3.1. Red Cells - Physiology and Congenital Anaemias Flashcards
What is Anaemia?
Reduction in Red Cells or their Haemoglobin Content due to:
- Blood Loss
- Increased Destruction
- Lack of Production
- Defective Production
What is the Red Cell Production Pathway in Marrow?
- Stem Cell - Haemocytoblast
- Committed Cell - Proerythroblast
Development Pathway: - Early Erythroblast - Ribosome Synthesis (Phase 1)
- Late Erythroblast - Haemoglobin Accumulation (Phase 2)
- Normoblast - Ejection of Nucleus (Phase 3)
- Reticulocyte - These can also appear in the Blood
- Erythrocyte
What Substances are Required for Red Cell Production?
- Metals - Iron / Copper / Cobalt / Manganese
- Vitamins - B12 / Folic Acid / Thiamine / B6 / C / E
- Amino-Acids
- Hormones - Erythropoietin / GM-CSF / Androgens / Thyroxine / SCF
In what System does Red Cell Breakdown occur?
The Reticuloendothelial System
What happens to the:
- Globin, in the Reticuloendothelial System?
- Haem, in the Reticuloendothelial System?
- Amino-Acids are Reutilised
- a) Iron - Reutilised, forming Bilirubin
- b) (Unconjugated) Bilirubin is Bound to Albumin and transported to the Liver in the Blood
- c) Bilirubin is Conjugated in the Liver to form Urobilinogen which is Excreted
What are the 3 areas which Erythrocyte Genetic Defects occur in?
- Cell Membrane - Skeletal Proteins
- Cell Enzymes (Metabolic Pathways)
- Haemoglobin
Note - These result in Reduced Erythrocyte Survival
What is the most common Cell Membrane Erythrocyte Genetic Defect?
Hereditary Spherocytosis (Red Cells are Spherical) - Defect in:
- Ankyrin
- Alpha Spectrin
- Beta Spectrin
- Band 3
- Protein 4.2
What is the Clinical Presentation of Hereditary Spherocytosis?
- Anaemia
- Jaundice (Neonatal)
- Splenomegaly
- Pigment Gallstones
Note - Due to these Cells being Abnormal, they are removed quicker from Circulation by the Spleen
What is the Treatment of Hereditary Spherocytosis?
- Folic Acid (Increased Requirements)
- Transfusion
- Splenectomy - Remove the Site of Destruction
What are Rare Cell Membrane Erythrocyte Genetic Defects?
- Hereditary Elliptocytosis
- Hereditary Pyropoikilocytosis
- South-East Asian Ovalocytosis
What is the Most Common Cell Enzyme (Metabolic Pathway) Erythrocyte Genetic Defect?
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Note - There are Many Genetic Variants
Note - This is X Linked (Affects Males, Female Carriers)
What is the Function of Glucose-6-Phosphate Dehydrogenase (G6PD) in the Normal Erythrocyte?
It is involved in Producing NADPH which protects against Oxidative Damage
What is the Clinical Presentation of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency?
- Neonatal Jaundice
- Drug / Broad Bean / Infection Precipitated Jaundice and Anaemia - Intravascular Haemolysis / Haemoglobinuria
- Splenomegaly
- Pigment Gallstones
In Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, what are the Triggers of Haemolysis?
- Infection
- Acute Illness - DKA
- Drugs:
- a) Antimalarials - Primaquine / Pamaquine
- b) Antibacterials - Nitrofurantoin
- c) Analgesics - Aspirin
What is the other Rare Cell Enzyme (Metabolic Pathway) Erythrocyte Genetic Defects?
Pyruvate Kinase Deficiency
What is the Function of Haemoglobin?
Gas Exchange:
1. O2 to Tissue
2. CO2 to Lungs
Note - Changes with the Oxygen Dissociation Curve
What are the Components of Adult Haemoglobin?
Haem Molecule +
1. 2 x Alpha Chains
2. 2 x Beta Chains
Note - Alpha / Beta Genes on Different Chromosomes
Note - Normal Adult Haemoglobin: Hb A (AABB) - 97% / Hb A2 (AADD) - 2% / Hb F (AAGG) - 1%
What are the Common Haemoglobinopathies?
- Mutations leading to Structurally Abnormal Globin Chain - HbS (Sickle Cell) / HbC / HbD / HbE / HbOl
- Reduced / Absent Globin Chain Production - Thalassaemia (Alpha / Beta / Delta / Gamma)
What type of Inheritance are Haemoglobinopathies?
Autosomal Recessive:
1: 4 - Normal
1: 2 - Carrier
1: 4 - Affected
Where is the Point Mutation in Sickle Cell Disease?
Sickle Haemoglobin (HbS) composed of Haem + :
- 2 x Alpha Chains
- 2 x Beta (Sickle) Chains
What is the Consequence of HbS Polymerisation?
- Red Cell Injury / Cation Loss / Dehydration
- Haemolysis
- Endothelial Activation / Promotion of Inflammation
- Coagulation Activation / Dysregulation of Vasomotor Tone by Vasodilator Mediators
- Vaso-occlusion
What is the Clinical Presentation of Sickle Cell Disease?
- Painful Vaso-Occlusive Crises - Bone
- Chest Crisis
- Stroke
- Increased Infection Risk - Hyposplenism
- Chronic Haemolytic Anaemia - Gallstones / Aplastic Crisis
- Sequestrian Crisis - Liver / Spleen
- Reduced Life Expectancy
What is the Management of Sickle Cell Disease?
- Life Long Prophylaxis - Vaccination / Folic Acid
- Hydration / I.V. Fluids
- Oxygenation / Respiratory Support
- Prompt Treatment of Infetcion - Antibiotics
- Analgesia - Opiates / NSAID’s
- Transfusion - Chest Crisis / Iron Overload / Alloimunusation / Episodic and Chronic
- Disease Modifying Drugs - Hydroxycarbamide
- Bone Marrow Transplantation
- Gene Therapy
What is the Pathology of Thalassaemia?
Reduced / Absent Chain Production due to Mutations / Deletions.
You normally get 2 Alpha Chains from the Mother, and 2 from the Father, but in this:
1. 1 x Alpha + 2 x Alpha = “a+”
2. 0 x Alpha + 2 x Alpha = “a0”
The Chain imbalance causes Chronic Haemolysis and Anaemia
What is the Spectrum of Clinical Severity of Thalassaemia?
- Homozygous Alpha Zero Thalassaemia (a0a0) - No Alpha Chains = Incompatible With Life
- Thalassaemia Major (Homozygous Beta Thalassaemia) - No Beta Chains = Transfusion Dependent Anaemia
- Thalassaemia Intermedia (Non-Transfusion Dependent)
- Thalassaemia Minor - “Trait” / Carrier State
What is the Treatment of Beta Thalassaemia Major?
- Chronic Transfusion Support
- Iron Chelation Therapy
- Bone Marrow Transplant
