Haemoglobinopathies Flashcards
Describe the structure of haemoglobin A?
Tetramer made up of 2 alpha globin like chains and 2 beta globin like chains.
One haem group attached to each globin chain.
What are the major forms of haemoglobin, and what globin chains do they contain?
What proportion are they present in adult blood?
HbA (2 alpha and 2 beta chains) - 97%
HbA2 (2 alpha and 2 delta chains) - 2.5%
HbF (2 alpha and 2 gamma chains) - 0.5%
What chromosome has the genes for alpha like chains? How many genes are there?
Chromosome 16
There are 2 genes per chromosome (i.e. 4 genes per cell)
What chromosome carries the genes for beta like chains?
How many genes are there?
Chromosome 11
1 gene per chromosome, 2 genes per cell.
What are the embryonic Hbs?
Gower 1
Portland
Gower 2
What chromosome carries the genes for gamma and delta globin chains?
Chromosome 11
By what age are adult levels of Hb reached?
6-12 months
What are the haemoglobinopathies?
Hereditary conditions affecting haemoglobin synthesis
What are the main groups of haemoglobinopathies?
Thalassaemias and structural haemoglobin variants
What are the thalassaemias?
Hereditary disorders of globin chain synthesis resulting in impaired haemoglobin production
(decreased rate of haemoglobin production)
What are structural haemoglobin variants?
Conditions in which there is normal rate of production of structurally abnormal globin chains leading to variant haemoglobin production (e.g. HbS)
What are the two main groups of thalassaemias?
Alpha and beta
What type of anaemia does thalassaemia cause?
Microcytic hypochromic anaemia
Why is there ineffective erythropoiesis in thalassaemia?
What else happens?
Because there is unbalanced accumulation of globin chains, leading to precipitations of globin chains in red cell precursors.
Precipitations of globin chains in mature red cells leads to haemolysis.
Why are thalassaemias increasingly prevalent in the UK?
Due to changing population demographics
Why have the mutations causing thalassaemias flourished in certain parts of the world?
Due to selective pressure in malaria endemic areas.
What causes alpha thalassaemia?
Deletions of one or both alpha genes from chromosome 16.
Point mutations are rare and cause non-deletional alpha thalassaemia.
What types of haemoglobin are affected by alpha thalassaemia?
All adult types - HbA, HbA2, HbF
What disease and genome does a patient who is missing one alpha gene have?
silent alpha thalassaemia trait
-a/aa
What disease and genome does a patient who is missing 2 alpha genes have?
alpha thalassaemia trait
-a/-a or –/aa
What disease and genome does a patient who is missing 3 alpha genes have?
HbH disease
–/-a
What disease and genome does a patient who has no functional alpha genes have?
Hb Barts hydrops fetalis
–/–
What are the symptoms and treatment of alpha thalassaemia trait?
It is clinically asymptomatic - no treatment needed
What are the findings on blood film of alpha thalassaemia trait?
Microcytic hypochromic red cells
Red cell inclusions (HbH bodies) can sometimes be seen with special staining
What is the Hb, ferritin and red cell count in alpha thalassaemia?
Mild anaemia
Normal ferritin
Raised red cell count
What proportion of alpha chain production is there in HbH disease in comparison to normal circumstances?
What are the Hb, MCV and MCH findings in HbH disease?
Low Hb, Low MCH, Low MCV
What is HbH?
Haemoglobin formed by four beta chains, which happens due to the presence of excess beta chains in HbH disease. HbH cannot carry oxygen.
Where is HbH disease commonest geographically?
SE Asia, Middle East, Mediterannean
How does HbH disease behave in terms of its inheritance/
It behaves like an autosomal recessive condition
What are the clinical features of HbH disease?
There is wide variation - nearly asymptomatic to transfusion dependent. Splenomegaly Jaundice Gallstones Growth retardation Iron overload
What is the management of mild HbH disease?
Transfusion only needed at times of intercurrent illness
Folic acid supplementation due to increased RBC turnover
What is the management of severe HbH disease?
Transfusions
Folic acid supplementation
Splenectomy may reduce transfusion need
What is the severest form of alpha thalassaemia?
Hb Bart’s hydrops fetalis syndrome
What forms of Hb are present at birth in Hb Bart’s hydrops fetalis syndrome?
Hb Bart’s (gamma4) and HbH (beta4)
Small amounts of embyronic Hb also present
What are the clinical features of Hb Bart’s hydrops fetalis?
Pallor Oedema Cardiac failure Growth retardation Skeletal and cardiovascular abnormalities Severe hepatosplenomegaly Most die in utero Some survive to term but die shortly after birth
What does the blood film show in Hb Bart’s hydrops fetalis?
Numerous nucleated RBCs in peripheral blood
What does the blood film show in alpha thalassaemia?
Target cells
anisopoikilocytosis
How is alpha thalassaemia diagnosed?
Suspected from ethnic origin and red cell indices (exclude iron deficiency)
Blood film
High performance liquid chromatography or Hb electrophoresis
How is a thal trait confirmed, and the mutation involved determined?
Molecular testing
If parents are at risk for alpha thalassaemia trait because of their ethnic background, what is used to screen for common mutations?
PCR
What type of haemoglobin is affected in beta thalassaemia?
HbA
What causes beta thalassaemia?
Usually point mutations
How is beta thalassaemia inherited?
It is autosomal recessive
How is beta thalassaemia classified?
Based on clinical severity as beta thalassaemia trait, beta thalassaemia intermedia and beta thalassaemia major.
What are the features of beta thalassaemia trait and how is it diagnosed?
Asymptomatic
Low MCV/MCH
Raised HbA2 is diagnostic
What is the treatment of beta thalassaemia major?
Lifelong transfusion dependency
What are the clinical features of beta thalassaemia major/
Presents 6-24 months
Failure to thrive
Pallor
Extramedullary haemopoiesis causing hepatosplenomegaly, skeletal changes, organ damage.
Similar features to HbH disease but more severe
What are the lab features of beta thal major?
Moderate to severe anaemia (Hb 30-90g/L)
Very low MCV and MCH
Reticulocytosis
Blood film shows target cells and anisopoikilocytosis
HPLC shows mainly HbF present with small amounts of HbA and slightly elevated HbA2.
What is the management of beta thal major?
Regular transfusion programme to maintain Hb 95-105g/L
Bone marrow transplant may be an option if carried out before complications develop
If treated effectively, what is the main cause of morbidity in beta thalassaemia?
Iron overload from repeated transfusions
What are the complications of iron overload?
Endocrine dysfunction (impaired growth and pubertal development, diabetes, osteoporosis) Cardiac disease (arrhythmias, cardiomyopathy) Liver disease (cirrhosis, hepatocellular carcinoma)
How is iron overload managed?
Iron chelating drugs e.g. desferrioxamine, deferiprone, deferasirox
How much iron is in a unit of red cells?
250mg
How is iron excreted naturally?
There is no natural mechanism for iron excretion.
What populations are primarily affected by the sickle cell syndromes?
Afro-caribbean populations
What is the common feature of the sickle cell syndromes?
Inheritance of abnormal Hb beta-chain gene (BetaS)
How many abnormal beta chains are inherited in a)sickle cell anaemia and b) sickle cell trait?
a) 2
b) 1
What is HbS?
α2βs2
Structurally altered Hb, caused by inheritance of the betaS gene
What is different about the beta chains produced by expression of the betaS gene to the normal beta chain gene?
There is a point mutation in codon 6 of the gene
This causes the amino acid in position 6 to be changed from glutamine to valine
What parasite does HbS give some protection against?
Falciparum malaria
Describe what happens to HbS (and the red cells that contain it) at low oxygen concentrations.
Deoxygenated HbS undergoes conformational change (i.e. if exposed to low oxygen levels for a prolonged period of time).
The abnormal HbS forms tetramers which aggregate to form large polymers leading to a loss of deformability of the red cell, which becomes sickle shaped.
The membrane becomes damaged and the cell becomes more rigid.
What sort of anaemia does sickle cell anaemia cause?
How?
Haemolytic anaemia
Due to sequestration of red cells in the reticuloendothelial system.
Why are the symptoms of anaemia in sickle cell anaemia often surprisingly mild?
Because HbS released oxygen more readily than HbA.
How is sickle cell anaemia inherited?
It is autosomal recessive
What types of Hb are present in the blood in sickle cell anaemia?
HbS (>80%)
No HbA
Variable amounts of HbF
Name 5 precipitants of sickle cell crises.
Hypoxia Infection Cold exposure Stress/fatigue Dehydration
What areas are most commonly affected by vaso-occlusive crises?
Hips
Vertebrae
Shoulders
What must bone infarction due to a vaso-occlusive crisis be differentiated from?
Salmonella osteomyelitis
Describe the management of sickle cell crises
Opiate analgesia Hydration Oxygen Rest Antibiotics if evidence of infection Red cell exchange transfusion in severe crises or if neurological symptoms present.
What is the longterm treatment of sickle cell anaemia?
Education/lifestyle measures to avoid precipitants
Folic acid supplementation
Prophylactic penicillin
Vaccination (pneumococcus, meningococcus, haemophilus)
Hydroxycarbamide can reduce disease severity by inducing HbF production
How is sickle cell anaemia diagnosed?
Blood film
Screening test for sickling (blood sample deoxygenated to induce sickling)
Hb electrophoresis - no HbA detectable
