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?
- Metals: Iron, copper, cobalt, manganese
- Vitamins: B12, folic acid, thiamine, Vit.B6, C,E
- Amino acids
- Hormones: Erythropoietin, GM-CSF, androgens, thyroxine
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, but from red cell breakdown it is unconjugated)
What are the components of the erythrocyte?
- Membrane
- Enzymes
- Haemoglobin
Normal red cell life span
120 days
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 carrier states of congenital anaemias present?
Often silent: asymptomatic
What maintains the shape of RBC?
Skeletal proteins
What do defects in skeletal proteins lead to?
Increased cell destruction
How is hereditary spherocytosis inherited?
Most common form is autosomal dominant
What is hereditary spherocytosis?
- Defects in 5 different structural proteins
- Cannot form biconcave disc shape
- Forms spherocytes
- Removed from circulation faster by reticulendothelial system
- Patient becomes anaemiac
- More bilirubin generated so can become jaundiced (especially neonate)
How does hereditary spherocytosis present?
- Anaemia
- Jaundice (neonatal)
- Splenomegaly
- Pigment gallstones (due to higher concentration of bilirubin)
How is hereditary spherocytosis treated?
- Folic acid (increased requirements)
- Transfusion
- Splenectomy (in severe cases)
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 RBCs do you get in G6PD deficiency?
- Blister cells
- Bite cells
Consequence of G6PD Deficiency
Cells vulnerable to oxidative damage
What is the clinical presentation of G6PD deficiency?
- Variable degrees of anaemia
- Neonatal Jaundice
- 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 to the right in the oxygen dissociation curve?
- Acidosis
- Increase DPG
- Increased temperature
- Increased CO2
Oxyhaemaglobin gives oxygen to tissues more readily.
How does HbF affinity for oxygen compare to HbA?
It has a higher affinity for oxygen
What is the proportion of types 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
Pathophysiology of haemoglobinopathies
- 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
What is the inheritance of haemoglobinopathies?
Autosomal recessive inheritance
Carrier asymptomatic and protected from malaria.
What is the composition of Sickle cell haemoglobin (HbS)?
Haem molecule and:
- 2 α chains
- 2 β (sickle) chains
What happens in Sickle cell anaemia?
- Normally RBCs take up and give up oxygen without changing 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 crisis (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 antibiotics
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 with 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 beta 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
How do porphyrias occur?
Defects in cytoplasmic steps of haem synthesis
