Haemoglobinopathies ✅ Flashcards
(128 cards)
1
Q
What are haemoglobinopathies?
A
A group of disorders that arise from abnormal haemoglobin production
2
Q
What can abnormal haemoglobin production result from in haemoglobinopathies?
A
- Inadequate globin chain production
- Production of abnormal global chain
3
Q
Give 2 examples of conditions where there is inadequate globin chain production?
A
- Alpha-thalassaemia
- Beta-thalassaemia
4
Q
Give an example of a condition where there is production of an abnormal globin chain?
A
Sickle cell anaemia
5
Q
What are haemoglobinopathies characterised by?
A
Chronic haemolytic anaemia
6
Q
What do thalassaemias occur due to?
A
Genetic defects that result in reduced rate of synthesis of either alpha-globin or beta-globin chains
7
Q
What is the genetic defect in alpha-thalassaemia?
A
Usually alpha-globin gene deletion
8
Q
What is the genetic defect in beta-thalassaemia?
A
Mainly point mutations in beta-globin gene
9
Q
Where is the alpha-globin gene found?
A
Chromosome 16
10
Q
How many copies of the alpha-globin gene are present on chromosome 16?
A
2
11
Q
How many alpha-globin genes do normal individuals have?
A
4
12
Q
What are the forms of alpha-thalssaemia?
A
- Alpha-thalassaemia trait
- Alpha-thalssaemia major
- HbH disease
13
Q
What produces alpha-thalassaemia trait?
A
Deletion of one or two copies of the alpha-globin gene
14
Q
How does alpha-thalassaemia present clinically?
A
Generally asymptomatic
15
Q
What produces alpha-thalassaemia major?
A
Loss of all 4 alpha-globin genes
16
Q
How does alpha-thalassaemia major present?
A
Death in utero or during first few hours of life
17
Q
What causes death in alpha-thalassaemia major?
A
Hydrops fetalis
18
Q
What produces HbH disease?
A
Deletion of 3 alpha-globin genes
19
Q
How does HbH disease present?
A
- Anaemia
- Splenomegaly
20
Q
What are the features of anaemia in HbH disease?
A
- Microcytic
- Hypochromic
21
Q
What is formed in HbH disease?
A
An abnormal haemoglobin called HbH
22
Q
How is HbH formed?
A
The excess of beta-globin chains forms HbH
23
Q
What does HbH haemoglobin consist of?
A
Only beta chains
24
Q
How can HbH haemoglobin be detected?
A
- High performance liquid chromatography (HPLC)
- Blood film using brilliant cresol blue stain
25
How can alpha-thalassaemia trait be detected?
Genetic testing to identify alpha-globin gene deletions
26
Does alpha-thalassaemia trait produce any abnormalities on HPLC?
No
27
Where is the beta-globin gene located?
Chromosome 11
28
What genetic abnormality causes beta-thalassaemia major?
Mutations in both copies of beta-globin gene on chromosome 11
29
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
30
What does anaemia result from in beta-thalassaemia major?
- Ineffective erythropoiesis
| - Haemolysis
31
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
32
What does the anaemia trigger in beta-thalassaemia major?
An increase in erythropoietin production
33
What does the increased erythropoietin production in beta-thalassaemia major drive?
Extramedullary haematopoiesis
34
What are the features of anaemia in beta-thalassaemia major?
- Severe
- Microcytic
- Hypochromic
35
What are the typical blood film changes in beta-thalassaemia major?
- Target cells
- Nucleated red blood cells
- Basophilic stippling
36
How is a diagnosis of beta-thalassaemia major confirmed?
Haemoglobin HPLC
37
What is found on haemoglobin HPLC in beta-thalassaemia major?
Absence of HbA
38
What is the purpose of genetic testing in beta-thalassaemia?
Can identify mutations
39
What are the mutations in beta-thalassaemia classed as?
Either β0 or ß+
40
What does ß0 mean?
No production of beta globin
41
What does ß+ mean?
Reduced production of beta-globin
42
What is the significance of the finding of ß+ globin?
May show milder phenotype
43
What is the milder phenotype of beta-thalassaemia known as?
Beta-thalassaemia intermedia
44
What is HPLC?
A laboratory technique that can identify and measure the different types of Hb present in a blood sample
45
What can the use of identification of patterns of Hb variants by HPLC be used for?
Diagnosis of most haemoglobinopathies
46
When does beta-thalassasemia present?
3-6 months of age
47
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
48
What does HbF consist of?
Alpha-globin and gamma-globin chains
49
What does HbA consist of?
Alpha-globin and beta-globin chains
50
What % of Hb is HbA in a healthy 6 month old infant?
95%
51
How is beta-thalassaemia major treated?
Regular blood transfusions
52
How often are blood transfusions required in beta-thalassaemia major?
3-6 weekly
53
What is the purpose of blood transfusion in beta-thalassaemia major?
- Raises Hb
| - Suppresses erythropoietic production
54
What are the complications of lifelong transfusions for beta-thalassaemia major?
- Progressive iron overload
- Transfusion related viral infection
- Development of red cell abnormalities
55
How is the extent of iron overload caused by transfusion in beta-thalassaemia major measured?
Monitoring serum ferritin levels
56
How is iron overload treated?
Iron chelation therapy
57
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
58
How was iron chelation therapy traditionally given?
Subcutaneous infusions of desferrioxamine
59
How is iron chelation therapy now given?
Oral preparations of desferrioxamine
60
How are iron levels monitored in children receiving transfusion for beta-thalassaemia?
- Serum ferritin
| - Assessment of potential sites of iron deposition
61
How often should serum ferritin be monitored in children with beta-thalassaemia being treated with transfusions?
3 monthly
62
How often should children receiving transfusions for beta-thalassaemia major have potential sites of iron deposition assessed?
1-2 year intervals
63
Where should be assessed for potential iron deposition in children with beta-thalassaemia major being treated with blood transfusion?
- Heart
| - Liver
64
How is iron deposition tested in children with beta-thalassaemia major being treated with blood transfusions?
MRI scans
65
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
66
How is beta-thalassaemia major cured?
Haemopoietic stem cell transplant
67
What is the limitation of haemopoietic stem cell transplant as a treatment for beta-thalassaemia major?
It carries significant risks
68
How is maternal screening for haemoglobinopathies carried out?
- FBC
| - HPLC
69
When is maternal screening for haemoglobinopathies part of routine antenatal testing?
In areas where there is a high prevalence of carriers
70
In low prevalence areas, who is targeted antenatal screening for haemoglobinopathies done in?
Women from ethnic groups at highest risk
71
Which ethnic groups are at highest risk of haemoglobinopathies?
- African
- Caribbean
- Indian subcontinent
- Mediterranean
72
Is newborn haemogloblinopathy screening performed in the UK?
Yes
73
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
74
What recently development has allowed for the prevention of haemoglobinopathies?
Pre-implantation g genetic diagnosis
75
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
76
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
77
What ethnicities does sickle cell disease predominantly affected?
- African
- Caribbean
- Middle Eastern
- Indian
78
What is the genetic abnormality in sickle cell disease?
Point mutation in beta-globin gene
79
What is the mutated beta-globin gene in sickle cell disease known as?
ßs-globin
80
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
81
What is the amino acid change in sickle cell disease?
Valine for glutamine
82
What is the haemoglobin chain produced in sickle cell known as?
HbS
83
How does HbS cause problems?
- Relatively insoluble
| - Polymerises when exposed to low oxygen tension
84
What does the polymerisation of HbS at low oxygen tension lead to?
The formation of characteristic sickle cells
85
How do sickle cells differ from normal haemoglobin cells?
They are dehydrated, rigid, and less deformable than normal red cells
86
What is the result of sickle cells being rigid and less deformable?
They can obstruct blood flow in the microcirculation
87
What predisposes to sickle cell crises?
Any factor which increases the risk of polymerisation
88
What factors are protective against sickle cell crises?
- Optimal hydration
- Oxygenation
- Increased quantities of HbF
89
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
90
What are the most common types of SCD?
- Sickle cell anaemia
- HbSC diseaes
- S ß-thalassaemia
91
What is the genetic abnormality in sickle cell anaemia?
Homozygous for beta-globin mutation (HbSS)
92
What is the genetic abnormality in HbSC disease?
Single beta-globin mutation in combination with HbC mutation (HbSC)
93
What is the genetic abnormality in S ß-thalassaemia?
People with ß-thalassaemia mutation in combination with ßS-globin
94
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
95
Which of the sickle cell diseases are most severe?
Sickle cell anaemia
96
Which of the sickle cell disease are least severe?
HbSC disease
97
What are the clinical features of all forms of sickle cell diseases?
- Chronic haemolytic anaemia
| - Prone to recurrent sickle cell crises
98
How might sickle cell crises present?
- Veno-occlusive (painful) crisis
- Sickle chest crisis
- Splenic/hepatic sequesteration
- Aplastic crisis
- Cerebral infarction
99
What causes aplastic crises in sickle cell disease?
Parvovirus B19 infection
100
What is the incidence of cerebral infarction in sickle cell disease?
11%
101
How is the incidence of cerebral infarction in sickle cell disease reduced?
Regular screening
102
What is the incidence of cerebral infarction in children with sickle cell disease who undergo regular screening?
<5%
103
How is sickle cell disease diagnosed?
HPLC
104
Can patients with sickle cell anaemia produce HbA?
No
105
What globins to patients with sickle cell anaemia rely on?
HbS and small amounts of HbF
106
What is the management of sickle cell disease aimed at?
- Preventing complications
| - Symptomatic treatment of painful sickle crises
107
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
108
What factors may precipitate a sickle cell crisis?
- Cold
- Dehydration
- Over-strenuous exercise
109
What kind of organisms need to be prevented against in sickle cell disease?
Encapsulated organisms
110
Give 2 examples of encapsulated organisms?
- Pneumococcus
| - Meningococcus
111
How is infection with encapsulated organisms prevented in sickle cell disease?
- Twice daily penicillin prophylaxis
| - Vaccination
112
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
113
Why is folic acid supplementation required in sickle cell disease?
Because of increased folate need due to chronic haemolysis
114
Is the severity of SCID variable?
Yes, very
115
What is the aim of treatments in SCID?
To modify the severity and natural history of the disease
116
What treatments are available for SCID?
- Hydoxycarbamide
- Regular blood transfusion
- Haematopoietic stem cell transplantation (HSCT)
117
What is the effect of hydroxycarbamide in sickle cell disease?
It reduces the occurrence of crises
118
How does hydroxycarbamide reduce the occurrence of crises in sickle cell?
It inhibits ribonucleotide reductase, which increases HbF
119
What is the purpose of regular blood transfusion in sickle cell disease?
- Prevent stroke
| - Reduce sickle chest crises
120
How often are blood transfusions given when used in sickle cell disease?
Monthly
121
When are regular blood transfusions used for the prevention of sickle chest crises in sickle cell disease?
When hydroxycarbamide has been ineffective
122
What is required when regular blood transfusions are used for more than a year in sickle cell disease?
Iron chelation therapy
123
When is HSCT used in sickle cell disease?
- CNS disease
- Recurrent chest crises
- Painful crises despite hydroxycarbamide treatment
124
What is the pathogenesis of stroke in children with sickle cell disease?
Cerebral vasculopathy
125
What vessel is particularly affected by cerebral vasculopathy in sickle cell disease leading to stroke?
Middle cerebral artery
126
What investigation finding correlates with the presence of cerebral vasculopathy in sickle cell disease?
Increased MCA blood flow on transcranial doppler scanning
127
What is the presumed mechanism of cerebral vasculopathy in sickle cell disease?
Chronic intravascular haemolysis
128
What is the best known method for reducing intravascular haemolysis in sickle cell disease?
Regular red cell transfusion
