Haemoglobinopathies Flashcards
What are the major forms of haemaglobin?
HbA (2 alpha and 2 beta)
HbA2 (2 alpha and 2 delta)
HbF (2 alpha and 2 gamma)
What are the proportions of each form of haemaglobin in adults?
HbA = 97% HbA2 = 2.5% HbF = 0-0.5%
What chromosome codes for alpha globin genes and how many are present?
Chromosome 16
2 alpha genes per chromosome (4 per cell)
What chromosome codes for beta globulin genes and how many are present?
Chromosome 11
One beta gene per chromosome (2 per cell)
At what point are adult levels of Hb reached in a child?
6-12 months - this is when beta chain problems will present
What are haemoglobinopathies?
Hereditary conditions affecting globin chain synthesis
What inheritance do haemoglobinopathies show?
AR
What are the 2 main groups of haemoglobinopathies?
Thalassaemias; decreased rate of globin chain synthesis
Structural haemaglobin variants; normal production of abnormal globin chain (variant haemaglobin e.g. HbS)
What are the different forms of thalassaemias?
Alpha
Beta
On FBC, how will thalassaemias present?
Microcytic, hypochromic anaemia with a normal ferritin
What are the consequences of thalassaemias?
Inadequate Hb production
Haemolysis
Ineffective erythropoiesis
What forms of Hb will be affected in alpha thalassaemia?
ALL forms; HbA, HbA2 and HbF
How are alpha thalassaemia’s classified?
Based on the number of alpha genes affected
What is alpha thal trait?
One or two alpha genes missing
What is HbH disease?
Only one alpha gene left out of 4
What is Hb Barts hydrops foetalis?
No functional alpha genes; tends to die in utero
Will people with alpha thalassaemia trait be symptomatic?
No; no treatment needed
Microcytic, hypochromic red cells with mild anaemia may be seen
Need to distinguish from iron deficiency (ferritin normal)
How will HbH disease present?
Anaemia with a very low MCV and MCH
Jaundice
Splenomegaly
What will HbH look like on a blood film?
Excess beta chains will form tetramers; HbH
Red cell inclusions of HbH can be seen with special stains
Does HbH disease require treatment?
May require transfusions
What is Hb Barts?
Tetramers of gamma Hb produced
How can Hb Bart’s Hydrops Foetalis Syndrome be avoided?
Antenatal screening
What are the clinical features of Hb Bart’s Hydrops Foetalis Syndrome?
Profound anaemia Cardiac failure Growth retardation Severe hepatosplenomegaly Skeletal and CV abnormalities Almost all die in utero May see nucleated red cells due to ineffective marrow funciton
By what genetic mechanism is beta thalassaemia caused?
Point mutations
Reduced beta or absent beta chain production depending on mutation
Only beta chains and hence only HbA affected
How is beta thalassaemia classified?
Clinical severity
Describe beta thalassaemia trait?
Asymptomatic, no/mild anaemia, low MCV/ MCH
Raised HbA2
What is the diagnostic test for beta thalassaemia?
Raised HbA2 (alpha and delta chained Hb)
Describe beta thalassaemia intermedia?
Moderate severity requiring occasional transfusion (similar to HbH)
Describe beta thalassaemia major?
Severe, lifelong transfusion dependency
When will beta thal major present?
6-24 months as HbF fallls
Pallor, failure to thrive
Extramedullary haematopoiesis
What will beta thal major show on Hb analysis?
Mainly HbF
No HbA
What are the signs of extramedullary haematopoiesis?
Hepatosplenomegaly
Frontal bossing
“Hair on end” appearance to skull
Spinal cord compression
What is the management of beta thal major?
Regular transfusion programme to maintain Hb at 95-105 g/L (suppresses ineffective erythropoiesis and inhibits over-absorption of iron)
What does regular blood transfusions allow for in beta thal major?
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
What are the consequences for iron overload?
Endocrine; impaired growth and pubertal development
Diabetes
Osteoporosis
Cardiac: cardiomyopathy, arrhythmias
Liver disease: cirrhosis, hepatocellular cancer
Why is iron overload so common in beta thal major/
Each unit of red cells contains 250mg
In beta thal major you will give 2-3 units every 3 weeks
Chronic anaemia drives increased iron absorption
Venesection not feasible as already anaemic
What is the treatment for iron overload in beta thal major?
Iron chelating drugs e.g. desferrioxamine
Chelators will bind to iron which is then excreted
What are complications specific to blood transfusions in beta thal major?
Viral infection; HIV, hep B and C
Alloantibodies
Transfusion reactions
Increased risk of sepsis
What causes sickle cell disease?
Point mutation in codon 6 of the beta globulin gene that substitutes glutamine to valine producing betaS
Why will cells with beta S sickle?
HbS polymerizes if exposed to low oxygen levels for a prolonged period of time
This will distort the cell, damaging the RBC membrane
What is the genotype of sickle cell trait?
HbAS One normal, one abnormal beta gene Asymptomatic carrier state May sickle in severe hypoxia Blood film NORMAL
What will be seen on the blood film in HbSS?
Sickle cells
Target cells
What are the consequences of sickle cell anaemia?
Sickle crisis Chronic haemolysis Sequestration of sickled RBCs in liver and spleen Prothrombotic Hyposplenism (repeated splenic infarcts)
What causes a sickle crisis?
Sickle vaso-occulsion
Results in tissue ischaemia and pain
What can precipitate a sickle crisis?
Hypoxia Dehydration Infection Cold exposure Stress/ fatigue
How is a sickle crisis treated?
Opiate analgesia Hydration Rest Oxygen Antibiotics if evidence of infection Red cell exchange transfusion
When is a red cell exchange transfusion indicated?
Severe crisis;
Lung (vicious cycle of chronic hypoxia)
Brain (stroke)
What is the long term management of sickle cell anaemia?
Hyposplenism infection risk: HiB, meningococcus and pneumococcus vaccination. Penicillin prophylaxis Folic acid supplementation Vit B12 (induce HbF production) Regular transfusion
How is infection risk reduced in hyposplenism?
Prophylactic penicillin
Vaccination; pneumococcus, meningococcus, haemophilus
What bacteria are those with hyposplenism most susceptible to?
Encapsulated organisms - pneumococcus, meningococcus, haemophilus
What is HPLC used for?
Quantify Hb present; identified HbS, HbH and a raised HbA2
