Sickle Cell Disease
Autosomal recessive haemoglobinopathy caused by a point mutation in the β-globin gene (HbS), leading to red cell sickling, vaso-occlusive crises, haemolytic anaemia, and progressive organ damage. Most common genetic disorder in the UK.
Key Facts
Most common inherited haemoglobinopathy in the UK; ~15,000 affected; predominantly affects people of Black African/Caribbean descent Point mutation: glutamic acid → valine at position 6 of β-globin (HbS); sickle cell trait (HbAS) is carrier state Vaso-occlusive crisis (VOC): most common acute presentation — severe pain (bones, chest, abdomen); triggered by infection, dehydration, cold, hypoxia Acute chest syndrome: leading cause of death in adults; fever + new CXR infiltrate + respiratory symptoms; treat with exchange transfusion Hydroxycarbamide (hydroxyurea): increases HbF production; reduces crisis frequency by ~50% (NICE TA743) Splenic sequestration: paediatric emergency; massive splenomegaly + rapid Hb drop; treat with transfusion Functional asplenia: autosplenectomy by age ~5 years → lifelong penicillin V prophylaxis + pneumococcal/meningococcal vaccination Newborn screening: universal in UK since 2006 (heel prick test)
Overview
Key Facts
Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy caused by a structural variant of haemoglobin (HbS). It is characterised by chronic haemolysis, vaso-occlusion, and progressive organ damage.
Epidemiology
- ~15,000 affected in the UK; ~300 births/year
- Predominantly Black African/Caribbean populations; also Mediterranean, Middle Eastern, Indian
- Carrier rate ~1 in 4 in West Africa; ~1 in 10 in UK Black African/Caribbean
- Most common genetic disorder in the UK
Aetiology
- Autosomal recessive: HbSS (sickle cell anaemia — most severe), HbSC, HbS-β-thalassaemia
- Point mutation: codon 6 of β-globin gene (GAG → GTG: glutamic acid → valine)
- Sickle trait (HbAS): carrier state; generally asymptomatic but may sickle under extreme conditions
Pathophysiology
- HbS polymerises when deoxygenated → rigid sickle-shaped RBCs
- Vaso-occlusion: sickled cells obstruct microcirculation → ischaemia, infarction, pain
- Chronic haemolysis: RBC lifespan ~10–20 days (normal 120 days)
- Endothelial activation, inflammation, nitric oxide depletion → vasculopathy
- Progressive organ damage: spleen, kidneys, lungs, brain, bones
Clinical Presentation
Acute Presentations
- Vaso-occlusive crisis (VOC): severe bone/joint pain (most common); dactylitis in infants (hand-foot syndrome)
- Acute chest syndrome: fever, cough, dyspnoea, new CXR infiltrate, hypoxia — LEADING CAUSE OF DEATH in adults
- Splenic sequestration: paediatric emergency; rapid splenic enlargement, falling Hb, shock
- Aplastic crisis: parvovirus B19 → temporary cessation of erythropoiesis → severe anaemia
- Stroke: ~10% of children; silent infarcts in ~30%
- Priapism: sustained painful erection
Chronic Complications
- Autosplenectomy: functional asplenia by age ~5 (fibrosis from repeated infarction)
- Chronic kidney disease: sickle nephropathy, proteinuria
- Avascular necrosis: femoral/humeral head
- Pulmonary hypertension: ~30%
- Leg ulcers, retinopathy, gallstones (pigment stones)
- Iron overload: from chronic transfusion
Red Flags
- Fever in SCD (functional asplenia → sepsis risk — emergency)
- Acute chest syndrome (may rapidly deteriorate)
- Sudden severe headache or neurological deficit (stroke)
- Rapid fall in Hb (sequestration, aplastic crisis)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Sickle cell trait | Usually asymptomatic, mild sickling under extreme conditions | Hb electrophoresis |
| Thalassaemia major | Microcytic, transfusion-dependent, Hb electrophoresis shows raised HbF/HbA2 | Hb electrophoresis |
| Other haemoglobinopathies (HbC, HbD, HbE) | Variable severity, specific Hb patterns | Hb electrophoresis |
| Osteomyelitis | Bone pain + fever (SCD at risk; Salmonella) | Blood cultures, MRI |
Diagnosis / Investigation
Bloods
- FBC: Hb 60–80 g/L (baseline); MCV usually normal or slightly raised
- Reticulocyte count: raised (compensatory for haemolysis; 10–20%)
- Blood film: sickle cells, target cells, Howell-Jolly bodies (functional asplenia)
- Hb electrophoresis: HbS ~80–95%, HbF variable, absent HbA in HbSS
- LDH, bilirubin: raised (haemolysis)
- Haptoglobin: low
- Ferritin: may be raised (chronic transfusion → iron overload)
During Acute Crisis
- FBC with reticulocytes: Hb drop from baseline
- CXR: acute chest syndrome
- Group and save/crossmatch: for transfusion
- Blood cultures: if febrile (sepsis risk)
- CT head: if stroke suspected
- ABG/SpO2: hypoxia in ACS
Screening
- Newborn screening: universal UK heel prick test (isoelectric focusing/HPLC)
- Transcranial Doppler: annual in children age 2–16 (stroke risk — velocity >200 cm/s indicates high risk)
Management
Acute VOC
- Strong analgesia within 30 minutes: IV morphine (0.1–0.15mg/kg), PCA; avoid pethidine (seizure risk)
- IV fluids: avoid dehydration
- Oxygen: if SpO2 <95%
- Monitor for ACS: daily CXR if respiratory symptoms, observations
Acute Chest Syndrome
- Oxygen, IV fluids, analgesia
- Antibiotics: cephalosporin + macrolide (atypical cover)
- Exchange transfusion: if deteriorating (aim HbS <30%)
- Incentive spirometry: prevent/treat
Long-term Disease Modification
- Hydroxycarbamide (hydroxyurea): increases HbF; reduces VOC by ~50%, ACS, transfusion need (NICE TA743)
- Dose: 15–35mg/kg/day; monitor FBC (myelosuppression)
- Crizanlizumab 5mg/kg IV monthly: anti-P-selectin; reduces VOC (SUSTAIN trial; NICE TA743)
- Voxelotor: HbS polymerisation inhibitor; improves Hb
Chronic Management
- Penicillin V prophylaxis: 250–500mg BD lifelong (functional asplenia)
- Vaccinations: pneumococcal, meningococcal (ACWY + B), Hib, annual influenza
- Folic acid 5mg daily: increased erythropoiesis
- Annual screening: renal (ACR, eGFR), ophthalmology (retinopathy), TCD (children), echocardiography (PHT)
- Chronic transfusion programme: for stroke prevention (primary/secondary), recurrent severe crises
- Iron chelation: deferasirox or desferrioxamine if transfusion-related iron overload (ferritin >1000)
Surgical/Interventional
- Allogeneic stem cell transplant: only curative option; best results in children with matched sibling donor
- Gene therapy: emerging (LentiGlobin/lovotibeglogene autotemcel — showing promise)
Referral Criteria
- Specialist haemoglobinopathy centre: all SCD patients
- Emergency: fever, ACS, stroke, priapism >4 hours
- Obstetrics: high-risk pregnancy management
Prognosis
- Median survival: ~45–55 years in UK (improving with modern care)
- Leading causes of death: acute chest syndrome, sepsis, stroke, multi-organ failure
- Hydroxycarbamide: reduces mortality by ~40%
- Stroke: ~10% in children; chronic transfusion reduces recurrence from 70% to <10%
- Quality of life: significantly impacted by chronic pain, organ damage, psychological morbidity
- SCT: ~90% cure rate in children with matched sibling donor
Other Relevant Information
SCD Genotypes
| Genotype | Severity | HbS % |
|---|---|---|
| HbSS | Most severe | ~80–95% |
| HbSC | Moderate | ~50% |
| HbS-β⁰ thal | Severe (like SS) | ~80–90% |
| HbS-β⁺ thal | Mild-moderate | ~60–80% |
| HbAS (trait) | Usually asymptomatic | ~40% |
Triggers for VOC
| Trigger |
|---|
| Infection |
| Dehydration |
| Cold exposure |
| Hypoxia |
| Stress |
| Alcohol |