Background Information

Definition

Sickle cell disease (SCD) ^[Ref]

• Defined as a group of inherited (autosomal recessive) haemoglobinopathies characterised by the presence of abnormal beta-globin alleles (carrying the sickle mutation), which results in haemoglobin S (HbS) production
  • Sickle cell anaemia (homozygous HbSS) is the most common and severe form of SCD
  • Other genotypes include (see the aetiology section for more details):
    • HbSC
    • HbS/β⁰-thalassemia & HbS/β⁺-thalassemia
    • HbS with other beta-globin variants

Sickle cell trait ^[Ref]

• Carrier state characterised by the inheritance of HbA and HbS (only 1 abnormal beta-globin gene)
• Strictly not a form of sickle cell disease

Epidemiology

Prevalence of SCD is highest in: ^[Ref]

• Sub-Saharan Africa
• Mediterranean basin
• Middle East
• India

Aetiology

Autosomal recessive point mutation in the beta-globin gene (on chromosome 11) (at codon 6) ^[Ref1][Ref2]

• Most common (‘sickle mutation’): glutamic acid replaced with valine (GAG → GTG) → haemoglobin S (HbS)
• Glutamic acid replaced with lysine (GAG → AAG) → haemoglobin C (HbC)

The most common genetic forms of SCD: ^[Ref1][Ref2]

Pathophysiology

1. Abnormal HbS molecules polymerise into long rigid fibres upon deoxygenation
2. Polymerised HbS causes RBCs to deform into rigid and sickle-shaped RBCs (sickling)
3. There are 2 major pathological consequences of sickle-shaped RBCs
   1. Haemolysis (as sickled cells lyse easily intravascularly and are removed by the spleen)
   2. Vaso-occlusion (sickled cells can obstruct microvasculature → organ ischaemia and infarction)

Diagnosis

Sickle Cell Trait

Sickle cell trait presents differently from SCD, it is generally asymptomatic and does NOT cause the classic manifestations that are discussed below

If symptomatic at all, sickle cell trait can cause exertional rhabdomyolysis and renal complications (esp. renal papillary necrosis and very rarely renal medullary carcinoma) which can present as: ^[Ref]

• Haematuria
• CKD and proteinuria

Exertional syncope or even sudden death can occur during or after extreme physical exertion. ^[Ref]

Sickle Cell Disease (SCD)

The same clinical features occur across sickle cell genotypes:

• Greatest severity in HbSS (classic sickle cell anaemia) and HbS/β⁰-thalassaemia
• Milder severity in HbS/β⁺-thalassaemia and HbSC disease

Acute Manifestation

There are 3 main acute manifestations of SCD to be aware of.

Vaso-Occlusive Crisis

Manifestation of vaso-occlusive crisis:

• Acute painful crisis – most common complication in all age groups
  • Severe pain, most commonly involving the limbs and back
  • Dactylitis (symmetrical painful swelling of the hands and feet) (common in children)
• Acute chest syndrome
  • Presents as fever, chest pain, dyspnoea, tachypnoea, hypoxia
  • Chest X-ray shows new pulmonary infiltrates
  • Clinically indistinguishable from pneumonia
• Priapism (painful prolonged erection, lasting >4 hours)
• Ischaemic stroke

Anaemias

Various forms of anaemia is another important acute manifestation:

Infection

SCD causes functional hyposplenism, thus leading to increased risk of infections:

• Invasive pneumococcal disease is the most significant cause of infection-related morbidity and mortality in SCD
• Osteomyelitis (one of the commonest infections)
  • Salmonella species (non-typhoidal) are classically the most common causative organism ^[Ref]
• Sepsis

Chronic Manifestation

Chronic manifestation include:

• Chronic haemolytic anaemia
• Gallstones 
• Sickle retinopathy – most important chronic complication as it can lead to visual impairment
• Pulmonary hypertension
• Leg ulcers
• Renal complications (ranging from painless haematuria, to end-stage renal disease)
• Impaired nutrition and growth in children

Investigation and Diagnosis

Majority of new cases of SCD are diagnosed as a result of the National Screening Programme

• Pregnant women in high-prevalence areas are screened (father is also screened if the mother is a carrier)
• All newborn babies are screened via the heel prick test (at 5 days old)

Additionally, all pregnant women are also offered screening for thalassaemia

Laboratory Tests

SCD causes non-immune haemolytic anaemia

• -ve Coombs test (non-immune)
• Non-specific haemolysis marker
  • ↓ Haemoglobin
  • Normal mean corpuscular volume and normal mean corpuscular haemoglobin (normocytic, normochromic anaemia)
  • ↓ Haptoglobin
  • ↑ Reticulocyte
  • ↑ Unconjugated bilirubin
  • ↑ LDH

Peripheral blood smear may show:

• Sickle cells (crescent-shaped RBCs)
• Howell-Jolly bodies (due to functional hyposplenism)

Confirmatory Tests

Test of choice: haemoglobin electrophoresis ^{[Ref1][Ref2][Ref3]}

Management

Sickle Cell Trait

Most patients do NOT require active medical treatment.

Patient education is key:

• Avoid triggers (e.g. dehydration, extreme exercise, high altitude)
• Genetic counselling prior conception
• Inform anaesthetist prior surgery

Any new onset of haematuria should be investigated to rule out other issues, including the extremely rare renal medullary carcinoma associated with the trait.

Acute Management

Admission Criteria

The following are important indications for immediate admission:

• Severe pain not controlled with simple analgesia / low-dose opioids
• Dehydration from significant vomiting or diarrhoea
• Severe sepsis defined by:
  • Temp >38.5 °C (or >38 °C if <2 yrs)
  • Temp <36 °C
  • Hypotension
• Suspected acute chest syndrome  
• Signs/symptoms of an acute fall in haemoglobin
• New neurological signs/symptoms
• Acute enlargement of the spleen / liver
• Marked increase in jaundice
• Any visual change
• Haematuria 

Sepsis Prevention (Antibiotics Therapy)

General indications:

• ALL patients with SCD who present with a fever (≥38.0^∘C)
• Should also be considered if there is NO fever, but with signs / symptoms of infection

Acute Painful Crisis

Mainstay of management is supportive care:

Acute Chest Syndrome

Anaemic Complications

Stroke

Urgent red cell exchange transfusion is necessary

Otherwise, manage as ischaemic stroke (see the Ischaemic Stroke article)

Long-Term Management

Disease-Modifying Therapy

There are 2 main disease-modifying therapies:

Infection Prevention

Similar to those with hyposplenism (see the Hyposplenism article), key points include:

• Lifelong daily oral penicillin is necessary for those who had a splenectomy or a history of invasive pneumococcal disease
• Vaccinations (esp. pneumococcal, meningococcal and influenza vaccine)

Chronic Organ Screening

Key screening to perform:

• Renal function
• Retinopathy screening
• Echocardiography (to assess for pulmonary hypertension risk)

References