Sickle cell anaemia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

vaso-occlusive crisis

1st line – analgesia

Back

1st line –

analgesia

Paracetamol is used to treat mild pain. There have been reports of hepatic and renal damage in overdose.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat mild to moderate pain. They should be used with caution in patients with mild hepatic or renal impairment.

In patients with sickle cell disease, creatinine is a poor measure of renal dysfunction. Where long-term use of NSAIDs is planned, careful monitoring for proteinuria should be done on a routine basis.

Codeine may be used to treat moderate pain. Codeine is contraindicated in children younger than 12 years of age, and it is not recommended in adolescents 12 to 18 years of age who are obese or have conditions such as obstructive sleep apnoea or severe lung disease as it may increase the risk of breathing problems.[94] It is generally recommended only for the treatment of acute moderate pain, which cannot be successfully managed with other analgesics. It should be used at the lowest effective dose for the shortest period and treatment limited to 3 days.[95][96]

Stronger opioids administered orally are used for moderate to severe pain. If the pain is severe, parenteral opioid therapy is often required. One randomised, placebo-controlled trial found no significant difference between oral controlled-release morphine and intravenous morphine in patients aged 5 to 17 years with respect to frequency of rescue analgesia, duration of pain, and frequency of adverse events.[79] Pain should be reassessed frequently (every 30 to 60 minutes in the emergency department) to optimise pain control.[78]

Older children, adolescents, and adults may be allowed to self-administer analgesia via a patient-controlled analgesia device (PCA).[82] Note that intermittent administration of shorter-acting opioid analgesics may fail to control pain if the patient falls asleep. In these patients, particularly those that are not opioid naive, the use of long-acting oral opioids along with PCA/bolus dosing can assist with pain management.

Patients receiving long-term opioid analgesia who develop tolerance will likely require higher doses of opioids. Baseline opioid therapy and previous effective therapy should be taken into account.[78] If pain remains uncontrolled with opioids, anaesthetic or pain specialist consult should be sought. High-quality evidence regarding pharmacological interventions for adults with painful vaso-occlusive crisis is lacking.[80][81]

Primary options

paracetamol: infants and children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; children >12 years of age and adults: 500-1000 mg every 4-6 hours when required, maximum 4000 mg/day

Secondary options

ibuprofen: infants and children: 4-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; adolescents and adults: 200-400 mg every 4-6 hours when required, maximum 2400 mg/day

ketorolac: adults: 30 mg intramuscularly/intravenously every 6 hours when required, maximum 5 days treatment

naproxen: children >2 years of age: 5-7 mg/kg orally every 8-12 hours when required; adults: 500 mg initially, followed by 250 mg every 6-8 hours when required, maximum 1250 mg/day

Tertiary options

codeine phosphate: adults: 15-60 mg every 4-6 hours when required, maximum 240 mg/day

oxycodone: adults <50 kg: 0.2 mg/kg orally (immediate-release) every 3-4 hours when required; adults >50 kg: 5-10 mg every 3-4 hours when required

morphine sulfate: children: consult specialist for guidance on dose; adults: 10-30 mg orally (immediate-release) every 4 hours when required, or 15-30 mg orally (controlled-release) every 8-12 hours when required, or 2.5 to 10 mg intramuscularly/intravenously/subcutaneously every 2-6 hours when required

Plus – supportive care + correction of cause

Back

Plus –

supportive care + correction of cause

Treatment recommended for ALL patients in selected patient group

Oxygen is given nasally at a rate of 2 L/minute to patients with moderate hypoxaemia (PaO₂ 70-80 mmHg or O₂ saturation 92% to 95%). Patients with more severe hypoxaemia will require a higher flow rate. Patients with chronic hypoxaemia whose admission PaO₂ is not lower than their usual level may also benefit from oxygen.

Treatment of any specific precipitating cause is required, such as correction of acidosis or warming the patient if an exposure to cold was a precipitant.

Consider – antihistamine

Back

Consider –

antihistamine

Additional treatment recommended for SOME patients in selected patient group

Many opioids cause pruritus, which should be managed with an oral antihistamine.

Primary options

diphenhydramine: children 2-5 years of age: consult specialist for guidance on dose; children 6-12 years of age: 12.5 to 25 mg orally every 4-6 hours when required, maximum 150 mg/day; children >12 years of age and adults: 25-50 mg orally every 4-6 hours when required, maximum 300 mg/day

Consider – hydration

Back

Consider –

hydration

Additional treatment recommended for SOME patients in selected patient group

Fluid replacement corrects intravascular volume depletion, compensates for any on-going volume losses caused by fever, hyposthenuria, vomiting, or diarrhoea, and compensates for increased urinary sodium losses during crises. Patients with chronic severe anaemia and those with pulmonary hypertension need careful monitoring during fluid replacement therapy due to the risk of congestive heart failure.

If dehydration is mild, oral rehydration may be possible. Patients may require supplemental intravenous fluids if unable or unwilling to take oral fluids.

If dehydration is severe, treatment with fluid boluses and strict measurement of intake and output followed by intravenous fluids at a rate of at least 1.5 times the maintenance rate is recommended. This rate will need to be adjusted if patients have a history of heart disease or pulmonary hypertension, and caution should be used in older patients who may have undiagnosed pulmonary/heart disease.

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics should be considered if there is evidence of infection. The appropriate antibiotics depend on whether community-acquired, hospital-acquired, or atypical pneumonia is suspected.

Consider – blood transfusion

Back

Consider –

blood transfusion

Additional treatment recommended for SOME patients in selected patient group

Blood transfusion (simple or exchange) is indicated for life-threatening vaso-occlusive events, symptomatic anaemia, acute organ dysfunction, high-risk procedures (including general anaesthesia), and in selected pregnancies.

Risks include over-transfusion (hyperviscosity, volume overload), transfusion reactions (acute, septic, febrile, and allergic), alloimmunisation to red cell antigens, iron overload, and transfusion-transmitted diseases (hepatitis B and C, HIV, and other agents).

In the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study, researchers found a 90% reduction in first stroke with chronic transfusion as compared with standard supportive care.[67] Further research showed that higher rates of stroke followed discontinuation of transfusions.[68]

Transfusion is not indicated in a patient who has asymptomatic anaemia with a vaso-occlusive crisis as there is no evidence that transfusion decreases the length of a crisis in this setting.

acute chest syndrome

1st line – oxygen + incentive spirometry

Back

1st line –

oxygen + incentive spirometry

Oxygen is used for hypoxic patients.

Incentive spirometry will further prevent atelectasis. Intensive care unit support can be life-saving in severe cases.

Plus – analgesia

Back

Plus –

analgesia

Treatment recommended for ALL patients in selected patient group

Paracetamol is used to treat mild pain. There have been reports of hepatic and renal damage in overdose.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat mild to moderate pain. They should be used with caution in patients with mild hepatic or renal impairment.

Codeine may be used to treat moderate pain. Codeine is contraindicated in children younger than 12 years of age, and it is not recommended in adolescents 12-18 years of age who are obese or have conditions such as obstructive sleep apnoea or severe lung disease as it may increase the risk of breathing problems.[94] It is generally recommended only for the treatment of acute moderate pain, which cannot be successfully managed with other analgesics. It should be used at the lowest effective dose for the shortest period and treatment limited to 3 days.[95][96] Pain should be reassessed frequently (every 30 to 60 minutes in the emergency department) to optimise pain control.[78]

Stronger opioids administered orally are used for moderate to severe pain. If the pain is severe, parenteral opioid therapy is often required.

Patients receiving long-term opioid analgesia who develop tolerance will likely require higher doses of opioids.

Primary options

Secondary options

ibuprofen: infants and children: 4-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; adolescents and adults: 200-400 mg every 4-6 hours when required, maximum 2400 mg/day

ketorolac: adults: 30 mg intramuscularly/intravenously every 6 hours when required, maximum 5 days treatment

naproxen: children >2 years of age: 5-7 mg/kg orally every 8-12 hours when required; adults: 500 mg initially, followed by 250 mg every 6-8 hours when required, maximum 1250 mg/day

Tertiary options

codeine phosphate: adults: 15-60 mg every 4-6 hours when required, maximum 240 mg/day

oxycodone: adults <50 kg: 0.2 mg/kg orally (immediate-release) every 3-4 hours when required; adults >50 kg: 5-10 mg every 3-4 hours when required

Plus – broad-spectrum antibiotics

Back

Plus –

broad-spectrum antibiotics

Treatment recommended for ALL patients in selected patient group

Intravenous broad-spectrum antibiotics are given because bacterial pneumonia cannot always be ruled out. In a large prospective cohort study the most common organisms identified were atypical, so both typical and atypical coverage is required.[83] Observational data suggest that children treated with guideline-adherent antibiotic therapy have a lower rate of re-admission to hospital in the next 30 days, for both acute chest syndrome and all causes.[85]

Consider – antihistamine

Back

Consider –

antihistamine

Additional treatment recommended for SOME patients in selected patient group

Many opioids cause pruritus, which should be managed with an oral antihistamine.

Primary options

Consider – blood transfusion

Back

Consider –

blood transfusion

Additional treatment recommended for SOME patients in selected patient group

Transfusions are recommended because they decrease the proportion of sickle red cells. Although guidelines suggest that a transfusion is indicated if patients have a PaO₂ <70 mmHg on room air or, in chronic hypoxaemia, if there is more than a 10% drop in PaO₂ from their usual baseline, clinical judgement will form the basis of the decision.[35] Transfusions are especially recommended in patients who have a history of cardiovascular disease, low platelet count, or have multi-lobar pneumonia, as these risks have been found to be associated with an increased risk of mechanical ventilation.[83]

Not all patients with acute chest syndrome will require a blood transfusion.

While offering blood transfusions is widely accepted practice, evidence from randomised controlled trials is currently lacking.[84]

Consider – hydration

Back

Consider –

hydration

Additional treatment recommended for SOME patients in selected patient group

If dehydration is mild, oral rehydration may be possible. Patients may require supplemental intravenous fluids if unable or unwilling to take oral fluids.

ONGOING

chronic disease

sickle cell anaemia (HbSS or HbSB0 thalassaemia genotype)

1st line – supportive care + prevention of complications

Back

1st line –

supportive care + prevention of complications

In young children, the main treatment goal is to improve survival by reducing the threat from infections. This can be achieved through: early diagnosis, pneumococcal immunisation, antibiotic prophylaxis with penicillin in children under 5 years of age, nutritional counselling, and prompt treatment when infections do occur.[35][37]

In patients who survive early childhood and have chronic disease, the main treatment goals are symptom control and management of disease complications. This can be achieved through: pain management (chronic and acute); pharmacological amelioration of disease severity with the use of hydroxycarbamide; prophylaxis and prompt treatment of infections; prevention and management of acute complications (e.g., acute chest syndrome, vaso-occlusive episodes); prevention of stroke; prevention and treatment of chronic organ damage (kidney, renal, pulmonary); genetic counselling; health and nutritional education of patient and/or parents; and counselling of patient and/or parents to avoid triggers (e.g., dehydration, cold and high altitudes, and strenuous exercise).[35][38][39][40][41][42]

Patients who have recurrent complications (moderate to severe vaso-occlusive crises, acute chest syndrome, or severe symptomatic anaemia) require additional treatment.

Consider – hydroxycarbamide

Back

Consider –

hydroxycarbamide

Additional treatment recommended for SOME patients in selected patient group

Hydroxycarbamide can be considered in patients aged ≥2 years with sickle cell anaemia.

In the short term, hydroxycarbamide has been shown to decrease the frequency of pain episodes, reduce transfusion requirements, and decrease the risk of acute chest syndrome.[43][44][45][46][47][48][49][50][51] It has also been shown to prevent life-threatening neurological events in patients at risk of stroke, and reduce the frequency of dactylitis in infants.[49][51]

The most common complication of hydroxycarbamide is neutropenia.[48][52][53] In one study, treatment with hydroxycarbamide for 12 months had no adverse effect on height, weight gain, or pubertal development in infants and older children.[48]

The long-term safety and efficacy of hydroxycarbamide is unclear due to the lack of good-quality evidence.[51] Long-term observational follow-up studies of adult patients have reported reduced mortality after long-term exposure to hydroxycarbamide, and no increased incidence of malignancy.[54][55][56]

Hydroxycarbamide should be used with caution in hepatic/renal impairment; a dose reduction may be necessary.

Hypersensitivity to hydroxycarbamide or marked bone marrow suppression (i.e., leukopenia, thrombocytopenia) are contraindications.

Full blood count and reticulocyte count should be monitored every 2-4 weeks until the completion of titration of the dose. Blood tests should be done monthly thereafter.

Primary options

hydroxycarbamide: children and adults: 10-20 mg/kg orally once daily initially, increase by 5 mg/kg/day increments every 12 weeks according to blood test results, maintaining neutrophil count >2500/mm³ and platelet count >95,000/mm³, maximum 35 mg/kg/day

Consider – L-glutamine

Back

Consider –

L-glutamine

Additional treatment recommended for SOME patients in selected patient group

L-glutamine can be considered in patients aged 5 years and older who are intolerant to hydroxycarbamide or who continue to have painful events while on hydroxycarbamide.[57]

In one randomised placebo-controlled trial involving 230 patients aged between 5 and 58 years with HbSS or HbSB0 thalassaemia genotypes and a history of two or more crises during the previous year, treatment with L-glutamine resulted in fewer sickle cell crises and fewer hospitalisations.[58]

L-glutamine should be avoided in patients with renal or hepatic impairment due to concerns about increased mortality when used in critically ill patients with multi-organ failure.[59]

No data are available yet regarding the use of L-glutamine with crizanlizumab.

L-glutamine is not available in Europe. The European Medicines Agency refused a marketing authorisation because the application failed to demonstrate that the drug was effective at reducing the number of sickle cell disease crises or hospital visits. However, the drug is available in the US and other countries.

Primary options

L-glutamine: children ≥5 years of age and adults: body weight <30 kg: 5 g orally twice daily; body weight 30-65 kg: 10 g orally twice daily; body weight >65 kg: 15 g orally twice daily

Consider – crizanlizumab

Back

Consider –

crizanlizumab

Additional treatment recommended for SOME patients in selected patient group

Crizanlizumab is approved by the US Food and Drug Administration to reduce the frequency of vaso-occlusive crises in patients aged ≥16 years, but availability may vary elsewhere. The European Medicines Agency has revoked its marketing authorisation based on preliminary results of a phase 3 trial (the STAND study) showing a lack of benefit compared with placebo.

In one randomised phase 2 trial of patients with sickle cell disease (any genotype, with a history of at least two sickle cell-related pain crises in the preceding 12 months, some of whom were taking concomitant hydroxycarbamide), crizanlizumab significantly lowered the rate of sickle cell-related pain crises, and increased median time to first and second crises, compared with placebo.[61] A post-hoc analysis reported similar results across different groups, including those with a high number of previous vaso-occlusive crises, receiving concomitant hydroxycarbamide, and/or with the HbSS genotype.[62]

Common adverse effects of crizanlizumab therapy include arthralgia, diarrhoea, pruritus, vomiting, and chest pain.[61]

Crizanlizumab is typically used in addition to hydroxycarbamide in patients with HbSS or HbSB0 thalassaemia sickle cell disease. It may be used as monotherapy in patients who cannot tolerate hydroxycarbamide, or who have variant sickle cell disease (HbSC or HbSB+ thalassaemia).

There are no data regarding the use of crizanlizumab concomitantly with L-glutamine.

Several ongoing clinical trials are trying to establish the role of crizanlizumab in paediatric patients with sickle cell disease.[63]

Primary options

crizanlizumab: adolescents ≥16 years and adults: 5 mg/kg intravenously at weeks 0, 2, and then every 4 weeks thereafter

Consider – repeated blood transfusions

Back

Consider –

repeated blood transfusions

Additional treatment recommended for SOME patients in selected patient group

A common prophylactic treatment, repeated simple transfusion is used to maintain HbS below 30%.[31]

Perioperative transfusion is often needed to prevent postoperative sickle cell complications in patients with sickle cell anaemia (HbSS) undergoing any form of surgery. One randomised controlled trial found that transfusion regimens designed to keep haemoglobin at 100 g/L (10 g/dL) were as effective as, and possibly safer than, exchange transfusions in these situations.[64] One Cochrane systematic review concluded that there is insufficient evidence from randomised controlled trials to determine whether conservative pre-operative blood transfusion is as effective as aggressive blood transfusion, owing to the risk of bias in the available trials.[65]

Patients with HbSC disease undergoing major surgery often require exchange transfusions prior to surgery, due to baseline haemoglobin levels that are already greater than 100 g/L (10 g/dL) and the need to avoid hyperviscosity in the blood.

Routine prophylactic transfusion is not generally recommended during pregnancy, but it may be considered for women:[70][73]

with previous or current medical, obstetric, or fetal problems related to sickle cell disease; previously on hydroxycarbamide due to severe disease; with additional features of high-risk pregnancy, or multiple pregnancy.

Pregnancy outcomes are worse in pregnant women with sickle cell disease than in those without.[74] One meta-analysis provides some evidence to suggest that prophylactic transfusion should be considered in high-risk pregnant women with sickle cell disease.[75]

Women who experience SCD-related complications in their current pregnancy would benefit from transfusion.[70][73] Transfusion may be required with worsening anaemia.[73]

Selection of red cells for transfusion is an important consideration. Experts currently recommend ABO D CcEe K-matched red blood cells, even in the absence of alloantibodies, to reduce the risk of alloimmunisation.[69][70][71] In patients with sickle cell disease who have developed clinically significant alloantibodies, selection of red blood cells antigen negative to the alloantibody is recommended.[69][71] If possible, selection of more extended phenotype-matched red blood cells will likely reduce the risk of further alloimmunisation in these patients.[69]

Observational studies provide some evidence that extended serological red blood cell antigen matching decreases the prevalence of alloimmunisation; further prospective randomised controlled trials are needed to determine the most effective ways of reducing alloimmunisation through serological and genotypical matching.[72]

2nd line – haematopoietic stem cell transplantation

Back

2nd line –

haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) is the only curative treatment for sickle cell disease, but is used infrequently owing to lack of suitable stem cell donors, cost, and risks.

Guidelines from the American Society of Hematology (ASH) make the following conditional recommendations on the use of HSCT in sickle cell anaemia:[86]

matched related allogeneic transplantation is suggested in patients who have neurological injury (e.g., stroke or abnormal transcranial Doppler ultrasound), patients experiencing frequent pain, or patients who continue to have recurrent episodes of acute chest syndrome (ACS) despite standard of care;

transplant from alternative donors in the context of a clinical trial is suggested for patients who lack a matched sibling donor; consideration should be given to risks related to transplant complications and potential benefits derived from transplantation;

either total-body irradiation ≤400 cGy or chemotherapy-based conditioning regimens is suggested for allogeneic transplantation

myeloablative conditioning is suggested over reduced intensity conditioning (that contains melphalan/fludarabine) for children with an indication for allogeneic transplantation and a matched sibling donor

nonmyeloablative conditioning is suggested over reduced intensity conditioning (that contains melphalan/fludarabine) for adults with an indication for allogeneic transplantation and a matched sibling donor

allogeneic transplantation is suggested at an earlier age rather than at an older age; impact of age on transplantation outcome may also be affected by the conditioning regimen employed

using human leukocyte antigen (HLA)-identical sibling cord blood when available (and associated with an adequate cord blood cell dose and good viability) is suggested over bone marrow.

variant sickle cell disease (including HbSC or HbSB+ thalassaemia genotype)

1st line – supportive care + prevention of complications

Back

1st line –

supportive care + prevention of complications

Patients who have recurrent complications (moderate to severe vaso-occlusive crises, acute chest syndrome, or severe symptomatic anaemia) require additional treatment (e.g., hydroxycarbamide and/or repeated blood transfusions).

Consider – hydroxycarbamide

Back

Consider –

hydroxycarbamide

Additional treatment recommended for SOME patients in selected patient group

Hydroxycarbamide can be considered in patients aged ≥2 years with sickle cell anaemia.

High-quality evidence to support the use of hydroxycarbamide in variant HbSC sickle cell disease is lacking.

Hydroxycarbamide should be used with caution in hepatic/renal impairment; a dose reduction may be necessary.

Hypersensitivity to hydroxycarbamide or marked bone marrow suppression (i.e., leukopenia, thrombocytopenia) are contraindications.

Full blood count and reticulocyte count should be monitored every 2-4 weeks until the completion of titration of the dose. Blood tests should be done monthly thereafter.

Primary options

Consider – crizanlizumab

Back

Consider –

crizanlizumab

Additional treatment recommended for SOME patients in selected patient group

In one randomised phase 2 trial of patients with sickle cell disease (any genotype, with a history of at least two sickle cell-related pain crises in the preceding 12 months, some of whom were taking concomitant hydroxycarbamide), crizanlizumab significantly lowered the rate of sickle cell-related pain crises, and increased median time to first and second crises, compared with placebo.[61] Subgroup analysis found a significant decrease in the number of vaso-occlusive crises in patients with variant sickle cell disease (approximately 30% of patients were non-HbSS genotype).[61]

Common adverse effects of crizanlizumab therapy include arthralgia, diarrhoea, pruritus, vomiting, and chest pain.[61]

Crizanlizumab may be used as monotherapy in patients with variant sickle cell disease (HbSC or HbSB+ thalassaemia).

Several ongoing clinical trials are trying to establish the role of crizanlizumab in paediatric patients with sickle cell disease.[63]

Primary options

crizanlizumab: adolescents ≥16 years and adults: 5 mg/kg intravenously at weeks 0, 2, and then every 4 weeks thereafter

Consider – repeated blood transfusions

Back

Consider –

repeated blood transfusions

Additional treatment recommended for SOME patients in selected patient group

A common prophylactic treatment, repeated simple transfusion is used to maintain HbS below 30%.[31]

Routine prophylactic transfusion is not generally recommended during pregnancy, but it may be considered for women:[70][73]

Women who experience SCD-related complications in their current pregnancy would benefit from transfusion.[70][73] Transfusion may be required with worsening anaemia.[73]

Selection of red cells for transfusion is an important consideration. Experts currently recommend ABO D CcEe K-matched red blood cells, even in the absence of alloantibodies, to reduce the risk of alloimmunisation.[69][71] In patients with sickle cell disease who have developed clinically significant alloantibodies, selection of red blood cells antigen negative to the alloantibody is recommended.[69][71] If possible, selection of more extended phenotype-matched red blood cells will likely reduce the risk of further alloimmunisation in these patients.[69]

2nd line – haematopoietic stem cell transplantation

Back

2nd line –

haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation for patients with variant sickle cell disease may be considered as part of a clinical trial.

Use of this content is subject to our disclaimer

Sickle cell anaemia

Treatment algorithm

vaso-occlusive crisis

analgesia

Primary options

Secondary options

Tertiary options

supportive care + correction of cause

antihistamine

Primary options

hydration

antibiotics

blood transfusion

acute chest syndrome

oxygen + incentive spirometry

analgesia

Primary options

Secondary options

Tertiary options

broad-spectrum antibiotics

antihistamine

Primary options

blood transfusion

hydration

chronic disease

supportive care + prevention of complications

hydroxycarbamide

Primary options

L-glutamine

Primary options

crizanlizumab

Primary options

repeated blood transfusions

haematopoietic stem cell transplantation

supportive care + prevention of complications

hydroxycarbamide

Primary options

crizanlizumab

Primary options

repeated blood transfusions

haematopoietic stem cell transplantation