Sickle Cell Disease — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Sickle cell disease (SCD) is a group of autosomal recessive inherited haemoglobin disorders caused by a single amino acid substitution (valine for glutamic acid at position 6 of the beta-globin chain), producing abnormal haemoglobin S (HbS). The most common and severe form, HbSS (sickle cell anaemia), involves homozygous inheritance. Other forms include HbSC (compound heterozygous with HbC — milder) and HbS-beta thalassaemia. Approximately 300,000 infants are born with SCD annually, predominantly in sub-Saharan Africa, the Middle East, India, and the Mediterranean. SCD is the most common serious inherited blood disorder in the world and represents a significant public health challenge. The disease is characterised by chronic haemolytic anaemia, episodic vaso-occlusive crises, progressive end-organ damage, and increased susceptibility to infections. The condition results from inheritance of two copies of the HbS gene, causing polymerisation of haemoglobin under low oxygen conditions and distortion of red blood cells into a rigid sickle shape that obstructs small blood vessels.

SCD is caused by inheritance of two copies of the HbS mutation (one from each parent) or one HbS plus another abnormal haemoglobin variant (HbC, beta-thalassaemia). Sickle cell trait (one copy of HbS — HbAS) is generally asymptomatic and protective against severe malaria — explaining the high frequency of the mutation in malaria-endemic regions through evolutionary selection. Carrier frequency is 1 in 4 in parts of West Africa; if both parents carry the trait, each pregnancy has a 25% chance of SCD, 50% chance of trait, and 25% chance of being unaffected. Factors precipitating sickle crises: hypoxia, dehydration, cold exposure, infection, physical exertion, stress, acidosis, and altitude. Low oxygen tension causes HbS to polymerise, distorting red blood cells into the characteristic rigid sickle shape — these cells block small blood vessels, causing tissue ischaemia and infarction.

Chronic haemolytic anaemia: pallor, jaundice (scleral icterus), fatigue, and reduced exercise tolerance — haemoglobin typically 6-9 g/dL in HbSS. Vaso-occlusive (painful) crises: the hallmark of SCD — episodes of severe, acute pain (most commonly in bones, chest, and abdomen) due to microvascular occlusion by sickled cells; can last hours to weeks. Acute chest syndrome: acute respiratory distress with new pulmonary infiltrate — a medical emergency, most common cause of death in adults. Stroke: 11% of HbSS children experience stroke before age 20; silent cerebral infarcts are even more common. Splenic sequestration: pooling of red cells in spleen causing acute anaemia and cardiovascular collapse — a paediatric emergency. Dactylitis (hand-foot syndrome): painful swelling of hands and feet — often the first presentation in infants 6-24 months. Avascular necrosis of femoral or humeral heads, leg ulcers, renal disease (sickle nephropathy), and priapism in males are chronic complications.

Newborn screening via blood spot (Guthrie card) using HPLC (high-performance liquid chromatography) identifies SCD before symptoms develop — enabling early preventive penicillin prophylaxis and parental education. This is routine in the UK, USA, and many high-prevalence countries. Haemoglobin electrophoresis or HPLC is the definitive diagnostic test in older patients — characterises the haemoglobin pattern (HbSS, HbSC, HbS-beta-thal). Peripheral blood film: classic sickle-shaped red cells, target cells, and Howell-Jolly bodies (reflecting functional hyposplenism). Full blood count: normocytic-macrocytic anaemia (raised MCV from reticulocytosis), reticulocytosis, leukocytosis. Prenatal diagnosis: chorionic villus sampling (CVS) at 11-13 weeks allows fetal diagnosis in at-risk couples. Transcranial Doppler (TCD) ultrasound screens for stroke risk in children — annual from age 2; elevated TCD velocity (above 200 cm/s) indicates high stroke risk requiring regular blood transfusions.

Hydroxyurea (hydroxycarbamide) is the cornerstone disease-modifying treatment: it induces fetal haemoglobin (HbF) production, diluting HbS and reducing sickling; reduces painful crises by 44%, acute chest syndrome, and transfusion requirements; recommended for all patients with HbSS or HbS-beta0-thalassaemia from 9 months of age. Vaso-occlusive crisis management: analgesia (paracetamol, NSAIDs, and opioids titrated to pain — patient-controlled analgesia for severe crises), IV fluids, warming, oxygen if hypoxic; avoid NSAIDs in renal impairment. Blood transfusions: simple transfusion for severe acute anaemia (Hb below 5 g/dL or cardiovascular compromise); chronic transfusion programme for primary and secondary stroke prevention in children with high TCD velocities. Crizanlizumab (anti-P-selectin monoclonal antibody): reduces vaso-occlusive crises by 45% — approved for SCD in adults. Voxelotor: increases oxygen affinity of HbS, reducing sickling and improving anaemia — approved in adults and children aged 4 and over. Penicillin prophylaxis: daily oral penicillin V from birth to at least age 5 (some centres continue lifelong) to prevent pneumococcal sepsis given functional hyposplenism. Vaccinations: pneumococcal, meningococcal, Hib, influenza, hepatitis B — all essential. Haematopoietic stem cell transplantation (HSCT): the only established curative treatment — best results in children with matched sibling donors (cure rate 95%). Gene therapy (betibeglogene spartacus — Zynteglo; lovo-cel): approved for SCD — inserts functional beta-globin gene, effectively curing the disease — transformative for patients without matched donors.

Vaso-occlusive crises cause severe bone, joint, and abdominal pain — the hallmark of sickle cell disease. Acute chest syndrome (pulmonary infarction combined with infection) is the leading cause of hospitalisation and death. Stroke occurs in 10-15% of children without preventive transfusion therapy. Repeated splenic infarction causes functional asplenia by age 5, increasing susceptibility to encapsulated bacteria (pneumococcus, Haemophilus, meningococcus). Avascular necrosis of the femoral head develops in 30-50% of adults. Pulmonary hypertension (6-11% of patients), retinopathy, nephropathy, priapism, and chronic leg ulcers are additional long-term complications. Life expectancy is reduced by 20-30 years without comprehensive care. Hydroxyurea reduces acute painful crises by 50%.

Newborn screening is the most important public health preventive measure — allowing early prophylactic penicillin and comprehensive care to reduce infant mortality (previously 90% of African children with SCD died before age 5). Genetic counselling and prenatal testing for at-risk couples (both carriers) allows informed reproductive choices. Avoid known crisis triggers: stay well hydrated (drink 2-3 litres daily), avoid extreme cold (use warm clothing), avoid high altitude or unpressurised aircraft, and seek prompt medical attention for fever (above 38.5°C — emergency in functional hyposplenism). Regular comprehensive care at a specialist sickle cell centre includes: annual transcranial Doppler ultrasound, renal function monitoring, echocardiography (screening for pulmonary hypertension), ophthalmological review (sickle retinopathy), and hydroxyurea dose optimisation. Folic acid 5mg daily to support red cell production. Vaccinations must be kept up to date.

Attend the emergency department immediately for: fever above 38.5°C (risk of overwhelming sepsis from functional asplenism), severe acute pain not controlled by home analgesia, chest pain or breathlessness (acute chest syndrome), acute neurological symptoms (stroke — sudden weakness, facial drooping, speech difficulty, severe headache), sudden severe abdominal pain or rapid enlargement of the spleen (splenic sequestration), priapism lasting more than 2 hours (urological emergency), and eye symptoms (sudden visual change — seek ophthalmology same-day). Seek planned appointments for: annual comprehensive review at a specialist centre, transcranial Doppler screening in children, and discussion of disease-modifying therapy (hydroxyurea, crizanlizumab, gene therapy) if not already established.