The most common type of haemoglobin present in the foetus and neonate is haemoglobin F (HbF). This is composed of two alpha chains and two gamma chains. By the time an infant reaches the age of 6 months, HbF production decreases such that it accounts for less than 1% of the total haemoglobin in circulation.1
The most common haemoglobin type present in people older than 6 months of age is haemoglobin A (HbA). This is composed of two alpha chains and two beta chains and accounts for 97% of all haemoglobin in adults.5
In SCD, a single point mutation in the beta-globin gene is inherited in an autosomal recessive fashion (Figure 1). This results in an amino acid replacement at position 6 in the beta-globin chain from glutamic acid to valine.6 This results in sickled haemoglobin (HbS).
In SCA, a mutation is present in both inherited beta-globin genes, resulting in haemoglobin SS (HbSS).
Patients who carry one abnormal sickle cell gene AND one normal haemoglobin gene are said to have sickle cell trait (HbAS). These patients do not have SCD and are said to be “carriers.” Their red blood cells do not sickle and therefore patients tend to live normal lives.1
Under physiological stress, sickled haemoglobin (HbSS) polymerises and causes erythrocytes to deform into a sickled shape (Figure 2). Physiological stressors include:*
Acidosis (e.g. lactic acidosis following exertion)6,7
*The above stressors do not usually induce sickling in patients with sickle cell trait (HbAS).
Clinical features of SCA begin between three and six months of age as this is when HbF levels fall and the proportion of HbSS in the blood rises.
Typical signs and symptoms of SCA may include:
Acute or chronic pain: due to vaso-occlusion
Features of anaemia such as pallor, weakness and lethargy: due to chronic haemolysis, transient red cell aplasia or splenic sequestration
Splenomegaly: due to increased haemolysis in the spleen. Notably recurrent splenic infarcts usually cause asplenism by two years of age.
Recurrent infections: as there is an increased risk of infection from encapsulated bacteria including pneumococcus, Haemophilus influenzae type b, meningococcus and salmonella species.
Jaundice: due to increased haemolysis
Over time, patients may adapt to the chronic anaemia but their disease is usually complicated by interspersed episodes of acute sickle cell crises.7
Vaso-occlusive crises are the most common reason for hospital admission among SCA patients (Figure 3).7 Sickled red blood cells can obstruct the microcirculation anywhere in the body leading to pain and ischemia +/- infarction. Pain may be severe and should be managed aggressively.
Vaso-occlusion, pain and ischemia commonly affect the following tissues:
Bones: leading to bone pain and avascular necrosis.
Joints: leading to painful swollen joints and dactylitis. More common in children.
Lungs: leading to chest pain, shortness of breath and tachypnoea. Up to 30% mortality in adult patients.
Brain: leading to headaches and strokes.
Bowel and mesentery: leading to abdominal pain and features of bowel ischemia.
Kidneys: leading to loin pain, renal papillary necrosis and haematuria.
Eyes: leading to retinal occlusion or a hyphaema.
Penis: leading to priapism.
Acute chest syndrome
This is the second most frequent reason for hospitalisation and is a leading cause of death in patients with SCA.7 Acute chest syndrome presents as new pulmonary infiltrates on the chest radiograph with one or more of the following manifestations: 6
The initial injury is multifactorial and may include infection, pulmonary infarction, pulmonary embolism or pulmonary fat embolism (as a complication from bone marrow infarction).7,9
This is the temporary cessation of erythropoiesis, causing severe anaemia. Aplastic crises are usually precipitated by infection with parvovirus B19. Patients may present with high-output congestive heart failure secondary to anaemia.
A transfusion is usually required but recovery may also occur spontaneously.
This is defined as the sudden enlargement of the spleen due to haemorrhage within it. It is associated with an acute drop in haemoglobin and a markedly raised reticulocyte count:
Sequestration may lead to circulatory collapse and hypovolemic shock
Recurrent splenic sequestration is an indication for splenectomy
On examination, typical clinical findings may include:
Conjunctival pallor +/- pallor: due to anaemia
Dactylitis: due to vaso-occlusion in fingers and toes
Jaundice: due to chronic haemolysis
Splenomegaly: due to chronic haemolysis
Possible differential diagnoses for SCA include:
Thalassemia: a group of haemoglobinopathies characterised by the reduced production or absence of haemoglobin peptide chains, rather than the production of abnormal haemoglobin peptide chains as seen in sickle cell. It is differentiated from a sickle cell by haemoglobin electrophoresis.1,7
Other causes of haemolysis: autoimmune haemolytic anaemia, hereditary spherocytosis, G6PD deficiency
Relevant laboratory investigations in the context of SCD/SCA, include:
FBC: Hb 60-80g/L, with a high reticulocyte count of 10-20% is often normal for the patient
Blood film: sickling of erythrocytes and features of hyposplenism including target cells and Howell-Jolly bodies (Figure 3)6,10
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.
Haemoglobin electrophoresis (this is required for diagnosis)
Investigations for SCD complications
Further tests may be required based on suspected complications:
CT pulmonary angiogram
Screening for SCD/SCA
In the UK, screening for SCD is offered to all newborn babies:
Neonatal heel prick blood spots are collected 3 to 10 days after birth for haemoglobin analysis.
Haemoglobin electrophoresis is necessary for a diagnosis of SCD/SCA to be made. The following are typically found in the context of SCD/SCA:
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
Management of a patient with SCA generally involves preventative measures and specific therapeutic interventions depending on the acute complication.
Prevention of crises by avoiding potential triggers including:
Exhaustion: may lead to lactic acidosis
Alcohol: may cause dehydration
Smoking: may cause the acute sickle chest syndrome
Prevention of infection with antibiotics, including:
Oral penicillin prophylaxis is recommended until at least age five but is often continued life-long.
Vaccinations: regular childhood vaccinations plus vaccinations against meningococcus, pneumococcus, hepatitis B and influenza.
Prevention of severe anaemia:
Folic acid supplementation is given(increased red cell synthesis due to chronic haemolysis leads to increased folate requirements).
Regular medical management
‘Top-up’ transfusions may be required if the patient is severely anaemic or if the proportion of HbSS in the blood needs to be reduced when an acute complication is present.
Exchange transfusions are preferred when the proportion of HbSS needs to be reduced quickly when acute complications are life-threatening and there is concern about hyperviscosity associated with ‘top-up’ transfusion.
Iron overload is a complication of regular transfusion so patients are often considered for iron chelation therapy at a young age.
Hydroxycarbamide is a once-daily medication which increases HbF production and thus reduces the proportion of HbS in the blood.
It is offered to all patients with sickle cell anaemia from the age of 9 months old onwards, unless pregnant or sexually active without contraception.12
Bone marrow transplant
An allogeneic bone marrow transplant is potentially curative.
Bone marrow transplant is only offered in exceptional circumstances to patients with a severe clinical course and an HLA-matched donor. This is a major obstacle for many patients as HLA types are more likely to be shared within ethnic groups, and people from Black and minority ethnic groups only make up a small proportion of the bone marrow donor registries.
Its use is limited by its high mortality rate (5-7%), long term complications and the limited availability of suitable donors.13
Gene therapy is a novel therapeutic option showing huge promise in ongoing clinical trials.14
Management of acute complications
Painful vaso-occlusive crisis
Most cases of painful vaso-occlusive crisis are managed in the community with simple analgesia (paracetamol +/-NSAIDs), warmth, rehydration and rest.
Patients should be admitted if strong opioids are required and the patient should be screened for a trigger (e.g. infection).
Inadequate management of painful crises (especially those affecting the chest wall) put patients at risk of atelectasis due to the subsequent reduced respiratory effort (in an attempt to reduce to pain). Atelectasis increases the risk of lower respiratory tract infections which leads to reduced pulmonary ventilation in the affected lung area and hypoxia; which may lead to further sickling. This vicious circle increases the risk of acute chest crisis which can cause critical illness and death.
Racial bias against patients with sickle cell anaemia is a recognised problem that needs addressing by all members of the MDT. It is not uncommon for patients with sickle cell to face resistance from staff with regards to the provision of analgesia; particularly opioid analgesia. Analgesia should be titrated to all patient needs, regardless of race, in order to minimise the morbidity and mortality associated with sickle cell crises and thus tackle the health inequities faced by Black patients.15
Many patients will have a treatment plan in place to guide clinicians in the acute setting.
Transcranial doppler ultrasonography is recommended in children to identify those at higher risk of stroke, and regular transfusions are offered to those with abnormal findings.
Acute chest syndrome
Acute chest syndrome is managed with oxygen: consider continuous positive airway pressure, intravenous antibiotics, transfusion or exchange transfusion and ventilation if necessary.
Long-term complications of SCD/SCA include:
Chronic pulmonary disease, cor pulmonale and pulmonary hypertension
Gallstones: the increased rate of haemolysis increases the risk of gallstones and acute cholecystitis1
Retinopathy, retinal infarcts, retinal haemorrhage and retinal detachment
Transfusion-associated complications: iron overload, exposure to transfusion-related infection, alloimunisation
Chronic leg ulcers
Avascular necrosis: commonly affecting the femoral or humeral head
Chronic kidney disease: may cause worsening anaemia requiring high doses of erythropoietin
Median life expectancy is 40-60 years in high-income countries but much lower in low-income areas.6
The most common cause of death in children under 2 years of age is an infection, with or without splenic sequestration episodes.7
The most common causes of death in adults are cerebrovascular events, acute chest syndrome, pulmonary hypertension and sepsis.
SCA is a multi-system disorder caused by the increased tendency of red blood cells to sickle, leading to the occlusion of blood vessels and chronic haemolysis.
SCA is inherited in an autosomal recessive fashion.
SCA is diagnosed by haemoglobin electrophoresis.
Patients typically present to hospital with an acute painful sickle crisis.
Therapeutic management options are dependent on the complication that requires intervention and its underlying cause; this may include analgesia, rehydration, antibiotics, blood transfusion or a bone marrow transplant.
Management of SCD also involves preventative measures which may include hydroxycarbamide, prophylactic antibiotics and avoidance of potential crisis triggers.
The main complications of SCD are chronic pain, infection, cerebrovascular events and acute chest crises.
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Dr Alex Langridge
Speciality Haematology Trainee (ST7)
Founder of Buku Medicine, a free app answering the commonest questions put to haematology, renal and endocrine specialties.
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