Haemaglobinopathies and sickle cell Flashcards
Structure of Haemoglobin (2)
Tetramer made up of 2 alpha globin like chains and 2 beta globin like chains
One haem group attached to each globin chain
Major Forms of Haemoglobin (3)
HbA = 2 alpha chains and 2 beta chains
HbA2= 2 alpha and 2 delta chains
HbF= 2 alpha and 2 gamma chains
Genetic control of globin chain production (3)
Alpha like genes are on chromosome 16
=Two alpha genes per chromosome (4 per cell)
Beta like genes are on chromosome 11
=One beta gene per chromosome (2 per cell)
Expression of globin genes changes during embryonic life and childhood
What are Haemoglobinopathies? (3)
Hereditary conditions affecting globin chain synthesis
Hundreds of mutations
Behave as autosomal recessive disorders
Why are Haemoglobinopathies Important? (3)
-Commonest monogenic disorders
-Major cause of morbidity worldwide
-Increasingly frequent in the UK due to changing population demographics
2 main groups of Haemoglobinopathies? (2)
Thalassaemias; decreased rate of globin chain synthesis
Structural haemoglobin variants; normal production of abnormal globin chain → variant haemoglobin eg HbS
Thalassaemias (3)
Reduced globin chain synthesis resulting in impaired haemoglobin production
-Alpha thalassaemia; α chains affected
-Beta thalassaemia; β chains affected
Thalassaemias- consequences (4)
Inadequate Hb production → microcytic hypochromic anaemia
If severe:
-Unbalanced accumulation of globin chains -toxic to the cell
-Ineffective erythropoiesis
-Haemolysis
Alpha Thalassaemia (5)
Mutations affecting α globin chain synthesis
Unaffected individuals have 4 normal α genes (denoted αα/αα as two per chromosome)
Results from deletion of one α+ (-α) or both α0 (–) alpha genes from chromosome 16
Results in reduced α+ or absent α0 alpha chain synthesis from that chromosome
α chains present in HbA, HbA2 and HbF therefore all are affected
Classification of Alpha thalassaemia (5)
Based on the number of alpha genes
Unaffected = 4 normal α genes (αα/αα)
α thalassaemia trait; one or two alpha genes missing, asymptomatic carrier state, microcytic hypochromic red cells but ferritin normal
HbH disease; only one alpha gene left (–/-α ) moderate to severe anaemia
Hb Barts hydrops fetalis; no functional α genes (–/–) incompatible with life
Alpha Thalassaemia Trait (3)
Asymptomatic carrier state, no Rx needed
Microcytic, hypochromic red cells with mild anaemia
Important to distinguish from iron deficiency ( but ferritin will be normal)
HbH Disease (7)
More severe form of alpha thalassaemia
Only one working α gene per cell (–/-α )
Anaemia with very low MCV and MCH
Excess β chains form tetramers (β4) called HbH
Red cell inclusions of HbH can be seen with special stains
Common in SE Asia
Jaundice, splenomegaly, may need transfusion
Hb Barts Hydrops Foetalis Syndrome (6)
Severest form of α thalassaemia
No α genes inherited from either parent (–/–)
Minimal or no α chain production →HbF and HbA can’t be made
No alpha chains to bind to so tetramers of Hb Barts (γ4) and HbH (β4) produced
Possible risk if both parents from SE Asia where α0 (–) thal trait prevalent
Antenatal screening to avoid risk (more on antenatal screening at end of slide set)
Clinical Features (6)
Profound anaemia
Cardiac failure
Growth retardation
Severe hepatosplenomegaly
Skeletal and cardiovascular abnormalities
Almost all die in utero
Beta Thalassaemia (4)
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
Classification of β thalassaemia (7)
Based on clinical severity
β thalassaemia trait (β+/β or β0/β)
=Asymptomatic, no/mild anaemia, low MCV/MCH, raised HbA2 diagnostic
β thalassaemia intermedia (β+/β+ or β0/β+)
=Moderate severity requiring occasional transfusion (similar phenotype to HbH disease)
β thalassaemia major (β0/β0)
=Severe, lifelong transfusion dependency
β Thalassaemia Major (6)
Presents aged 6-24 months (as HbF falls)
Pallor, failure to thrive
Extramedullary haematopoiesis causing;
=Hepatosplenomegaly
=Skeletal changes
=Organ damage
Complications- extramedullary haematopoiesis which causes cord compression
Management of β Thal Major (6)
Regular transfusion programme to maintain Hb at 95-105g/l
=Suppresses ineffective erythropoiesis
=Inhibits over-absorption of iron
Allows for 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
Consequences of Iron Overload (10)
Endocrine dysfunction= Impaired growth and pubertal development, Diabetes, Osteoporosis
Cardiac disease= Cardiomyopathy, Arrhythmias
Liver disease= Cirrhosis, Hepatocellular cancer
Management of Iron Overload (2)
250mg of iron per unit of packed red cells
Iron chelating drugs (eg desferrioxamine) necessary
Other Complications (6)
Transfusion related
=Viral infection - HIV, Hepatitis B and C
=Alloantibodies – hard to crossmatch
=Transfusion reactions
=More detail in transfusion lecture!
Increased risk of sepsis – bacteria like iron!
Sickling Disorders- Pathophysiology (4)
Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine producing βS
This alters the structure of the resulting Hb→ HbS (α2βs2)
HbS polymerises if exposed to low oxygen levels for a prolonged period
This distorts the red cell, damaging the RBC membrane
Sickle Cell Trait (HbAS) (7)
One normal, one abnormal β gene (β/βs)
Asymptomatic carrier state
300 million carriers worldwide
Few clinical features as HbS level too low to polymerise
May sickle in severe hypoxia eg high altitude, under anaesthesia
Blood film normal
Mainly HbA, HbS <50%
Sickle Cell Anaemia (HbSS) (6)
-Two abnormal β genes (βs/βs)
-HbS > 80%, no HbA
-Episodes of tissue infarction due to vascular occlusion – sickle crisis
-Chronic haemolysis – shortened RBC lifespan
-Sequestration of sickled RBCs in liver and spleen
-Hyposplenism due to repeated splenic infarcts
