alpha globin genes and how many are present?

Answer 3

Chromosome 16

2 alpha genes per chromosome (4 per cell)

Question 4

What chromosome codes for beta globulin genes and how many are present?

Answer 4

Chromosome 11

One beta gene per chromosome (2 per cell)

Question 5

At what point are adult levels of Hb reached in a child?

Answer 5

6-12 months - this is when beta chain problems will present

Question 6

What are haemoglobinopathies?

Answer 6

Hereditary conditions affecting globin chain synthesis

Question 7

What inheritance do haemoglobinopathies show?

Answer 7

AR

Question 8

What are the 2 main groups of haemoglobinopathies?

Answer 8

Thalassaemias; decreased rate of globin chain synthesis

Structural haemaglobin variants; normal production of abnormal globin chain (variant haemaglobin e.g. HbS)

Question 9

What are the different forms of thalassaemias?

Answer 9

Alpha

Beta

Question 10

On FBC, how will thalassaemias present?

Answer 10

Microcytic, hypochromic anaemia with a normal ferritin

Question 11

What are the consequences of thalassaemias?

Answer 11

Inadequate Hb production
Haemolysis
Ineffective erythropoiesis

Question 12

What forms of Hb will be affected in alpha thalassaemia?

Answer 12

ALL forms; HbA, HbA2 and HbF

Question 13

How are alpha thalassaemia’s classified?

Answer 13

Based on the number of alpha genes affected

Question 14

What is alpha thal trait?

Answer 14

One or two alpha genes missing

Question 15

What is HbH disease?

Answer 15

Only one alpha gene left out of 4

Question 16

What is Hb Barts hydrops foetalis?

Answer 16

No functional alpha genes; tends to die in utero

Question 17

Will people with alpha thalassaemia trait be symptomatic?

Answer 17

No; no treatment needed
Microcytic, hypochromic red cells with mild anaemia may be seen
Need to distinguish from iron deficiency (ferritin normal)

Question 18

How will HbH disease present?

Answer 18

Anaemia with a very low MCV and MCH
Jaundice
Splenomegaly

Question 19

What will HbH look like on a blood film?

Answer 19

Excess beta chains will form tetramers; HbH

Red cell inclusions of HbH can be seen with special stains

Question 20

Does HbH disease require treatment?

Answer 20

May require transfusions

Question 21

What is Hb Barts?

Answer 21

Tetramers of gamma Hb produced

Question 22

How can Hb Bart’s Hydrops Foetalis Syndrome be avoided?

Answer 22

Antenatal screening

Question 23

What are the clinical features of Hb Bart’s Hydrops Foetalis Syndrome?

Answer 23

Profound anaemia 
Cardiac failure 
Growth retardation
Severe hepatosplenomegaly 
Skeletal and CV abnormalities
Almost all die in utero
May see nucleated red cells due to ineffective marrow funciton

Question 24

By what genetic mechanism is beta thalassaemia caused?

Answer 24

Point mutations
Reduced beta or absent beta chain production depending on mutation
Only beta chains and hence only HbA affected

Question 25

How is beta thalassaemia classified?

Answer 25

Clinical severity

Question 26

Describe beta thalassaemia trait?

Answer 26

Asymptomatic, no/mild anaemia, low MCV/ MCH | Raised HbA2

Question 27

What is the diagnostic test for beta thalassaemia?

Answer 27

Raised HbA2 (alpha and delta chained Hb)

Question 28

Describe beta thalassaemia intermedia?

Answer 28

Moderate severity requiring occasional transfusion (similar to HbH)

Question 29

Describe beta thalassaemia major?

Answer 29

Severe, lifelong transfusion dependency

Question 30

When will beta thal major present?

Answer 30

6-24 months as HbF fallls Pallor, failure to thrive Extramedullary haematopoiesis

Question 31

What will beta thal major show on Hb analysis?

Answer 31

Mainly HbF | No HbA

Question 32

What are the signs of extramedullary haematopoiesis?

Answer 32

Hepatosplenomegaly Frontal bossing "Hair on end" appearance to skull Spinal cord compression

Question 33

What is the management of beta thal major?

Answer 33

Regular transfusion programme to maintain Hb at 95-105 g/L (suppresses ineffective erythropoiesis and inhibits over-absorption of iron)

Question 34

What does regular blood transfusions allow for in beta thal major?

Answer 34

Normal growth and development Iron overload from transfusion then becomes the main cause of mortality Bone marrow transplant may be an option if carried out before complications develop

Question 35

What are the consequences for iron overload?

Answer 35

Endocrine; impaired growth and pubertal development Diabetes Osteoporosis Cardiac: cardiomyopathy, arrhythmias Liver disease: cirrhosis, hepatocellular cancer

Question 36

Why is iron overload so common in beta thal major/

Answer 36

Each unit of red cells contains 250mg In beta thal major you will give 2-3 units every 3 weeks Chronic anaemia drives increased iron absorption Venesection not feasible as already anaemic

Question 37

What is the treatment for iron overload in beta thal major?

Answer 37

Iron chelating drugs e.g. desferrioxamine | Chelators will bind to iron which is then excreted

Question 38

What are complications specific to blood transfusions in beta thal major?

Answer 38

Viral infection; HIV, hep B and C Alloantibodies Transfusion reactions Increased risk of sepsis

Question 39

What causes sickle cell disease?

Answer 39

Point mutation in codon 6 of the beta globulin gene that substitutes glutamine to valine producing betaS

Question 40

Why will cells with beta S sickle?

Answer 40

HbS polymerizes if exposed to low oxygen levels for a prolonged period of time This will distort the cell, damaging the RBC membrane

Question 41

What is the genotype of sickle cell trait?

Answer 41

``` HbAS One normal, one abnormal beta gene Asymptomatic carrier state May sickle in severe hypoxia Blood film NORMAL ```

Question 42

What will be seen on the blood film in HbSS?

Answer 42

Sickle cells | Target cells

Question 43

What are the consequences of sickle cell anaemia?

Answer 43

``` Sickle crisis Chronic haemolysis Sequestration of sickled RBCs in liver and spleen Prothrombotic Hyposplenism (repeated splenic infarcts) ```

Question 44

What causes a sickle crisis?

Answer 44

Sickle vaso-occulsion | Results in tissue ischaemia and pain

Question 45

What can precipitate a sickle crisis?

Answer 45

``` Hypoxia Dehydration Infection Cold exposure Stress/ fatigue ```

Question 46

How is a sickle crisis treated?

Answer 46

``` Opiate analgesia Hydration Rest Oxygen Antibiotics if evidence of infection Red cell exchange transfusion ```

Question 47

When is a red cell exchange transfusion indicated?

Answer 47

Severe crisis; Lung (vicious cycle of chronic hypoxia) Brain (stroke)

Question 48

What is the long term management of sickle cell anaemia?

Answer 48

``` Hyposplenism infection risk: HiB, meningococcus and pneumococcus vaccination. Penicillin prophylaxis Folic acid supplementation Vit B12 (induce HbF production) Regular transfusion ```

Question 49

How is infection risk reduced in hyposplenism?

Answer 49

Prophylactic penicillin | Vaccination; pneumococcus, meningococcus, haemophilus

Question 50

What bacteria are those with hyposplenism most susceptible to?

Answer 50

Encapsulated organisms - pneumococcus, meningococcus, haemophilus

Question 51

What is HPLC used for?

Answer 51

Quantify Hb present; identified HbS, HbH and a raised HbA2