Sickle cell disease (SCD) is of disease characterised by varying degrees of anaemia, red cell haemolysis and pain crises (due to obstruction of small blood capillaries) along with increased susceptibility to infection.
It is a qualitative haemoglobinopathy (as opposed to quantitative haemoglobinopathies such as thalassaemia).
It is an autosomal-recessive single gene defect of the beta chain in haemoglobin. A single copy of the gene will result in sickle-cell trait which is usually asymptomatic, but two abnormal copies will result in sickle cell disease
Pathophysiology
Let’s recap the composition of haemoglobin and its different forms:
Haemoglobin is the functional unit of the RBC and its job is to bind to oxygen and transport it. It is a quarternary structure protein that is made up of 4 glob in chains along with haem groups (Fe2+ ions held within a porphyria ring).
At birth, the predominant form is HbF which is a2y2. This converts to HbA by ~20 weeks in most cases.
The predominant form of haemoglobin in adults is a2ß2. This is known as HbA. The a chain is encoded for on chromosome 16 while the ß is on chromosome 11. There is another form present in ~2% of adults which is HbA2 (a2δ2)
As we can see, the 2 a-chains are always present in both adults and children. We will discuss what happens if there is no a-chain in the CCC on thalassaemia, but for now let’s focus on the ß chain.
As we mentioned, the B-globin gene is found on chromosome 11. What occurs in sickle cell is there is a single point mutation where adenine is converted to thymine. This then changes the codon from being glutamic acid (GAG) to now becoming valine (GTG). This is an abnormal form of haemoglobin known as HbS that occurs when there are 2 copies of the abnormally gene.
An alteration in this single amino acid causes polymerisation and fibrous changes to the haemoglobin which changes the shape of the RBCs. Normally they are biconcave in shape and are deformable. However, with HbS the RBCs become sickle shaped. These sickle shapes are less deformable and cause blockages in blood flow at bifurcations leading to vaso-occlusive pain crises due to microinfarcts or organ damage with macroinfarcts. Severe haemolysis can occur if they become stuck in the spleen
If there is a single copy of the altered gene, then it is known as sickle cell trait (SCT) and this is usually asymptomatic (and provides protection against malaria).
Malarial parasites invade normal red blood cells and rearrange their content. The parasites breed and produce proteins that make red blood cells sticky. These blood cells explode, releasing parasites capable of infecting other red blood cells.
The misshapen haemoglobin of sickle cell trait affects a parasite’s ability to complete this cycle. The parasite triggers the haemoglobin to sickle. The immune system then clears the infected red blood cells before the parasite can complete its life cycle and infect other red blood cells. This means fewer parasites and milder illness.
🏡 Epidemiology
In England, SCD affects 1 in 2000 live births.
It predominantly affects central and Western Africa, with 25-30% being carriers of the trait. It can also be found in Southeast Asia and individuals of Mediterranean origin. These areas are often endemic to malaria which is beneficial as sickle cell is protective for malaria.
😷 Presentation
Individuals who are heterozygous are asymptomatic.
Individuals with sickle cell can suffer from sickle cell crises which include a spectrum of issues that occur with sickle cell disease. They may be spontaneous or triggered by infection, dehydration or cold.
- Anaemia - this is due to reduction in RBCs due to extravascular hameolysis when the RBCs get stuck in the spleen. The reticular endothelial system phagocytoses these sickle cells. Features of sickle cell anaemia include:
- Lethargy
- Jaundice
- Tachycardia
- Pallor
- Splenomegaly and hyposplenism - hyposplenism refers to a reduction in the function of the spleen. The spleen is not only for RBC destruction, it plays a very important role in immune function as it serves as a secondary lymphoid organ where phagocytosis of bacteria occurs. When the spleen is compromised due to sickle cell (as it becomes congested and works overtime to destroy RBCs) it causes splenomegaly with a reduction in its immune function (hyposplenism). This makes individuals prone to infection and bacteraemia.
- Pain crisis - this is a vaso-occlusive crisis caused by vessel occlusion with trapped sickle cells blocking blood flow. It causes the following symptoms:
- Pain
- Fever
- Priapism - due to trapping of blood within the penis. It is a urological emergency and treated with penile aspiration.
- Bone pain - due to bone infarction. It increases risk of AVN especially of the femoral head.
- Dactylitis (hand-foot syndrome) - inflammation of the toes or fingers.
🚨 Complications
- Splenic sequestration
- Infection
- Osteomyelits
- Stroke
- Chronic kidney disease
- Gallstones
- Retinal issues
- Pulmonary hypertension and fibrosis
- Iron overload - due to repeated blood transfusions.
- Aplastic crisis
- Priapism
A blockage within the spleen can cause an acutely enlarged and painful spleen which leads to severe anaemia and hypovolaemic shock.
It is also an emergency, managed by blood transfusions and fluid resuscitation, however, splenectomy is preventative.
A complication when there is a lack of creation of new blood cells. Commonly triggered by parvovirus B19. It also causes severe anaemia.
Once again it is managed by blood transfusions (if needed) but usually spontaneously resolves.
Acute chest syndrome presents with features such as fever, tachypnoea, wheeze, cough, hypoxia and pulmonary infiltrates.
It may occur due to infection (such as pneumonia) or may be non infective such as pulmonary vaso-occlusion). Often the cause is unknown, but it does carry a high mortality rate 3%.
It is managed with:
- Oxygen
- Incentive spirometry - prevents atelectasis by encouraging deep breathing.
- Analgesia - be careful of using NSAIDs if there is renal impairment
- Broad-spectrum antibiotics - these are given IV it is commonly atypical bacteria so we need to give sufficient coverage with broad-spectrums
🔍 Investigations
- 🏆 Haemoglobin electrophoresis - this is required for diagnosis:
- Sickle cell anaemia: there is no HbA, 80-95% HbSS and 1-20% HbF
- Sickle cell trait: both HbA and HbS are present on electrophoresis
- FBC - low Hb with raised reticulocyte count
- Blood film - shows sickling of erythrocytes and features of hyposplenism including target cells and Howell-Jolly bodies (nuclear remnants that are found in the RBCs of patients with reduced or absent splenic function)
- Sickle solubility test - when blood with HbS is mixed with sodium dithionite, a precipitate is formed and the solution becomes turbid. When blood with normal haemoglobin is mixed with sodium dithionite, the solution remains clear.
👀 Screening
Pregnant women who are carriers/at risk of being carriers are screened during pregnancy.
It is also tested for at 5 days of age with the heel prick test.
🧰 Management
To prevent crises, one should be advised to avoid triggers such as:
- Cold temperatures
- Dehydration
- Exhaustion
- Alcohol
- Smoking - may induce acute chest syndrome.
Infection prophylaxis:
- Penicillin V - prophylactically given until the age of 5 but often continued life-long.
- Vaccinations - due to hyposplenism/splenectomy, we should give vaccinations for MenB and MenC, hepatitis B vaccine and annual influenza vaccine.
Folate supplementation should be given to prevent severe anaemia also.
- Blood transfusions - top-up-transfusions may be given if the patients is severely anaemia. They may also be given in situations with acute complications, but exchange transfusions are preferred in these instances.
- Iron chelation therapy (such as desferoxamine) is needed to prevent secondary haemochromatosis.
- Hydroxycarbamide - this stimulates production of HbF which lacks the beta-globin and therefore will not form sickle cells. A common, but notable complication is neutropenia.
- 🏆 Haematopoietic stem cell transplantation is the only curative option. It is only given in exceptional circumstances when there is an HLA-matched donor.
- Gene therapy - clinical trials on gene therapy show potential for implementation in future practice.
Supportive management is needed most of the time for sickle cell crises. This includes:
- Hospital admissions
- Antibiotics or antivirals for infections.
- Keeping warm
- Keeping hydrated
- Analgesia - simply paracetamol most of the time.
- Blood transfusions - for life-threatening vaso-occlusive events, symptomatic anaemia, and in acute chest syndrome (if saturations drop <70%).