Sickle Cell Disease

Sickle cell disease (SCD) can affect anyone but is more common in people from African and African-Caribbean backgrounds. In 2021, NICE estimated that it affects 1 in every 2000 live births, and there are approximately 12,000-15,000 people with SCD in England.¹

NHS digital data indicates that there were 30,544 admissions in England in 2022/23 where the primary diagnosis was “Sickle Cell Disorders”. This is comparable to the number of patients admitted with a pulmonary embolus (35,845 admissions in the same time period), and yet it feels that we consider pulmonary embolus as a differential much more frequently.

40% of the admissions with Sickle Cell Disorders were emergency admissions. The mean age was 30 years, however it is also important to consider in paediatrics presentations as of these admissions, 23% were aged 16 or under.²

SCD is a multisystem chronic disease that shortens life expectancy. There is marked individual variation on severity of disease, however due to screening, patient education, antibiotic prophylaxis, and immunisations this is improving across high income countries.

In the UK, the median survival by a study is estimated to be 67 years. Unfortunately, this isn’t true across the world. 99% of children in the UK survive to adulthood, whereas, in Africa 50-90% of children die before the age of 5.³

It is important to recognise the need for these patients to have a prompt assessment in the ED; a low awareness of how to manage these patients was raised in the “No One’s Listening” report in 2021 following an inquiry into avoidable deaths and failures of care for sickle cell patients.⁴

Sickle cell disease (SCD) encompasses a group of related haematological conditions in which sickle haemoglobin is present with sickle cell anaemia being the most serious type.

They are hereditary haemoglobinopathies, with sickle cell anaemia being caused by an autosomal recessive single base mutation in the haemoglobin beta-globin chain resulting in sickle haemoglobin (HbS). This causes it to polymerise when deoxygenated, reducing the flexibility of the cell, and leading it to produce the characteristic sickle appearance. These rigid, sickle erythrocytes can then form clusters which block blood vessels, become sequestered in the liver and spleen, cause intense pain (sickle cell crisis), anaemia and increased vulnerability to severe infections.⁵ SCD is associated with lifelong morbidity and reduced life expectancy.⁶

Complications of SCD such as vaso-occlusive crisis are usually the reason why patients present acutely to the ED. Given the range of pathophysiological manifestations of SCD, this can be challenging when assessing these patients as they can sometimes mimic other conditions.

Learning bite

• An understanding of the geographical distribution, population migration and early recognition is important for the emergency physician.
• Sickle cell anaemia has an autosomal recessive inheritance pattern.

Haemoglobin is made up of two pairs of globin chains. Each carry a heme group as demonstrated in Figure 1. The type of haemoglobin is determined by the globin chain combinations, and this varies from embryonic, fetal to adult life.

During fetal development the predominant haemoglobin is fetal haemoglobin HbF (this is made up of two alpha chains and two gamma chains, represented as α2γ2). After birth and with development almost all HbF is replaced by HbA (two alpha and two beta chains, α2β2). By 6 months of age this accounts for 95% of haemoglobin.

Figure 1. Haemoglobin A demonstrating 4 subunits comprising of 2 alpha and 2 beta globin chains each with a heme group (represented as “H”). – [Courtesy of the author]

HbS (sickle haemoglobin), is formed when there is a single amino acid mutation in the 6^th position of the β-globin chain, this results in glutamic acid being substituted by valine. This has different properties that change the shape of the molecule when deoxygenated. It causes it to aggregate and polymerise to form bundles that change the shape of the red blood cells (RBCs) into a crescent shape – “sickling”.

This sickling is initially reversible with reoxygenation, however repeated sickling leads to cell membrane damage, loss of potassium, an influx of calcium and cell dehydration. This leads to haemolysis and a release of haemoglobin into the circulation.

There are certain conditions which will increase the chance of sickling including acidosis that decreases haemoglobin’s affinity for oxygen, infection, dehydration, cold, and hypoxia.⁷

There are two major consequences for this repeated sickling:

1. Reduced RBC life span leading to chronic haemolytic anaemia. The mean lifespan for red cells in SCD is 20 days (usually 120 days).
2. Microvascular obstruction – the slow passage through the microcirculation leads to deoxygenation, and polymerisation. The sickled RBCs are also more “sticky” and adhere to endothelial cells, further causing obstruction in blood flow. This process leads to tissue ischemia and inflammation, which in turn lead to a vicious cycle of inflammation triggering more vaso-occlusion. This process can occur in any part of the body.

Figure 2. Overview of the pathophysiology resulting in the clinical presentation in Sickle Cell Disease – [Courtesy of the author]

In childhood there is splenomegaly caused by congestion of RBCs. Chronically, this leads to tissue damage which reduces splenic function and leads to fibrosis by adulthood. This is known as autosplenectomy. This predisposes individuals to infection particularly importantly of encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus Influenza, Neisseria meningitidis, and Salmonella species.

Learning bite

• Sickling can produce two mechanisms that lead to pathology: a shortened red cell survival and impaired passage through the microcirculation leading to obstruction and infarction.
• Autosplenectomy by adulthood predisposes to infection by encapsulated bacteria.

The β-chain of haemoglobin has two alleles, one allele each on Chromosome 11 that is inherited from the maternal and paternal chromosomes. Sickle cell anaemia is inherited in an autosomal recessive pattern. The term SCD encompasses the group of disorders with at least one HbS allele. Within this group, patients who have both affected alleles have Sickle cell anaemia (HbSS), and patients with only one allele affected, have Sickle cell trait (HbAS).

Figure 3: Autosomal recessive inheritance pattern of sickle cell anaemia – [Courtesy of the author]

As described, depending on the type of haemoglobin chain combinations there are four clinical syndromes described below with increasing severity.

Figure 4. Four clinical syndromes with increasing severity – [Courtesy of the author]

It is also possible to get sickle beta-thalassaemia, where people inherit a HbS gene from one parent and a beta thalassaemia (HbB thalassaemia) gene from the other.

SCD occurs predominantly in people of African or African-Caribbean origin but can also occur in families of Mediterranean, Indian, Middle Eastern, South or Central American descent.¹ The commonality of this distribution is the history of malaria or migration from a malarial area as the sickle cell trait or disease offers protective effect against Plasmodium Falciparum malaria in endemic regions leading to positive selection for the gene mutation.

Pregnancy

Screening for SCD is offered to all pregnant women in England. In areas of higher prevalence pregnant women are offered a blood test to see if they are a carrier; in lower prevalence areas, the answers to a questionnaire about their family and their partner’s family origins are used to decide on this blood test. The test is usually offered before 10 weeks gestation, and if the pregnant woman is a carrier her partner will be offered screening too in order to determine the risk of the baby being affected.

Newborn

Screening for SCD is offered as part of the newborn blood spot test (heel prick test).

Learning bite

• Screening for sickle cell disease has allowed earlier diagnosis.
• Remember to always consider this as a differential in patients whom this has not yet been diagnosed – especially those that might have moved to the UK from ethnic backgrounds described above who may not have had screening tests. These patients are likely to have additional barriers such as language or access to healthcare, so considering this on their presentation to the ED is a key opportunity.

Unwell patients presenting to the ED with SCD should trigger consideration for several specific complications of SCD such as vaso-occlusive crisis, acute chest crisis, sequestration, and stroke.

History

Acute sickling of RBCs can be triggered by temperature changes, acidosis, hypoxia, dehydration, infection, and stress. Therefore, it is important to ask about these precipitating factors as well as the general features of the history.

Generic features of the history are described below followed by certain specific features to consider related to the complications of sickle cell anaemia in the table below.

• Pain history
  • Acute or chronic
  • Location
  • Severity – patient’s (or parent’s) perspective. It is helpful to use pain charts to help with this in paediatrics.
  • Previous episodes if known SCD and previous crises – these patients are often experts! Information about treatments received and their effectiveness.
• History of infection
  • Currently, or history of recurrent infections
• History that may suggest dehydration.
• Exposure to cold
• Stress/Exertion
• Symptoms of anaemia
  • Lethargy, pallor, shortness of breath, dizziness
  • Paediatrics: reduced feeding, failure to thrive
• Jaundice
• Medication and medication changes
  • Are they taking prophylactic penicillin?
• FH
  • Specifically, SCD, if undiagnosed.
• Vaccination history
  • Predisposition to infection by encapsulated bacteria
• SH
  • Smoking

If the patient has recently moved to the UK, then consider potentially undiagnosed SCD.

Patients with SCD should be assessed using an ABCDE approach with these possible complications described below in mind.

Table 1. Specific features to consider related to the complications of sickle cell anaemia^1,6,9

Complication	Symptoms	Signs
Vaso-occlusive crisis	Pain can affect any part of the body. In infants: pain and swelling in the hands/feet (dactylitis) Older children/adults: severe pain in other bones e.g., femur, humerus, ribs, pelvis, spine.	Fever often accompanies the pain. Swollen digits/hands/feet Limp or pain examining area affected.
Respiratory Acute chest syndrome Pulmonary hypertension	Chest pain, wheeze, breathlessness, cough, fevers, generalised pain. Shortness of breath, fatigue	Hypoxia, tachypnoea, dyspnoea, fever.
Neurological Stroke	Headache, seizures, focal neurology, speech problems, visual impairment, drowsiness.	Focal neurology, altered consciousness.
Sequestration (splenic/ hepatic)	Abdominal pain, symptoms of anaemia, unwell	Pallor, tachycardia, abdominal tenderness, organomegaly, signs of shock/circulatory collapse
Infections	Often in the tissues susceptible to vaso-occlusion.	Focus on careful assessment of the source. Fever, tachycardia, tachypnoea.
Joints/bone: Osteomyelitis Avascular necrosis	Pain, swelling of joints, night pain. Limp, or abnormal gait Femoral and humeral heads affected in avascular necrosis.	Abnormal gait Pain, localised warmth, swelling, tenderness. Shortening of bones Possible fever
Chronic anaemia	Fatigue, malaise, shortness of breath, dizziness, syncope. Failure to thrive, lethargy in infants.	Pallor, jaundice, tachycardia. Systolic flow murmur in infants.
Aplastic crisis (Sudden, usually temporary cessation of erythropoiesis)	Usually following parvovirus B19 infection. Fever, headache, myalgia, arthralgia, respiratory and GI symptoms.	Pallor, tachypnoea, tachycardia. Usually without splenomegaly. Fever
Cardiac	Palpitations, symptoms of heart failure, chest pain.	Arrhythmia, cardiomegaly, consider myocardial infarction
Ophthalmology	Flashes, floaters Vision changes	Retinal haemorrhage, detachment, neovascularisation
Priapism	First episode usually occurs before the age of 20. Unwanted sustained painful erection (due to obstruction of venous drainage). Ask about duration, pain, previous episodes, trauma and medication.	More than 3 hrs is a surgical emergency.
Renal Sickle nephropathy Renal medullary carcinoma	Haematuria (painless); can cause large amounts of dilute urine; nocturnal enuresis in children. Weight loss, haematuria, abdominal pain, back pain	Haematuria Dehydration Monitor urine output
Venous thromboembolism	Unilateral leg swelling, redness Pleuritic chest pain, shortness of breath	Suggestion of deep vein thrombosis Hypoxia, tachypnoea, tachycardia

Abdominal pain

Patients with SCD are at risk of the usual causes of abdominal pain but also specifically increased risk of cholecystitis (due to haemoglobin breakdown), pancreatitis, mesenteric syndrome, and very importantly sequestration.

Splenic sequestration

Splenic sequestration is an important complication of SCD. It is more common in children than adults. It occurs when large numbers of red blood cells accumulate within the spleen, and patients may exhibit signs of hypovolaemic shock. It is life threatening and important to recognise. Bloods may demonstrate a drop in haemoglobin (>20g/L), increased reticulocyte count (immature red bloods cells, to compensate for the former), and thrombocytopenia.

Acute chest syndrome (ACS)

This is a form of lung injury that can be severe and life-threatening. It is the third leading cause of mortality in patients with SCD. 30% of patients with SCD will have one episode of ACS in their lifetime.¹ It is caused by multiple factors, namely infection and infarction (from fat emboli from necrotic marrow or sickle cell sequestration).

Patients present with respiratory symptoms, chest pain, hypoxia, cough, and fever, and a CXR will demonstrate patchy infiltrates (although it can be normal early in the illness).

Neurological – Stroke

It has been demonstrated that there are higher rates of ischaemic stroke in SCD; 11% before the age of 20 and 24% by the age of 45 years. A study found silent cerebral infarcts on MRI in 30% of children with SCD (8). There are also higher rates of haemorrhagic stroke in these patients, these are usually the result of ruptured aneurysms or the friable vessels in Moya Moya (formation of a mass of blood vessels, “puff of smoke” appearance, to compensate for stenosis or occlusion elsewhere).

Infection

The most common infections are pneumococcal sepsis, Gram-negative sepsis, lower respiratory tract infections, urinary tract infections, and osteomyelitis.

The commonest sites for osteomyelitis are the femur, tibia and humerus and most commonly caused by Salmonella species, Gram negative enteric bacteria and Staphylococcus aureus.¹

In acute chest syndrome Chlamydia pneumoniae and Mycoplasma pneumoniae are the most common cause in adults and children respectively.

Pregnancy

There are increased maternal and fetal complications including impaired placental blood flow that could cause spontaneous miscarriage, intrauterine growth restriction, pre-eclampsia and perinatal mortality.

Learning bite

• Ask about precipitating factors that may have triggered a crisis such as temperature changes, acidosis, hypoxia, dehydration, infection, and stress.
• Osteomyelitis is more common in SCD. Salmonella sp. being a common cause.
• In acute chest syndrome, Chlamydia pneumoniae and Mycoplasma pneumoniae are the most common causative organisms in adults and children respectively.

ED investigations for acute management:

• Bloods
  • Full blood count and reticulocyte count
    • Microcytic anaemia and reticulocyte count are usually elevated.
    • Splenic sequestration: low haemoglobin (below baseline), thrombocytopaenia and reticulocytosis
    • Aplastic anaemia: low haemoglobin (below baseline), low reticulocyte count (<1%).
  • Group and save (or crossmatch)
  • Renal and Liver function tests
• CXR: if acute chest syndrome, or infection suspected
• ECG: if coronary event suspicion
• PlainX-rays: if osteomyelitis, or concern for avascular necrosis.
  • Remember that the location of red marrow changes with age; in children it is present in all bones, in older children more commonly in epiphyses, and in adults, limited to the axial skeleton which explains the clinically observed infarcts in these different age groups.
• Bacterial culture
• Urine: possible proteinuria, haematuria
• CT (non-contrast) or MRI if neurological complications

 

Haematology investigations to help make a diagnosis:

• Blood films
  • Microcytic microchromic anaemia with sickling, and features of hyposplenism (Howell Jolly Bodies).

Image 1. Howell Jolly Bodies via ASH Image Bank by John Lazarchick. Title: Sickle cell disease – RBC morphology – 4. American Society of Hematology, 2009.

• Iron studies
  • Can help to distinguish haemolytic anaemia from iron deficiency.
  • Can also help detect iron overload from multiple transfusions.
• How is SCD diagnosed?
  • Sickle solubility test
    • Rapid screening test
    • Mixture of HbS in a reducing solution causes a turbid appearance due to precipitation whereas normal Hb is clear.
    • Difficult to distinguish sickle cell trait and sickle cell anaemia.
  • Haemoglobin electrophoresis
    • Needed to confirm the diagnosis. There will be no HbA, 80-95% HbS, and 2-20% HbF.

Learning bite

• Haemoglobin electrophoresis is needed to confirm the diagnosis.
• Reticulocyte count is useful to differentiate cause in an unwell patient with an acute drop in Hb; it will be high in splenic sequestration, and low (<1%) in aplastic anaemia.

This can be separated into acute management, longer-term management, and prevention of future complications.

Acute management in the ED and management of SCD complications

• Rapid assessment and early discussion with the on-call haematology team as patients are often well known to their parent team and may already have a crisis plan in place.
• Treatment and reversal of the trigger
• Oxygen
  • Minimise hypoxia and respiratory distress – aim to keep >96%, or if a patient says they feel better with the oxygen this is also an indication to keep it on.
  • Be aware that some sats probes can overestimate saturations in darker skin.⁹
• Analgesia
  • Crises can be extremely painful, therefore it’s management usually requires opioids such as morphine.
  • Adjuvant oral simple analgesia such as paracetamol, and NSAIDs can also be given.
  • In children, intranasal diamorphine can be used to rapidly improve severe pain whilst gaining intravenous access.
  • RCEM guidance is that adequate pain relief for moderate and severe pain should be given within 15 minutes of arrival and re-evaluation within 15-30 minutes in severe and moderate pain.¹⁰
  • Consider antiemetic, antihistamine and laxatives with opiate use.
• Fluid management
  • PO/IV fluids for fluid resuscitation or maintenance after clinical assessment.
  • Caution in those with pulmonary hypertension or heart failure.
• Antimicrobials
  • If there is evidence of infection. Follow local guidelines depending on the source – usually broad spectrum, 3^rdgeneration cephalosporins.
  • In acute chest syndrome studies demonstrate that Chlamydia pneumoniae and Mycoplasma pneumoniae are the most common causative organisms in adults and children respectively, therefore also add in atypical coverage in these patients¹¹
• Keep warm
  • Cold triggers vasoconstriction which in turn triggers vaso-occlusion
• Blood transfusion
  • Discuss with the on-call haematologist – different methods of transfusion such as simple or exchange transfusion and to discuss transfusion thresholds.
  • There is no indication for transfusion in asymptomatic anaemia with a vaso-occlusive crisis.
• Recognition and treatment of complications
  • Vaso-occlusive crisis
    • Analgesia, supportive care, fluid, correction of cause
    • If indicated: antibiotics, blood transfusion.
  • Acute chest syndrome:
    • Oxygen, antibiotics, pain control, optimise hydration, incentive spirometry.
    • Blood transfusion – discuss with haematology but to consider if PaO₂ <70mmHg on room air, or if >10% drop in PaO2 from their usual baseline¹²

 

Longer term complications and prevention

• Prophylactic treatment:
  • Hydroxycarbamide (hydroxyurea): Some patients may be on this already and there is no immediate advantage for administering it during emergency care as its clinical effect takes time to occur.
    • It works by increasing the HbF concentration, which does not polymerise, therefore interfering with HbS polymerisation. This leads to less sickling complications.
    • Importantly, it can cause neutropenia and thrombocytopenia, so check FBC if the patient is presenting with a fever or bleeding symptoms.
  • Crizanlizumab: Approved to reduce frequency of vaso-occlusive crises in patients aged 16 or over. It is a monoclonal antibody that targets an adhesion molecule on endothelium and platelets.
• Hyposplenism and susceptibility to infection
  • Vaccinations: All patients should be fully vaccinated in line with national immunisation schedule. With additional:
    • Pneumococcal immunisation at 2 years. In older children and adults, it is recommended every 5 years.
    • Influenza vaccine annually from 6 months old.
    • Meningitis ACWY vaccine: the schedule depends on the age at diagnosis.
    • Meningitis B vaccine in older children and adults.
  • Antibiotic prophylaxis: with penicillin in children under 5 years.
• Monitoring/screening
  • Primary stroke prevention/screening:
    • Transcranial Doppler (TCD): recommended from the age of 2, annually if it is normal, and more frequently if marginal or abnormal.
  • Surveillance of cognitive impairment with simplified signalling questions and screening with MRI brain (to detect silent cerebral infarcts) at least once in early school aged children and in adults.¹³
  • Retinopathy: screening begins at the age of 10.
• Prophylactic regular transfusions
  • Repeated simple transfusion to maintain HbS below 30% e.g. in children with an abnormal transcranial doppler.¹³
  • STOP (Stroke Prevention Trial in Sickle Cell Anaemia) study researchers found a 90% reduction in first stroke with chronic transfusion compared to standard supportive care.¹⁴
• Patient education
  • Counselling on triggers, guidance on home management, complications and when to seek help, nutritional advice and early diagnosis.¹⁵

Curative treatment?

• Haematopoietic stem cell transplantation is the only curative treatment, however due to cost, donors, and risks it is infrequently used.

Learning bite

• Prompt assessment and treatment is important in these patients including pain relief, oxygen, consideration of fluids, antibiotics and need for transfusion.
• Ask about Immunisation status and prophylactic penicillin.
• Antibiotic prophylaxis:with penicillin in children under 5 years.

No One’s Listening

In November 2021, the All-Party Parliamentary Group published a report on Sickle Cell to describe the quality of care received by sickle cell patients, prompted by the death of a patient (Evan Smith) in 2019 following a sickle cell crisis.⁴

Its key findings were related to low awareness of sickle cell disease, and adherence to national standards. There were racial inequalities raised, related to negative attitudes towards sickle cell patients. These concerns could lead to avoidance and fear for patients living with sickle cell.

More recently, the Health Inequalities Program have highlighted the health inequality for these patients. In a study, 54% of patients from the most deprived areas were readmitted compared to 28% in the least deprived group with a similar pattern for mortality; patients admitted from the most deprived areas were twice as likely to die in hospital than those from the least deprived areas.¹⁶ They have produced a free 30 minute e-learning module (accessible via e-learning for healthcare) to help understand these inequalities, recognise the causes and reflect on our roles to help narrow this gap.¹⁷

Take home:

• Remember to take pain seriously and be mindful to give appropriate pain relief.
• RCEM guidance states that adequate pain relief for moderate and severe pain should be given within 15 minutes of arrival and re-evaluation within 15-30 minutes in severe and moderate pain.⁶
• Use an age-appropriate pain scoring tool
• Check if the patient has their own personalised care plan
• If a patient is telling you something (or the patient’s parent/carer) regard them as an expert in their condition. Listen to them, and discuss the planned treatment, previous treatment, and their concerns.

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4. Paula. No One’s Listening – A Report » Sickle Cell Society [Internet]. Sickle Cell Society. 2021 [cited 2023 Oct 20].
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11. Vichinsky EP, Neumayr LD, et al. Causes and Outcomes of the Acute Chest Syndrome in Sickle Cell Disease. New England Journal of Medicine. 2000 Jun 22;342(25):1855–65.
12. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014 | NHLBI, NIH [Internet]. [Accessed Oct 26 2023].
13. DeBaun MR, Jordan LC, King AA, Schatz J, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Advances. 2020 Apr 16;4(8):1554–88.
14. Lee MT, Piomelli S, Granger S, Miller ST, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1;108(3):847–52.
15. Sickle Cell Disease in Childhood: Standards and Recommendations for Clinical Care » Sickle Cell Society [Internet]. Sickle Cell Society. [Accessed Oct 26 2023].
16. Aljuburi G, Laverty AA, Green SA, Phekoo KJ, Bell D, Majeed A. Socio-economic deprivation and risk of emergency readmission and inpatient mortality in people with sickle cell disease in England: observational study. J Public Health (Oxf). 2013 Dec;35(4):510–7.
17. Health Inequalities. elearning for healthcare (ELFH), NHS England [Internet]. [Accessed Oct 25 2023].
18. Davies SC, Oni L. Fortnightly review: Management of patients with sickle cell disease. BMJ. 1997 Sep 13;315(7109):656–60.