103 - Heart, Lungs and Blood

• sickle cell disease

  •Caused by a point mutation in b globin gene•Homozygous recessive disease (carriers are heterozygous)•Substitution of valine to glutamic acid at 6th amino acid position causes HbS (substitution of valine to lysine causes HbC)••On deoxygenation, HbS forms parallel aggregates•Valine substitution stabilises this conformational change causing sickling (aggregate formation) – this is a qualitative Hb change•Red cell shape is deformed into sickle shape
• sickle cell disease

  
• what disease morphology is this ?

  sickle cell disease

  
• sickle cell anemia

  •Patients inherit sickle b globin genes from each parent••Sickle cell trait is a single sickle b globin gene•This is generally asymptomatic••If both parents have sickle trait, then there is a 25% chance of the offspring inheriting both sickle genes••HbC is genetic variant of sickle Hb (6th aa, lysine)•HbSC disease clinically very similar to SS disease
• sickle cell anaemia

  •Increased mechanical fragility of red cells in sickle cell disease results in shortened lifespan (approx 10 days)••Crises are caused by pathological effects of sickled red cells in the blood vessels••The rigidity of sickle cells results in increased blood viscosity with occlusion of small blood vessels••Adhesion of sickle cells to endothelium blocks vessels
• sickle cell anemia

  •Primarily affects Black Afro-Caribbean population••Also present in India, Middle East and North Africa••Distribution of SCD correlates with regions where malaria is endemic (Plasmodium falciparum carried by female Anopheles mosquito)••Small selective advantage of sickle trait against malaria infection
• global disease burden

  •Most common  genetic haemoglobinopathy•Estimated 6 million individuals are affected globally•Over 275,000 children are born with SCD annually•80% global SCD burden in Africa••UK:•12,500 to 15,000 people living with SCD in UK•240,000 sickle cell trait carriers in the UK
• sickle cell anaemia

  •Most common  genetic haemoglobinopathy•Estimated 6 million individuals are affected globally•Over 275,000 children are born with SCD annually•80% global SCD burden in Africa••UK:•12,500 to 15,000 people living with SCD in UK•240,000 sickle cell trait carriers in the UK
• sickle cell anemia

  •Median survival without good management•42 years men•46 years women••Anaemia compensated by increase in 2,3-DPG••This moves the oxygen dissociation curve to the right••Oxy-haemoglobin releases its oxygen to the tissues at higher levels of tissue oxygen
• is HbS high or low affinity Hb ?

  HbS is a low affinity Hb

  
• clinical features of anaemia ?

  •Presentation in infancy (newborns protected by HbF)

  •Chronic anaemia and intermittent jaundice

  •Recurrent classical vaso-occlusive crises

  •Major complications include chest crisis and stroke

  •Numerous other complications:

  •Splenic sequestration in children

  •Avascular necrosis of femoral heads – hip arthritis

  •Dactylitis, epiphyseal damage and shortened digits

  •Risk of pneumococcal septicaemia

  •Priapism

  •Gallstones
• Vaso-occlusive crisis

  
• life threatening complications of SCD

  •Chest syndrome•Progressive hypoxia +/- fever

  •Pleuritic chest pain, patchy shadowing on CXR

  •Brain syndrome

  •Presents as stroke

  •Indication for exchange transfusion programme

  •Aplastic crisis

  •Associated with parvovirus infection

  •Causes transient severe fall in Hb level

  •Acute sepsis•Caused by hyposplenism

  •Major cause of death in Africa
• Dactylitis ?

  its a condition where the fingertips ar elost due to infarction

  
• SCD Blood Film features ?

  sickle cell blood film

  
• how do you diagnose SCD ?

  sickle cell solubility screening test

  it is positive for both sickle carrier and disease

  
• preventative management of SCD

  •Antenatal screening•Carried out in high prevalence areas•Can provide suitable genetic counselling at birth•

  •Prophylaxis against infections•Penicillin prophylaxis•Vaccination•Pneumovax / meningovax / haemophilus (HIB)•

  •Prevention of crises•Avoid infections, hypoxia, dehydration•Hydroxycarbamide, exchange transfusions
• SCD - Management of crises

  •Exclude underlying infection•Oxygen•Analgesia•NSAID’s•Opiates (morphine – sub-cut injections weaned to oral)•Avoid pethidine (seizures and addiction)•Intravenous fluids•Antibiotics•Monitor FBC and reticulocyte count
• prevention of stroke - SCD

  •STOP trial, 1998•Transcranial Doppler scan predictive of stroke•If blood flow >200cm/sec the risk of stroke is significantly increased•Risk reduced by exchange transfusions•Aim to reduce HbS level to below 30%•Hydroxycarbamide therapy if unable to transfuse
• exchange transfusion - SCD

  •Manually or with cell separator machine•Aim to reduce HbS level to <30%•Extended blood cross-matching to get good blood match•Indications:•Chest syndrome•Stroke•Major surgery•Recurrent severe crises•Priapism
• what are the complications of sickle cell disease ?

  •Sepsis•Bone infarcts •Avascular necrosis of femoral/humoral heads•Gallstones (pigment stones)•Proliferative retinopathy•Osteomyelitis (salmonella)•Papillary necrosis/renal failure•Leg ulcers
• hydroxycarbamide therapy

  •Landmark paper in the NEJM 1995•Trial of hydroxycarbamide showed it reduced the frequency of crises, chest syndromes and transfusions in SCD••Hydroxycarbamide (also known as hydroxyurea):•Ribonucleotide reductase inhibitor•Induces stress haematopoiesis•Increases in HbF (fetal Hb) production•Reduces WCC and platelets•Reduces expression of adhesion molecules•Increases nitric oxide production
• globin gene loci

  
• Hb gene switching

  
• hereditary persistence of FH

  
• allogeneic stem cell transplant

  •Transplantation - potentially curative in sickle cell disease•Survival 90-95%, 80-85% cured•Patients usually below 16 years•SCT may be indicated in patients with history of strokes, recurrent chest syndromes or severe painful crises•Post-transplant infertility is likely•5-10% risk of chronic GvHD

  
• gene therapy for SCD

  •Gene therapy:

  1. to correct the beta-globin mutation

  2) to increase expression of fetal HbF

  ••Targeting BCL11a to reactivate gamma globin•CRISPR therapy – to delete the BCL11a gene, increase HbF•shRNA silencing – to knockdown BCL11a gene, increase HbF

  
• voxelotor - to disrupt polymerization of HbS Hb