Sickle Cell Disease (SCD)
NICE Clinical Guideline [CG143] Sickle cell disease: managing acute painful episodes in hospital. Published: Jun 2012.
NICE CKS Sickle cell disease. Last revised: Jan 2025.
Sickle Cell Society Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK 2nd Edition, 2018.
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
This is because sickle cell trait protects against severe malaria in endemic regions. This protection occurs because infected red cells are more likely to sickle and are rapidly cleared by the spleen, limiting parasite survival and replication.
However, it does not provide immunity, and individuals can still contract malaria.
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]
| Form | Genotype | Description | Clinical manifestation |
|---|---|---|---|
| Sickle cell trait (carrier state) | HbAS | 1HbS gene + 1 normal HbA gene | Typically asymptomatic |
| Sickle cell anaemia | HbSS | 2 HbS genes | Symptomatic (most severe) |
| Sickle β-thalassaemia | HbS/β⁰-thalassaemia | 1 HbS gene + β⁰-thalassaemia (no HbA production) | Symptomatic (similar to HbSS) |
| HbS/β⁺-thalassaemia | 1 HbS gene + β+-thalassaemia (reduced HbA production) | Symptomatic but milder than HbSS | |
| Haemoglobin SC disease | HbSC | 1 HbS gene + 1 HbC gene |
Pathophysiology
- Abnormal HbS molecules polymerise into long rigid fibres upon deoxygenation
- Polymerised HbS causes RBCs to deform into rigid and sickle-shaped RBCs (sickling)
- There are 2 major pathological consequences of sickle-shaped RBCs
- Haemolysis (as sickled cells lyse easily intravascularly and are removed by the spleen)
- 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
Infants do not usually manifest any signs and symptoms until 6 m/o.
This reflects high levels of fetal haemoglobin (HbF) until 6 m/o which lack the abnormal β-globin chains and do not undergo sickling. However by 6 months, HbF is gradually replaced by adult haemoglobin (HbA) – which has the form of HbS in SCD – leading to clinical manifestations.
Acute Manifestation
There are 3 main acute manifestations of SCD to be aware of.
Vaso-Occlusive Crisis
Vaso-occlusive crisis arise from sickling of RBCs upon de-oxygenation causing subsequent microvascular occlusion, common triggers include:
- Infection
- Cold temperatures
- Dehydration
- High altitude
- Extreme exercise
- Psychological stress
- Pregnancy
- Acidosis
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:
| Feature | Haemolytic crisis | Aplastic crisis | Sequestration crisis |
|---|---|---|---|
| Definition | Acute increase in red cell destruction | Temporary failure of red cell production | Acute pooling of blood in the spleen |
| Main mechanism | Accelerated haemolysis | Bone marrow suppression | Splenic trapping of RBCs |
| Triggers | Infection, stress | Parvovirus B19 (classic) | Infection, spontaneous |
| Key diagnostic clues |
|
|
|
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]
| Genotype | Interpretation |
|---|---|
| HbAS (sickle cell trait) |
|
| HbSS (classic sickle cell disease / anaemia) |
|
| HbSC |
|
| HbS/β thalassaemia |
|
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.
SCD – 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
Choice of antibiotics:
- Broad-spectrum antibiotics (exact choices depends on local microbiological guidelines)
- Antibiotics must cover pneumococcus and gram -ve organisms (esp. salmonella)
Route:
- IV: if patients are systemically unwell / admitted in hospital
- Oral (outpatient management): isolated fever or signs of infection ONLY (but otherwise systemically well / NO need for admission)
Rationale: Threshold for antibiotics is exceptionally low in SCD as they are significantly increased risk of rapid, overwhelming sepsis and death. The primary reason for this is functional hyposplenism, see the Hyposplenism article for more information.
Acute Painful Crisis
Mainstay of management is supportive care:
| Oxygen | Supplementary oxygen is recommended if SpO2 ≤95% |
| Hydration | IV fluids should be given if the patient is unable to drink enough to stay hydrated |
| Analgesia | Opioids should be given
Patients should receive regular paracetamol and NSAIDs alongside opioids, unless contraindicated |
Patients with mild to moderate pain can be managed at home, based on an individual care plan from secondary care.
This usually involves paracetamol and/or ibuprofen + weak opioids.
Do not use corticosteroids in the management of an uncomplicated acute painful sickle cell episode.
Blood transfusions are NOT recommended for treating an uncomplicated painful crisis.
Acute Chest Syndrome
| Oxygen | Supplementary oxygen is recommended if SpO2 ≤95%
High-flow oxygen or CPAP may be necessary for severe hypoxia (to avoid need for invasive ventilation) |
| Antibiotics | ALL patients should receive IV broad-spectrum antibiotics (even if blood and sputum cultures are initially -ve) |
| Bronchodilators | To be given if patient is asthmatic or there are signs of acute bronchospasm |
| Transfusion | There are 2 main types of transfusion strategies
Importantly, post-transfusion Hb should be <110 g/L to avoid hyperviscosity which significantly increases the risk of complications like stroke. |
Anaemic Complications
| Complication | Management |
|---|---|
| Aplastic crisis |
|
| Sequestration crisis |
|
| Haemolytic crisis |
|
Transfusion threshold is generally a drop in Hb of 20 g/L below the patient’s baseline.
Stroke
Urgent red cell exchange transfusion is necessary, regardless of Hb level
Otherwise, manage as ischaemic stroke (see the Ischaemic Stroke article)
SCD – Long-Term Management
Disease-Modifying Therapy
There are 2 main disease-modifying therapies:
| Therapy | MoA / description | Indications |
|---|---|---|
| Hydroxycarbamide (hydroxyurea) | Stimulates production of HbF (which lacks the abnormal β-globin chains) | ANY of the following
|
| Chronic blood transfusion | Exchange transfusion to reduce HbS levels without causing iron overload | ANY of the following
|
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)
Contrary to common belief, SCD / sickle cell trait does not provide immunity against malaria. Standard antimalarial prophylaxis is required if patients were to travel to endemic areas.
Chronic Organ Screening
Key screening to perform:
- Renal function
- Retinopathy screening
- Echocardiography (to assess for pulmonary hypertension risk)
References