Haemoglobinopathies ✅ Flashcards
What are haemoglobinopathies?
A group of disorders that arise from abnormal haemoglobin production
What can abnormal haemoglobin production result from in haemoglobinopathies?
- Inadequate globin chain production
- Production of abnormal global chain
Give 2 examples of conditions where there is inadequate globin chain production?
- Alpha-thalassaemia
- Beta-thalassaemia
Give an example of a condition where there is production of an abnormal globin chain?
Sickle cell anaemia
What are haemoglobinopathies characterised by?
Chronic haemolytic anaemia
What do thalassaemias occur due to?
Genetic defects that result in reduced rate of synthesis of either alpha-globin or beta-globin chains
What is the genetic defect in alpha-thalassaemia?
Usually alpha-globin gene deletion
What is the genetic defect in beta-thalassaemia?
Mainly point mutations in beta-globin gene
Where is the alpha-globin gene found?
Chromosome 16
How many copies of the alpha-globin gene are present on chromosome 16?
2
How many alpha-globin genes do normal individuals have?
4
What are the forms of alpha-thalssaemia?
- Alpha-thalassaemia trait
- Alpha-thalssaemia major
- HbH disease
What produces alpha-thalassaemia trait?
Deletion of one or two copies of the alpha-globin gene
How does alpha-thalassaemia present clinically?
Generally asymptomatic
What produces alpha-thalassaemia major?
Loss of all 4 alpha-globin genes
How does alpha-thalassaemia major present?
Death in utero or during first few hours of life
What causes death in alpha-thalassaemia major?
Hydrops fetalis
What produces HbH disease?
Deletion of 3 alpha-globin genes
How does HbH disease present?
- Anaemia
- Splenomegaly
What are the features of anaemia in HbH disease?
- Microcytic
- Hypochromic
What is formed in HbH disease?
An abnormal haemoglobin called HbH
How is HbH formed?
The excess of beta-globin chains forms HbH
What does HbH haemoglobin consist of?
Only beta chains
How can HbH haemoglobin be detected?
- High performance liquid chromatography (HPLC)
- Blood film using brilliant cresol blue stain
How can alpha-thalassaemia trait be detected?
Genetic testing to identify alpha-globin gene deletions
Does alpha-thalassaemia trait produce any abnormalities on HPLC?
No
Where is the beta-globin gene located?
Chromosome 11
What genetic abnormality causes beta-thalassaemia major?
Mutations in both copies of beta-globin gene on chromosome 11
What is the result of deletion of both copies of the beta-globin gene on haemoglobin production?
Complete absence or severe reduction of beta-globin production, and an excess of alpha-globin chains
What does anaemia result from in beta-thalassaemia major?
- Ineffective erythropoiesis
- Haemolysis
What causes haemolysis in beta-thalassaemia major?
There is an excess of alpha-globin chain, and the free alpha-globin chains are highly unstable and precipitate in erythrocytes, which causes haemolysis
What does the anaemia trigger in beta-thalassaemia major?
An increase in erythropoietin production
What does the increased erythropoietin production in beta-thalassaemia major drive?
Extramedullary haematopoiesis
What are the features of anaemia in beta-thalassaemia major?
- Severe
- Microcytic
- Hypochromic
What are the typical blood film changes in beta-thalassaemia major?
- Target cells
- Nucleated red blood cells
- Basophilic stippling
How is a diagnosis of beta-thalassaemia major confirmed?
Haemoglobin HPLC
What is found on haemoglobin HPLC in beta-thalassaemia major?
Absence of HbA
What is the purpose of genetic testing in beta-thalassaemia?
Can identify mutations
What are the mutations in beta-thalassaemia classed as?
Either β0 or ß+
What does ß0 mean?
No production of beta globin
What does ß+ mean?
Reduced production of beta-globin
What is the significance of the finding of ß+ globin?
May show milder phenotype
What is the milder phenotype of beta-thalassaemia known as?
Beta-thalassaemia intermedia
What is HPLC?
A laboratory technique that can identify and measure the different types of Hb present in a blood sample
What can the use of identification of patterns of Hb variants by HPLC be used for?
Diagnosis of most haemoglobinopathies
When does beta-thalassasemia present?
3-6 months of age
Why does beta-thalassaemia present at 3-6 months of age?
Hb production switches from HbF to HbA during the first 3-6 months of life - HbF does not use beta-globin, but HbA does
What does HbF consist of?
Alpha-globin and gamma-globin chains
What does HbA consist of?
Alpha-globin and beta-globin chains
What % of Hb is HbA in a healthy 6 month old infant?
95%
How is beta-thalassaemia major treated?
Regular blood transfusions
How often are blood transfusions required in beta-thalassaemia major?
3-6 weekly
What is the purpose of blood transfusion in beta-thalassaemia major?
- Raises Hb
- Suppresses erythropoietic production
What are the complications of lifelong transfusions for beta-thalassaemia major?
- Progressive iron overload
- Transfusion related viral infection
- Development of red cell abnormalities
How is the extent of iron overload caused by transfusion in beta-thalassaemia major measured?
Monitoring serum ferritin levels
How is iron overload treated?
Iron chelation therapy
When is iron chelation therapy used for overload caused by blood transfusion in beta-thalassaemia major?
Once 10-15 red cell transfusions has been given, and/or the serum ferritin increases above 1000ng/mL
How was iron chelation therapy traditionally given?
Subcutaneous infusions of desferrioxamine
How is iron chelation therapy now given?
Oral preparations of desferrioxamine
How are iron levels monitored in children receiving transfusion for beta-thalassaemia?
- Serum ferritin
- Assessment of potential sites of iron deposition
How often should serum ferritin be monitored in children with beta-thalassaemia being treated with transfusions?
3 monthly
How often should children receiving transfusions for beta-thalassaemia major have potential sites of iron deposition assessed?
1-2 year intervals
Where should be assessed for potential iron deposition in children with beta-thalassaemia major being treated with blood transfusion?
- Heart
- Liver
How is iron deposition tested in children with beta-thalassaemia major being treated with blood transfusions?
MRI scans
What is the advantage of using MRI to assess potential sites of iron deposition in children with beta-thalassaemia major being treated with blood transfusion?
Avoids the need for invasive biopsies
How is beta-thalassaemia major cured?
Haemopoietic stem cell transplant
What is the limitation of haemopoietic stem cell transplant as a treatment for beta-thalassaemia major?
It carries significant risks
How is maternal screening for haemoglobinopathies carried out?
- FBC
- HPLC
When is maternal screening for haemoglobinopathies part of routine antenatal testing?
In areas where there is a high prevalence of carriers
In low prevalence areas, who is targeted antenatal screening for haemoglobinopathies done in?
Women from ethnic groups at highest risk
Which ethnic groups are at highest risk of haemoglobinopathies?
- African
- Caribbean
- Indian subcontinent
- Mediterranean
Is newborn haemogloblinopathy screening performed in the UK?
Yes
What is the purpose of newborn screening for haemoglobinopathies?
Primarily aimed at detecting cases of sickle cell disease, but will also identify most cases of beta-thalassaemia major
What recently development has allowed for the prevention of haemoglobinopathies?
Pre-implantation g genetic diagnosis
How does pre-implantation genetic diagnosis prevent haemoglobinopathies?
IVF is used in combination with molecular testing for globin mutations/deletions to allow unaffected embryos to be selected from embryo transfer
What is the limitation of pre-implantation genetic diagnosis to prevent haemoglobinopathies?
It is a very specialised and expensive technique and is not yet widely available
What ethnicities does sickle cell disease predominantly affected?
- African
- Caribbean
- Middle Eastern
- Indian
What is the genetic abnormality in sickle cell disease?
Point mutation in beta-globin gene
What is the mutated beta-globin gene in sickle cell disease known as?
ßs-globin
What does the point mutation in the beta-globin gene in sickle cell disease result in?
A single amino acid change in the beta-globin protein
What is the amino acid change in sickle cell disease?
Valine for glutamine
What is the haemoglobin chain produced in sickle cell known as?
HbS
How does HbS cause problems?
- Relatively insoluble
- Polymerises when exposed to low oxygen tension
What does the polymerisation of HbS at low oxygen tension lead to?
The formation of characteristic sickle cells
How do sickle cells differ from normal haemoglobin cells?
They are dehydrated, rigid, and less deformable than normal red cells
What is the result of sickle cells being rigid and less deformable?
They can obstruct blood flow in the microcirculation
What predisposes to sickle cell crises?
Any factor which increases the risk of polymerisation
What factors are protective against sickle cell crises?
- Optimal hydration
- Oxygenation
- Increased quantities of HbF
What do all forms of sickle cell disease have in common?
All have the presence of one or more copies of a beta-globin gene mutation
What are the most common types of SCD?
- Sickle cell anaemia
- HbSC diseaes
- S ß-thalassaemia
What is the genetic abnormality in sickle cell anaemia?
Homozygous for beta-globin mutation (HbSS)
What is the genetic abnormality in HbSC disease?
Single beta-globin mutation in combination with HbC mutation (HbSC)
What is the genetic abnormality in S ß-thalassaemia?
People with ß-thalassaemia mutation in combination with ßS-globin
How do the clinical features of all types of sickle cell disease compare with each other?
The clinical features are similar, but vary in severity
Which of the sickle cell diseases are most severe?
Sickle cell anaemia
Which of the sickle cell disease are least severe?
HbSC disease
What are the clinical features of all forms of sickle cell diseases?
- Chronic haemolytic anaemia
- Prone to recurrent sickle cell crises
How might sickle cell crises present?
- Veno-occlusive (painful) crisis
- Sickle chest crisis
- Splenic/hepatic sequesteration
- Aplastic crisis
- Cerebral infarction
What causes aplastic crises in sickle cell disease?
Parvovirus B19 infection
What is the incidence of cerebral infarction in sickle cell disease?
11%
How is the incidence of cerebral infarction in sickle cell disease reduced?
Regular screening
What is the incidence of cerebral infarction in children with sickle cell disease who undergo regular screening?
<5%
How is sickle cell disease diagnosed?
HPLC
Can patients with sickle cell anaemia produce HbA?
No
What globins to patients with sickle cell anaemia rely on?
HbS and small amounts of HbF
What is the management of sickle cell disease aimed at?
- Preventing complications
- Symptomatic treatment of painful sickle crises
What are the most important aspects of prevention of complications in sickle cell disease?
- Avoidance of factors that may precipitate a crisis
- Prevention of infection
- Folic acid
What factors may precipitate a sickle cell crisis?
- Cold
- Dehydration
- Over-strenuous exercise
What kind of organisms need to be prevented against in sickle cell disease?
Encapsulated organisms
Give 2 examples of encapsulated organisms?
- Pneumococcus
- Meningococcus
How is infection with encapsulated organisms prevented in sickle cell disease?
- Twice daily penicillin prophylaxis
- Vaccination
Why are infections with encapsulated organisms more common in sickle cell disease?
Because most patients develop auto-infarction of the spleen before the age of 4 years
Why is folic acid supplementation required in sickle cell disease?
Because of increased folate need due to chronic haemolysis
Is the severity of SCID variable?
Yes, very
What is the aim of treatments in SCID?
To modify the severity and natural history of the disease
What treatments are available for SCID?
- Hydoxycarbamide
- Regular blood transfusion
- Haematopoietic stem cell transplantation (HSCT)
What is the effect of hydroxycarbamide in sickle cell disease?
It reduces the occurrence of crises
How does hydroxycarbamide reduce the occurrence of crises in sickle cell?
It inhibits ribonucleotide reductase, which increases HbF
What is the purpose of regular blood transfusion in sickle cell disease?
- Prevent stroke
- Reduce sickle chest crises
How often are blood transfusions given when used in sickle cell disease?
Monthly
When are regular blood transfusions used for the prevention of sickle chest crises in sickle cell disease?
When hydroxycarbamide has been ineffective
What is required when regular blood transfusions are used for more than a year in sickle cell disease?
Iron chelation therapy
When is HSCT used in sickle cell disease?
- CNS disease
- Recurrent chest crises
- Painful crises despite hydroxycarbamide treatment
What is the pathogenesis of stroke in children with sickle cell disease?
Cerebral vasculopathy
What vessel is particularly affected by cerebral vasculopathy in sickle cell disease leading to stroke?
Middle cerebral artery
What investigation finding correlates with the presence of cerebral vasculopathy in sickle cell disease?
Increased MCA blood flow on transcranial doppler scanning
What is the presumed mechanism of cerebral vasculopathy in sickle cell disease?
Chronic intravascular haemolysis
What is the best known method for reducing intravascular haemolysis in sickle cell disease?
Regular red cell transfusion
