haemoglobinopathies Flashcards
what are they?
Hereditary conditions affecting globin chain synthesis
o Hundreds of mutations
o Behave as autosomal recessive disorders
what are the 2 main groups of them?
Thalassaemias, decreased rate of globin chain synthesis
Structural haemoglobin variants – normal production of abnormal globin chain – variant haemoglobin e.g. HbS
what is a thalassaemia?
• Reduced globin chain synthesis resulting in impaired haemoglobin production
o Alpha thalassaemia – alpha chains affected
o Beta thalassaemia – beta chains affected
how do thalassaemias present?
inadequate Hb production - microcytic hypchromic anaemia
if severe:
- unbalanced accumulation of globin chains which are toxic to the cell
- ineffective erythropoiesis
- haemolysis
how are thalassaemias diagnosed?
Simple things first!
o FBC; Hb, red cell indices
o Blood film
o Ethnic origin
High performance liquid chromatography (HPLC) or electrophoresis to quantify haemoglobins present
o Identifies abnormal haemoglobins eg HbS
o Raised HbA2 diagnostic of beta thal trait
antenatal screening for thalassaemias
antenatal screening to identify carrier parents - now standard
family origin questionnaire and FBC
further testing if high-risk area or abnormal RBC indices
couples at risk are counselled
prenatal diagnosis is offered where appropriate
newborn screening programme is also in place
what is an alpha thalassaemia
- Mutations affecting the alpha globin chain synthesis
- Unaffected individuals have 4 normal alpha genes
- Occurs because of deletion in the alpha genes from chromosome 16. Results in reduced α+ or absent α0 alpha chain synthesis from that chromosome
- Alpha chains present in HbA, HbA2 and HbF therefore all are affected
what are the classifications of alpha thalassemia?
unaffected = 4 normal α genes (αα/αα)
α thalassaemia trait
HbH disease
Hb Barts hydrops fetalis;
what is α thalassaemia trait
1 or 2 alpha genes missing, asymptomatic carrier state, microcytic, hypochromic red cells but normal ferritin
how does α thalassaemia trait present
o Asymptomatic carrier state, no Rx needed
o Microcytic, hypochromic red cells with mild anaemia
o Important to distinguish from iron deficiency (but ferritin will be normal)
what is HbH disease
only one alpha gene left (–/-α ), moderate to severe anaemia – anaemia with very low MCV and MCH
presentation of HbH disease
o Excess β chains form tetramers (β4) called HbH
o Red cell inclusions of HbH can be seen with special stains
o Common in SE Asia
o Jaundice, splenomegaly, may need transfusion
what is Hb Barts hydrops fetalis
no functional α genes (–/–) , incompatible with life
most severe form of alpha thalassaemia
No alpha chains to bind to so tetramers of Hb Barts (γ4) and HbH (β4) produced
who gets Hb Barts hydrops fetalis
o Possible risk if both parents from SE Asia where α0 (–) thal trait prevalent
o Antenatal screening to avoid risk
clinical features of Hb Barts hydrops fetalis
o Profound anaemia o Cardiac failure o Growth retardation o Severe hepatosplenomegaly o Skeletal and cardiovascular abnormalities o Almost all die in utero
what are beta thalassaemias
- Disorder of beta chain synthesis
- Usually caused by point mutations
- Reduced ( β+), or absent ( β0 ) beta chain production depending on the mutation
- Only β chains and hence only HbA (α2β2) affected
what are the classifications of beta thalassaemias?
β thalassaemia trait (β+/β or β0/β)
β thalassaemia intermedia (β+/β+ or β0/β+)
β thalassaemia major (β0/β0)
how does β thalassaemia trait (β+/β or β0/β) present?
asymptomatic
no/mid anaemia
low MCV/MCH
raised HbA2 diagnostic
how does β thalassaemia intermedia (β+/β+ or β0/β+) present?
moderate severity requiring occasional transfusion (similar phenotype to HbH disease)
how does β thalassaemia major (β0/β0) present?
o Severe, lifelong transfusion dependency
o Presents aged 6-24 months (as HbF falls)
o Pallor, failure to thrive
o Extramedullary haematopoiesis causing hepatosplenomegaly, skeletal changed, organ damage
o Haemoglobin analysis – mainly HbF, no HbA
how is β thalassaemia major (β0/β0) managed?
regular transfusion programme to maintain Bh at 95-105g/l (suppresses ineffective erythropoiesis, inhibits over-absorption of iron)
allows for normal growth and development
iron overload from transfusion becomes main cause of mortality
bone marrow transplant may be an option if carried out before complications develop
