Haemoglobinopathies (Thalassaemia & Sickle Cell) Flashcards
Describe haemoglobin structure
Tetramer with 4 haem groups (one attached to each globin)
Name the 4 different chains in the major forms of haemoglobin (HbA, HbA2, HbF)
•HbA 2 alpha chains and 2 beta chains α2β2
•HbA2 2 alpha and 2 delta chains α2δ2
•HbF 2 alpha and 2 gamma chains α2γ2
•In adults HbA is the major form present (~97%)
•In foetus HbF is the major form present
Describe how the form of Hb changes in early life and explain the clinical relevance of this
Prenatal/ foetus - HbF
Birth to ~6 months - Mix of HbA & HbF
~6 months onwards - HbA
Define haemoglobinopathy & state the two main types
Hereditary (monogenic, autosomal recessive) conditions affecting globin chain synthesis
1) Thalassaemia - decreased globin chain synthesis (quantity)
2) Sickle cell - abnormal globin chain (quality)
Define thalassaemia, state the two main types and describe the consequences
- Thalassaemia - Reduced globin chain synthesis resulting in impaired haemoglobin production
- Alpha thalassaemia; α chains affected
- Beta thalassaemia; β chains affected
- Inadequate Hb production => microcytic hypochromic anaemia
- If severe => ineffective erythropoiesis & haemolysis
Describe the difference between alpha thalassaemia trait vs disease (HbH disease) vs Hb Bart’s Hydrops Foetalis Syndrome
Alpha thalassaemia trait
- Missing one or two alpha genes
- Asymptomatic or mild anaemia with low MCV & MCH
Alpha thalassaemia disease (HbH disease)
- Missing three alpha genes (only have one)
- Anaemia with very low MCV & MCH
- Impaired erythropoiesis & Haemolysis (jaundice & splenomegaly)
Hb Bart’s Hydrops Foetalis Syndrome
- No alpha genes, HbF & HbA can’t be made
- Usually die in utero
How to rule iron deficiency out when diagnosing alpha/beta thalassaemia trait
Ferritin will be normal
Describe the difference between beta thalassaemia trait vs intermedia vs major
Beta thalassaemia trait (minor)
- Missing one or two beta genes
- Asymptomatic or mild anaemia, low MCV & MCH
Beta thalassaemia intermedia
- Missing three beta genes (only have one)
- Anaemia with very low MCV & MCH
- Impaired erythropoiesis & Haemolysis (jaundice & splenomegaly)
Bet thalassaemia major
- No beta genes, (only) HbA can’t be made
- lifelong transfusion dependency
What test is diagnostic for beta thalassaemmia trait
Raised HbA2
Why does beta thalassaemia major not present at birth
Only presents when HbF falls and HbA rises (~6 months)
Beta thalassaemia major initial and definitive management and explain how they each work.
Initial - Regular transfusion programme
- suppresses ineffective erythropoiesis
- allows normal growth and development
- must monitor for and then treat iron overload from transfusion
Definitive - Bone marrow transplant
- Not regularly done
- Must be carried out before complications
Iron overload consequences
Cardiac disease
- cardiomyopathy
- arrhythmias
Liver disease
- cirrhosis
- hepatocellular cancer
Endocrine
- impaired growth & puberty
- diabetes
- osteoporosis
Iron overload treatment
Iron chelating drugs e.g. desferrioxamine
(Bind to Fe and excrete)
Sickling disorders aetiology & pathophysiology
- point mutation causes an abnormal beta chain
- this creates a different Hb called HbS
- HbS polymerises in the cytoplasm when exposed to oxygen
- This changes the RBC shape and damages the membrane
Compare the two main types of sickling disorders (sickle cell disease)
Sickle cell trait (HbAS)
- one normal and one abnormal beta gene
- asymptomatic carrier (HbS levels too low to polymerise)
- may sickle in severe hypoxia (high altitude, anaesthesia)
Sickle cell anaemia (HbSS)
- two abnormal beta genes
- episodes of tissue infarction due to vascular occlusion (sickle crisis)
- chronic haemolysis
- hyposplenism due to repeated splenic infarcts
What is sickle crisis and what can precipitate it
Vaso-occlusion due to sickle cells
Leading to tissue ischaemia & pain
Preciptants include hypoxia, dehydration, infection, cold, stress
Sickle crisis management
- High flow oxygen
- IV analgesia & fluids
If severe e.g. (acute chest/stroke) - RBC exchange transfusion
If infection - antibiotics
What long term management measures are used to reduce the risk of death in patients with sickle cell anaemia.
- Prophylactic penicillin and vaccinations (to reduce risk of infection with hyposplenism)
- Folic acid supplements (to cope with increased RBC turnover)
- Hydroxycarbamide can reduce severity of disease by inducing HbF production
- Regular transfusion to prevent stroke in selected cases
Summarise investigation for haemoglobinopathies
First line tests
- FBC, Hb, RBC indices
- blood film
- ethnic origin
Diagnostic tests
- High performance liquid chromatography or electrophoresis to quantify haemoglobin types present
What are the complications of beta thalassaemia major
- failure to thrive
Extramedullary haematopoiesis causing…
- Hepatomegaly & splenomegaly
- Skeletal changes
- Organ damage
Medulla overgrowth
- Front bossing
- Maxillary overgrowth
Summarise the diagnostic investigations for each type of alpha & beta thalassaemia
Alpha (diagnostic) - genetic testing
Beta trait (diagnostic) - raised HbA2 levels on HPLC or electrophoresis
Beta major (diagnostic) - HbF elevation on HPLC or electrophoresis
How would alpha thalassaemia differ from beta thalassaemia trait & beta thalassaemia major on a high-performance liquid chromatography/ electrophoresis? Why?
Alpha thalassaemia - Can be normal
Beta thalassaemia trait - Raised HbA2
Beta thalassaemia major - Raised HbF & mildly raised HbA2
Alpha globin is in all Hb (HbF, HbA, HbA2)
Beta globin is only in HbA
HbF levels increase as severity of beta thalassaemia increases
If a patient came in and you suspected thalassaemia, what investigation would you order?
- FBC & RBC indices (microcytic, hypochromic anaemia)
- Blood film (target cells with bull’s-eye appearance)
- Ferritin levels (to exclude iron deficiency)
- Genetic testing (in alpha thalassaemia)
- HPLC or electrophoresis (in beta thalassaemia)
Summarise Alpha & beta thalassaemia management
- ‘Minor’ disease - may not require treatment
- ‘Severe’ disease - lifelong blood transfusions
Other treatments
- Splenectomy in HbH disease (controversial)
- Bone marrow transplant (if before complications, can be curative)
What drug can be used in severe sickle crisis to stimulate HbF production and what risks does it have?
Hydroxycarbamide
- It stimulates HbF production
- It also interferes with blood cell DNA production
- bone marrow suppression & pancytopenia
- It also reduces fertility
Sickle cell patients have an increased risk of pulmonary hypertension. True or False?
True
First line & diagnostic investigations for sickle cell disease (trait/ anaemia).
First line - FBC, Hb, RBC indices, blood film
Diagnostic - HPLC or electrophoresis (show abnormal HbS)
What is the cause, symptoms/signs and management of acute chest syndrome in sickle cell disease
Aetiology
- infection,
- fat embolism from necrotic bone marrow,
- pulmonary infarction due to sequestration of sickle cells
Symptoms/Signs
- SOB,
- Chest pain,
- Pyrexia,
- Hypoxia
- New X-ray consolidation
Management
- Similar to sickle cell crisis
+/- antibiotics if infection
+/- blood transfusion
+/- hydroxycarbamine
How many alpha and how many beta genes are there
Alpha - 4
Beta - 2
