Sickle cell anaemia

Normal red blood cells are biconcave discs that remain flexible as they pass through the microvasculature. They carry oxygen via haemoglobin (Hb) and live approximately 120 days. In sickle cell anaemia, a single amino acid substitution (valine for glutamic acid at position 6 of the β-globin chain) produces haemoglobin S (HbS). When HbS is deoxygenated, it polymerises into long rigid fibres, distorting the red cell into a crescent (sickle) shape.

Sickle cells are: - Rigid and non-deformable — they cannot pass through small capillaries - Adhesive — they adhere to the vascular endothelium and to each other - Short-lived — haemolysed after 10–20 days, causing chronic anaemia

**Genetics**

Sickle cell anaemia is autosomal recessive — both copies of the HbB gene must carry the HbS mutation. Sickle cell trait (one normal copy + one HbS copy) is a carrier state; carriers rarely have symptoms but can pass the gene to their children.

**Complications**

*Vaso-occlusive crises:* the most common acute manifestation. Sickling in the microcirculation causes ischaemia, infarction, and pain — most often in bones (especially the femoral head), joints, chest, and abdomen. Episodes last hours to weeks and vary greatly in severity.

*Acute chest syndrome:* new chest infiltrate on chest X-ray + symptoms (chest pain, fever, hypoxia). The most common cause of death in adults. Requires urgent transfusion and oxygen; ventilatory support in severe cases.

*Stroke:* occurs in ~10% of children with sickle cell disease; silent cerebral infarction is more common. Chronic transfusion to maintain HbS < 30% reduces stroke risk by 90%.

*Avascular necrosis:* ischaemic infarction of the femoral and humeral heads, causing chronic joint pain and disability.

*Pulmonary hypertension:* a late complication resulting from chronic haemolysis and recurrent pulmonary vascular damage; affects ~10% of adults and significantly reduces survival.

*Splenic dysfunction:* recurrent sickling in the spleen causes progressive infarction (functional asplenia by childhood), predisposing to life-threatening encapsulated bacterial infections (pneumococcus, meningococcus, Haemophilus influenzae).

**Disease-modifying and curative treatment**

*Hydroxyurea:* the most important disease-modifying drug. Increases fetal haemoglobin (HbF), which does not polymerise; dramatically reduces vaso-occlusive crises, acute chest syndrome, and hospitalisation. Used lifelong in moderate-to-severe disease.

*L-glutamine, crizanlizumab, voxelotor:* newer agents that reduce adhesion, crises, and haemolysis.

*Exchange transfusion:* replaces HbS-containing blood with normal donor blood; used acutely for stroke, acute chest syndrome, and pre-operatively; used chronically in high-risk patients.

*Stem cell transplant:* the only established cure; limited by donor availability (best results with matched sibling), treatment-related toxicity, and patient eligibility. Gene therapy is under active investigation.

**Pain management**

Vaso-occlusive crises require multimodal analgesia: NSAIDs and paracetamol for mild episodes; opioids for moderate-to-severe crises; patient-controlled analgesia (PCA) during hospital admissions. Chronic pain — from avascular necrosis, neuropathy, and organ damage — is common and requires chronic pain management approaches including neuromodulation.