Sickle cell disease

Sickle cell anaemia is a potentially life-threatening genetic condition that is caused by inheritance of genes that encode abnormal beta-globin proteins. The sickle haemoglobin (or HbS) variant produces haemoglobin that polymerises into a distorted conformation when in the deoxygenated state. This results in erythrocyte deformation into the classic sickle shape. A sickle cell crisis ensues when the misshapen and rigid erythrocytes form clumps that block blood vessels. Symptoms include intense pain, anaemia (due to haemolysis), splenomegaly, dactylitis (swollen digits), stroke, infections and acute chest syndrome (tachypnoea, low oxygen saturation).

Genetics

Individuals who are homozygous for sickle haemoglobin will suffer from sickle cell anaemia, which is the most common, and the most severe form of the disease. Heterozygotes, with one sickle haemoglobin gene and a normal haemoglobin gene have sickle cell trait, and will rarely develop symptomatic disease. They can however, pass their sickle haemoglobin gene onto their children. People of African or African-Caribbean ethnicity are in the high-risk group for sickle cell diseases. In the UK, all newborn babies are screened for sickle cell disease. Anyone who is pregnant is also offered screening.

Management

Patients should be provided with an individual care plan that includes regular follow-ups, alongside self-management guidance on measures to prevent (or reduce the risk of) complications of sickle cell disease, plus clear indications of when urgent medical attention should be sought. Patients should be advised to avoid triggers, such as exposure to cold or windy weather, excessive physical activity and dehydration.

Acute sickle crises: Standard pain medications such as paracetamol or ibuprofen can be useful for self-management during a sickle crisis. For those presenting with fever (temperature >38°C) should be offered empirical broad-spectrum antibiotic treatment with choice guided by local microbiological guidelines.

Chronic treatment: Patients with sickle cell disease should be offered appropriate immunisations (e.g., pneumococcus, meningococcus). Penicillin prophylaxis should be offered to all children with sickle cell disease, started by 3 months of age and continued until the child is 5 years old. Hydroxycarbamide (hydroxyurea) may be recommended for those who experience regular episodes of pain.

Regular blood transfusions (preferably exchange transfusions) that are used to keep the sickle haemoglobin percentage below 30%, may be recommended, particularly if anaemia becomes severe or persistent.

Two novel therapeutics were recently approved for preventing sickle cell anaemia and crises:

1. Voxelotor is an orally administered drug that is taken daily. It is indicated as a treatment for sickle cell disease (in individuals ≥ 4 years old). It locks sickle haemoglobin into its oxygen-binding conformation, and thus reduces abnormal polymerisation and erythrocyte sickling.
2. Crizanlizumab is an anti-selectin P monoclonal antibody has been approved as a preventative therapy for sickle cell crises. Inhibition of the interaction between selectin P and its primary ligand P-selectin glycoprotein ligand-1 (PSGL-1), produces an antithrombotic effect that is exploited to reduce the vaso-occlusive damage caused by sickled erythrocytes.