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

Sickle cell disease (SCD) is a group of inherited haemoglobinopathies caused by mutations in the beta-globin gene resulting in production of abnormal haemoglobin S (HbS). Under conditions of low oxygen tension (hypoxia), dehydration, acidosis, or cold, HbS polymerises within red blood cells, causing them to deform into a rigid, crescent (sickle) shape. Sickled erythrocytes are inflexible and adhere abnormally to vascular endothelium, causing vaso-occlusion of small blood vessels — leading to ischaemic organ damage, severe pain crises, and haemolysis. SCD is autosomal recessive — both copies of the beta-globin gene must carry pathogenic variants. The most severe form is HbSS (homozygous — two sickle genes); other genotypes include HbSC (compound heterozygosity for HbS and HbC — intermediate severity) and HbS-beta-thalassaemia (severity depends on beta-thalassaemia type). SCD affects approximately 20–25 million people globally, with highest prevalence in sub-Saharan Africa, the Middle East, India, and the Caribbean — and significant prevalence in the UK, USA, and Brazil due to migration. It is one of the most common serious genetic disorders in the world, and newborn screening in the UK (since 2006) has dramatically transformed early diagnosis and prevention of early childhood deaths.

SCD is caused by mutations in the HBB gene encoding the beta-globin chain of haemoglobin. The most severe and common genotype is HbSS (homozygous sickle mutation — two HbS alleles) — classic 'sickle cell anaemia', the most clinically severe form. HbSC disease (compound heterozygosity for HbS and HbC — a different beta-globin mutation) causes a milder but still significant clinical syndrome — important because it is frequently underestimated; it can cause severe acute chest syndrome, retinopathy, and avascular necrosis. HbS-beta-thalassaemia: HbS with a concurrent beta-thalassaemia mutation — severity depends on whether no beta-globin is made (HbS-beta0-thal — as severe as HbSS) or reduced beta-globin (HbS-beta+-thal — milder). All SCD genotypes are autosomal recessive — both parents must each carry at least one pathogenic beta-globin variant for a child to be affected. Sickle cell trait (HbAS): one HbS and one normal HbA allele — carriers are generally asymptomatic under normal physiological conditions, but extreme hypoxia (high-altitude exercise, unpressurised flight) can rarely trigger sickling events. The high carrier frequency in malaria-endemic regions (up to 25–30% of the population in West Africa) reflects a strong heterozygote advantage — HbAS carriers are substantially protected against severe Plasmodium falciparum malaria, driving positive evolutionary selection of the HbS allele in these regions. Triggers for sickling and vaso-occlusive crises in affected individuals include: hypoxia, dehydration, acidosis, extreme cold, fever, infection, excessive physical exertion, and psychological stress.

Vaso-occlusive (painful) crises are the most common and hallmark acute complication — severe, acute pain in bones (predominantly the long bones, spine, sternum, and ribs), joints, chest, and abdomen caused by microvascular occlusion from sickled erythrocytes; crises last hours to days and can require strong opioid analgesia (IV morphine or diamorphine) and IV fluids in hospital. Acute chest syndrome (ACS): a potentially fatal syndrome defined by a new pulmonary infiltrate on chest X-ray with at least one of — chest pain, fever, or respiratory symptoms (tachypnoea, falling oxygen saturation, cough); ACS is the most common cause of premature death in SCD and may require exchange transfusion, oxygen, IV antibiotics, and ICU admission. Stroke: ischaemic stroke occurs in 10% of children with HbSS by age 18 without transcranial Doppler (TCD) screening — caused by cerebral vascular occlusion; haemorrhagic stroke also occurs in adults. Aplastic crisis: acute, sudden fall in haemoglobin due to temporary cessation of red cell production — classically caused by Parvovirus B19 (which infects erythroid progenitor cells); most dangerous in children, causing severe anaemia and cardiac decompensation. Splenic sequestration crisis: sudden pooling of blood in the spleen (predominantly in children under 5) causing acute anaemia, rapid splenic enlargement, circulatory collapse, and potentially fatal haemodynamic compromise. Priapism: prolonged, painful penile erection from sickled erythrocyte occlusion of the corpora cavernosa venous drainage — a urological emergency if lasting more than 2 hours (risk of permanent erectile dysfunction if untreated). Avascular necrosis (osteonecrosis): most commonly affecting the femoral head (causing hip pain and disability) and humeral head — from vascular occlusion to bone epiphyses. Chronic haemolytic anaemia: baseline haemoglobin 6–9 g/dL in HbSS (sustained haemolysis); jaundice, gallstones (cholelithiasis — bilirubin pigment stones from chronic haemolysis, in 30–70% of adults).

Newborn bloodspot screening (NHS heel prick test at day 5 in the UK): high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF) of dried blood spots detects haemoglobin variants — this is the cornerstone of early SCD diagnosis, enabling prophylactic penicillin and vaccination to be started before the first infection risk. SCD genotype is confirmed by haemoglobin electrophoresis (HPLC, capillary electrophoresis, or isoelectric focusing) in older patients or to characterise the specific genotype (HbSS, HbSC, HbS-beta-thal). Full blood count (FBC): baseline Hb 6–9 g/dL in HbSS (lower values indicate aplastic crisis, sequestration, or haemolytic exacerbation); elevated reticulocyte count (5–15% — reflects chronic haemolysis and compensatory erythropoiesis); leukocytosis (white cell count 12–15 — an independent risk factor for ACS). Blood film (peripheral smear): sickled erythrocytes (crescent-shaped), target cells (HbSC and HbS-thal), Howell-Jolly bodies (reflecting functional asplenia — seen from 6 months of age). Haemolysis markers: elevated LDH, elevated unconjugated bilirubin, low haptoglobin — all proportional to haemolytic rate. Renal function and urine analysis: sickle cell nephropathy develops progressively (haematuria, proteinuria, elevated creatinine). Transcranial Doppler ultrasonography (TCD): performed annually in all children with HbSS aged 2–16 — measures blood flow velocity in the middle cerebral artery; velocity above 200 cm/s identifies children at very high stroke risk who require regular prophylactic red cell transfusions. MRI/MRA brain: for acute stroke diagnosis and to assess silent infarcts.

Hydroxyurea (hydroxycarbamide — HU): the most important and widely recommended disease-modifying treatment for SCD. It induces foetal haemoglobin (HbF) production — HbF inhibits HbS polymerisation — and reduces the frequency of vaso-occlusive crises by approximately 50%, acute chest syndrome episodes, hospitalisation rates, and red cell transfusion requirements. It also improves haemoglobin by 1–2 g/dL (by reducing haemolysis). NICE recommends HU for all adults and children (from 9 months of age) with SCD who have had two or more severe vaso-occlusive crises or ACS episodes in the past 12 months. Weekly FBC monitoring is required during dose escalation (target maximum tolerated dose — usually 20–35 mg/kg/day). Acute vaso-occlusive pain crisis management: strong opioid analgesia (IV morphine or oral oxycodone with regular paracetamol and NSAIDs unless contraindicated); IV or oral fluid hydration; warming; and regular clinical monitoring for ACS (new respiratory symptoms). Acute chest syndrome: oxygen, IV broad-spectrum antibiotics (covering atypical organisms — azithromycin plus cefuroxime), bronchodilators, and top-up or exchange red cell transfusion (target HbS fraction below 30%). Blood transfusion: top-up transfusion for acute anaemia (aplastic crisis, sequestration); regular (monthly) exchange transfusion for primary and secondary stroke prevention (TCD-guided). L-glutamine (Endari): reduces oxidative stress in HbS erythrocytes — approved by FDA as adjunctive therapy. Voxelotor (Oxbryta): allosteric HbS polymerisation inhibitor — increases haemoglobin levels and reduces haemolysis markers; approved FDA 2019. Crizanlizumab (Adakveo): anti-P-selectin monoclonal antibody — reduces frequency of vaso-occlusive crises by reducing sickled cell adhesion to vascular endothelium. Curative therapy: allogeneic haematopoietic stem cell transplant (HSCT) from a matched sibling donor — curative in approximately 95% of children without prior organ damage; gene therapy (betibeglogene autotemscel — Zynteglo; FDA-approved 2023) and exagamglogene autotemcel (Casgevy — CRISPR-based; FDA-approved 2023) offer curative options for those without matched donors.

Ischaemic stroke (overt stroke in 10% of children with HbSS by age 18 without TCD-guided prophylaxis; 'silent cerebral infarcts' — detectable only on MRI — in approximately 35% of all SCD patients, causing cognitive impairment and academic difficulties). Pulmonary hypertension (raised pulmonary arterial pressure — in 6–11% of adults with HbSS, associated with high mortality; screened with echocardiography; associated with tricuspid regurgitant velocity above 2.5 m/s as a marker). Sickle cell nephropathy: progressive renal damage — papillary necrosis (haematuria), proteinuria, hyposthenuria (inability to concentrate urine), and chronic kidney disease (CKD), with up to 12% of HbSS adults eventually reaching end-stage renal disease. Proliferative sickle cell retinopathy (most common in HbSC): retinal vascular occlusion leads to neovascularisation and risk of vitreous haemorrhage and retinal detachment — leading cause of blindness in SCD; requires annual ophthalmology review from adolescence. Avascular osteonecrosis of the femoral and humeral heads: painful, progressive, and frequently bilateral — eventually requiring joint replacement. Cholelithiasis (gallstones — bilirubin pigment type from chronic haemolysis): in up to 30–70% of adults; can cause biliary colic, cholecystitis, and cholangitis. Chronic pain syndrome from repeated tissue ischaemia and opioid-induced hyperalgesia. Leg ulcers (malleolar) in adults — painful, chronic, difficult to heal. Functional asplenia (auto-splenectomy from repeated splenic infarctions, by age 5 in most HbSS children): massively increased risk of overwhelming sepsis from encapsulated bacteria — Streptococcus pneumoniae (most dangerous), Haemophilus influenzae type b, and Neisseria meningitidis; penicillin prophylaxis and vaccination are lifesaving.

Penicillin V prophylaxis (phenoxymethylpenicillin 125 mg twice daily from diagnosis until age 5 — reduces pneumococcal sepsis risk by 84%; continued lifelong for those with persisting functional asplenia or recurrent bacterial infections; erythromycin or amoxicillin if penicillin-allergic). Vaccinations (critical for functionally asplenic SCD patients): pneumococcal vaccines (PCV15 or PCV20 from 2 months, then PPV23 booster at 2 years and 5-yearly thereafter); meningococcal ACWY and B vaccines; Haemophilus influenzae type b (Hib, as part of routine schedule); annual influenza; COVID-19; and hepatitis B. Folic acid 5 mg daily: compensates for increased folate demand from chronic haemolysis and accelerated erythropoiesis — prevents megaloblastic anaemia. Hydroxyurea: started as early as 9 months of age (BABY-HUG trial) for HbSS and HbS-beta0-thal — the single most impactful disease-modifying intervention available; reduces crises, ACS, stroke risk, and organ damage. Transcranial Doppler (TCD) screening annually for all HbSS and HbS-beta0-thal children aged 2–16: identifies those with high cerebral artery velocities (above 200 cm/s) who require monthly exchange transfusions to reduce stroke risk. Ophthalmology review every 1–2 years from adolescence (screening for sickle cell retinopathy — particularly important in HbSC). Avoid precipitating factors: dehydration (aim for 2–3 litres of fluid daily), excessive cold, high altitudes without supplemental oxygen, overexertion, hypoxia, and smoking. Genetic counselling: all carriers (HbAS) and SCD patients should receive pre-conception counselling about inheritance risk and options including prenatal diagnosis (chorionic villus sampling at 10–13 weeks, or amniocentesis at 15–18 weeks) and pre-implantation genetic testing (PGT-M) with IVF.

Go to A&E immediately or call 999 for any of the following in a patient with known sickle cell disease: fever above 38.5°C (functional asplenia means there is very high risk of fulminant bacterial sepsis from Streptococcus pneumoniae, Haemophilus influenzae, and meningococcus — IV antibiotics must start within minutes of presentation, not hours); chest pain with fever and breathlessness (acute chest syndrome — the most common cause of death, may require emergency exchange transfusion and oxygen); sudden neurological symptoms (facial droop, arm weakness, speech difficulty, severe headache — stroke, which occurs in 10% of children with SCD without TCD-based intervention); priapism lasting more than 2 hours (penile ischaemia — a haematological and urological emergency that can cause permanent erectile dysfunction if not treated promptly); sudden severe abdominal pain with rapid fall in haemoglobin, especially in children under 5 (splenic sequestration crisis — potentially fatal without transfusion). For home management of mild-to-moderate pain crisis: oral hydration, paracetamol, ibuprofen, and warmth — but contact your sickle cell centre if pain is not controlled within 4 hours or any other symptoms develop. All patients should carry a personalised SCD emergency plan and wear a medical alert bracelet.