Key Facts

Sickle cell disease is a group of inherited haemoglobin disorders characterised by the production of abnormal haemoglobin S (HbS). When deoxygenated, HbS polymerises, causing red cell sickling, vaso-occlusion, haemolytic anaemia, and progressive end-organ damage. It is the most common genetic condition in the UK newborn screening programme.

Epidemiology

Approximately 15,000 people live with SCD in the UK, with the highest prevalence in London. About 300 affected babies are born annually in England. Most prevalent in populations from sub-Saharan Africa, Caribbean, Middle East, Mediterranean, and Indian subcontinent. Carrier frequency is approximately 1 in 4 in Afro-Caribbean populations in the UK.

Aetiology

• HbS mutation: Point mutation in the β-globin gene (chromosome 11) → glutamic acid → valine at position 6
• HbSS: Homozygous — most severe form (sickle cell anaemia)
• HbSC: Compound heterozygous with HbC — generally milder
• HbS/β-thalassaemia: Compound heterozygous — severity depends on β-thal mutation (β⁰ = severe, β⁺ = milder)
• Sickle trait (HbAS): Carriers — usually asymptomatic but sickle in extreme conditions

Pathophysiology

Deoxygenated HbS polymerises → rigid, crescent-shaped (sickled) red cells → increased viscosity → vaso-occlusion → tissue ischaemia and infarction. Sickled cells are also fragile → chronic haemolytic anaemia (Hb typically 60-90 g/L). Repeated splenic infarction → functional asplenia by age 5 → increased susceptibility to encapsulated organisms. Chronic haemolysis releases free haemoglobin → nitric oxide scavenging → endothelial dysfunction → vasculopathy, pulmonary hypertension, stroke.

Vaso-Occlusive Crisis (Most Common)

• Severe bone pain (dactylitis in infants — hand-foot syndrome)
• May affect any bone; common in long bones, spine, ribs
• Triggered by: cold, dehydration, infection, hypoxia, stress

Acute Chest Syndrome

• Fever, chest pain, tachypnoea, hypoxia
• New pulmonary infiltrate on CXR
• Leading cause of death in SCD

Splenic Sequestration

• Acute enlargement of spleen with pooling of blood
• Rapidly falling Hb, cardiovascular collapse
• Mainly in young children (before auto-splenectomy); can be fatal

Stroke

• Affects ~11% of children with HbSS by age 20
• Ischaemic stroke most common; presents with focal neurological deficit
• Transcranial Doppler (TCD) screening from age 2 identifies high-risk children

Other Complications

• Aplastic crisis (parvovirus B19 — temporary cessation of erythropoiesis)
• Priapism
• Avascular necrosis of femoral/humeral head
• Gallstones (pigment stones from chronic haemolysis)
• Chronic kidney disease
• Retinopathy (especially HbSC)

Red Flags

• Fever >38°C in SCD child — assume sepsis until proven otherwise (functional asplenia)
• Acute chest syndrome — oxygen, IV antibiotics, exchange transfusion if severe
• Splenic sequestration — urgent transfusion
• Acute neurological deficit — stroke: urgent MRI/MRA + exchange transfusion
• Priapism >4 hours — urological emergency

Bedside

• Observations: Temperature, HR, BP, SpO2, RR, pain score
• Abdominal examination: Spleen size (compare to baseline)
• Neurological assessment: Focal deficit (stroke screen)

Bloods

• FBC: Baseline Hb (typically 60-90 g/L in HbSS), reticulocyte count (usually raised unless aplastic crisis)
• Blood film: Sickle cells, target cells, Howell-Jolly bodies (functional asplenia)
• Hb electrophoresis/HPLC: Confirms genotype — HbSS: mostly HbS with HbF and HbA2; absent HbA
• Reticulocyte count: Low in aplastic crisis (parvovirus B19); high baseline
• Crossmatch: Extended phenotype matching essential to reduce alloimmunisation risk
• U&Es, LFTs, LDH, bilirubin: Baseline and acute monitoring; elevated LDH/bilirubin from haemolysis
• Parvovirus B19 IgM: If aplastic crisis (Hb dropping with low reticulocytes)

Imaging

• CXR: Acute chest syndrome screening — new infiltrate
• Transcranial Doppler (TCD): Annual from age 2 to 16; velocity >200cm/s = high stroke risk → start chronic transfusion programme
• MRI/MRA brain: If abnormal TCD or neurological symptoms
• USS abdomen: Gallstones, splenic size

Special Tests

• Echocardiography: Screening for pulmonary hypertension (tricuspid regurgitation velocity >2.5m/s)
• Renal function monitoring: Annual urine ACR from age 5 (microalbuminuria is early CKD marker)
• Ophthalmology: Annual retinal screening from age 10 (especially HbSC)

Non-pharmacological

• Education: Teach families to recognise fever, acute chest, splenic sequestration, stroke — emergency actions
• Hydration: Encourage adequate oral fluids; IV fluids during crises
• Keep warm: Avoid cold exposure (triggers vaso-occlusion)
• Avoid triggers: Dehydration, hypoxia, strenuous exercise without preparation, alcohol
• Psychological support: Chronic disease management, transition support

Pharmacological

• Penicillin V prophylaxis: From diagnosis — 62.5mg BD (<1 year), 125mg BD (1-5 years), 250mg BD (>5 years) — reduces pneumococcal sepsis by ~84%
• Vaccinations: Pneumococcal (conjugate + polysaccharide), meningococcal ACWY + B, annual influenza, hepatitis B (Green Book)
• Hydroxycarbamide: Disease-modifying — 15-35mg/kg OD; increases HbF → reduces sickling, vaso-occlusive crises (~50%), ACS, transfusion requirements; NICE NG143 recommends from age 9 months for HbSS/HbSβ⁰; monitor FBC fortnightly initially then 2-monthly
• Folic acid: 5mg OD (increased red cell turnover)
• Pain management: WHO analgesic ladder — paracetamol → NSAIDs (ibuprofen 5mg/kg TDS) → weak opioids → strong opioids (morphine 0.1mg/kg IV/SC); rapid assessment and treatment of vaso-occlusive crisis
• Acute chest syndrome: Oxygen, IV antibiotics (co-amoxiclav + clarithromycin), analgesia, incentive spirometry; exchange transfusion if severe (aim HbS <30%)
• Crizanlizumab: Anti-P-selectin antibody — reduces vaso-occlusive crises; NICE TA743

Surgical/Interventional

• Blood transfusion: Simple or exchange transfusion for acute indications (ACS, stroke, severe anaemia, splenic sequestration)
• Chronic transfusion programme: For stroke prevention (primary after abnormal TCD, secondary after stroke) — aim HbS <30%
• Haematopoietic stem cell transplant: Curative — matched sibling donor transplant; >90% cure rate in children; NICE recommends considering for severe disease
• Gene therapy: Emerging — lovotibeglogene autotemcel (Casgevy/exagamglogene autotemcel using CRISPR) — NICE evaluating
• Cholecystectomy: For symptomatic gallstones
• Splenectomy: After recurrent splenic sequestration

Referral Criteria

• All children with positive newborn screen — immediate referral to specialist haemoglobinopathy centre
• Fever >38°C — emergency department (within 1 hour)
• Managed by specialist haemoglobinopathy MDT

• Life expectancy: Median ~55-60 years in developed countries (HbSS); significantly longer for HbSC and HbSβ⁺
• Stroke: ~11% of children with HbSS by age 20 without screening; TCD screening + chronic transfusion reduces risk by ~90% (STOP trial)
• Hydroxycarbamide: Reduces mortality by approximately 40% and significantly reduces crisis frequency
• HSCT: >90% cure rate with matched sibling donor; TRM ~5-10%
• Acute chest syndrome: Mortality ~3% in children; higher in adults
• Chronic organ damage: Progressive — CKD, pulmonary hypertension, retinopathy, avascular necrosis; screening essential
• Quality of life: Chronic pain, school absence, psychological burden — significantly improved with hydroxycarbamide and comprehensive care

SCD Genotype Severity

Key Landmark Trials