Sickle Cell Disease

Overview

Sickle cell anaemia is an autosomal recessive single gene defect in the beta chain of haemoglobin leading to the production of sickle cell haemoglobin (HbS). HbS is more fragile and crescenteric in shape compared to normal haemoglobin, leading to an increased risk of haemolysis (destruction of red blood cells).

The severity of sickle cell disease can vary. Some individuals can have subclinical symptoms, and some can have severe complications. Sickle-cell crises can occur. They are acute conditions associated with sickle-cell anaemia that require urgent management.

Sickle cell trait

Sickle cell trait describes an individual carrying one of the genes that causes sickle cell disease but does not have the disease itself. Two copies of the abnormal allele are required for sickle cell disease to manifest.

It may be helpful to look at the chapter on Anaemia: Data Interpretation alongside reading this section to help wrap your head around when to suspect what type of anaemia.

Epidemiology

• More prevalent in people of African descent
• There is evidence to suggest that sickle cell anaemia is protective against malaria
  • This does not guarantee protection and all patients must still take prophylaxis
  • If patients were to develop malaria, it would likely be severe due to hyposplenism
• Around 1 in 10 people of Afro-Caribbean descent have sickle-cell trait 

Example History

A 1-year-old boy has a fever and painful swelling of the hands and feet. He has been crying nonstop and nothing has helped the pain. He has been refusing feeds. On examination, there is oedema in his fingers and feet which are tender to palpation.

Presentation

The signs and symptoms of sickle cell disease usually manifest between 3-6 months when foetal haemoglobin (HbF) levels are falling. Some features seen are:

• Features due to vaso-occlusive crisis – where sickle cells block vessels leading to ischaemia and potential infarction:
  • Swollen fingers (dactylitis)
  • Bone pain due to infarction and avascular necrosis
  • Visual floaters if the retinal vessels are occluded
• Other sickle-cell crises (discussed below)
• Failure to thrive
• Pallor – due to splenic sequestration or haemolysis
• Jaundice – haemolysis can release bilirubin, increasing its levels
• Lethargy – splenic sequestration or haemolysis
• Overbite – due to extramedullary haematopoiesis

Sickle-Cell Crises

Overview

Sickle-cell crises are acute conditions associated with sickle-cell anaemia that require urgent management.

Vaso-occlusive crises

These are the most common and can be triggered by:

• Idiopathic
• Cold weather
• Infections
• Dehydration
• Exertion
• Ischaemia

Symptoms seen depend on where the vaso-occlusive crisis occurs:

• Swollen feet and/or hands – often the first presentation of sickle-cell anaemia in children
• Flashes and floaters
• Abdominal distension and pain due to bowel ischaemia
• Priapism
• Flashes and floaters due to retinal occlusion
• Thrombotic strokes
• Acute sickle chest syndrome

Vaso-occlusive crises are diagnosed clinically.

Aplastic crises

These are characterised by temporary periods where erythropoiesis stops, leading to severe anaemia. It is usually triggered by an infection with parvovirus B19.

• There is usually a sudden drop in haemoglobin
• Bone marrow suppression usually causes a reduced reticulocyte count

Sequestration crises

This is where sickle cells accumulate in organs such as the spleen:

• Haemoglobin is reduced
• Reticulocytes are increased
• Splenomegaly may be seen

Splenectomy is considered in patients who have recurrent splenic sequestration crises. Repeated episodes of splenic sequestration crises lead to splenic infarction and atrophy.

Acute chest syndrome

This is a vaso-occlusive crisis affecting the lungs. It is defined as new pulmonary infiltrates seen on a chest X-ray along with one or more of:

• Fever
• Tachypnoea
• Dyspnoea
• New hypoxia
• Cough
• Sputum production

Haemolytic crises

This is where excessive haemolysis takes place. It is characterised by a fall in haemoglobin and an increased rate of haemolysis. It is uncommon.

Investigations

All patients

• Full blood count (FBC):
  • Varying levels of anaemia are seen
• Reticulocyte count:
  • Usually elevated but may be reduced in aplastic crises/bone marrow infarction
• Iron studies:
  • Used to differentiate haemolytic anaemia from iron-deficiency anaemia (IDA)
  • In haemolytic anaemia, serum iron, ferritin, transferrin and TIBC are normal or elevated
• Blood film:
  • Sickle-shaped cells are seen
  • Howell-Jolly bodies are seen – due to hyposplenism
• Unconjugated (indirect) bilirubin:
  • Raised in a haemolytic crisis
• Serum haptoglobin:
  • Reduced in haemolysis – haptoglobin binds to free haemoglobin which is released in haemolysis
• Haemoglobin electrophoresis:
  • The definitive test

Referral

All patients should be urgently admitted to hospital if they have any of the following:

• Severe pain unresponsive to basic analgesia/low-dose opioids:
  • This suggests a vaso-occlusive crisis
• Dehydration due to severe vomiting/diarrhoea
  • This can trigger a sickle-cell crisis
• Any signs and symptoms of acute chest syndrome:
  • Features may be tachypnoea, reduced oxygen saturations or signs of consolidation
• Signs or symptoms of an acute drop in haemoglobin
• Jaundice
• Haematuria
• Neurological signs or symptoms
• Priapism lasting >2 hours or worsening of recurrent episodes

Screening

Sickle-cell anaemia can be picked up via the newborn heel-prick blood spot, which is usually collected 3-10 days after birth. Preconceptual and antenatal screening options are available in select scenarios.

Management

Sickle-cell crisis

All patients:

• 1^st-line: analgesia, IV hydration, oxygen, antibiotics if infection suspected
  • Consider blood transfusion and exchange transfusion (removing blood and replacing it with fresh donor blood/plasma)
• If acute chest syndrome: oxygen + incentive spirometry + CPAP + exchange transfusion
  • Intubation and ventilation may need to be considered
• If priapism: aspiration + irrigation with adrenaline or etilefrine
• If stroke: manage as normal + exchange transfusion

Ongoing management:

• 1^st-line: hydroxyurea (hydroxycarbamide) – increases levels of HbF
• Penicillin prophylaxis + 5-yearly pneumococcal vaccine + annual influenza vaccine
  • Due to hyposplenism which carries an increased risk of infection with Streptococcus pneumoniae and Haemophilus influenzae
• Haematopoietic stem cell transplantation can be considered

Monitoring

• Patients should be followed up with specialists regularly for growth, development, and organ function.
• Children aged 2-16 years should have annual transcranial Doppler ultrasounds as part of stroke prevention

Patient Advice

• Patients should avoid scenarios that can trigger sickle-cell crises:
  • Being cold
  • Dehydration
  • Exhaustion
• Patients should be taught how to palpate the spleen to identify splenic sequestration earlier
• Patients should avoid excess alcohol consumption as it can cause dehydration and avoid smoking which can trigger an acute chest syndrome
• Patients must be reminded that sickle-cell anaemia does not protect them from malaria and they should take malaria prophylaxis.
  • They should also be informed that malaria is likely to be more severe due to their hyposplenism.

Complications

Acute complications

• Acute painful crises leading to ischaemia and infarction
• Gallstones are common in people with sickle-cell anaemia
  • This is due to increased cell turnover and hyperbilirubinaemia
• Anaemia
• Acute chest syndrome – 3^rd leading cause of death in sickle-cell disease
• Severe infection
• Osteomyelitis – most commonly due to Salmonella species
• Priapism
• Acute kidney injury
• Stroke
• Multisystem organ failure

Chronic complications

• Liver disease
• Pain
• Anaemia
• Pulmonary hypertension
• Sleep apnoea
• Cognitive impairment due to silent infarcts in the brain
• Sickle retinopathy and vision impairment
• Gallstones
• Impaired growth and development in children
• Leg ulcers
• Sickle nephropathy – ranges from painless haematuria to end-stage renal disease

Pregnancy complications

• Premature labour
• Foetal growth restriction
• Stillbirth
• Pre-eclampsia
• Infection
• Miscarriage

Prognosis

• The severity of sickle-cell anaemia varies significantly from person to person
• Median life expectancy is around 60 years
• In adults, the most common causes of death are strokes, sepsis, acute chest syndrome, and pulmonary hypertension
• In the first two years of life, the most common causes of death are infection with or without splenic sequestration