Haemoglobinopathies Flashcards
How many Haem groups are there per globin chain?
1 per globin chain => 4 per Hb molecule (each can pick up one O2)
What are the major forms of Hb?
HbA (α2β2 ), HbA2 (α2δ2) HbF (α2γ2)
What chromosomes control globin chain production?
Alpha genes (aa,aa) chromosome 16, Beta genes (bb) chromosome 11
When does adult haemoglobin (HbA) production take over from foetal haemoglobin (HbF)?
6-12 months of age
How are haemoglobinopathies genetically inherited?
autosomal recessive
What are the two main groups of haemoglobinopathies?
Thalassaemias (less globin chain synthesis), Structural haemoglobin variants (normal production but chain abnormal)
What globin chains can be affected in a thalassemia?
Alpha thalassaemia (α chains), Beta thalassaemia (β chains)
What are the possible consequences of a thalassemia?
Accumulation of globin chains (toxic to cell), Haemolysis, Ineffective erythropoiesis
Where in the world are thalassemias most prevalent?
Africa and Asia
What are the different types of alpha thalassemia (based on the number of working genes)?
Unaffected = 4 normal α genes (αα/αα)
TRAIT = one or two alpha genes missing
HbH = only one alpha gene left (–/-α )
Hb Barts hydrops fetalis = NO functional α genes (–/–)
Patients with alpha thalassemia trait will be asymptomatic. TRUE/FALSE?
TRUE
- no treatment req’d
HOw do RBCs appear on a blood film of a patient with an alpha thalassemia trait? What is this similar to, and how are the two distinguished?
Microcytic, hypochromic red cells with mild anaemia
Similar to iron deficiency
=> but FERRITIN NORMAL
Describe the blood results of a patient with HbH disease?
Anaemia with very low MCV and MCH
How is HbH formed in HbH disease?
Excess β chains form tetramers (β4)
as no alpha chains to bind to
Where is HbH disease (and alpha thalassemias in general) most common?
South East Asia
HOw may patients with HbH disease present, and what treatment may they require?
Jaundice and splenomegaly
Patients may need transfusion
What is Hb Barts Hydrops Foetalis?
- Severest form of α thalassaemia
- Minimal or no α chain production
=> HbF and HbA can’t be made - Instead tetramers of Hb Barts (γ4) and HbH (β4) produced
Where in the world is there a higher risk of Hb Barts Hydrops Foetalis?
Risk if both parents from SE Asia
- as this is where α0 (–) thalassemia trait prevalent
How is the risk of Hb Barts Hydrops Foetalis minimised?
Antenatal screening
Babies who are born with Hydrops Foetalis have what distinct clinical features?
- Profound anaemia
- Cardiac failure
- Growth retardation
- Severe hepatosplenomegaly
- Skeletal and cardiovascular abnormalities
- HOWEVER Almost all die in utero**
What type of Hb production is affected in beta thalassemias?
HbA (α2β2) affected
=> as only β chains depleted
What are the different classifications of beta thalassemia?
β thalassaemia trait
- Asymptomatic
- No/mild anaemia
- Low MCV/MCH
- Raised HbA2 diagnostic
β thalassaemia intermedia
- Moderate severity
- requires occasional transfusion
β thalassaemia major (β0/β0)
- Severe
- Lifelong transfusions
When does Beta thalassemia major usually present?
Presents aged 6-24 months (as HbF falls)
What Hb is found in beta thalassemia major?
Mainly HbF
No HbA
HOw do patients with beta thalassemia major usually present clinically.
- Pallor, failure to thrive
- Skeletal changes (erythropoiesis in skull e.g frontal bossing)
- Hepatosplenomegaly
- Organ damage
What is a potential consequence of extramedullary haematopoiesis in the vertebrae?
Spinal cord compression
What are the main causes of death in beta thalassemia major once patients are ON treatment?
- Iron overload from transfusions
- deposits in organs causing damage/failure
e. g. pituitary (inhibits growth/puberty), causes cardiac arrythmias, liver cirrhosis/ HCC
HOw can beta thalassemia be cured?
Bone marrow transplant (if carried out before complications develop)
How is iron overload due to transfusion treated?
cant venesect - this revereses transfusion!
=> Iron chelating drugs (eg desferrioxamine)
=> bind to iron which is then excreted
Describe the pathophysiology of sickle cell anaemia
- Point mutation in β globin gene
- alters structure of Hb→ HbS
- HbS polymerises if exposed to low O2 for long time
- distorts red cell => damaging RBC membrane
What is sickle cell trait and are patients usually symptomatic?
- One normal and one abnormal β gene
- Asymptomatic as HbS level too low to polymerise
- May sickle in severe hypoxia (eg high altitude or anaesthesia)
What is the main type of Hb found in patients with sickle cell trait?
Mainly HbA, HbS <50%
What happens to Hb sickle cell disease (HbSS)?
- Two abnormal β genes (βs/βs)
- Patients have mainly HbS (> 80%) and no HbA
What symptoms are experienced by patients with sickle cell anaemia?
- Episodes of tissue infarction due to vascular occlusion by odd shaped sickle cells
=> sickle crisis - Pain may be extremely severe
- Hyposplenism due to repeated splenic infarcts
- Chronic haemolysis – shortened RBC lifespan
- Sequestration of sickled RBCs in liver and spleen
What can precipitate a sickle cell crisis?
Hypoxia Dehydration Infection Cold exposure Stress/fatigue
HOw is a sickle cell crisis treated?
- Opiates
- Hydration
- Rest
- Oxygen
- Antibiotics if evidence of infection
- Red cell exchange transfusion (venesect/tranfuse and repeat)
=> in severe crisis eg (lung) chest crisis or (brain)stroke
How is sickle cell anaemia managed in the long term?
- prophylactic penicillin for hyposplenism
- vaccinations for hyposplenism => pneumococcus, meningococcus, haemophilus
- Folic acid supplementation (↑ RBC turnover so ↑demand)
- Regular transfusion to prevent stroke
How should you approach a potential haemoglobinopathy?
- FBC - Hb, red cell indices
- Blood film
- Ethnic origin
- Liquid chromatography OR electrophoresis to quantify Hb present
- Identify abnormal haemoglobins
- Raised HbA2 diagnostic of beta thal trait
