Congenital Anaemias Flashcards
Define anaemia
Reduction in red cells/their Hb content
What can cause anaemia?
Blood loss
Decreased production
Increased destruction
Abnormal production
Where are red cells produced?
Bone marrow
What are the main substances required for the production of red cells?
Iron, B12, folate and erythropoietin
What is a reticulocyte?
A red blood that has just reached the circulation (still has a little bit of RNA in it)
How long do red blood cells live for?
120 days
Where is erythropoietin produced? What is its function?
Produced in kidneys
Function: stimulate red cell production
How are red cells broken down?
By reticuloendothelial system (i.e. macrophages in spleen and liver)
Globin broken down into amino acids, which can be built back into globin
Haem: iron reused, haem converted to biliverdin –> bilirubin
How can you divide up congenital anaemias?
Problems with:
Membrane
Enzymes
Haemoglobin
What are the characteristics of erythrocytes?
Deformable to allow them to move through vasculature
Biconcave disc
No nucleus
What do most congenital anaemias result in?
Haemolysis (as abnormal cells are produced which get broken down quicker in the blood)
What are the main proteins in the cell membrane of the red cells?
Ankyrin
Spectrin alpha and spectrin beta
Band 3
What are the function of proteins in the cell membrane of the red cells?
Maintaining red cell shape and deformability
What is hereditary spherocytosis?
Defects in proteins of red cell membrane lead to abnormally spherical shaped red cell which is removed from the circulation by the RES (in spleen)
What is the clinical presentation of hereditary spherocytosis?
Variable
Anaemia (increased red cell breakdown)
Neonatal jaundice (bilirubin rises, neonatal RES less able to cope)
Splenomegaly
Pigmented gallstones (precipitating of bilirubin)
How do you treat hereditary spherocytosis?
Folic acid
Transfusion (tends to be in acute situations, e.g. if someone unwell –> increased haemolysis)
Splenectomy (as spleen main site of red cell destruction)
What is the name of the system that protects red cells from oxidative damage?
Pentose phosphate shunt
What is the role of G6PD in protecting the cell from oxidative damage?
Increases level of reduced glutathione which breaks down free radicals into water
(only source of NAPDH which is vital for reduction of glutathione)
What occurs in G6PD deficiency?
Free radical’s damage the cell membrane leading to intravascular haemolysis
What is the appearance of the cells in G6PD deficiency?
Blister and bite cells (burst cells)
What kind of inheritance is G6PD deficiency?
X linked
What does G6PD deficiency confer a selective survival advantage against?
Malaria
What is the clinical presentation of G6PD deficiency?
Neonatal jaundice
Splenomegaly
Pigmented gallstones
TRIGGER that tends to cause symptoms
Intravascular haemolysis in G6PD deficiency can lead to what?
Haemoglobinuria which means haemoglobin leaks through the kidneys
What can trigger symptoms in G6PD deficiency?
Infection Acute illness, e.g. DKA Broad beans Antimalarials Antibacterials Aspirin (at high doses) Others
What does pyruvate kinase deficiency lead to?
Reduced ATP –> increased 2, 3-DPG –> cells become rigid and more liable to be haemolysed in the circulation
What is the presentation of pyruvate kinase?
Anaemia
Gallstones
Jaundice
What is the structure of haemoglobin?
4 globin chains
Haem
Relaxed when carrying oxygen 2, 3-DPG makes it tighter when giving away oxygen
What factors shift the Hb-Oxygen binding chart to the right (i.e. make Hb more likely to let go of its oxygen)?
Acidosis Hyperthermia Increased DPG Increased CO2 I.e. when you need oxygen
What is the function of haemoglobin?
Carry carbon dioxide to the lungs and oxygen to the tissues
How many genes code for alpha globin chains?
4 (2 x each parent)
How many genes code for beta globin chains?
2 (1 x each parent)
Which chromosome is the alpha gene on?
16
Which chromosome is the beta gene on?
11
What is HbA composed of and what % of blood does it make up?
2 alpha and 2 beta
97%
What is HbA2 composed of and what % of blood does it make up?
2 alpha and 2 delta
2%
What is HbF composed of and what % of blood does it make up?
2 alpha and 2 gamma
1%
If you have no functioning alpha genes how will you present?
No alpha genes incompatible with life
If you have no functioning beta genes what will happen?
Delta and gamma genes will compensate
Define thalassaemia
Reduced/absent globin chain production
What is the most common thalassaemia?
Sickle cell disease
What type of inheritance is sickle cell disease?
Autosomal recessive
What is the Hb like in sickle cell disease?
2 normal alpha chains
2 beta sickle chains (GLUTAMINE replaced by VALINE) –>
HbS
What is the problem with HbS?
HbS doesn’t respond well to hypoxia and crystallises (all the HbS’s stick together) and this forms a sickle shaped cell (this is irreversible)
What happens to the sickle cells in the vasculature?
Abnormal cells have a weak cell membrane and undergo intravascular haemolysis –> endothelial activation, promotion of inflammation, cogulation activation, dysregulation of vasomotor tone by vasodilator mediators (NO) –> vaso-occulsions
What is the clinical presentation of sickle cell disease?
PAIN - requiring opiates (due to vaso-occlusive crises, esp in bone)
Strokes
Chest crisis
Increased infection risk (infarcts of spleen/spleen atrophy –> increased infection)
Chronic haemolytic anaemia (gallstones, ,aplastic crisis)
Sequestration crises
What is an aplastic crisis?
When reticulocyte is reduced, e.g. during infection with Parovirus
In individuals with sickle cell disease, they rely on a high turn over of blood cells and can become very ill when not enough reticulocytes are being produced & present with acute severe anaemia
What are sequestration crises?
Blood pools due to occlusion of vessels
Occurs in liver and spleen
How do you manage a painful crisis of sickle cell disease?
Opiates (within 30m)
Hydration
Oxygenation
Consider antibiotics
Don’t transfuse
Find trigger
What occurs in sickle cell chest crisis?
Sickling in lung leads to hypoxia –> more sickling –> more hypoxia and so on
Can be lifethreatening
What are the symptoms/signs of sickle cell chest crisis?
Chest pain
Fever
Worsening hypoxia
Infiltrates on XRay
How do you treat sickle cell chest crisis?
Respiratory support Antibiotics IV fluids Analgesia Transfusion - get HbS <30%
What is involved in long term prophylaxis of sickle cell disease?
Vaccination
Penicillin and malarial prophylaxis
Folic acid
How do you treat acute events in sickle cell disease?
Hydration Oxygenation Prompt treatment of infection Analgesia (opiates, NSAIDs) ?Blood transfusion
What is the only disease modifying drug for sickle cell disease?
Hydroxycarbamide - increases Hb
What are last resort treatments for sickle cell disease?
Bone marrow transplantation and gene therapy - for high risk patients only
What is the name of the condition that results from homozygous alpha zero thalassaemia?
Hydrops fetalis
What is beta thalassaemia major?
Homozygous beta thalassaemia
No beta chains
Transfusion dependent
What are the non-transfusion dependent thalassaemias?
Smaller mutations of beta gene
may still require transfusions at time of stress
What is thalassaemia minor?
Trait/carrier state
May get hypochromic microcytic red cells (small red cells, mild anaemia)
What is the clinical presentation of beta thalassaemia minor?
Severe anaemia (present at 3-6 months) Expansion of ineffective bone marrow Bony deformities Splenomegaly (as spleen tries to make red cells and take over) Growth retardation
If beta thalassaemia isn’t treated what will occur?
Death
How do you treat beta thalassaemia major?
Chronic transfusion support every 4-6 weeks
BEWARE of iron overloading - so also require iron chelation therapy (s/c desferrioxamine until able to take oral deferasirox)
Bone marrow transplantation curative
What are sideroblastic anaemias?
Defects in mitochondrial steps of haem synthesis
