24th May 2023

Sickle Cell Disease

Overview of sickle cell disease

Sickle cell disease is one of the most common monogenic, hereditary haemoglobinopathies. It is inherited in an autosomal recessive manner, where individuals with both alleles develop sickle cell anaemia (HbSS), and those who carry one allele acquire the sickle cell trait (HbSA).

Mutation in the beta globin gene results in substitution of glutamic acid with valine at the sixth amino acid of the beta globin chain. This alters the structure and properties of haemoglobin and causes red blood cells to sickle. This results in polymerisation of the abnormal haemoglobin within the red blood cell and the formation of haemoglobin tetramers.

Sickle cells on peripheral blood film.

Image Source: Wikimedia Commons (2012). Sickle cells, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Sickle_cells.jpg (Accessed on: 10 January 2023).

Acidosis, hypoxia, infection, dehydration, cold temperatures, pregnancy, and stress can all trigger polymerisation of abnormal haemoglobin and hence, sickling of red blood cells. These sickle cells adhere to the vascular endothelium, resulting in vaso-occlusion. The abnormal structure of the sickle cell makes them prone to haemolysis, which contributes to anaemia. Patients with sickle cell disease are subjected to acute and chronic complications of this disease.

There is a high prevalence of sickle cell in countries where malaria is endemic; sickle cell has protective properties against severe malaria. These include Sub-Saharan Africa, India, Eastern Mediterranean, and the Middle East.

The only cure for sickle cell disease is bone marrow transplantation. Management of sickle cell focuses on the following:

• Infection prevention – immunisation, lifelong prophylactic penicillin
• Symptom control – analgesia, hydroxycarbamide (reduces frequency of acute pain, blood transfusion and chest syndrome), crizanlizumab (reduces vaso-occlusive crises), blood transfusions
• Management of clinical complications

Foetal haemoglobin (HbF) and sickle cell

HbF is composed of two alpha chains and two gamma chains. Unlike HbS, HbF does not enter the polymerization phase when sickling occurs and helps to slow this process. This explains why patients are asymptomatic in the first few months of life, when HbF is the predominant haemoglobin type. Hydroxycarbamide is a treatment used in sickle cell disease which increases the production of gamma globin chains, resulting in increased levels of HbF.

Some individuals have hereditary persistence of foetal haemoglobin, where high levels of HbF are due to beta-globin gene deletions or point mutations in the promoters of the HbF genes.

Clinical syndromes in sickle cell disease

Sickle cell crisis

This describes several acute conditions seen in sickle cell, although typically refers to painful episodes secondary to vaso-occlusion. These episodes can be precipitated by cold environments, dehydration, infection, and exercise.

Management of these crises focuses on managing pain while minimising the adverse effects of vaso-occlusion. Patients may require opioid analgesia, intravenous fluids, supplemental oxygen, and antibiotics if suspected infection. Blood transfusions are only indicated in patients experiencing anaemia with life-threatening vaso-occlusive events, symptomatic anaemia, organ dysfunction and during high-risk procedures e.g. surgery.

Acute chest syndrome

This can follow a vaso-occlusive crisis and accounts for 25% of deaths in sickle cell disease. Hypoxia secondary to hypoventilation causes sickling of red blood cells and occlusion of the pulmonary microvasculature. This in turn results in localised hypoxia in the lung tissue which contributes to the vicious cycle of more sickling red blood cells.
Patients present with shortness of breath, hypoxia, chest pain, cough, and tachypnoea. Severe cases can present as respiratory distress or even failure. Patients may also have a fever.

The aim of management in acute chest syndrome is to prevent progression to respiratory failure. Patients are treated with blood transfusion, optimal analgesia to improve respiratory effort which prevents atelectasis, and intravenous antibiotics as bacterial pneumonia cannot be ruled out. Incentive spirometry is also used to prevent further atelectasis.

Splenic sequestration crisis

This is a life-threatening crisis that causes a significant haemoglobin drop secondary to trapping and pooling of red blood cells in the spleen. Consequently, patients can present with hypovolemic shock with a rapidly enlarging spleen. Splenic sequestration crises mainly present in childhood where patients have yet to develop fibrotic spleens from repeated splenic infarcts.

Treatment is with blood transfusion and splenectomy.

Aplastic crisis

Aplastic crisis is characterised by an acute drop in haemoglobin with transient cessation of erythropoiesis and hence, reduced reticulocytes in the peripheral bloodstream. This commonly lasts between 7 to 10 days. It is most commonly precipitated by infection e.g. Parvovirus B19, Epstein-Barr virus, and streptococcus pneumoniae.

Management is with blood transfusion in severe cases.

Other complications

The complications of sickle cell disease are extensive due to the multi-organ impact of vaso-occlusion from sickled cells.

Complications of sickle cell disease