Sickle Cell Disease

Meet the patient

A 6-year-old boy born to Nigerian parents is brought in screaming with deep pain in his shins and back for the second time this year. He is pale, mildly icteric, tachycardic, and febrile to 38.4. His mother says he had a cold three days ago.^[1]

The registrar calls it a "pain crisis" and reaches for morphine. The consultant asks three questions before the analgesia even hangs: is his oxygen saturation normal, is his spleen bigger than last time, and is this fever sepsis? Because in a child who lost his splenic function to autosplenectomy two years ago, that fever is overwhelming pneumococcal sepsis until proven otherwise — and the chest film taken an hour later will decide whether this is also acute chest syndrome, the leading killer of his disease.^[5]

One mutation, three consequences — the whole disease

Sickle cell disease is the commonest inherited haematological disorder in people of African, Middle Eastern, Mediterranean and South Asian ancestry, and one of the commonest life-threatening monogenic disorders in the world. A single DNA base change transforms haemoglobin into a molecule that polymerises whenever it releases oxygen, distorting the red cell into a rigid sickle that blocks small vessels, destroys itself prematurely, and inflames the endothelium of every organ.^[1][2]

The clinical discipline is to prevent crises (hydroxycarbamide, vaccination, transfusion, trigger avoidance), treat them aggressively when they occur (analgesia, hydration, oxygen, transfusion), screen for the silent complications (annual transcranial Doppler for stroke, retinopathy, nephropathy, pulmonary hypertension), and offer cure where possible (stem-cell transplant, CRISPR gene therapy). The recurring insight: every organ is eventually affected — this is a multi-system vasculopathy, not merely a blood disease.^[1]

Genetics and classification — the genotype sets the severity

Enlarge

SCD is autosomal recessive — a point mutation in the beta-globin (HBB) gene on chromosome 11p15.5. A single adenine-to-thymine substitution in the sixth codon changes glutamic acid to valine at position 6 of the beta-globin chain (Glu6Val, E6V), producing haemoglobin S. One amino acid out of 146 — enough to reshape the entire molecule.^[1][2]

Homozygous HbSS (sickle cell anaemia) is the commonest and most severe genotype. Compound heterozygotes — HbS from one parent, a different beta-globin variant from the other — produce the milder sickling syndromes. Heterozygous HbAS (sickle cell trait) is a largely asymptomatic carrier state that confers partial protection against severe falciparum malaria — which explains the high gene frequency across the malaria belt. This is the textbook example of balanced polymorphism: the heterozygote advantage keeps a lethal recessive gene at high frequency.^[2]

Pathophysiology — polymerisation, then three downstream streams

Enlarge

Normal adult HbA is soluble and flexible. When Glu6Val places a hydrophobic valine on the outer surface of deoxy-HbS, neighbouring beta chains lock together via a complementary hydrophobic pocket (valine-6 fitting phenylalanine-85 or leucine-88 on an adjacent molecule). Deoxy-HbS then polymerises into rigid 14-strand fibres (tactoids) that align and stretch the red cell into the characteristic crescent.^[1]

Polymerisation is kinetically delayed, which is why sickling is triggered by anything that lowers oxygen, raises acidity, or concentrates the cell. The triggers every student must name: deoxygenation (the dominant trigger), acidosis, dehydration and raised MCHC, fever, infection, cold, high altitude, hypoxia, pregnancy, surgery. The protective modifiers: HbF (cannot enter the polymer — the basis of hydroxycarbamide), HbA in compound heterozygotes, and alpha-thalassaemia co-inheritance (reduces MCHC).^[1]

Initially sickling is reversible — the cell recoils on reoxygenation. But repeated cycles damage the membrane irreversibly: calcium influx, potassium loss via the Gardos channel, oxidative injury and dehydration produce the irreversibly sickled cell (ISC), which stays sickled even when fully oxygenated. These are the cells on the film that drive haemolysis.^[1][2]

Three pathological consequences define the entire clinical phenotype

1. Vaso-occlusion is not simple mechanical plugging. Up-regulation of P-selectin on endothelial cells and platelets drives the cell-cell interactions of vaso-occlusion: sickled cells, reticulocytes and neutrophils adhere to vascular endothelium, recruit platelets and coagulation factors, and form heterocellular aggregates in the microvasculature. The result is ischaemia, infarction and pain in bone, spleen, lung, brain, kidney and retina — the target of crizanlizumab (anti-P-selectin).^[6]
2. Chronic haemolysis destroys sickled cells early (a normal red cell survives about 120 days; the sickled cell far less), producing chronic anaemia, compensatory reticulocytosis, jaundice and pigment gallstones. The marrow expands to compensate, causing frontal bossing and maxillary overgrowth in children — the target of voxelotor, an HbS-polymerisation inhibitor that raises haemoglobin.^[7]
3. Endothelial dysfunction and vasculopathy — haemolysis decompartmentalises cell-free haemoglobin, arginase 1 and adenine nucleotides into plasma. Cell-free haemoglobin inactivates nitric oxide, while haeme and haemoglobin act as erythrocytic danger signals that activate the innate immune system and endothelium into a proadhesive state. The resulting vasomotor dysfunction and proliferative vasculopathy drive pulmonary hypertension, leg ulcers, priapism, chronic kidney disease and large-artery ischaemic stroke.^[10]

Epidemiology — a disease shaped by malaria and inequity

SCD is globally distributed but concentrated in the malaria belt. The HbS gene frequency tracks falciparum malaria across sub-Saharan Africa, the Mediterranean, the Middle East and parts of India. About 300 million people carry the sickle gene, and an estimated 300,000 to 500,000 infants are born with HbSS each year — the majority in sub-Saharan Africa, where, without newborn screening and penicillin prophylaxis, the great majority die in early childhood from infection or undiagnosed crisis.^[1]

In high-income settings the picture is transformed by screening. In the United States, about 1 in 365 African-American births has HbSS and about 1 in 12 African-Americans carries sickle cell trait. In the United Kingdom it is the most common serious inherited condition, included in the newborn blood-spot screening programme. India, Saudi Arabia and the eastern Mediterranean have substantial tribal and regional cohorts.^[2]

Risk factors for crisis and severity include infection (the commonest trigger), dehydration, cold, high altitude, hypoxia, acidosis, pregnancy, surgery, emotional stress and alcohol. Co-inheritance of alpha-thalassaemia reduces haemolysis and stroke risk; high fetal haemoglobin (genetic or hydroxycarbamide-induced) is the single most important ameliorating factor; a high steady-state white-cell count predicts more frequent crises.^[1]

Clinical presentation — read it by age and organ

Because fetal haemoglobin prevents HbS polymerisation, infants are protected in utero and for the first months of life. Symptoms appear only as HbF falls over the first six months — which is why the earliest manifestation, dactylitis, appears precisely then.^[2]

Chronic haemolytic anaemia

Chronic haemolysis produces a well-compensated anaemia: the haemoglobin is low but stable, and the reticulocyte count is high because the marrow replaces destroyed cells at an accelerated rate. Patients look pale and mildly icteric, have a flow murmur, and develop pigment gallstones by adolescence. Growth retardation and delayed puberty are common, and frontal bossing and maxillary prominence reflect marrow expansion.^[1]

Vaso-occlusive (painful) crisis — the commonest manifestation

The hallmark of the disease. Recurrent episodes of severe, deep, gnawing pain in the long bones, spine, ribs, sternum, chest and abdomen, often precipitated by infection, dehydration, cold or stress. Pain reflects bone-marrow and visceral micro-infarction. Infants present with dactylitis (hand-foot syndrome) — painful, symmetric, non-pitting swelling of the hands and feet from infarction of the small bones, often the first presentation after HbF falls.^[2]

Acute chest syndrome — the leading cause of death

The most common reason for intensive care and the leading cause of death in SCD. Defined as a new pulmonary infiltrate on chest imaging plus at least one of fever, chest pain, tachypnoea, wheeze, cough or hypoxia in a patient with SCD. Triggers include infection, fat embolism from bone-marrow infarction, pulmonary vaso-occlusion and atelectasis. It can complicate any painful crisis (especially one involving ribs or thoracic spine, where splinting causes hypoventilation) and progresses rapidly to respiratory failure.^[1]

Neurological — stroke

Without screening, about 11 percent of children with HbSS suffer a clinically evident stroke by age twenty, and another 20 percent have silent cerebral infarction on MRI, causing cognitive impairment. Ischaemic stroke predominates in children (intimal hyperplasia and sickling in the large intracranial vessels, the circle of Willis); haemorrhagic stroke predominates in adults (moyamoya-like collaterals). Any acute neurological deficit in SCD is a stroke until proven otherwise.^[2][4]

Splenic sequestration and functional asplenia

Acute splenic sequestration is a childhood emergency: sickled cells trap in the splenic sinusoids, the spleen enlarges rapidly, and a large volume of blood sequesters, producing sudden severe anaemia, hypovolaemia and shock — classically in infants aged six months to two years with a still-palpable spleen. Over the first years of life, repeated infarction produces autosplenectomy: the spleen scars and shrinks until impalpable, and functional asplenia is established by around age five — removing splenic clearance of encapsulated bacteria and making invasive pneumococcal, Hib and meningococcal infection a leading cause of death in young children.^[5]

Aplastic crisis — the parvovirus trap

A transient red-cell aplasia triggered almost always by parvovirus B19, which specifically infects and destroys erythroid precursors. Because the sickled red cell is short-lived and the marrow already runs at maximum output, shutting down erythropoiesis for even a week causes a precipitous fall in haemoglobin with a paradoxically low reticulocyte count (reticulocytopenia). It is self-limiting — the virus clears in one to two weeks — but transfusion may be needed to bridge the nadir.^[12]

Other organ-specific manifestations

Priapism (prolonged, painful erection from sickling in the corpora cavernosa) is a urological emergency; stuttering episodes precede major events and recurrent priapism causes erectile dysfunction. Avascular necrosis of the femoral head causes hip and groin pain, a limp, and eventual joint collapse. Lower-leg ulcers (over the malleoli, slow to heal) reflect the haemolysis-NO-depletion vasculopathy. Renal disease spans hyposthenuria (inability to concentrate urine — nocturia and dehydration from early childhood), haematuria from papillary necrosis, proteinuria and focal segmental glomerulosclerosis, and progressive chronic kidney disease. Proliferative retinopathy (especially in HbSC) threatens sight.^[2]

Hyperhaemolytic crisis

A less common crisis in which haemolysis accelerates dramatically — haemoglobin drops with a RISING reticulocyte count, jaundice deepens. It can be triggered by infection, transfusion or drugs, and overlaps with delayed haemolytic transfusion reactions. It is distinguished from aplastic crisis (which has a low reticulocyte count) by the reticulocyte response.^[1]

Differential diagnosis

When a patient of the right ancestry presents with chronic haemolysis or an acute pain crisis, the differential splits into other haemolytic anaemias and the mimics of each acute complication.^[1]

Clinical and bedside assessment

The focused examination looks for anaemia and haemolysis, end-organ damage, and signs of acute complication.^[1]

• General — pallor, scleral icterus, jaundice, growth and puberty (delayed), frontal bossing and maxillary prominence (marrow expansion in children).
• Abdomen — early splenomegaly that regresses as autosplenectomy supervenes (an absent spleen in an older child or adult is the rule in HbSS); hepatomegaly; gallbladder tenderness if cholecystitis.
• Cardiorespiratory — flow murmur of anaemia; tachypnoea, hypoxia, crackles and right-heart strain (pulmonary hypertension) in acute chest or chronic lung disease.
• Musculoskeletal — dactylitis in infants; tenderness and swelling over long bones; a limp or limited hip rotation from avascular necrosis of the femoral head.
• Skin — malleolar leg ulcers, pallor.
• Neurological — focal deficit suggesting stroke; cognitive impairment from silent infarcts.
• Genitourinary — priapism; haematuria from papillary necrosis.^[1]

Investigations — film suggests, electrophoresis decides

Diagnosis combines the blood film (suggestive) with haemoglobin electrophoresis or HPLC (definitive genotype). In the newborn, screening is by heel-prick HPLC or isoelectric focusing; in prenatal diagnosis, by chorionic villus sampling with DNA (PCR) analysis.^[1][8]

^{[1] [8]}

In an acute crisis, send a full blood count and reticulocytes (the single most useful test — a low reticulocyte count in a falling haemoglobin points to aplastic crisis), blood film, group and screen, blood and urine cultures, LDH, bilirubin, and a chest radiograph if respiratory. A reticulocyte count inappropriately low for the degree of anaemia, especially with a febrile prodrome, should prompt parvovirus B19 PCR.^[1]

Management — the four pillars

Management rests on four pillars: (1) prevent crises (hydroxycarbamide, vaccination, penicillin prophylaxis, trigger avoidance, folate); (2) screen for and prevent organ complications (TCD for stroke, retinal and renal surveillance); (3) treat acute crises aggressively (analgesia, hydration, oxygen, transfusion); and (4) offer curative therapy (stem-cell transplant, gene therapy).^[8]

Pillar one — disease-modifying prevention

Hydroxycarbamide (hydroxyurea) is the backbone of modern care. It raises fetal haemoglobin (HbF) by stimulating gamma-chain production (with additional benefits: myelosuppression lowering the neutrophil count, improving red-cell hydration, and increasing NO). The landmark Multicenter Study of Hydroxyurea (MSH) showed it roughly halves the frequency of painful crises and reduces acute chest syndrome, transfusion need and mortality.^[3] It is now recommended for nearly all patients with HbSS or HbS-beta-zero-thalassaemia from nine months of age, regardless of severity.^[8]

The newer disease-modifying drugs are added on top of (not instead of) hydroxycarbamide when control is inadequate. Crizanlizumab is a humanised monoclonal antibody against P-selectin that blocks adhesion of sickled cells to endothelium — the SUSTAIN trial showed it significantly reduces the rate of painful crises.^[6] Voxelotor is a haemoglobin-S polymerisation inhibitor that stabilises oxygenated (R-state) haemoglobin — the HOPE trial showed it raises haemoglobin and reduces haemolysis markers.^[7]

^{[3] [6] [7] [11]}

Pillar two — functional asplenia prophylaxis

Because the spleen is lost to autosplenectomy, every infant with HbSS needs penicillin V prophylaxis from birth or diagnosis — the PROPS trial proved it reduces mortality from pneumococcal septicaemia.^[5] Any fever in a child with SCD is functional asplenia with possible overwhelming sepsis until proven otherwise and demands urgent empirical IV antibiotics within one hour.

Pillar three — stroke screening and transfusion

Stroke is preventable. The STOP trial showed that annual transcranial Doppler (TCD) ultrasonography identifies children at high risk: a timed-averaged mean velocity at or above 200 cm per second in the internal carotid or middle cerebral artery on two examinations predicts high stroke risk, and instituting chronic transfusion (to keep HbS below 30 percent) cut first strokes by 92 percent versus standard care. Children with HbSS should have annual TCD from age two until age sixteen. Chronic transfusion is also used for secondary stroke prevention after a first stroke, where recurrence risk without it is high.^[4][8]

The cost of chronic transfusion is iron overload, which damages the liver, heart and endocrine organs. Iron chelation is essential in regularly transfused patients — options are deferasirox (oral), deferiprone (oral) and deferoxamine (subcutaneous infusion), guided by serum ferritin and imaging of liver iron.^[1][8]

Transfusion and exchange transfusion

Transfusion is the second pillar of SCD therapy after hydroxycarbamide, but it is a family of techniques chosen by indication. Simple (top-up) transfusion raises the haemoglobin and dilutes HbS — for acute severe anaemia (aplastic or sequestration crisis, symptomatic anaemia in pregnancy), to raise a low preoperative haemoglobin, and as the chronic modality in primary-stroke prevention after an abnormal TCD. Exchange transfusion (automated erythrocytapheresis, or manual two-volume exchange) removes the patient's HbS-rich blood and replaces it with donor cells, rapidly lowering the HbS fraction to below 30 percent without raising viscosity — the modality of choice for acute stroke, severe acute chest, refractory priapism.^[1]

^{[1] [8]}

Chronic transfusion programmes (typically repeated every three to four weeks, maintaining the HbS fraction below 30 percent) are indicated for secondary stroke prevention, for primary prevention after abnormal TCD, and sometimes for recurrent acute chest or severe refractory pain. Their two great burdens are iron overload (chelation is required) and red-cell alloimmunisation — in a recent global meta-analysis of transfused adults with SCD, overall alloimmunization prevalence was about 29 percent, with anti-E, anti-C and anti-Kell the most frequent antibodies; extended antigen matching dramatically reduces prevalence. Always document antibodies.^[1][16]

Pillar four — curative therapy

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Haematopoietic stem-cell transplant (HSCT) from an HLA-matched sibling donor is the only widely established cure, with overall survival above 95 percent and event-free survival around 85 to 90 percent in well-selected children. It is offered to children with severe disease (stroke, recurrent acute chest, refractory pain) who have a matched sibling. Matched unrelated donor and haploidentical transplantation are expanding access.^[1]

Gene therapy is the great advance of the past few years. Exagamglogene autotemcel (exa-cel, Casgevy) uses CRISPR-Cas9 to disrupt the BCL11A enhancer, re-activating fetal haemoglobin production in the patient's own autologous stem cells; the CLIMB-121 trial showed most treated patients became vaso-occlusive-crisis-free, and exa-cel was approved by the MHRA and FDA in 2023 to 2024. Betibeglogene autotemcel (beti-cel) uses lentiviral addition of a modified beta-globin gene.^[9]

Management — resuscitation of acute crises

The four acute crises — vaso-occlusive pain, acute chest, splenic sequestration, aplastic — share the same resuscitation bundle, tailored to severity.^[1]

Acute vaso-occlusive (painful) crisis

A structured ABCDE assessment first, looking especially for a precipitant (infection, dehydration) and for chest involvement. The crisis bundle:^[8]

• Rapid analgesia — treat within thirty minutes of arrival. Use titrated opioids (intravenous morphine is standard; patient-controlled analgesia for severe pain) combined with paracetamol and an NSAID where not contraindicated. The ASH 2020 pain guideline recommends prompt assessment and early opioid dosing, with reassessment and further doses until pain is controlled. Never under-treat pain — the historical fear of opioid dependence in SCD caused immense suffering.
• Oxygen to maintain saturations at the patient's baseline (typically 94 to 98 percent).
• Intravenous hydration with isotonic saline — maintenance plus replacement of deficit; avoid over-hydration, which precipitates pulmonary oedema and worsens acute chest.
• Treat the trigger — cultures and empirical antibiotics for infection; correct dehydration and hypoxia.
• Incentive spirometry while hospitalised — a strong NHLBI recommendation to prevent atelectasis and acute chest syndrome in patients with rib or thoracic pain.^[8]

Acute chest syndrome

New infiltrate plus hypoxia or fever in an SCD patient = acute chest syndrome — escalate immediately:^[1]

• Broad-spectrum antibiotics — a cephalosporin (ceftriaxone or cefuroxime) plus a macrolide (azithromycin) to cover typical, atypical and encapsulated organisms.
• Oxygen and respiratory support — escalate to CPAP, BiPAP or invasive ventilation for respiratory failure.
• Transfusion — simple top-up if the haemoglobin has fallen; exchange transfusion if severe (worsening hypoxia, multilobar infiltrate, rapid progression), aiming for HbS below 30 percent.
• Incentive spirometry, bronchodilators, and treat pain and the trigger.^[1]

Acute stroke

Any new neurological deficit in SCD is a stroke until proven otherwise. Do NOT thrombolyse (as with adult atherosclerotic stroke) — the treatment is emergency exchange transfusion to reduce HbS below 30 percent. Confirm with urgent CT or MRI or MR angiography. After recovery, chronic transfusion for secondary prevention is mandatory.^[4]

Splenic sequestration

An infant with sudden pallor and an enlarging spleen has acute splenic sequestration — emergency transfusion (and fluid resuscitation for shock). Parents are taught to palpate the spleen at home and to attend urgently if it enlarges or the child looks pale. Recurrent episodes may warrant splenectomy (which, after infancy, is safe given the trajectory toward autosplenectomy anyway).^[1]

Aplastic crisis

A falling haemoglobin with a low reticulocyte count, classically after a febrile viral illness, is parvovirus B19 aplastic crisis. Confirm with B19 PCR. Transfuse to bridge until marrow recovery (typically one to two weeks). The patient is then infectious to pregnant women (congenital infection risk) until cleared.^[1]

Specific subtypes and scenarios

The severity of disease is governed largely by which beta-globin variant is paired with HbS and by the level of HbF.^[1]

HbSS is the most severe. HbSC disease is milder overall but carries a particular risk of proliferative retinopathy and osteonecrosis, and the spleen may remain enlarged into adulthood. HbS-beta-zero-thalassaemia (no normal HbA) resembles HbSS; HbS-beta-plus-thalassaemia retains some HbA and is milder, with a raised HbA2 on electrophoresis the distinguishing clue. HbSD, HbSE and HbSO-Arab are rarer compound heterozygotes of variable severity.^[2]

Sickle cell trait (HbAS) is a carrier state, not a disease: normal haemoglobin, normal life expectancy, protection against severe falciparum malaria. Complications are rare and occur only at extreme physiological stress — renal papillary necrosis with haematuria, splenic infarction at high altitude, exertional rhabdomyolysis and sudden death in extreme exertion (elite sport, military training), and a small increase in venous thromboembolism. Genetic counselling is the main intervention.^[2]

Complications and pitfalls

The complications of SCD are the disease — every organ is eventually affected. They divide into acute and chronic, and into the three mechanistic streams (vaso-occlusion, haemolysis, vasculopathy).^[1]

The classic pitfalls: (1) under-treating pain out of fear of opioids; (2) missing acute chest syndrome by attributing a new infiltrate to simple pneumonia and not escalating to macrolide cover and transfusion; (3) over-hydrating and precipitating pulmonary oedema; (4) forgetting parvovirus B19 when the haemoglobin drops with a low reticulocyte count; (5) not screening with TCD; (6) assuming a fever is viral in a functionally asplenic child; (7) not chelating a chronically transfused patient until organ damage is done.^[1]

Managing the chronic complications

Each chronic complication has its own evidence-based management. Priapism lasting more than four hours is a urological emergency: first-line is intracavernosal aspiration plus phenylephrine injection, with concurrent hydration, analgesia and oxygen; exchange transfusion is reserved for refractory cases, and a surgical shunt is the last resort. Recurrent stuttering priapism is suppressed by an eta-blocker (e.g. etilefrine or terbutaline) at night and, where needed, hydroxycarbamide.^[2]

Avascular necrosis of the femoral head is managed with analgesia, protected weight-bearing and physiotherapy early; core decompression for pre-collapse disease; and total hip replacement once the joint collapses (often needed bilaterally in young adults). Leg ulcers require meticulous wound care, compression, infection control, and transfusion or hydroxycarbamide to raise haemoglobin and reduce haemolysis. Proliferative sickle retinopathy (especially in HbSC) needs laser photocoagulation and, for vitreous haemorrhage or retinal detachment, vitrectomy — which is why annual retinal screening from around age ten matters. Sickle nephropathy is managed with an ACE inhibitor or angiotensin-receptor blocker for proteinuria and tight blood-pressure control.^[2]

Prognosis and disposition

Historically, HbSS was fatal in childhood. With newborn screening, penicillin prophylaxis, hydroxycarbamide, TCD screening and transfusion, median survival in high-income settings is now about 45 to 55 years (somewhat longer for HbSC and HbS-beta-plus-thalassaemia). The leading causes of death are acute chest syndrome (in children and young adults) and organ failure, pulmonary hypertension and renal failure in older adults. In sub-Saharan Africa, without screening and prophylaxis, the great majority of children with SCD still die before age five — a stark global inequity.^[1][2]

Hydroxycarbamide improves survival; curative transplant and gene therapy offer the prospect of a normal life expectancy for the minority who can access them. Adverse prognostic markers include a low steady-state haemoglobin, a high white-cell count, frequent crises, documented pulmonary hypertension, and proteinuria.^[3]

Most acute crises are managed with admission for analgesia, hydration and observation; discharge is safe when pain is controlled on oral analgesia and acute chest is excluded. Patients with acute chest, stroke, sequestration or aplastic crisis need high-dependency or intensive care and a haematology-led plan.^[8]

Special populations

Children

The paediatric priorities are newborn screening, penicillin prophylaxis to age five, full encapsulated-organism vaccination, hydroxycarbamide from nine months, and annual transcranial Doppler from age one to two until sixteen. Parents are taught to recognise splenic sequestration (pallor, enlarging spleen) and fever-as-an-emergency. Growth, puberty and schooling (silent cerebral infarcts impair cognition) require attention.^[8]

Pregnancy

Pregnancy in SCD is high-risk: increased vaso-occlusive crises, thrombosis, anaemia, placental insufficiency, pre-eclampsia, fetal growth restriction, preterm birth and fetal loss. Care is multidisciplinary (obstetrics, haematology, anaesthetics) with early and comprehensive specialist involvement — the approach recommended by the Australian SCD Working Group position statement. Hydroxycarbamide is stopped before conception and during pregnancy and breastfeeding (teratogenicity concerns). Prophylactic red-cell transfusion is the only disease-modifying therapy available in pregnancy: randomised-trial and meta-analysis evidence shows it reduces maternal and fetal death, painful crises, thrombosis and acute respiratory failure, and ASH classifies chronic transfusion in pregnancy as low risk — wider use is increasingly advocated. Thromboprophylaxis is considered as part of the delivery plan.^[14][15]

Anaesthesia and surgery

Perioperative sickling is a major hazard. Preoperative transfusion reduces perioperative complications in elective surgery; in the US National Preoperative Transfusion Study, a conservative top-up regimen (raise the haemoglobin to about 100 g/L) was as effective as an aggressive exchange regimen (HbS below 30 percent) at preventing perioperative complications — and caused half as many transfusion-associated complications (7 versus 14 percent). Acute chest syndrome developed in about 10 percent of both groups and is the principal postoperative danger. Pair transfusion with meticulous avoidance of hypoxia, dehydration, hypothermia and acidosis, regional techniques where possible, and early mobilisation with incentive spirometry.^[17][8]

Any fever above 38 degrees in a child with SCD is a medical emergency — take cultures and give empirical IV ceftriaxone within one hour (covering pneumococcus), observe, and look for a focus. The risk of overwhelming post-splenectomy infection persists for life.^[1]

Evidence, guidelines and regional differences

The evidence base for modern SCD care is built on landmark randomised trials, each of which transformed practice:^[1]

The main controversies are: the optimal duration of chronic transfusion (and whether it can ever be safely stopped for secondary stroke prevention); whether and when to transition from transfusion to hydroxycarbamide after abnormal TCD (STOP II showed rebound risk on early switch); the long-term safety and accessibility of gene therapy; and equitable global provision of screening, penicillin and hydroxycarbamide.^[4]

The mantra

Prevent (hydroxycarbamide, penicillin, TCD, vaccinate), treat pain like you mean it, exchange-transfuse stroke and chest — and remember every organ is eventually affected.^[1]

Ward-round test

Stem 1 — the infant who went paleShowHide

A 14-month-old with HbSS, previously well, is brought in pale and tachycardic; the mother says his spleen feels bigger than usual and he had a viral illness last week. Hb 38, reticulocytes 1 percent. What is the diagnosis and the immediate action?^[1]

AnswerShowHide

The low reticulocyte count in a falling haemoglobin is parvovirus B19 aplastic crisis (a high reticulocyte count with an enlarging spleen would be splenic sequestration). Confirm with B19 PCR and transfuse to bridge until marrow recovery (typically one to two weeks); the patient is infectious to pregnant women until cleared.^[1]

Stem 2 — the chest film that changed the planShowHide

A 9-year-old in for a pain crisis develops a cough, hypoxia to 90 percent, and a new right lower-lobe infiltrate. What is the diagnosis, the antibiotic bundle, and when do you exchange-transfuse?^[1]

AnswerShowHide

Acute chest syndrome — new infiltrate plus hypoxia in SCD. Give a cephalosporin (ceftriaxone) plus a macrolide (azithromycin), oxygen and respiratory support, and add incentive spirometry. Use a simple top-up transfusion if the haemoglobin has fallen; exchange transfusion aiming for HbS below 30 percent if severe (worsening hypoxia, multilobar infiltrate, rapid progression).^[1]

Stem 3 — the number that prevents strokeShowHide

A 4-year-old with HbSS has a routine transcranial Doppler showing a timed-averaged mean velocity of 210 cm per second in the right middle cerebral artery. What do you do, and what outcome does it achieve?^[4]

AnswerShowHide

A TCD velocity at or above 200 cm per second on two occasions is compulsively abnormal — start chronic transfusion therapy to suppress HbS below 30 percent. The STOP trial showed this prevents about 90 percent of first strokes. Annual TCD from age one to two is one of the highest-yield interventions in medicine.^[4]

Stem 4 — the fever that cannot waitShowHide

A 3-year-old with HbSS is febrile to 39.2 with no focus. Why is this an emergency, and what is the first action?^[5]

AnswerShowHide

By age three this child is functionally asplenic from autosplenectomy — any fever is overwhelming encapsulated sepsis (pneumococcus, Hib, meningococcus) until proven otherwise. Take cultures and give empirical IV ceftriaxone within one hour, observe, and look for a focus. Penicillin V prophylaxis and vaccination are why he is still alive to present.^[5]

References17ShowHide

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2. [2]Rees DC, Williams TN, Gladwin MT. Sickle-cell disease Lancet, 2010.PMID 21131035
3. [3]Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia N Engl J Med, 1995.PMID 7715639
4. [4]Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography N Engl J Med, 1998.PMID 9647873
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12. [12]Rahman Z, Watford S, Carlson S. Aplastic Crisis Triggered by Parvovirus B19 in an Adult Man With Sickle Cell Disease Cureus, 2026.PMID 42428213
13. [13]Rankine-Mullings AE, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease Cochrane Database Syst Rev, 2021.PMID 33724440
14. [14]Yue M, Mason K, Rowlands S, et al. Position statement on the management of pregnancy in sickle cell disease Aust N Z J Obstet Gynaecol, 2025.PMID 39333023
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