Sickle cell anaemia

• Sickle cell disease (SCD) is the name given to a group of disorders associated with the deformation of red blood cells into a sickled shape
• Sickle cell anaemia (SCA) is the name given to the most common and serious form of SCD. SCA is caused by the inheritance of two abnormal sickle cell genes. 
• SCD is most commonly seen in patients of African and Caribbean ancestry
• Genetics:

  • Most common type of haemoglobin present in the foetus and neonate is haemoglobin F
  • HbF = 2 alpha chains and 2 gamma chains
  • Most common haemoglobin type in people older than 6 months is haemoglobin A
  • HbA = 2 alpha chains and 2 beta chains
• Genetics in sickle cell anaemia:

  • Single point mutation in the beta-globin gene on chromosome 11
  • Autosomal recessive
  • Amino acid replacement at position 6 in the beta-globin chain
  • Glutamic acid to valine
  • Results in sickled haemoglobin
  • In sickle cell anaemia - a mutation is present in both inherited beta-globin genes resulting in haemoglobin SS
• Pathophysiology:

  • Under physiological stress, sickled haemoglobin polymerises and causes erythrocytes to deform into a sickled shape
  • Hypoxia
  • Dehydration
  • Infection
  • Cold temperatures
  • Acidosis e.g. lactic acidosis following exertion
• Clinical features of SCA begin between three and six months of age as this is when HbF levels fall and the proportion of HbSS in the blood rises.
• Typical signs and symptoms:

  • Acute or chronic pain due to vaso-occlusion
  • Features of anaemia - pallor, weakness or lethargy
  • Growth restriction
  • Delayed puberty
  • Splenomegaly - due to increased haemolysis in the spleen
  • Recurrent infections - from encapsulated bacteria
  • Jaundice due to increased haemolysis
• SCA patients get recurrent splenic infarcts due to increased haemolysis - usually causes asplenism by 2 years of age
• Encapsulated bacteria:

  • Pneumococcus
  • Haemophilus influenzae type b
  • Meningococcus
  • Salmonella
• Over time, patients may adapt to the chronic anaemia but their disease is usually complicated by interspersed episodes of acute sickle cell crises
• Vaso-occlusive crises:

  • Most common reason for hospital admission
  • Sickled red blood cells can obstruct the microcirculation anywhere leading to severe pain and ischemia +/- infarction
• Vaso-occlusion, pain and ischemia commonly affect the following tissues:

  • Bones: leading to bone pain and avascular necrosis.
  • Joints: leading to painful swollen joints and dactylitis. More common in children.
  • Lungs: leading to chest pain, shortness of breath and tachypnoea. Up to 30% mortality in adult patients.
  • Brain: leading to headaches and strokes.
  • Bowel and mesentery: leading to abdominal pain and features of bowel ischemia.
  • Kidneys: leading to loin pain, renal papillary necrosis and haematuria.
  • Eyes: leading to retinal occlusion or a hyphaema.
  • Penis: leading to priapism.
• Acute chest syndrome:

  • Leading cause of death in patients with sickle cell anaemia
  • New pulmonary infiltrates on a chest x-ray with one or more of the following manifestations:
  • Fever
  • Cough
  • Tachypnoea
  • Dyspnoea
  • Sputum production
  • New-onset hypoxia
• Aplastic crisis:

  • Temporary cessation of erythropoiesis causing severe anaemia
  • Usually precipitated by infection with parvovirus B19
  • May present with high-output heart failure secondary to anaemia
  • Transfusion usually required
• Sequestration crisis:

  • Sudden enlargement of the spleen due to haemorrhage within it
  • Acute drop in haemoglobin
  • Markedly raised reticulocyte count
  • May lead to circulatory collapse and hypovolemic shock
  • Recurrent splenic sequestration is an indication for splenectomy
  • Occurs mainly in babies and young children.
• On examination, typical clinical findings may include:

  • Conjunctival pallor +/- pallor: due to anaemia
  • Dactylitis: due to vaso-occlusion in fingers and toes
  • Jaundice: due to chronic haemolysis
  • Splenomegaly: due to chronic haemolysis
• Relevant laboratory investigations in the context of SCD/SCA, include:

  • FBC: Hb 60-80g/L, with a high reticulocyte count of 10-20% is often normal for the patient
  • Blood film: sickling of erythrocytes and features of hyposplenism including target cells and Howell-Jolly bodies (Figure 3)
  • Sickle solubility test: when blood with HbS is mixed with sodium dithionite a precipitate is formed and the solution becomes turbid. When blood with normal haemoglobin is mixed with sodium dithionite the solution remains clear.
  • Haemoglobin electrophoresis (this is required for diagnosis)
• In the UK, screening for SCD is offered to all newborn babies:

  • Neonatal heel prick blood spots are collected 3 to 10 days after birth for haemoglobin analysis.
• Haemoglobin electrophoresis is necessary for a diagnosis of SCD/SCA to be made. The following are typically found in the context of SCD/SCA:

  • Sickle cell anaemia: there is no HbA, 80-95% HbSS and 1-20% HbF
  • Sickle cell trait: both HbA and HbS are present on electrophoresis
• Preventative management:

  • Avoid potential triggers
  • Oral penicillin prophylaxis - until at least age 5 but often life long
  • Vaccinations for meningococcus, pneumococcus, hepatitis B and influenza
• Prevention of severe anaemia:

  • Folic acid supplementation is given(increased red cell synthesis due to chronic haemolysis leads to increased folate requirements).
• Blood transfusions:

  • Top up transfusions may be required if the patient is severely anaemic or the proportion of HbSS in the blood needs to be reduced when an acute complication is present
  • Exchange transfusion - less chance of hyper viscosity
  • Iron chelation therapy
• Hydroxycarbamide:

  • One daily medication
  • Increases HbF production and thus reduces the proportion of HbS in the blood
  • Offered to all patients over 9 months
  • Contraindicated in pregnancy
• An allogeneic bone marrow transplant is potentially curative.

  Bone marrow transplant is only offered in exceptional circumstances to patients with a severe clinical course and an HLA-matched donor. 
• Management of acute chest syndrome:

  • medical emergency with high mortality
  • Analgesia
  • Good hydration - IV fluids
  • Antibiotics or antivirals for infection
  • Blood transfusions for anaemia
  • Incentive spirometry using a machine that encourages effective and deep breathing
  • Respiratory support
• Long-term complications:

  • Cardiac failure
  • Chronic pulmonary disease, cor pulmonale and pulmonary hypertension
  • Gallstones: the increased rate of haemolysis increases the risk of gallstones and acute cholecystitis
  • Retinopathy, retinal infarcts, retinal haemorrhage and retinal detachment
  • Transfusion-associated complications: iron overload, exposure to transfusion-related infection, alloimunisation
  • Chronic leg ulcers
  • Avascular necrosis: commonly affecting the femoral or humeral head
  • Chronic kidney disease: may cause worsening anaemia requiring high doses of erythropoietin
• Crizanlizumab is a monoclonal antibody that targets P-selectin. P-selectin is an adhesion molecule found on endothelial cells on the inside walls of blood vessels and platelets. It prevents red blood cells from sticking to the blood vessel wall and reduces the frequency of vaso-occlusive crises.