RBC: Congenital Anaemias Flashcards
What is anaemia?
Reduction in red cells or their haemoglobin content?
What is the aetiology of anaemia?
- Blood loss
- Increased destruction
- Lack of production
- Defective production
What substances are essential for red cell production in marrow?
- Iron
- B12
- Folic acid
- Erythropoietin
Where does red cell breakdown occur?
Reticuloendothelial system by macrophages in the spleen, liver, lymph nodes, lungs etc.
What are the products of red cell breakdown?
Globin
-Amino acids reutilised
Haem
- Iron reutilised
- Haem converted to bilirubin (bound to albumin in the plasma, unconjugated)
What are the components of the erythrocyte?
- Membrane
- Enzymes
- Haemoglobin
What types of genetic defects can cause congenital anaemias?
Genetic defects described
- In red cell membrane
- In metabolic pathways (Enzymes)
- In haemoglobin
What do most genetic defects of RBC/haemoglobin result in?
Reduced RBC survival by haemolysis
How do carried states of congenital anaemias present?
Often silent: asymptomatic
What maintains the shape of RBC?
Skeletal proteins
What do defects in skeletal proteins leads to?
Increased cell destruction
How is hereditary spherocytosis inherited?
Most common form is autosomal dominant
What is the hereditary spherocytosis?
Defects in 5 different structural proteins described
- Ankyrin
- Alpha Spectrin
- Beta Spectrin
- Band 3
- Protein 4.2
What is the pathogenesis of hereditary spherocytosis?
- Red cells are spherical
- They are removed from the circulation by the RE system (extravascular)
How does hereditary spherocytosis present?
- Anaemia
- Jaundice (neonatal)
- Splenomegaly
- Pigment gallstones
How is hereditary spherocytosis treated?
- Folic acid (increased requirements)
- Transfusion
- Splenectomy
Give examples of rare membrane disorders.
- Hereditary Elliptocytosis
- Hereditary Pyropoikilocytosis
- South East Asian Ovalocytosis
What are 2 importance enzyme pathways in RBCs?
Glycolysis
-Provides energy
Pentose phosphate shunt
-Protects from oxidative stress
What is the most common red cell metabolism disorder?
Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency
What does Glucose 6 Phosphate Dehydrogenase (G6PD) do?
Protects red cell proteins (Haemoglobin) from oxidative damage
- Produces NADPH - Vital for reduction of glutathione
- Reduced glutathione scavenges and detoxifies reactive oxygen species
Why are there high rates of G6PD deficiency in malarial areas?
Confers protection against malaria
What is the inheritance of G6PD deficiency?
X linked
- Affects males
- Female carriers
What types of RBC do you get in G6PD deficiency?
- Blister cells
- Bite cells
What is the clinical presentation of G6PD defiecency?
-Variable
-Neonatal Jaundice
Drug, broad bean or infection precipitated jaundice and anaemia (intravascular haemolysis, haemoglobinuria)
-Splenomegaly
-Pigment Gallstones
What can trigger haemolysis in G6PD deficiency?
- Infection/acute illness
- Broad beans
- Certain drugs
Name an enzyme deficiency apart from G6PD deficiency.
Pyruvate kinase deficiency
What is the pathogenesis of pyruvate kinase deficiency?
- Reduction in ATP
- Increase in 2-3DPG
- Cells become rigid
How does pyruvate kinase deficiency present?
- Variable severity
- Anaemia
- Jaundice
- Gallstones
What is the structure of haemoglobin?
4 globin chains
- 2 alpha
- 2 beta
4 haem groups containing iron
What is the function of haemoglobin?
Gas exchange
- O2 to tissues
- CO2 to lungs
What causes a compensatory shift in the oxygen dissociation curve?
- Acidosis
- Increase DPG
- Increased temperature
- Increased CO2
How does HbF affinity for oxygen compare to HbA?
It has a higher affinity for oxygen
What is the normal composition of adult haemoglobin?
Haem molecule and
- 2 alpha chains= 4 alpha genes (Chr16)
- 2 beta chains= 2 beta genes (Chr11)
What is the composition of haemoglobin in a normal adult?
- Hb A (aa,BB) =97%
- Hb A2 (aa,δδ) = 2%
- Hb F (aaγγ) =1%
What are haemoglobinopathies?
Inherited abnormalities of haemoglobin synthesis
How can haemoglobinopathies occur?
Reduced or absent globin chain production
-Thalassaemia (alpha α, Beta β, delta δ, gamma γ)
Mutations leading to structurally abnormal globin chain
-HbS (Sickle cell ), HbC, HbD, HbE, HbO Arab……
What is the inheritance of haemoflobinopathies?
Autosomal recessive inheritance
- 1 in 4 chance of having affected child
- 1 in 2 chance of being a carrier or “trait”
What is the composition of Sickle cell haemoglobin (HbS)?
Haem molecule and:
- 2 α chains
- 2 β (sickle) chains
What happens in Sicklce cell anaemia?
- Normally RBCs take up and give up oxygen without chnageing shape
- In Sickle cell anaemia, the cells become sickled in shape when they give up oxygen. This is irreversible
What are the consequences of HbS polymerisation?
- Red cell injury, cation loss and dehydration
- Haemolysis
- Endothelial activation
- Promotion of inflammation
- Coagulation activation
- Dysregulation of vasomotor tone by vasodilator mediators (NO)
- All leading to vaso-occlusion
What are the clinical presentations of sickle cell disease?
- Painful vaso-occlusive crisis (bone)
- Chest crisis
- Stroke
- Increased infection risk due to hyposplenism
- Chronic haemolytic anaemia (gallstones, aplastic crisis)
- Sequestration crises *spleen, liver)
What is the life expeactancy of sickle cell disease?
Median age of death
- Males 42
- Females 48
Childhood and perinatal mortality contribute to this reduction
What is the treatment for a painful crisis in sickle cell disease?
- Opiates ASAP for severe pain
- Hydration
- Oxygen
- Consider antibiotic
- Transfusion not routine
How does a sickle cell chest crisis present?
- Chest Pain
- Fever
- Worsening hypoxia
- Infiltrates on CXRay
How should a chest crisis in sickle cell disease be managed?
- Respiratory Support
- Antibiotics
- IV Fluids
- Analgaesia
- Transfusion – top up or exchange, target HbS <30%
What prophylactic treatment should those sickle cell disease receive?
Life long prophylaxis
- Vaccination
- Penicillin (and malarial) prophylaxis
- Folic acid
How should acute events be managed in sickle cell disease?
- Hydration
- Oxygenation
- Prompt treatment of infection
- Analgaesia (opiates or NSAIDs)
What treatment is there for sickle cell disease?
- Prophylaxis
- Acute event management
- Blood transfusion (beware of iron overloading)
- Disease modifying drugs: hydroxycarbamide
- Bone marrow transplantation reserved as a last resort
- Gene therapy in the future?
What is thalassaemia caused by?
Reduced or absent globin chains caused by mutations or deletion in alpha or beat genes
What does chain imbalance cause?
Chronic haemolysis and anaemia
What are the different types of thalassemia?
- Homozygous alpha zero thalassaemia
- Beta thalassaemia major
- Non-transfusion dependent thalassaemia
- Thalassemia minor
What happens in homozygous alpha zero thalassaemia?
- No alpha chains
- Hydrops Fetalis –incompatible with life
What happens in beta thalassaemia major?
- No beta chains
- Transfusion dependent anaemia
What happens in thalassaemia minor?
- ‘Trait’ or carrier state
- Hypochromic microcytic red cell indices
How does beta thalassaemia major present?
- Present at 3-6 months of age
- Expansion of ineffective bone marrow
- Bony deformities
- Splenomegaly
- Growth retardation
What is the prognosis of beta thalassaemia major?
Life expectancy untreated or with irregular transfusions <10 years
What is the treatment for beta thalassaemia major?
Chronic transfusion support - 4-6 weekly
- Normal growth and development
- BUT - Iron overload risk
- Death in 2nd or 3rd decades due to heart/liver/endocrine failure if iron loading untreated
Iron chelation therapy
- SC desferriozamin infusions or oral tablets
- Good adherence= life expectancy >40 years
Bone marrow transplant
-Curative
How do sideroblastic anaemias occur?
Defects in mitochondrial steps of haem synthesis
- ALA synthase mutations
- Hereditary (X-Linked)
- Aquired - Myelodysplasia
How do porphyrias occur?
Defects in cytoplasmic steps of haem synthesis
