Sickle cell disease

• Sickle cell disease (SCD) is an inherited haemoglobin disorder, most often from homozygous HbS (HbSS). Deoxygenated HbS polymerises, distorting red cells and driving vaso-occlusion, haemolysis and inflammation.
• It presents across life as dactylitis, painful vaso-occlusive crises, acute chest syndrome, splenic sequestration, stroke, infection with encapsulated organisms, priapism, osteonecrosis, nephropathy, retinopathy and leg ulcers.
• Diagnosis rests on newborn screening and haemoglobin electrophoresis (or high-performance liquid chromatography, HPLC); sickle trait is screened out at the same time.
• Hydroxyurea is the main disease-modifying drug; penicillin prophylaxis, pneumococcal and other vaccines, and regular surveillance reduce infection and stroke. Analgesia is aggressive and opioid-based for severe crises.
• Transfusion and exchange transfusion treat or prevent complications; allogeneic stem cell transplantation and, more recently, gene therapy are the only potentially curative options.

By the end of this page you should be able to:

1. Explain the HbS mutation and why polymerisation produces sickling, vaso-occlusion and haemolysis.
2. Distinguish HbSS, HbSC, HbS/β-thalassaemia and sickle trait, and say who is affected.
3. Recognise the age-specific presentations and complications of SCD, and the red flags in each.
4. Plan investigations, including newborn screening, confirmatory electrophoresis, transcranial Doppler (TCD) and MRI.
5. Manage an acute vaso-occlusive crisis and acute chest syndrome, and choose transfusion versus exchange transfusion.
6. Counsel patients on hydroxyurea, penicillin and vaccines, pregnancy, and the current status of newer agents and curative therapies.

The disorder is named, not after its gene, but for the sickle-shaped red blood cells first seen under the microscope. Sickle cell trait (HbAS) is not a disease: it is heterozygosity for HbS and is usually silent, except under extreme hypoxia. ^[11]

SCD is the commonest serious monogenic disorder worldwide. An estimated 300,000 infants are born with sickle cell anaemia each year, most in sub-Saharan Africa, the Middle East, India and the Mediterranean basin. ^[11] The disorder tracks with malaria-endemic regions because heterozygotes (sickle cell trait) were protected against severe malaria. ^[11]

In the United States, about 100,000 people live with SCD; most are of African ancestry, with smaller numbers of Hispanic, Middle Eastern and Asian Indian descent. ^[1] Life expectancy is reduced, particularly for those with HbSS, though modern care has improved survival substantially. ^[1]

A severe complication can appear in the first year of life: vaso-occlusive crisis (VOC) usually begins only after the first few months, because high fetal haemoglobin (HbF) early in life protects against polymerisation. ^[1]

The fundamental lesion is genetic. SCD is autosomal recessive and arises from a point mutation in the β-globin gene (HBB): substitution of valine for glutamic acid at the sixth position of the β-globin chain (Glu6Val). ^[11] Homozygosity for this mutation produces HbS; compound heterozygosity with another abnormal haemoglobin or β-thalassaemia also produces disease. ^[11]

The only true risk factor is inheritance. Carrier frequency is highest where malaria is, or historically was, endemic. ^[11] Modifiers of severity include co-inherited α-thalassaemia, BCL11A polymorphisms (which govern HbF levels) and environmental triggers (cold, dehydration, infection, hypoxia, acidosis, strenuous exercise). ^{[1] [3]}

The story of SCD is the story of what happens to a single molecule when oxygen is removed.

HbS polymerisation. HbS is soluble when oxygenated. When deoxygenated, the valine residue at position 6 (instead of glutamic acid) creates a hydrophobic patch that slots into a complementary pocket on a neighbouring deoxy-HbS molecule. The two fit together, and long HbS polymers form: this is the sickling step. ^[11] Polymerisation is favoured by low oxygen tension, acidosis, dehydration and raised temperature. ^[4]

Sickling. The polymer fibres distort the red cell into a sickle. Sickled cells are rigid and have abnormal adherence to endothelium, platelets and leukocytes. ^[1]

Vaso-occlusion. Rigid, sticky red cells, plus dense neutrophil-platelet aggregates and activated endothelium, obstruct small and post-capillary venules. The result is ischaemia-reperfusion injury, painful crises and organ infarction. ^[1]

Haemolysis. Sickled red cells are fragile and are destroyed both in the circulation and the spleen. Haemolysis (intravascular and extravascular) produces anaemia, jaundice, gallstones and a chronic vasculopathy driven by free haem (which scavenges nitric oxide, promotes endothelial dysfunction and oxidant stress). ^[1]

Asplenia. The spleen is initially engorged by sickled cells; repeated infarction (autosplenectomy) occurs during early childhood, producing functional (then anatomic) asplenia. ^[1] This is why young children are vulnerable to invasive infection with encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae type b and Salmonella, and why vaccination and penicillin prophylaxis matter. ^[1]

Nitric oxide and vasculopathy. Chronic haemolysis depletes nitric oxide and raises plasma free haem. This endothelial dysfunction underlies cerebrovascular disease, pulmonary hypertension and priapism (see complications). ^[1]

Figure 1Howell-Jolly smear 2010-11-17

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Long description

Blood smear for Howell-Jolly bodies, the small nuclear remnants seen in red cells after splenectomy or in functional asplenia, as in sickle cell disease.

Figure 2Sickle Cell Anemia (5610746554)

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Long description

Blood smear in sickle cell anaemia with many sickled, elongated red cells and some target cells.

Repeated sickling damages the red cell membrane, so that some cells remain sickled even when re-oxygenated (irreversibly sickled cells). The spleen enlarges in infancy, then shrinks (autosplenectomy). Bone, kidney, lung and brain all show ischaemic damage. ^[1]

• Sudden severe pain in the limbs, chest, back or abdomen (a VOC), often with few objective signs. ^[1]
• Breathlessness, cough or chest pain with a new lung infiltrate - acute chest syndrome (ACS). ^[1]
• Acute neurological symptoms: limb weakness, facial droop, aphasia, seizure or headache. ^[4]
• Sudden loss of vision, yellowing of the eyes, dark urine, bone pain, leg ulcers.
• In men: painful erection lasting more than 4 hours (priapism).
• In children: swollen hands/feet (dactylitis), severe infection with fever, or pallor with a large abdomen (splenic sequestration).

• Anaemia (pallor, tachycardia), jaundice, hepatosplenomegaly.
• Dactylitis in infants (tender, swollen digits).
• New chest signs (tachypnoea, hypoxaemia, reduced air entry) in ACS.
• Focal neurological deficit or reduced level of consciousness in stroke.
• Signs of dehydration; objective pain behaviour is often modest despite severe stated pain.

Infancy (first year). Dactylitis is often the first manifestation (as early as six months). Splenic sequestration causes sudden pallor, tachycardia and an enlarging abdomen; it is an emergency. Because of asplenia, fever is a common red flag and sepsis with encapsulated organisms can be rapidly fatal. ^[1]

Childhood. Recurrent pain crises; ACS (often with fever and middle-lobe involvement); stroke; priapism; delayed growth; avascular necrosis of the femoral head (osteonecrosis); and the start of retinopathy and renal complications. ^{[1] [4]} Transcranial Doppler (TCD) screening begins at 2 years because stroke risk is highest in childhood. ^[1]

Adolescence and adult life. Chronic daily pain develops and is estimated in 30 to 40% of adolescents and adults. ^[3] Priapism, osteonecrosis, nephropathy, retinopathy, pulmonary hypertension, leg ulcers and acute chest syndrome dominate. ^{[1] [3]}

No laboratory test is needed to suspect SCD beyond a history-compatible presentation and African/Mediterranean/South Asian ancestry. Confirmation is laboratory-based (below).

• Newborn screening. Every infant should be screened with HPLC or isoelectric focusing to identify HbS and to distinguish SCD from sickle cell trait. ^[1] Screening is performed in the first days of life and is most effective when linked to active recall and prompt counselling.
• Confirmatory testing. Haemoglobin electrophoresis (or HPLC) at any age confirms the genotype (HbSS, HbSC, HbS/β-thalassaemia). Solubility tests (such as Sickledex) are screening tools only, are unreliable in neonates (because of high HbF) and cannot separate trait from disease. ^[1]
• Full blood count and film. Anaemia (Hb usually 6 to 9 g/dL in HbSS), raised reticulocytes, sickled cells on the film. ^[1]
• Biochemistry. Raised bilirubin, lactate dehydrogenase and reduced haptoglobin (haemolysis); renal function and urinalysis.

• Transcranial Doppler (TCD). Annual screening from age 2 to at least 16 years in HbSS/HbSβ⁰ disease; a velocity of 200 cm/s or greater correlates with about a 10% annual stroke risk. ^[1]
• MRI of the brain to detect silent cerebral infarcts and to investigate any neurological event. ^[4] (Clinically silent infarcts occur in around 39% of children by 18 years and in more than 50% of adults by 30 years in HbSS/HbSβ⁰ disease. ^[4])
• Chest X-ray / CT for chest pain or hypoxaemia; echocardiography when pulmonary hypertension is suspected; ophthalmology screening from age 10 for retinopathy. ^[1]
• Renal screening. Annual spot urine testing for microalbuminuria and proteinuria from age 10. ^[1]

There is no single diagnostic score. The diagnosis is established when an abnormal haemoglobin pattern (HbS as the dominant haemoglobin, with the genotype identified) is present in an appropriate clinical context. ^[1] Newborn screening makes the diagnosis at birth before symptoms appear; this is what makes preventive care possible. ^[1]

Assess severity using complications rather than a single number: haemoglobin baseline, number of VOCs in 12 months, history of ACS, TCD velocity, renal and retinal findings, and functional status. ^[1] The ASH guidelines (see below) grade many interventions as conditional because the underlying evidence is sparse; patients' values and preferences should shape decisions. ^[2]

A vaso-occlusive crisis (VOC) is a medical emergency of pain, not a behaviour problem.

• Analgesia. For mild to moderate pain, NSAIDs if not contraindicated. ^[1] For severe pain, opioids are first-line and should be given rapidly (within 1 hour of arrival in hospital), at doses guided by the patient's history and severity, with frequent reassessment every 30 to 60 minutes. ^{[1] [3]} Around-the-clock or patient-controlled analgesia is preferred. Meperidine should be avoided because of the risk of seizures. ^[1] ASH suggests ketamine infusion (0.1 to 0.3 mg/kg per hour, maximum 1 mg/kg per hour) as adjunctive therapy for pain refractory to opioids. ^[3]
• Hydration. Oral and intravenous as needed to correct dehydration; fluid therapy alone does not treat pain. ^[3]
• Oxygen. Only for hypoxaemia; routine oxygen is not indicated. ^[1]
• Incentive spirometry every hour while awake for hospitalised patients with VOC or ACS. ^[1]
• Infection. Fever higher than 38.3 °C is a danger sign in SCD. Take blood cultures and start broad-spectrum antibiotics (including coverage for encapsulated organisms) until infection is excluded. ^[1]
• Transfusion. Indications in acute complications are listed in Table 1. ^[1]

Flowchart 1: an approach to an acute sickle cell crisis

Exchange transfusion must be set up promptly for neurological symptoms: blood should be given within 2 hours of presentation. ^[4] The goal in secondary stroke prevention is to maintain haemoglobin above 9 g/dL and HbS below 30% of total haemoglobin until the next transfusion. ^[4]

Hydroxyurea increases fetal haemoglobin (HbF), which does not sickle, and improves several clinical outcomes (fewer VOCs and ACS episodes, fewer transfusions, lower mortality). ^[1] It is rapidly absorbed and taken once daily. ^[1]

• Who. Offer counselling from 9 months of age for all children with sickle cell anaemia and initiate therapy regardless of clinical severity (strong recommendation). ^[1] Initiate in adults with 3 or more moderate to severe pain crises in 12 months, severe or recurrent ACS, severe symptomatic chronic anaemia, or pain that limits quality of life. ^[1] Compound heterozygous patients (HbSC, HbS/β⁺-thalassaemia) need specialist input. ^[1]
• Dose. Adults start at 15 mg/kg/day (round up to the nearest 500 mg; AAFP/NHLBI 2014 gives 5 to 10 mg/kg/day in chronic kidney disease, whereas the SIKLOS label recommends reducing the dose by 50% when creatinine clearance is below 60 mL/min); infants and children start at 20 mg/kg/day. Escalate by 5 mg/kg every 8 weeks to a maximum of 35 mg/kg/day, aiming at mild myelosuppression (absolute neutrophil count 2,000-4,000 per μL; platelets at least 80,000 per μL). A clinical response may take 3 to 6 months. ^[1]
• Monitoring. Full blood count with differential and reticulocyte count at least every 4 weeks during dose escalation, and every 2 to 3 months once stable (AAFP/NHLBI 2014; the SIKLOS label advises monitoring blood counts every 2 weeks). If cytopenias occur, withhold until recovery, then restart 5 mg/kg lower. ^[1]
• Contraindication. Hydroxyurea is contraindicated in pregnancy and breastfeeding. ^[1]
• Adherence. Effectiveness depends on daily dosing; do not double missed doses. Therapy should continue during hospitalisation or illness. ^[1]

Folic acid supplementation is widely used as an adjunct because of increased erythropoiesis and haemolysis, although no standard dose is established in the sources consulted here.

Children homozygous for HbS should receive oral penicillin (125 mg twice daily under 3 years; 250 mg twice daily from 3 years) once the diagnosis is made, continuing until at least 5 years of age (and longer after splenectomy or invasive pneumococcal disease). ^[1] Complete the pneumococcal vaccination series before stopping, and ensure all patients with SCD are vaccinated against Streptococcus pneumoniae. ^[1] Live vaccines should be given according to routine schedules; influenza and COVID-19 vaccination should follow local guidance.

Hydration, keeping warm (avoiding cold exposure and high altitudes without oxygen), avoiding tobacco, prompt treatment of infections, and dental surveillance. ^[1]

Beyond the acute indications above, chronic transfusion (simple or automated red cell exchange) is used for primary stroke prevention in children with abnormal TCD velocities, secondary stroke prevention, and (in selected cases) severe, recurrent crises despite other therapy. ^{[2] [4]} Chronic transfusions need careful matching to Rh and K antigens at minimum (and an extended phenotype), with ferritin monitoring (under the ASH 2020 transfusion guideline, MRI for liver iron content is likely not needed when ferritin is below 1000 ng/mL during chronic red cell exchange with a neutral or negative iron balance) and iron chelation when overload develops. ^[2] Automated RCE is preferred over simple transfusion or manual RCE for chronic programmes. ^[2]

Preoperative transfusion is recommended for operations requiring general anaesthesia lasting more than 1 hour, aiming for haemoglobin above 9 g/dL; exchange transfusion is used when a high baseline haemoglobin precludes simple transfusion. ^[2]

For pregnancy, the ASH transfusion guideline suggests either planned prophylactic transfusion at regular intervals (starting in early pregnancy) or transfusion only when clinically indicated, acknowledging very low certainty of evidence. Prophylactic regular transfusion should be considered for women with a history of severe SCD complications, additional high-risk features or complications that develop in the current pregnancy. ^[2]

L-glutamine oral powder is licensed in the USA for patients aged 5 years and older to reduce acute complications of SCD. The dose is 5, 10 or 15 g twice daily according to body weight (less than 30 kg, 30-65 kg, greater than 65 kg). ^[7] In a randomised trial, the median number of sickle crises was 3 versus 4 over 48 weeks and the average cumulative crisis count was reduced by about 25%; benefit was seen irrespective of hydroxyurea use. ^[7] A mechanism improving the NAD redox potential via reduced glutathione is proposed, and the drug does not appear to replace hydroxyurea. ^[7]

Crizanlizumab is a monoclonal antibody against P-selectin given as 5 mg/kg by intravenous infusion on Week 0, Week 2 and every 4 weeks thereafter, indicated to reduce VOC frequency in patients aged 16 years and older. ^[9] It blocks red-cell, leukocyte, endothelial and platelet adhesion. ^[9] In the SUSTAIN trial, the median annual VOC rate was 1.63 versus 2.98. ^[9] However, the larger STAND trial did not confirm superiority, and the EMA revoked the EU marketing authorisation in August 2023 because the benefit no longer outweighed risk. ^{[9] [10]} Patients established on the drug in the EU were advised to switch to alternatives; in other regions prescribing status should be checked against current labels. ^[10]

Voxelotor was an oral haemoglobin-oxygen-affinity modulator that inhibited HbS polymerisation. It was withdrawn from worldwide markets in September 2024 (and its EU authorisation suspended) because post-marketing data showed a higher rate of vaso-occlusive crisis and deaths, so the benefit no longer outweighed risk. ^[8] No new patient should be started on it. ^[8]

The FDA approved two autologous gene therapies for SCD in patients 12 years and older with recurrent vaso-occlusive events in December 2023. ^[6]

• Casgevy (exagamglogene autotemcel) uses CRISPR editing of the erythroid enhancer of BCL11A to raise HbF production. ^[6]
• Lyfgenia (lovotibeglogene autotemcel) uses a lentiviral vector encoding βᴬ-T87Q, an anti-sickling globin. ^[6]

Both require stem cell collection, myeloablative conditioning (high-dose chemotherapy) and infusion of the modified cells as a one-time transplant. ^[6] Lyfgenia carries a black-box warning for haematological malignancy. ^[6] Under the approved product labels, long-term follow-up runs to at least 15 years (CASGEVY patients may enrol in up to 15 years of follow-up and LYFGENIA requires a complete blood count every 6 months for at least 15 years). ^{[12] [13]} These therapies remain restricted to specialist centres. ^[6]

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only established cure for SCD: more than 90% of patients with a matched sibling donor are cured in short-term follow-up. ^[5] ASH suggests it rather than standard care for patients with neurologic injury, frequent pharmacologically refractory pain, or recurrent ACS. ^[5] Matched sibling donors exist for fewer than 20% of patients; alternative-donor transplants are advised only in trials. ^[5] Harms include death (5 to 20% depending on age in large series), graft failure (5 to 10%), graft-versus-host disease and infertility, which is nearly universal after myeloablative conditioning in postpubertal patients. ^[5] No randomised trials compare HSCT with conservative therapy, so recommendations rest on very low-certainty evidence. ^[5]

• The NHLBI 2014 Expert Panel Report remains the backbone of adult and paediatric community care: penicillin until 5 years, TCD from age 2 to at least 16, hydroxyurea from 9 months, annual retinal screening from 10 years, renal screening from 10 years. ^[1]
• The ASH 2020 series addresses transfusion support, acute and chronic pain, cerebrovascular disease, cardiopulmonary/kidney complications and stem cell transplantation (2021).
• Many recommendations are conditional because direct high-certainty evidence is sparse; centres should adapt them with haematology input. ^{[2] [3]}

These are the complications that determine prognosis; presentation is as in the Task brief. ^{[1] [4]}

• Functional asplenia and infection with encapsulated organisms. Early autosplenectomy raises the risk of invasive pneumococcal, Haemophilus and Salmonella infection; hence penicillin and vaccination. ^[1]
• Painful vaso-occlusive crisis. The cardinal problem; recurrent pain damages quality of life.
• Acute chest syndrome. A new lung infiltrate with acute respiratory symptoms; fever and middle-lobe disease in children, multilobe and often afebrile in adults. ^[1]
• Splenic sequestration. Sudden fall in haemoglobin with an enlarging spleen and circulation failure; mainly in infants.
• Aplastic crisis. Parvovirus B19 can arrest erythropoiesis for days; transfusion is supportive. ^[1]
• Stroke and silent cerebral infarcts. The lifetime risk of overt stroke is around 20% in HbSS and 10% in HbSC by age 40. ^[4] Silent infarcts occur in ~39% of children and >50% of adults with HbSS/HbSβ⁰ disease and drive cognitive and school problems. ^[4]
• Priapism. Stuttering (under 4 hours) or major (4 hours or longer); the latter is a urological emergency. ^[1]
• Osteonecrosis (avascular necrosis). Especially of the femoral head.
• Nephropathy. Annual microalbuminuria/proteinuria screening detects early glomerular injury. ^[1]
• Retinopathy. Proliferative sickle retinopathy begins in adolescence. ^[1]
• Leg ulcers. Chronic, painful lesions around the ankle, often in adults with severe haemolysis.

With modern care (penicillin, vaccines, hydroxyurea, TCD screening and safe transfusion practice), childhood survival has improved dramatically in high-income settings. ^{[1] [4]} In low-income settings, survival to adolescence and adulthood remains much worse, and infection (rather than stroke) is often the dominant early cause of death. ^[11] Morbidity accumulates with age (renal, pulmonary, bone), so transition from paediatric to adult care is a high-risk period that merits planned handover. ^[1]

• Newborn screening and genotype confirmation at birth. ^[1]
• Penicillin and pneumococcal immunisation from infancy. ^[1]
• Annual TCD from age 2 to at least 16 in HbSS/HbSβ⁰ disease. ^[1]
• Preventive transfusion for children with abnormal TCD velocities (keeping maximal HbS below 30% and haemoglobin above 9 g/dL) in settings where chronic transfusion is feasible. ^[4]
• Hydroxyurea for all with sickle cell anaemia from 9 months; hydroxyurea as a bridge to transfusion in low-income settings where transfusion safety is unavailable. ^{[1] [4]}
• Retinal, renal, and neurocognitive surveillance at the ages listed above. ^{[1] [4]}
• Contraception and reproductive counselling. Hydroxyurea is contraindicated in pregnancy; progestin-only methods are suitable. ^[1]

Pregnancy. SCD in pregnancy is high-risk: increased maternal and fetal anaemia, pain crises, acute chest syndrome, pre-eclampsia, preterm delivery, stillbirth and severe fetal anaemia. ^{[1] [2]} Care should be shared with a maternal-fetal medicine specialist with SCD expertise, with extra prenatal surveillance. ^[1] Hydroxyurea should be stopped. ^[1] Transfusion strategy (prophylactic regular versus clinically indicated) is a shared decision, because the ASH evidence is very low certainty. ^[2]

Children. Stroke prevention, as above, is the most important and evidence-supported intervention of childhood. ^[4] Growth, neurodevelopmental and cognitive milestones should be monitored. ^[4]

Older adults. With successful ageing, the burden shifts to chronic kidney disease, pulmonary hypertension, osteonecrosis and leg ulcers; polypharmacy and opioid toxicity risks rise. ^[3]

Low-resource settings. Most patients live where the disease is commonest. ^{[11] [4]} Practical adaptations:

Related reading within MedGrasp (titles link once those pages are published): the approach to anaemia; the haemolytic anaemias; thrombotic microangiopathies; stroke prevention in children; pain management; infection in the immunocompromised host; obstetric haemorrhage; transfusion medicine; and gene therapy in haematology. Protocols and thresholds vary by centre, so the numbers here should be checked against local haematology, transfusion and pharmacy guidance.