Sickle Cell Disease PDF

Sickle Cell Disease UK 15,000 total Life Expectancy 40-60 years GLOBAL 300,000 born annually 50-90% child mortality Genetic Basis Single base change (A → T) mutates glutamic acid...

Sickle Cell Disease UK 15,000 total Life Expectancy 40-60 years GLOBAL 300,000 born annually 50-90% child mortality Genetic Basis Single base change (A → T) mutates glutamic acid (charged) → valine (neutral) on the 6th position of a beta globin chain The balanced polymorphism arrives from the heterozygous advantage of malaria immunity Sickle haemoglobin interacts with actin in the RBC’s cytoskeleton Prevents parasite entering cytoskeleton (& prevents the parasite making the cell “sticky”) Biochemical Basis Change in charge causes structural change that exposes the valine Change in structure exposes valine at the deoxygenated Hb surface Valine allows hydrophobic interactions with other Hb molecules Can polymerise into long chains (deoxygenated) Distorts RBC into a long form, with sharp ends Prevents normal flexing - impaired blood flow 💡 Sickling shape is reversible Sickle Cell Disease 1  Sickling reverses when the RBC returns to high oxygen levels Sickle cells have a range of shapes True sickle Boat New blue shaded Reticulocytes Dense irregular Target 💡 Sickling is not an immediate process Slow step: Nucleation Rapid step: Chain formation Most cells return to the lungs and reoxygenate before major sickling occurs 💡 Babies do not get sickle cell, as they do not contain beta haemoglobin chains Babies under 3 months have HbF in place of Hb-beta Some individuals have a hereditary persistence of foetal haemoglobin (HPFH), allowing a concentration of up to 20% of HbF in adult RBCs The effects of SCD are only evident during 1. Chronic RBC damage Irreversible haemoglobin polymerisation Haemoglobin denatures Sickle Cell Disease 2  Permanent partial shape change - boat cells Damaged membrane pumps - cell dehydration Reduces RBC survival to 8 days (from 120) RBC production in increased to compensate, but not enough Results in chronic anaemia Haemoglobin levels half to 70g/l from (135) 2. Acute crisis Hypoxia Fever Dehydration If sickle cells enter small vessels in their sickle shape, they cannot flow This blocks the vessels and thus blood supply This causes tissue damage Chronic Effects Chronic anaemia Bone pain Can damage growth-plate in developing children Dead bone has a high chance of infection Stroke White matter = dead brain tissue Spleen infection Repeated sickling destroys tissue Causes fibrosis and calcification Spleen becomes non-functional & can’t capture bacteria Chest crisis Blocks oxygen uptake in capillaries at the lungs Sickle Cell Disease 3  Further hypoxia & sickling Heart under stress to increase blood flow Treatments Mild cases: Pain relief Improves Movement/Breathing/Self-care Hydration Preserves blood flow and RBC hydration Reverse cause of ongoing sickling Severe cases: Transfusion Increase healthy haemoglobin & oxygen levels Exchange transfusion For life-threatening cases Decreases sickle cells to < 30% Experimental therapies* Long term: Preventative measures Education Screening Vaccination (e.g. Malaria) Antibiotics Folic acid (supports RBC production) Modify RBC physiology Increases foetal haemoglobin Sickle Cell Disease 4  Hydroycarbamide drug - raises HbF Chronic transfusion Replaces all sickle blood for healthy blood Bone marrow transplant *Experimental therapies Gene therapy Replace sickle haemoglobin Increase HbF Anti-sickling molecules Prevent sickle haemoglobin interactions Anti-adhesion molecules Prevent RBC adhesion Modify vascular tone Relax capillaries to improve blood flow Diagnosis 1. Cell biological approach: Look for sickle cells i.e. Blood smear Cheap Fairly rapid Low sensitivity in patients with few sickle cells Requires expertise Not good for complex diagnosis (multiple problems affecting cel shape) 2. Physiological approach: Detect sickle haemoglobin polymerisation i.e. Sickle test Sickle Cell Disease 5  Lyse RBCs with detergent & add reducing agent Normal: Clear suspension of monomers Sickle: Cloudy suspension of polymers Cheap Rapid Very Sensitive Minimal training Doesn’t distinguish homo/heterozygotes 3. Biochemical analysis: Detect abnormal charge properties of haemoglobin Different charges cause haemoglobins to travel at different rates in an electrical field (flat-bed electrophoresis or high-pressure column chromatography) Sickle haemoglobin moves slower Accurate Good for complex cases Not too expensive Scalable for multiple samples Slow Requires expertise to interpret gel/spectra 4. Gene analysis: Detect typical mutation Accurate Good for complex cases Expensive Slow Requires expertise Often used in pre-natal testing, where accuracy is essential Sickle Cell Disease 6