Sickle cell disease
Exam Tips
- In OSCEs, treat fever in sickle cell disease as sepsis until proven otherwise because of functional asplenia.
- Acute chest syndrome = new infiltrate on chest X-ray plus respiratory symptoms/fever; it can mimic pneumonia and may need urgent exchange transfusion.
- A falling haemoglobin with low reticulocyte count points to aplastic crisis; a falling haemoglobin with high reticulocytes suggests haemolysis/sequestration.
- Know genotype severity pattern: HbSS and HbS/beta0-thalassaemia are usually more severe than HbSC.
- If both parents have sickle trait (HbAS), each pregnancy has 25% risk of sickle cell disease and 50% risk of trait.
- See Figure: peripheral smear showing sickled cells and Howell-Jolly bodies (high-yield image interpretation station).
Definition
Sickle cell disease is a group of inherited haemoglobinopathies in which at least one beta-globin gene encodes haemoglobin S (HbS), causing red cells to deform under deoxygenated conditions. Recurrent sickling leads to chronic haemolytic anaemia and intermittent vaso-occlusion, producing acute pain crises and progressive multi-organ ischaemic damage. The most severe phenotypes are typically HbSS and HbS/beta0-thalassaemia.
Pathophysiology
A point mutation in the beta-globin gene (Glu6Val) produces HbS, which polymerises when deoxygenated. Polymerisation causes red-cell dehydration, membrane damage, reduced deformability, and episodic sickling; repeated cycles lead to irreversible sickled cells, chronic extravascular/intravascular haemolysis, nitric oxide depletion, endothelial dysfunction, and a pro-thrombotic inflammatory state. Vaso-occlusion (microvascular obstruction by sickled erythrocytes, leukocytes, and activated endothelium) causes ischaemia-reperfusion injury, severe pain, acute chest syndrome, stroke, and avascular necrosis, while progressive splenic infarction causes functional hyposplenism and susceptibility to encapsulated organisms. See Figure: peripheral blood film with sickled cells/target cells and schematic of HbS polymer formation (classic exam image set).
Risk Factors
- Autosomal recessive inheritance: highest risk when both parents carry HbS (25% affected pregnancy risk)
- Genotype severity (HbSS and HbS/beta0-thalassaemia generally more severe than HbSC)
- Ethnic ancestry linked to historical malaria regions (African, African-Caribbean, Middle Eastern, Mediterranean, Indian, parts of South/Central America)
- Physiological triggers for sickling: dehydration, hypoxia (including high altitude/anaesthesia), acidosis, infection, cold exposure, extreme exertion, pregnancy, psychological stress
Clinical Features
Symptoms
- Recurrent severe bone or limb pain (vaso-occlusive crisis), often with back pain
- Fatigue, exertional breathlessness, and pallor from chronic haemolytic anaemia
- Chest pain, cough, dyspnoea, fever in acute chest syndrome
- Abdominal pain (including biliary colic from pigment gallstones or sequestration syndromes)
- Headache, focal neurology, or seizures suggesting cerebrovascular involvement
- Priapism, leg ulcer pain, or chronic musculoskeletal pain (including avascular necrosis)
Signs
- Pallor, mild jaundice/scleral icterus, tachycardia
- Pyrexia and systemic upset in infection/sepsis
- Splenomegaly in children or acute splenic sequestration (often absent in older HbSS due to autosplenectomy)
- Hepatomegaly/right upper quadrant tenderness in hepatic sequestration
- Tachypnoea, hypoxia, crackles/reduced air entry in acute chest syndrome
- Growth delay in children; chronic organ damage signs (pulmonary hypertension, CKD, retinopathy)
Investigations
Management
Lifestyle Modifications
- Maintain hydration, avoid temperature extremes and prolonged hypoxic exposure (including caution with high altitude flights/travel)
- Prompt assessment for fever or chest symptoms; clear safety-net advice for emergency attendance
- Vaccination optimisation (including pneumococcal, meningococcal, Hib, influenza, hepatitis B per UK risk schedules)
- Travel planning with malaria prophylaxis for endemic areas even though trait/disease has evolutionary malaria linkage
- Smoking cessation, graded exercise, and psychosocial support for chronic pain/school-work impact
Pharmacological Treatment
Analgesia for vaso-occlusive crisis
- Paracetamol 1 g orally every 4-6 hours (max 4 g/day)
- Ibuprofen 400 mg orally three times daily with food (max 2.4 g/day; avoid if renal impairment/GI risk)
- Morphine sulfate 0.1-0.15 mg/kg IV every 2-4 hours as needed (or PCA in severe pain)
Give analgesia rapidly (target within 30 minutes in acute care). Monitor sedation/respiratory rate with opioids; prescribe laxative and antiemetic where appropriate.
Infection prophylaxis and treatment
- Phenoxymethylpenicillin prophylaxis: 62.5 mg twice daily (<1 year), 125 mg twice daily (1-5 years), 250 mg twice daily (>5 years)
- Empirical IV ceftriaxone 2 g once daily in severe sepsis risk (adult typical dose; use local protocol and weight-based paediatric dosing)
Penicillin allergy requires alternative regimen per local microbiology guidance. Any fever can represent life-threatening sepsis in functional hyposplenism.
Disease-modifying therapy
- Hydroxycarbamide (hydroxyurea) initial 15 mg/kg once daily, titrated to response/tolerability (often up to about 35 mg/kg/day)
- Crizanlizumab 5 mg/kg IV at week 0 and week 2, then every 4 weeks (specialist indication in recurrent crises)
Hydroxycarbamide reduces crisis frequency and acute chest syndrome risk by increasing HbF. Safety: myelosuppression risk (requires regular FBC), teratogenic potential (effective contraception advised), and caution in significant renal/hepatic impairment.
Haematinic support
- Folic acid 5 mg orally once daily
Supports erythropoiesis in chronic haemolysis; not a substitute for crisis prevention or infection prophylaxis.
Surgical / Interventional
- Haematopoietic stem cell transplantation (potentially curative in selected patients)
- Splenectomy in selected recurrent splenic sequestration/hypersplenism cases after specialist review
- Cholecystectomy for symptomatic pigment gallstones
Complications
- Recurrent vaso-occlusive crises and chronic pain syndromes
- Acute chest syndrome (major cause of adult mortality)
- Severe infection/sepsis due to functional hyposplenism (especially pneumococcal disease)
- Acute splenic sequestration, hepatic sequestration, and aplastic crisis (often parvovirus B19)
- Stroke and silent cerebral infarction; cognitive sequelae
- Avascular necrosis (femoral/humeral heads), osteomyelitis, and bone infarction
- Chronic kidney disease, albuminuria, and reduced concentrating ability
- Pulmonary hypertension, chronic lung disease, proliferative retinopathy, priapism, leg ulcers, and pregnancy complications
Prognosis
Prognosis is heterogeneous and depends on genotype, complication burden, and access to specialist care. In the UK, childhood survival into adulthood is now very high, with median survival reported around the late 60s for HbSS and generally better for HbSC, although recurrent pain, acute chest syndrome, stroke, renal and cardiopulmonary complications worsen outcomes. Long-term morbidity remains substantial from cumulative organ damage; stem cell transplantation offers potential cure in selected individuals.
Sources & References
🏥BMJ Best Practice(2)
💊BNF Drug References(3)
- Erythromycin[management.pharmacological]
- Hydroxycarbamide[management.pharmacological]
- Phenoxymethylpenicillin[management.pharmacological]
✅NICE Guidelines(1)
- Sickle cell disease[overview]
📖Textbook References(20)
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1344)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 875)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 847)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1125, 1126)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1808)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1341)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 866)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1342)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 214, 215)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1752, 1753)[context]
- Emergencies in - Obstetrics and Gynaecology, Second Edition (Stergios K. Doumouchtsis, S. Arulkumaran) (Z-Library).pdf(pp. 51, 52)[context]
- Emergencies in - Obstetrics and Gynaecology, Second Edition (Stergios K. Doumouchtsis, S. Arulkumaran) (Z-Library).pdf(pp. 352, 353)[context]
- Guyton and Hall Textbook of Medical Physiology (John E. Hall, Michael E. Hall) (Z-Library).pdf(pp. 449)[context]
- Oxford Handbook of Clinical Diagnosis (Huw Llewelyn, Hock Aun Ang, Keir Lewis etc.) (Z-Library).pdf(pp. 377, 378)[context]
- [Oxford Medical Handbooks] Ian Wilkinson, Tim Raine, Kate Wiles, Anna Goodhart, Catriona Ha - Oxford Handbook of Clinical Medicine (2017, Oxford University Press) - libgen.li.pdf(pp. 209, 210)[context]
- [Oxford Medical Handbooks] Ian Wilkinson, Tim Raine, Kate Wiles, Anna Goodhart, Catriona Ha - Oxford Handbook of Clinical Medicine (2017, Oxford University Press) - libgen.li.pdf(pp. 353, 354)[context]
- [Oxford Medical Handbooks] Ian Wilkinson, Tim Raine, Kate Wiles, Anna Goodhart, Catriona Ha - Oxford Handbook of Clinical Medicine (2017, Oxford University Press) - libgen.li.pdf(pp. 356)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 589)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 935)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 1305, 1306)[context]