Sickle cell disease.

# Sickle cell disease *The Lancet 2026* Seminar Sickle cell disease Raffaella Colombatti, Wasil Jastaniah, Julie Makani, Biree Andemariam Sickle cell disease is a genetic red blood cell disorder, affecting millions of people globally. This Seminar provides a Lancet 2026; 407: 1095–111 comprehensive update on the disease, emphasising its complex pathophysiology involving sickle haemoglobin Department of Woman’s and polymerisation, vaso-occlusion, haemolysis, and inflammation that lead to acute, life-threatening complications and Child’s Health, University of progressive organ damage. We review the spectrum of the most frequent acute manifestations—vaso-occlusive crises, Padova, Padova, Italy (R Colombatti MD); Pediatric acute chest syndrome, stroke, and infections—alongside chronic complications affecting virtually all organ systems. Hematology-Oncology Unit, Recent advances include expanded implementation of hydroxyurea in low-resource settings and the optimisation of Azienda Ospedale-Università di hydroxyurea protocols, refined transfusion therapy, improved haematopoietic stem cell transplantation outcomes Padova, Padova, Italy with alternative donor strategies, and gene therapies now approved for clinical use. Additionally, new drugs are being (R Colombatti); Oncology Department, King Faisal evaluated in clinical trials globally. We examine successful implementation strategies in low-income and middle- Specialist Hospital and income countries using point-of-care diagnostics and integrated care models. Controversies and challenges include Research Centre, Jeddah, Saudi the management of sickle haemoglobin-C and haemoglobin S/β+ variants, cerebrovascular complication prevention, Arabia (Prof W Jastaniah MD); hydroxyurea use in pregnancy, and the transition from paediatric to adult care. Sickle Pan-African Research Consortium (SPARCO)– Tanzania, Dar es Salaam, Introduction mostly in sub-Saharan Africa, where the mortality of Tanzania (J Makani MD); The history of sickle cell disease is profoundly intertwined children younger than age 5 years can exceed 50% in the Department of Haematology and Blood Transfusion and with the evolution of modern medicine and integrates absence of early diagnosis and treatment. The disease Sickle Cell Program, Muhimbili medical discovery with cultural and geographic heritage, also remains a leading cause of death in children aged University of Health and Allied particularly in Africa where the disease is most 5–14 years, and its burden is globally increasing Sciences, Dar es Salaam, prevalent.1,2 Since James Herrick’s description of compared with global trends for most common causes of Tanzania (J Makani); New England Sickle Cell Institute, “peculiar elongated and sickle-shaped” red cells in a death.7,10 University of Connecticut Black dental student from Grenada in 1910,3 sickle cell The global distribution of sickle cell disease reflects Health, Farmington, CT, USA disease has served as a model for genetic, molecular, and patterns of historic malaria endemicity and is particularly (Prof B Andemariam MD) translational research. Sickle cell disease was the first high in west and central Africa, the Middle East, India, Correspondence to: condition to be understood as a molecular disease, as and parts of the Mediterranean.11 Population movements Raffaella Colombatti, described by Pauling and colleagues in 1949, and later have led to increasing prevalence in Europe and the Department of Woman’s and Child’s Health, University of helped to elucidate principles of gene expression, Americas.12 Cultural understandings of the disease are Padova, 35128 Padova, Italy haemoglobin switching, and globin gene regulation.3–6 diverse, as reflected in local names used in west Africa, raffaella.colombatti@unipd.it Yet, despite this central role in medical discovery, sickle such as “chwechweechwe”, “nuidudui”, or cell disease remains under-recognised as a global health “akokufalobi”—the first two words referring to the sound priority and is underserved in clinical care.7 of joint pain and the third meaning “he will die Sickle cell disease refers to a group of inherited red blood cell (RBC) disorders caused by pathogenic variants in the HBB gene, resulting in the production of sickle Search strategy and selection criteria haemoglobin S (HbS). Individuals with one copy of the We performed a careful search of the scientific literature in mutation have sickle cell trait—a condition that confers English from Jan 1, 2017 to May 31, 2025 using the terms partial protection against severe malaria—while those “sickle cell”, “hydroxyurea or hydroxycarbamide”, “red blood with pathogenic variants on both alleles (eg, sickle cell cell transfusion”, “transcranial Doppler”, and anaemia [HbSS], sickle haemoglobin-C [HbSC], and “alloimmunization”, “cardiac”, “heart”, “kidney”, HbS–β-thalassemia) develop the clinical syndrome of “vasculopathy”, “SC disease”, “SBetathalassemia”, and sickle cell disease. The defining pathophysiological “Transition”. We reviewed major guidelines, including the mechanism of sickle cell disease is the polymerisation of 2014 National Heart, Lung, and Blood Institute evidence- deoxygenated HbS, leading to red cell sickling, based guidelines, the 2020 American Society of Hematology haemolysis, and vaso-occlusion accompanied by a guidelines, the 2018 Sickle Cell Society’s Standards for Clinical cascade of complex pathophysiological events. This Care of Adults with sickle cell disease, the 2018 British Society cascade drives the multisystem complications of the for Haematology (BSH) guideline on hydroxycarbamide use disease, including acute painful crisis, acute chest in children and adults, and the 2021 BSH guideline on syndrome, stroke and cognitive impairment, and managing sickle cell disease in pregnancy. We also used the progressive organ damage.1,8,9 terms “low- and middle-income countries”, “LMIC”, “Africa”, Sickle cell disease is now recognised as one of the most “India”, “resource limited”, “models of care”, “transfusion”, common serious inherited diseases worldwide and is “newborn screening”, and “point-of-care testing”. We among the top 50 causes of non-communicable disease searched ClinicalTrials.gov for all ongoing trials identified as mortality. Global estimates suggest that more than “sickle cell” or “open or recruiting”. 500 000 infants are born annually with sickle cell disease, Seminar Despite great clinical need, progress in care delivery and HbA (%) HbS (%) HbC (%) HbF (%) HbA (%) MCV Clinical course 2 health system response remain slow. WHO has issued Normal 95–98 0 0 <1 <3·5 ·· ·· resolutions on sickle cell disease, and several international Trait conditions campaigns have recently been launched, but most affected HbS trait HbAS 55–65 30–40 0 <1 <3·5 Normal Benign individuals still lack access to timely diagnosis and HbC trait HbAC 55–65 0 30–40 <1 <3·5 Normal Benign essential treatments. This fragmented response has led to β-thalassemia 90–95 0 0 1–3 >3·5 Low Benign major discrepancies in survival, with HICs seeing 80–90% trait survival into adulthood, but with a peak mortality in late Disease conditions adolescence, while in low-income regions, most children Sickle cell anaemia 0 80–95 0 5–15 <3·5 Normal Severe with sickle cell disease die without ever being diagnosed.7 HbSS This Seminar is not an exhaustive summary of the Sickle HbC disease 0 50–55 30–40 <3 <3·5 Normal Moderate pathophysiology, management, or treatment of sickle cell HbS–β°- 0 80–90 0 5–15 >3·5 Low Severe disease, for which readers are referred to recent guidelines. thalassemia This Seminar provides an updated synopsis of sickle cell HbS–β+- 10–25 70–80 0 <3 >3·5 Low Variable thalassemia* disease with a global perspective on its pathophysiology, HbS and other 0 50–60 0 Variable <3·5 Normal Variable clinical manifestations, therapeutic landscape, and public haemoglobin health implications. Persistent gaps in access and variant outcomes, emerging therapeutic and diagnostic Trait conditions refer to β-globin heterozygous states, while disease conditions refer to compound heterozygous or innovations, and the urgent need for integrated strategies homozygous states. Concomitant α-thalassaemia can coexist with all these conditions and affects the ratio of HbA to that align scientific progress with global equity are HbS or HbC, as shown by the range of values for each haemoglobin listing. Sickle cell genotypes are shown with the highlighted here. In doing so, we aim to reframe sickle typical haemoglobins present on electrophoresis, and clinical course. The sickle or other disease conditions typically have 50–60% HbS with 20–45% of a variant haemoglobin, such as HbD, HbE, or HbOArab. Combined heterozygosity cell disease not only as a medical condition, but as a with thalassaemia also features microcytosis with low MCV. HbSS and HbSC with coinheritance of α-thalassaemia trait barometer of the capacity—and willingness—of global features a low MCV and should prompt testing for α-globin deletion. HbA=haemoglobin A. HbA=HbA αδ subunit. 2 2 2 health systems to deliver on the promise of modern HbAC=HbA-haemoglobin C trait. HbAS=HbA-sickle trait. HbC=haemoglobin C. HbD=haemoglobin D. HbE=haemoglobin E. HbOArab=haemoglobin O Arab, prevalent in Arab populations. HbS=haemaglobin S. HbSS=sickle medicine for all. cell anaemia. MCV=mean corpuscular volume. *S–β+-thalassaemia in the USA, Caribbean, UK, and northern Europe typically has 10–25% HbA, but moderate and severe forms of HbS–β+-thalassaemia have been identified in Europe, Epidemiology and the global burden of disease with a clinical phenotype similar to HbSS and HbSC.35,36 The global epidemiology of sickle cell disease is evolving Table 1: Common forms of sickle cell disease and related haemoglobinopathies by genotypes due to demographic shifts, improved survival, and population movement.7 While national incidence rates tomorrow”. These terms reflect the visibility, pain, remained relatively stable from 2000 to 2021, the absolute stigma, and fatalism historically associated with sickle number of births with sickle cell disease increased by cell disease in many communities.7,8,13 nearly 14%, reaching an estimated 515 000 annually, Although major improvements in paediatric outcomes primarily driven by population growth in sub-Saharan have been achieved in high-income countries (HICs) Africa and parts of Asia. The number of individuals with universal newborn screening, penicillin prophylaxis, living with sickle cell disease increased by more than pneumococcal vaccination, treatment with hydroxyurea, 40% during the same period, surpassing 7·7 million and stroke prevention programmes,14–19 adult life globally.10 This expansion reflects both higher birth expectancy remains substantially shortened.20,21 In low- prevalence and improved childhood survival, particularly resource and middle-resource settings, access to these in HICs, contributing to the emergence of a growing interventions remains limited or absent.7 Historical adult population with sickle cell disease and evolving neglect, structural inequities, and a legacy of racial and clinical complexity. Nevertheless, sickle cell disease geographical marginalisation have contributed to under- remains a major contributor to mortality in those investment in research, clinical infrastructure, and younger than age 5 years in low-income regions where pharmaceutical innovation for sickle cell disease— access to newborn screening, disease-modifying although this trend is beginning to shift globally.22,23 therapies, and essential care is limited.7 At the same time, Recent years have seen a growing pipeline of disease- increased global population movement has reshaped the modifying therapies, including crizanlizumab, voxelotor, epidemiology of sickle cell disease in high-income and L-glutamine, alongside curative options, such as regions, including Europe, where the disease is still haematopoietic stem cell transplantation (HSCT) and classified as rare but has rising prevalence.32 Despite the transformative gene therapy.24–29 However, access remains growing number of patients in HICs in the EU and geographically disparate with high-prevalence countries North America, reliable epidemiological data remain having the fewest clinical trial sites and scarce or no scarce due to fragmented registries, inconsistent use of commercial availability of approved treatments. diagnostic coding, and limited harmonisation across Withdrawal of new drugs and new treatments from the health systems.32,33 A recent systematic review confirmed market30,31 have had a global impact, even in high-resource substantial gaps in birth prevalence and genotype- setting. specific data, particularly in regions with high expected 1096 Seminar A B C 20 µm 20 µm 20 µm Figure 1: Peripheral blood smear morphology in patients with sickle cell disease of different genotypes (A) Homozygous HbSS: numerous sickled erythrocytes (triangle) and reticulocytes (green circle). (B) Compound heterozygous HbS–β0-thalassaemia: sickled cells (triangle), numerous target cells (diamond), and target reticulocytes (white circle). (C) Compound heterozygous HbSC: similar feature to panel B, with the addition of characteristic cells with mild sickling (arrow) typical of this genotype. Images were taken with LEICA DM2000 LED optical microscope, DMC4500 Camera, and ×100 oil lenses. HbS=haemoglobin S. HbSC=sickle haemoglobin-C. HbSS=sickle cell anaemia. burden.34 These data limitations hinder the development of adequate health policies, guidelines, resource allocation, and care models. Addressing these challenges will require sustained global investment in harmonised surveillance, cross-border collaboration, and equitable Recurrent Cell Increased Vaso-occlusion sickling adhesion coagulation access to prevention and treatment strategies.7,21–23,32 Diagnosis Sickle cell disease results from the inheritance of O22– abnormal β-globin alleles carrying the sickle mutation in the HBB gene (Glu6Val; βS). The most common and ROS usually most severe form of sickle cell disease is Haemolysis Inflammation Endothelial activation homozygous HbSS, where both parents pass on the βS Oxidative stress allele that allows the formation of the pathological Activated T cell releasing cytokines Monocyte haemoglobin tetramer (αβS; HbS). Other clinically relevant genotypes includ 2 e 2 compound heterozygous H re a le e a m si o n l g y s f i r s e o e f h r a e e d m b o lo g o lo d b c i e n l l a s, nd Degranulating neutrophil states, such as HbS–β⁰-thalassaemia (also known as heme Neutrophil extracellular traps sickle cell anaemia), HbSC, HbS–β+-thalassaemia, and Platelet combinations of HbS with rare variants, including HbSD (double hetereozygous) or HbSOArab (haemoglobin O, Active platelet Oxidative stress prevalent in Arab populations). All these genotypes Cell adhesion with coagulation produce sufficient HbS to cause sickling (table 1 and factors, soluble adhesion molecules, and von Willebrand figure 1).35,36 In contrast, HbAS (haemoglobin A, sickle factor cell trait) is not a form of sickle cell disease, although evidence shows an association with specific health risks.37 Figure 2: Cyclic pathophysiology of sickle cell disease and main cellular interactions and processes that lead to vaso-occlusion and tissue injury Diagnosis of sickle cell disease is straightforward due to Erythrocytes undergo hypoxia-induced sickling due to intracellular HbS polymerisation with resultant blood the abundance of haemoglobin in blood. HbS and other hyperviscosity and stasis, damage to endothelium, transient micro-vascular ischaemia, and subsequent intimal variants can be reliably detected by electrophoresis, hyperplasia. Moreover, other circulating blood cells and plasma factors (eg, von Willebrand factor and ADAMTS13, isoelectric focusing, capillary electrophoresis, or high- coagulation factors, soluble adhesion molecules, inflammatory molecules, and products of haemolysis) have abnormal interactions with the endothelium. This multistep and multicellular process leads to short-term tissue performance liquid chromatography. Solubility and hypoxia, long-term inflammation, and endothelial vasculopathy.1,2,44–47 HbS=haemoglobin S. ROS=reactive oxygen chemical tests are less reliable and should not be used species. alone. DNA-based techniques and mass spectrometry are promising in large scale screening programmes, although implementation of life-saving interventions that they have not altered diagnostic approaches to date.38 considerably reduce morbidity and mortality in early Point-of-care testing is increasingly being used both for childhood. Prompt diagnosis allows for the initiation of population screening and newborn screening, especially penicillin prophylaxis and pneumococcal vaccination to in low-income and middle-income countries (LMICs).39,40 prevent life-threatening infections. Newborn screening Early diagnosis from newborn screening is a also facilitates early parental education to recognise cornerstone of modern sickle cell disease management crucial signs, such as fever, splenic sequestration, and and universal newborn screening is recommended.7,41–43 stroke. Additional benefits include folic acid supple- Universal newborn screening enables timely mentation, transcranial Doppler screening to assess Seminar polymers distort the shape of the RBCs leading to Acute complications CChhronic complications characteristic crescent moon or sickling morphology. • CNS (acute ischaemic and • CNS (silent infarcts, arterial stenosis, These sickled RBCs occlude blood vessels causing haemorrhagic stroke) moyamoya disease, cognitive ischaemic tissue damage and cyclical ischaemia or • Eye (retinal detachment, acute deterioration) vision loss, retinal artery occlusion) • Eye–ear, nose, and throat (retinopathy, reperfusion. Sickled RBCs undergo premature • Pain crisis and dactylitis adenotonsillar hypertrophy, noctural haemolysis, releasing toxic erythrocyte contents into the • Lung (acute chest syndrome, hypoxia, hearing loss) pulmonary embolism, airway • Cardiac (diastolic dysfunction, plasma, such as free haemoglobin and arginase that in hyper-reactivity) pulmonary hypertension, arrythmias) turn deplete nitric oxide bioavailability, thus triggering • Gastrointestinal (hepatic and • Lung (restrictive lung disease) vasoconstriction.1–3 The downstream consequences of splenic sequestration, cholecystitis) • Gastrointestinal (sickle cell liver • Genitourinary (papillary necrosis, disease, cholelitiasis) HbS polymerisation are not fully understood, but enuresis, priapism) • Genitourinary (hyposthenuria– include abnormalities across biological processes, • Osteomyelitis proteinuria–chronic kidney disease, • Invasive bacterial infections, fever delayed puberty, erectile dysfunction, including inflammation, oxidative stress, blood • Acute anaemia at-risk pregnancies) coagulability, vascular endothelial function, nitric oxide • Bone–skin (osteonecrosis and leg ulcers) metabolism, expression of adhesion molecules, and • Chronic pain, fatigue, and thromboembolism immune function (figure 2).44–47 Additionally, sickle cell disease leads to progressive multiorgan damage during the lifespan, which includes hyposplenism, renal impairment, cerebrovascular disease, avascular necrosis of bones and joints, cardiopulmonary complications, retinopathy, hepatopathy, and priapism. These underlying pathophysiological processes remain active throughout life, silently causing cumulative organ Figure 3: Acute and chronic complications, increasing with age The list is not exhaustive. damage with time. Consequently, patients have a reduced quality of life and have variable clinical manifestations that evolve with aging.48 Clinical manifestations Pathophysiology Treatment Acute painful Dactylitis; pain in the Vaso-occlusion with hypoxia- Hydration; analgesia Clinical manifestations, monitoring, and crisis sternum, ribs, or vertebrae; reperfusion injury, inflammation, management pain in the long bones; increased red blood cell adhesion, priapism and nervous system sensitisation Clinical manifestations of sickle cell disease start in (central and peripheral) infancy and can present as acute and life-threatening Infection–fever Bacteraemia or sepsis; Splenic dysfunction; Antibiotics; surgery emergencies or as progressive organ damage (figure 3). meningitis; osteomyelitis; inflammation; necrotic bone pneumonia; malaria Acute complications Acute anaemia Splenic sequestration; Erythrocyte sickling; infection; Red blood cell A wide spectrum of acute complications (table 2) transient aplastic crisis; sequestration; hyperhaemolysis transfusion; transfusion reaction; papillary management of characterise sickle cell disease, reflecting the intricate necrosis in the kidney hyperhaemolysis pathophysiology of intravascular sickling, endothelial Acute chest Chest pain; dyspnoea Ischaemia; infection; infarction Antibiotics; dysfunction, inflammation, ischaemia-reperfusion injury, syndrome transfusion; incentive and immune compromise. Despite advances in spirometry; oxygen comprehensive care in high-resource settings, acute events Stroke Haemorrhagic or ischaemic Ischaemia; infarction; Red blood cell haemorrhage transfusion remain unpredictable, have variable frequency and severity between patients, and continue to cause considerable This list is not exhaustive. morbidity and mortality.1,2,49,50 Acute complications drive Table 2: Most frequent clinical acute complications in sickle cell disease health resource use and deleteriously affect patient quality of life, socioeconomic opportunities, and survival.21,51 Acute vaso-occlusive episodes are the most common stroke risk, and access to genetic counselling, which clinical manifestation of sickle cell disease and result empowers families to make informed reproductive primarily from microvascular occlusion and tissue choices. Collectively, these interventions have ischaemia. Acute vaso-occlusive episodes are subdivided transformed sickle cell disease from a frequently fatal into the following categories: acute uncomplicated pain paediatric condition into a chronic disease with improved crisis or painful vaso-occlusive crises, acute chest outcomes when identified early. syndrome, splenic or hepatic sequestration, and priapism. Acute uncomplicated pain crisis or painful vaso- Pathophysiology occlusive crisis is defined as an acute episode of pain The pathophysiological mechanisms of sickle cell with no other attributable cause aside from sickle cell disease start from the inheritance of the mutation disease. In infants, vaso-occlusive crisis often manifests leading to the production of HbS, which polymerises as dactylitis—the earliest clinical sign—while in older when deoxygenated. These intraerythrocytic HbS children, adolescents, and adults, pain typically affects 1098 Seminar the extremities, back, and chest. Vaso-occlusive crises are Indications Indications the leading cause of emergency visits and hospital Simple transfusion admissions across all age groups, with frequency and Acute Chronic severity increasing with age. Rates of hospitalisation for • Symptomatic anaemia (aplastic Exchange transfusion preferred for crisis and splenic and hepatic all chronic indications but consider acute pain are also associated with increased mortality.52,53 sequestration) the patient's individual situation Vaso-occlusive crisis results from complex interactions • Mild or moderate ACS • Primary and secondary stroke • Preoperative for surgeries requiring prevention between sickled erythrocytes, endothelial cells, general anaesthesia and lasting >1 h • Recurrent painful crises and ACS leukocytes, and platelets, leading to microvascular not responsive to hydroxyurea occlusion, tissue ischaemia, and hypoxia-reperfusion Indications injury. This cascade is amplified by inflammation, Automated exchange Manual exchange increased RBC adhesion, and both central and peripheral Acute transfusion transfusion • Acute stroke or TIA nervous system sensitisation. Nociceptor hypersensitivity • Severe ACS to mechanical, heat, and cold stimuli, exacerbated by • Multiorgan failure • Severe sepsis recurrent hypoxia or reoxygenation, contributes to pain • Acute complications with Hb >9 g/dL persistence. Management follows established protocols • Preoperative for surgeries requiring emphasising rapid analgesia—typically non-steroidal general anaesthesia and lasting >1 h and Hb >9–10 g/dL anti-inflammatory drugs and opioids titrated to pain severity—yet emerging research implicates mast cell activation, peripheral hyperalgesia, and altered pain pathways, underscoring the need for new targeted Figure 4: Simple versus exchange transfusion for acute and chronic complications of sickle cell disease analgesic strategies. Recent guidelines advocate for a In settings where automated exchange transfusion is not possible, manual exchange transfusion can be more comprehensive conceptual framework that performed.61–65 ACS=acute chest syndrome. Hb=haemoglobin. TIA=transient ischaemic attack. distinguishes acute pain episodes from chronic sickle cell disease pain and recognises so called acute-on- sickled RBCs. Medical intervention for priapic episodes chronic pain states, which might require distinct lasting beyond 4 hours is essential as prolonged episodes therapeutic approaches.54–56 can lead to impotence. Acute chest syndrome is characterised by the presence Invasive bacterial infections remain a leading cause of of a new pulmonary infiltrate plus symptoms, such as mortality in young children with sickle cell disease, owing fever, chest pain, tachypnoea, cough, wheeze, and acute to functional asplenia that typically develops within the hypoxia. Acute chest syndrome is a major cause of first few years of life. Loss of splenic function increases hospitalisation and mortality, particularly in adolescents susceptibility to encapsulated organisms, such as and adults. The aetiology is multifactorial, often involving Streptococcus pneumoniae and Haemophilus influenzae infection, fat embolism, or rib infarction. Management type b.61 The widespread use of pneumococcal conjugate includes early administration of broad-spectrum vaccines has considerably reduced the incidence of antibiotics targeting Streptococcus pneumoniae, Chlamydia invasive pneumococcal disease, although emerging non- pneumoniae, and Mycoplasma pneumoniae, with vaccine serotypes and limited vaccine access in low-income supplemental oxygen, positive pressure, and transfusion settings remain concerns, prompting a shift in attention therapy as needed. In cases of progressive respiratory to other causes of invasive bacterial infections, such as decline or hypoxaemia, urgent exchange RBC transfusion Salmonella, and the need for effective broader vaccines. is indicated with prompt and well-structured organisation Penicillin prophylaxis from birth to age 5 years, parental to deliver emergent and specialised care.57,58 education, and prompt medical evaluation with empirical Splenic sequestration crisis is defined based on patient antibiotic administration for febrile episodes are essential presentation with acute left upper quadrant pain, the pillars of care.62 presence of an enlarged spleen, and an acute decrease in Acute anaemia can result from splenic sequestration, haemoglobin concentration of at least 2 g/dL greater transient aplastic crisis typically due to parvovirus B19, or than baseline. Although splenic sequestration crisis is accelerated haemolysis, including delayed haemolytic historically more frequent in those younger than age transfusion reactions. Transfusion support is often 5 years, it is now associated with onset later in life due to required, but care should be taken to avoid overcorrection the widespread use of hydroxyurea in infancy.59,60 Splenic and hyperviscosity. Target haemoglobin and use of sequestration crisis can be under-recognised in non-SS simple versus exchange transfusion (manual or genotypes, particularly in older individuals. Hepatic automated) should be individualised.63–66 Indications for sequestration crisis is defined based on manifestations of transfusion are summarised in figure 4. acute right upper quadrant pain, hepatomegaly, and an Stroke is among the most devastating complications of acute decrease in haemoglobin concentration of around sickle cell disease as it can lead to neurocognitive deficits, 2 g/dL compared with baseline. physical deficits, or both. Stroke is typically ischaemic in Priapism is the presence of a sustained, unwanted children and haemorrhagic in adults. Before the erection due to obstruction of penile venous outflow by implementation of annual transcranial Doppler Seminar screening in children aged 2–16 years, stroke affected up parenteral antibiotic therapy, analgesia, and, rarely, to 10% of children with HbSS. Acute stroke presentation debridement in advanced cases.1,2,41 includes the sudden onset of neurological deficits, which Retinal detachment is an ophthalmological emergency, should be presumed to indicate cerebrovascular injury presenting with sudden visual changes, such as flashes, until proven otherwise. Brain MRI and magnetic floaters, and curtain-like shadows. Retinal detachment resonance angiogram—with diffusion-weighted, results from repeated sickling in the retinal perfusion, and angiographic sequences—are preferred, microvasculature, causing ischaemia, neovascularisation, although CT remains acceptable when MRI is not fibrovascular proliferation, and vitreoretinal traction. immediately available. Acute ischaemic stroke requires Prompt surgical intervention is required to maximise the emergent exchange transfusion, followed by chronic chance of preserving vision.41 transfusion therapy to prevent recurrence.1,2,48,67 Despite improvements in early diagnosis and Cholecystitis in patients with sickle cell disease supportive care, these acute complications are life- presents similarly to the general population with right altering and in some cases life-threatening and upper quadrant pain, nausea, vomiting, fever, and disproportionately affect individuals with restricted jaundice. Gallstones are pigment stones from chronic access to specialised care. Strategies to prevent and haemolytic anaemia. Symptomatic stones are managed manage these events should be integrated into broader with elective cholecystectomy.1,2,41 health system responses to reduce preventable morbidity Osteomyelitis occurs more frequently in children with and mortality in sickle cell disease.7 sickle cell disease and can mimic an uncomplicated pain crisis with intense pain usually in the extremity. Patients Chronic complications are often febrile and have persistent focal pain despite Compared with acute sickling events, the pathogenesis administration of analgesics. Imaging is not always of chronic organ damage in sickle cell disease is less well definitive but is preferably performed with MRI when understood but is a major driver of reduced quality of available. S aureus remains the most common cause of life, morbidity, and premature mortality. Organ osteomyelitis in sickle cell disease, but Salmonella is dysfunction results from the cumulative effects of vaso- disproportionately represented compared with patients occlusion, chronic haemolytic anaemia, repeated with non-sickle cell disease. Treatment requires ischaemia-reperfusion injury, and endothelial Key manifestations Screening and monitoring Specialist to involve Treatment Kidney Hyposthenuria; glomerular Annual renal function; Nephrologist ACE inhibitors, angiotensin hyperfiltration; albuminuria; microalbuminuria; proteinuria receptor blockers, hydroxyurea chronic kidney disease Eye Retinopathy Retinal exam from age 10 years Ophthalmologist Laser photocoagulation or vitreo- retinal surgery according to stage and complication Heart Diastolic dysfunction; Electrocardiogram; echocardiogram; Cardiologist According to clinical manifestation arrythmias; cardiomyopathy electrocardiogram Holter Lung Restrictive lung disease; Echocardiogram with tricuspid valve Pulmonologist or pulmonary Disease modifying therapy pulmonary hypertension regurgitation measurement and hypertension specialist (eg, hydroxyurea or RBC N-terminal pro-B-type natriuretic transfusion); vasodilator therapy peptide if symptomatic for selected patients; anticoagulation if no moyamoya disease Liver Jaundice; gallstones Abdominal ultrasound Gastroenterologist or Cholecystectomy general surgeon Bone and joints Osteonecrosis Assess chronic intermitting pain; Orthopaedics or physical Physical therapy; waking aid; core x-ray imaging followed by MRI if therapist decompression; joint replacement present Skin Clinical exam Wound exam Dermatologist, plastic or Local treatment; antibiotics and general surgeon, or wound- painkillers when need care specialist Brain Ischaemic and haemorrhagic Transcranial Doppler in children; MRI Neurologist or Hydroxyurea, RBC transfusion stroke; silent infarcts; at least once when older than age neuropsychologist cognitive decline 6 years and then in adults*; cognitive assessment Chronic pain or Chronic pain or mental health Assess regularly Pain specialist or According to multidisciplinary team psychosocial psychologist evaluation This list is not exhaustive.7,41,56,67–69 ACE=angiotensin-converting enzyme. RBC=red blood cell. *Surveillance protocols differ according to setting. Table 3: Main chronic organ complications with suggested monitoring and multidisciplinary management 1100 Seminar dysfunction. Although they are harder to quantify, elevated extracellular volume fraction even in repeated acute events requiring interface with the health- asymptomatic adolescents, correlating with reduced care system increases the likelihood of iatrogenic functional capacity and early left atrial stiffening.78 complications, including drug-induced renal insults, Cardiac arrhythmias, particularly atrial fibrillation nosocomial infection, and thromboembolic com- and supraventricular tachycardias, are increasingly plications. Repeated blood transfusions can lead to iron recognised in adults with sickle cell disease and are overload with resultant hepatopathy, endocrinopathy, associated with myocardial scarring, chamber dilation, and cardiomyopathy if untreated. By age 30 years, chronic and autonomic dysfunction. Hospitalisations for complications become the dominant clinical challenge arrhythmia are rising in sickle cell disease cohorts, and for most individuals with sickle cell disease, considerably these events often coincide with acute chest syndrome or impairing quality of life and increasing health-care high-output states. Continuous electrocardiogram use.48,51 monitoring or Holter assessments could be warranted in Virtually all organ systems can be affected by sickle cell patients at high risk, especially those with diastolic disease (table 3), but the most life-threatening dysfunction or myocardial fibrosis.78–81 complications involve the kidney, heart, and lungs. Echocardiographic indices, particularly elevated Retinopathy, osteonecrosis, chronic pain syndromes, tricuspid regurgitant velocity and abnormal diastolic priapism-related impotence, and silent cerebral infarcts filling patterns, are strong predictors of early mortality in with cognitive decline also substantially affect quality of sickle cell disease, while echocardiography and cardiac life. MRI provide important prognostic insights.41,57,68,82,83 Sickle nephropathy often begins in childhood with Pulmonary hypertension, which requires confirmation impaired urine concentrating ability and glomerular by right heart catheterisation, is also associated with hyperfiltration, eventually progressing to albuminuria, increased mortality.41,57,82 Recent studies suggest that left reduced glomerular filtration rate, and end-stage renal atrial dysfunction and diffuse myocardial fibrosis might disease.70 Recent data confirm that up to one-third of represent a restrictive cardiomyopathy phenotype, adults with sickle cell disease develop overt proteinuria linking myocardial fibrosis, pulmonary pressures, and or decreased glomerular filtration rate, and kidney adverse outcomes.83 Disease-modifying therapies, such dysfunction is independently associated with early as hydroxyurea and chronic transfusions, could mitigate mortality. Hydroxyurea and angiotensin-converting the progression of myocardial fibrosis, but the benefit of enzyme inhibitors remain first-line therapies for pulmonary hypertension-targeted drugs (eg, bosentan or reducing albuminuria and slowing progression. Enuresis riociguat) is unproven.57,68 Since organ damage begins in is another frequent complication that affects quality of childhood, screening for its presence followed by life. Genetic modifiers, such as high fetal haemoglobin management with a multidisciplinary team and referral (HbF) levels and α-thalassaemia trait have a protective to organ specialists with experience in sickle cell disease effect on nephropathy, possibly by reduced haemolysis should start in childhood.69 and endothelial stress.70–72 Retinopathy is commonly begins during adolescence, Established treatments particularly in those with HbSC. Recent evidence Comprehensive care has been for many years the suggests that not only haemodynamic factors but also framework of care delivery for sickle cell disease.84 blood viscosity and red cell deformability play a major Multidisciplinary management throughout life and role in the pathogenesis of retinopathy.73–75 A 2025 study service provision for day-by-day management, acute showed that individuals with higher HbF levels have emergencies, and chronic complications require significantly lower prevalence of proliferative sickle coordination between primary care, subspecialists, retinopathy, supporting HbF as a key preventive target.76 regional hospitals, and expert centres. Minimal Optical coherence tomography angiography and ultra- requirements of care are newborn screening and early widefield imaging now enable earlier detection of retinal diagnosis, penicillin prophylaxis, vaccinations against microvascular changes, even in children. These encapsulated bacteria and influenza, protocols for technologies could allow targeted early intervention management of fever, stroke screening with annual before visual impairment occurs.77 transcranial Doppler screening at ages 2–16 years, and Cardiac dysfunction—particularly diastolic dysfunction, the ability to offer treatment with hydroxyurea. Parent myocardial fibrosis, arrhythmias, and pulmonary education and involvement in health management, and hypertension—has emerged as a major contributor to guidance on how to access pathways of care for acute and mortality in patients with sickle cell disease. While high- chronic complications are also necessary.41,61,66,69 output cardiomyopathy from chronic anaemia was long considered important, newer imaging and biomarker Hydroxyurea studies reveal that diffuse myocardial fibrosis develops Hydroxyurea remains the cornerstone of disease- early, often silently, and contributes to both systolic and modifying therapy for sickle cell disease, with more than diastolic dysfunction. Cardiovascular MRI has revealed three decades of clinical evidence confirming its ability to Seminar induce fetal haemoglobin (HbF), reduce vaso-occlusive careful discussion of risks and benefits.97,98 The lack of morbidity, and improve survival.16,85–87 Its principal hydroxyurea-induced mutational effects further supports mechanism—ribonucleotide reductase inhibition a higher use for the treatment of sickle cell disease.99 leading to S-phase arrest and stress erythropoiesis— Together, these developments support a shift from reactive promotes HbF induction, while additional prescription for recurrent complications to proactive, HbF-independent effects include improved erythrocyte universal, and preventive therapy across the life course hydration and rheology, reduced leucocytosis and while implementing adequate strategies to improve access inflammation, and nitric oxide-mediated vasodilation.1,2 and adherence.100 National guidelines provide evidence-based recom- mendations for initiating and monitoring the use of RBC transfusion hydroxyurea therapy in sickle cell disease and consensus RBC transfusion remains a cornerstone of therapy in treatment protocols for its implementation. Indications sickle cell disease, with established indications in both for the initiation of hydroxyurea vary according to sickle acute and chronic settings. In fact, while all individuals cell disease genotype and among countries. Indications with sickle cell disease have chronic haemolytic anaemia are typically based on the frequency and severity of vaso- and most adapt to their steady state low haemoglobin occlusive crises; however, recent years have seen a concentration such that anaemia per se is not an harmonisation of practices, with a more widespread indication for blood transfusion, acute exacerbation of indication to start hydroxyurea at age 9 months for the chronic anaemia can occur.1,2,7 Acute transfusion is used most severe genotypes.41,87,88 Long-term studies have to correct symptomatic anaemia, such as in acute splenic shown sustained reductions in painful crises, acute chest sequestration, transient aplastic crisis, and severe syndrome, transfusion needs, and mortality.89,90 infection-related haemolysis.63–66 Exchange transfusion— Hydroxyurea is administered orally once daily, typically manual or automated—is preferred for acute organ starting at 15–20 mg/kg per day, with upward titration complications where rapid HbS reduction is required, every 8–12 weeks to achieve the maximum tolerated including acute ischaemic stroke, severe acute chest dose, defined by mild myelosuppression. Clinical trials syndrome, and multiorgan failure, with a goal of have established hydroxyurea efficacy across the lifespan: reducing HbS to lower than 30% while avoiding in infants, the BABY HUG trial showed reduced vaso- hyperviscosity by maintaining total haemoglobin at occlusive events and acute chest syndrome even at low 9–11 g/dL.63–66 Transfusion is also indicated for hepatic fixed doses;17 in children, TWiTCH showed non- sequestration, perioperative optimisation, and in severe inferiority of hydroxyurea compared with transfusion for sepsis with profound anaemia. Perioperative trials show primary stroke prevention;91 and in adults, long-term that transfusion to achieve haemoglobin around 10 g/dL follow-up of the original Multicenter Study of is sufficient, and the TAPS trial showed increased Hydroxyurea documented sustained survival benefit.90 complications without transfusion, establishing These data underpin contemporary strategies of early preoperative transfusion as the standard of care.101 and proactive hydroxyurea initiation. Contemporary Chronic transfusion therapy is most firmly established pharmacokinetics-guided and individualised escalation for stroke prevention: the STOP and STOP2 trials approaches allow attainment of higher HbF levels confirmed that indefinite transfusion prevents first and (>30%) with near pan-cellular distribution, which are recurrent strokes in children with abnormal transcranial outcomes that approach those achieved by curative Doppler screening velocities,18,19 while the SIT trial therapies92 and point towards a pharmacokinetics-guided showed reduced overt strokes in children with silent approach instead of a weight-based strategy for cerebral infarcts.102 Additional indications for long-term personalised therapy. transfusion include recurrent acute chest syndrome in Recent advances have reframed hydroxyurea as a spite of hydroxyurea therapy, progressive pulmonary preventive, neuroprotective, and organ-preserving therapy. hypertension, severe chronic anaemia with organ Early initiation, ideally in infancy, mitigates cumulative dysfunction, and selected high-risk scenarios, such as tissue injury and preserves long-term function. Children recurrent priapism or early renal disease. Automated treated before age 5 years have cognitive performance exchange transfusion is increasingly favoured in chronic similar to unaffected peers, and the hydroxyurea Prevent programmes due to superior HbS suppression and lower trial confirmed reductions in silent cerebral infarcts and iron accumulation, although access remains restricted in vasculopathy with very early use.93,94 In parallel, emerging many settings. evidence is reshaping views on the effects of hydroxyurea Despite these benefits, RBC transfusion carries on fertility and pregnancy. Hydroxyurea does not seem to important risks.103,104 Alloimmunisation is common, affect spermatogonial pool in males or follicle density in reflecting antigenic disparities between predominantly females.95,96 Moreover, although prospective data remain African-ancestry recipients and largely non-African scarce, observational studies suggest that continuing donor pools in Europe and North America, and can result hydroxyurea during pregnancy, including beyond the first in delayed haemolytic transfusion reactions or trimester, might be reasonable in selected women after hyperhaemolysis, both of which can be life-threatening 1102 Seminar and difficult to manage. Best practice includes extended graft failure and graft-versus-host disease, refinements antigen matching (Rh C/c, E/e, and K at minimum), with (eg, thiotepa-containing conditioning and cord molecular genotyping increasingly used to reduce expansion) are improving engraftment and survival.27 alloimmunisation risk. Iron overload is another major The most rapid progress has been with haploidentical complication of chronic transfusion, mandating transplantation,107 which offers greater than 90% donor MRI-based monitoring of liver iron content and timely availability across the lifespan and now encompasses chelation. Automated exchange can mitigate but not several platforms—T-cell-replete bone-marrow grafts eliminate this burden. In pregnancy, transfusion is not with post-transplant cyclophosphamide (often with recommended routinely for all women but should be thiotepa), in vivo T-cell-depleted peripheral blood stem used selectively for maternal or fetal complications (eg, cell aiming for stable mixed chimerism, and ex vivo T-cell recurrent vaso-occlusive crises, acute chest syndrome, receptor-αβ or CD19-depleted grafts—reporting severe anaemia, and intrauterine growth restriction), and encouraging early outcomes: the 2-year event-free for women with previous severe pregnancy morbidity, survival and OS rates were 88·0% (95% CI 73·5–94·8%) while prophylactic transfusion remains debated.63–66 The and 95·0% (95% CI 81·5–98·7%), respectively. The TWiTCH trial91 further showed that hydroxyurea can be a incidence of grade 3–4 acute graft-versus-host disease at safe alternative to chronic transfusion for primary stroke day 100 was 4·8% (95% CI 0·9–14·4%), while the 2-year prevention in selected children with abnormal chronic graft-versus-host disease rate was 22·4% (95% CI transcranial Doppler velocities after at least 1 year of 10·9–36·4%) after haploidentical transplantation.107 transfusion therapy. Current guidelines emphasise Overall, transplant candidacy and regimen intensity individualised transfusion planning, regular monitoring, should be individualised (eg, age, comorbidity, and preferential use of exchange transfusion in high-risk cerebrovascular disease, or fertility goals) with decisions settings, such as stroke prevention.63,64,66 In low-resource benchmarked against the benefits and risks of modern regions, major challenges include scarce blood disease-modifying therapies and emerging curative availability, insufficient donor screening, and cost, which options. Several trials are ongoing to explore the restrict feasibility. Overall, RBC transfusion remains an optimisation of conditioning regimens for adults and for essential, life-saving therapy that complements haploidentical transplantation. In this evolving context, hydroxyurea and curative approaches, providing both shared decision making and patients’ and families’ acute stabilisation and long-term organ protection when perspectives are crucial to identify the most appropriate delivered within structured care pathways. treatment for each individual, coupled with long-term evaluation of sickle cell disease-related and HSCT-related HSCT morbidity.108–111 HSCT remains the only established cure for sickle cell disease. In children with a human leucocyte antigen New therapies under investigation (HLA)-matched sibling donor, contemporary New disease-modifying therapies programmes report outstanding results: HSCT outcomes In recent years, there has been an increase in clinical by conditioning regimen in paediatric patients with trials of new therapeutic agents with different sickle cell disease from the European Bone Marrow mechanisms of action for sickle cell disease, primarily in Transplantation registry after a median follow-up of adults and adolescents. We refer to other reviews for 2·7 years showed that 2-year overall survival (OS) was detailed coverage.112 However, despite the commitment of 98·7% (95% CI 90·9–99·8) with busulfan-fludarabine the scientific community, patients and their families, and and 99·3% (95% CI 95·2–99·9) with treosulfan- pharmaceutical companies, progress in the development, fludarabine.105 Excellent long-term outcomes, with OS of approval, and accessibility of new drugs has been 95% and an event-free survival rate of 93%, show that disappointing.30,31 Inadequate trial endpoints and a lack of HSCT with an HLA-matched sibling donor as a curative consideration of the environmental characteristics and of option is a role warranted even in young patients.27 the differences in health-care organisations across In adolescents and adults—where cumulative organ settings might explain the recent failures and the injury limits tolerance of full myeloablation—reduced- complex multifactorial pathophysiology of sickle cell intensity or non-myeloablative platforms have broadened disease, along with unanticipated safety challenges and eligibility. A recent study in adults showed a 3-year event- regulatory and economic barriers. More efforts are free survival of 88·2% and OS of 94·6%, with low rates of needed not only to ensure the successful implementation graft-versus-host disease (3·5% acute and 0·5% chronic), of clinical trials, but also to secure regulatory approval, stable mixed chimerism, and significantly reduced commercialisation, and broad access to these much health-care use post-transplant, although graft failure needed treatments. (8·5%) remained a challenge.106 Crizanlizumab, L-glutamine, and voxelotor were For patients lacking a matched sibling, donor options recently approved by the US Food and Drug continue to expand. Although matched-unrelated and Administration after successful trials.24–26 The European cord-blood HSCT have historically carried higher rates of Medicines Agency did not approve L-glutamine and Seminar Phase Primary endpoint Clinical trial number Fetal haemoglobin inducers Oral decitabine–tetrahydrouridine 2 Change in total haemoglobin at 24 weeks NCT05405114 Oral decitabine–tetrahydrouridine plus nicotinamide 1 Change in total haemoglobin NCT04055818 FTX-6058 1 Safety, tolerability, pharmacokinetics, and pharmacodynamics NCT05169580 BMS-986470 1/2 Safety, tolerability, pharmacokinetics, and pharmacodynamics NCT06481306 Panobinostat 1 Safety, dose-limiting toxic effects NCT01245179 GSK4172239D 1 Safety, tolerability, pharmacokinetics, and pharmacodynamics NCT05660265 ITU512 1/2 Safety and tolerability NCT06546670 Anti-haemolytic agents Vamifeport 2a Mean change from baseline in haemolysis markers NCT04817670 GBT021601 2/3 Co-primary endpoints: haemoglobin response (increase from NCT05431088 baseline of >1 g/dL); annualised rate of vaso-occlusive crises at week 48 Pyruvate-kinase activators Mitapivat 3 Percentage of participants with haemoglobin response at NCT05031780 week 52; annualised rate of pain crises Etavopivat 2, open label Change in cerebral haemodynamics at week 24 NCT05725902 Etavopivat 2, open label Change in transcranial Doppler velocity NCT05953584 Etavopivat 2/3 Haemoglobin response rate at week 24 (increase of >1 g/dL NCT04624659 [>10 g/L] from baseline); annualised vaso-occlusive crisis rate Etavopivat 1/2; children Pharmacokinetics and safety NCT06198712 Tebapivat 1 Safety, tolerability, pharmacokinetics, and pharmacodynamics NCT06924970 Anti-adhesion agents Inclacumab 3 Rate of vaso-occlusive crises during the 48-week treatment NCT04935879 period Individual agents Epeleuton (synthetic ω-3 fatty acid) 2 Pharmacokinetics, pharmacodynamics, and safety NCT05861453 Tadalafil (PDE-5 inhibitor) 2 Change in the recurrence rate of priapism NCT05142254 HBI-002 (oral carbon monoxide) 2a Safety NCT06144749 Tocilizumab (IL-6 inhibitor) 2 Time-weighted pulse oximetry oxygen saturation to fraction of NCT05640271 inspired oxygen ratio in patients with acute chest syndrome L-citrulline (increase nitric oxide production) 2 Time to crisis resolution NCT06635902 TAK-755 (recombinant ADAMTS13 enzyme) 1 Safety and development of anti-ADAMTS13 antibodies NCT03997760 CSL889 (human-derived haemopexin) 2/3 Time to resolution of vaso-occlusive crises NCT06699849 Oral ketamine 3 Change in pain intensity during vaso-occlusive crises NCT05378555 Crovalimab (anti-C5 inhibitor) 1b Safety NCT04912869 Crovalimab (anti-C5 inhibitor) 2a Annualised rate of medical facility vaso-occlusive episodes NCT04912869 Rilzabrutinib (Bruton tyrosine kinase inhibitor) 3 Annualised rate of clinical vaso-occlusive crises NCT06975865 Ongoing trials by mechanism of action class and individual agents that have different mechanisms of action. The list is not exhaustive and serves as an example. Table 4: Ongoing clinical trials with new drugs retired the approval of crizanlizumab after dissemination β-globin addition (lovo-cel) and CRISPR–Cas9 BCL11A of the results from the STAND trial.113 Voxelotor was enhancer editing (exagamglogene autotemcel, Casgevy) removed from the global market in 2024 for safety both achieved high rates of transfusion independence and concerns. Several drugs targeting different patho- resolution of vaso-occlusive complications, with approvals physiological mechanisms of sickle cell disease are subsequently extended to the EU and UK,27,28 where the currently in various stages of clinical trials and offer first is not available. Beyond the approved therapies, promising alternatives for the future (table 4). several gene-editing trials are underway, including the BEACON (autologous base edited CD34+ haematopoietic New gene therapies progenitor stem cells–BEAM-101 [NCT05456880]), Recent years have seen the emergence of transformative CRISPR_SCD001 (NCT03745287), and SAGES1 therapies.114 Gene therapy has shifted from experimental (NCT06506461) trials. Additional approaches—eg, proof-of-concept to a licenced therapy for sickle cell re-engineered base editors, RNA-interference constructs, disease. Two gene therapies received simultaneous and novel lentiviral vectors—are in early development but approval in the USA in December, 2023. Lentiviral have not yet entered phases with formal trial listings. 1104 Seminar Despite remarkable efficacy, challenges remain, including A systematic and context-adapted approach to improve the reliance on myeloablative conditioning, the risk of diagnosis, treatment, and follow-up is urgently needed. insertional mutagenesis and secondary malignancies, manufacturing bottlenecks, and inequitable access in Universal newborn screening and point-of-care testing high-burden regions. The next phase of development will Universal newborn screening enables early identification focus on less toxic conditioning, in vivo editing, and cost- and timely interventions, such as penicillin prophylaxis, effective delivery to ensure that curative gene therapies vaccinations, and caregiver education. However, in benefit the global sickle cell population. LMICs, fewer than 5% of affected infants are diagnosed within the first year of life.118 Laboratory-based approaches Recent advances: management in LMICs are hindered by logistical delays and resource constraints. One of the most important recent advances globally has Point-of-care tests, such as HemoTypeSC and Sickle been the development of sickle cell disease SCAN, show high sensitivity and specificity (>99%), comprehensive programmes, clinical trials, and data require no electricity, and can be administered by non- collection systems in LMICs. These achievements are laboratory staff.119–121 Integration into maternal and child particularly important because LMICs in sub-Saharan health programmes allows decentralised and scalable Africa and south Asia account for more than 80% of the implementation122 that can improve diagnostic accuracy, global burden of sickle cell disease.7,10 Health systems in reduce late diagnoses, and enhance efforts at premarital these regions are highly under-resourced with restricted screening. The Newborn Screening in Africa initiative diagnostic capacity, fragmented care pathways, and has shown feasibility in Ghana, Nigeria, Kenya, Tanzania, inadequate access to disease-modifying therapies. In Liberia, and Zambia, incorporating family education and Nigeria and the Democratic Republic of the Congo, linkage to comprehensive care.123,124 50–90% of children with sickle cell disease die before age 5 years, frequently undiagnosed until late or never Hydroxyurea safety and efficacy in LMICs diagnosed at all, and without access to basic Despite the well-known benefit of hydroxyurea for interventions.10,115,116 individuals with sickle cell disease, its uptake in LMICs The implementation of such programmes has has been limited by concerns regarding infection risk, encountered and still faces many challenges. Sickle cell toxicity, cost, and the need for laboratory monitoring. disease is not prioritised in many national health Hydroxyurea remains underused globally. Among agendas, surveillance systems are weak, registries are 2145 patients in the global SWAY survey, only 30% scarce, and dedicated funding mechanisms are lacking.117 reported hydroxyurea use; in Africa, none reported using Setting Population Study design Dosing strategy Key findings REACH125 Angola, Democratic 606 children Single arm at fixed dose with 15–20 mg/kg per day; mean Reduced vaso-occlusive crises, Republic of Congo, escalation 17·5±1·8; escalation infections, malaria, Kenya, Uganda transfusions, and mortality; feasible and safe NOHARM126 Uganda 207 children Randomised, double-masked, 20±2·5 mg/kg per day vs No increased malaria; improved placebo-controlled placebo outcomes; safe in endemic settings NOHARM MTD127 Uganda 187 children Randomised fixed vs placebo Fixed 19·2±1·8 mg/kg vs Dose escalation has superior escalated 29·5±3·6 efficacy; equivalent safety; trial stopped early SPRING128 Nigeria 220 children Double-masked, parallel-group, Fixed low (10 mg/kg) dose vs Both superior to no treatment randomised, controlled, phase 3 moderate (20 mg/kg) dose for primary stroke prevention in case of abnormal transcranial Doppler SPRINT129 Nigeria 60 children Double-masked, parallel-group, Fixed low (10 mg/kg) dose vs Similar recurrence for secondary randomised, controlled, phase 3 moderate (20 mg/kg) dose stroke prevention to SWiTCH trial; trial stopped early; hydroxyurea feasible as secondary prevention in settings where transfusion is not feasible PIVOT130 Ghana 212 children Double-masked, randomised, Fixed 20 mg/kg vs placebo in Similar dose-limiting toxic and adults placebo-controlled, non- sickle haemoglobin C disease effects and vaso-occlusive inferiority phase 2 trial events NOHARM=Novel use Of Hydroxyurea in an African Region with Malaria trial. NOHARM MTD=NOHARM maximum tolerated dose trial. PIVOT=Prospective Identification of Variables as Outcomes for Treatment trial. REACH=Realizing Effectiveness across Continents with Hydroxyurea trial. SPRING=hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria trial. SPRiNT=Secondary Stroke Prevention Trial in Nigeria trial. Table 5: Key trials on hydroxyurea use in sub-Saharan Africa Seminar task-shifting, and leverage community health workers National referral centre for outreach and monitoring.131,132 WHO framework (coordination) suggests a pyramidal, three-level system: primary or community health centres (level 1) for identification, first referral or district hospitals (level 2) for routine Regional centre of excellence (training, complications, stroke prevention) care, and secondary or tertiary specialist centres (level 3) for specialised management.129 Key strategies include hub-and-spoke networks connecting regional centres to District hospital (hydroxyurea initiation, basic laboratories, transcranial district hospitals and primary facilities;116,124,131,132 task- Doppler screening) shifting to nurses and community health workers to deliver hydroxyurea, preventive care, and follow-up;132,133 and integration with maternal-child health, HIV, Primary health facility or community health worker (point-of-care newborn screening, penicillin, vaccination, immunisation, and nutrition programmes to optimise fixed-dose hydroxyurea delivery, education and follow-up, resources and retention.129,130 Embedding sickle cell digital tracking tools) disease care within the WHO Package of Essential Noncommunicable Disease Interventions (PEN) at the Figure 5: Integrated, decentralised model for sickle cell disease care in low- primary level and PEN-Plus at the district level income and middle-income countries strengthens chronic care management.131 Digital tools, such as mobile health and telemedicine support Effect Proposed solution monitoring, adherence, and data collection, while national registries enhance surveillance.116,124,132 Delayed or absent High early Point-of-care testing; Strengthened transfusion services are essential, diagnosis118–120,123 mortality national newborn screening programmes requiring reliable supply chains, community donor Underuse of Preventable Local manufacturing; task- engagement, and integration into care models, and hydroxyurea51,125–127,133 complications, shifting; policy adoption where transfusion is restricted, hydroxyurea for stroke mortality prevention is crucial.134 Lack of transfusion Restricted stroke Low dose hydroxyurea for Capacity building remains fundamental, with sickle infrastructure128,129,134 prevention stroke prevention cell disease competencies incorporated into medical, Workforce Restricted access Nurse-led clinics; nursing, and community curricula, and continuous shortages117,131–133 to care community-based care; training delivered via centres of excellence. These tertiary training networks hubs should not function in isolation and should be part Stock-outs and cost Interrupted Inclusion in essential barriers51,126,133 treatment medicines lists; pooled of national networks that provide advanced therapies, procurement conduct research, and support training—thereby Poor retention and Loss to follow-up Integration into mother and reducing the need for patients to travel abroad and adherence123,124,131,132 child health or HIV services; ensuring more equitable access to comprehensive care. digital reminders and These models are further illustrated in figure 5 and are registries summarised in table 6. Table 6: Challenges, gaps, and solutions for sickle cell disease care in low- income and middle-income countries Controversies Pregnancy Pregnancy in sickle cell disease remains high-risk despite hydroxyurea, reflecting barriers, including scarce structured multidisciplinary care and clearer antenatal availability, high costs, and insufficient monitoring pathways. Current guidelines emphasise preconception infrastructure.51 However, several pivotal African studies counselling, integration of fertility services, and have addressed these concerns and shown feasibility, intensified surveillance.135,136 RBC transfusion is often safety, and efficacy in reducing the frequency of vaso- used but its optimal strategy is unresolved. Previous occlusive crises and lowering transcranial Doppler meta-analyses suggest the benefit of prophylactic screening velocities. Key hydroxyurea trials conducted in transfusion, yet quality of evidence is low and Africa are summarised in table 5.125–130 heterogeneous. A recent feasibility randomised controlled trial (TAPS2) showed acceptability and signals Sickle cell disease care models in LMICs of reduced vaso-occlusive crises and preterm birth with Delivering sickle cell disease care in LMICs requires serial exchange transfusion, but was underpowered, decentralised, integrated, and context-adapted models. which underscores the need for a definitive international Reliance on tertiary centres alone cannot achieve broad trial.137 Hydroxyurea, the main disease-modifying therapy, or equitable coverage. A recent scoping review is generally discontinued during pregnancy. Emerging highlighted that successful programmes integrate into cohort and registry data summarised in reviews indicate existing health system structures, prioritise no clear teratogenic signal but highlight the possible 1106 Seminar increased risks of miscarriage, stillbirth, and low mutations can have a milder phenotype.35,36 Therefore, birthweight, leaving continuation during gestation optimal management of HbSC and HbSβ+ disease uncertain and individualised.86,138 Accordingly, when to remains a major controversy, underscoring the urgent transfuse and whether or when hydroxyurea can be safely need for genotype-specific research, inclusion in clinical continued remain the principal controversies. Until trials, and development of evidence-based standards of stronger trial data are available, care should be care. individualised based on disease severity and obstetric history within specialist multidisciplinary teams, with Challenges and opportunities: transition from enrolment in prospective studies encouraged. paediatric and adolescent care to adult care As survival improves with advances in paediatric care, the Prevention of neurovascular complications number of adolescents and young adults with sickle cell Silent and overt cerebral infarcts remain a major cause of disease has grown worldwide.20,21,144 This success exposes a morbidity in sickle cell disease despite early screening crucial gap: the transition from paediatric to adult care and transfusion-based prevention.66,67 Abnormal remains fragile and poorly coordinated, leading to sharp transcranial Doppler screening velocities identify declines in outcomes. In HICs, mortality rises between children at risk of overt stroke, but recent cohort studies ages 18–24 years, with reduced adherence, missed show that silent infarcts also occur in those with normal appointments, and inappropriate emergency use.145 In transcranial Doppler screening linked to severe anaemia, low-resource settings, challenges are magnified by absent acute anaemic events, and extracranial carotid protocols, limited workforce training, and weak follow-up arteriopathy. Even with systematic monitoring and systems. Families, adolescents, and young adults also disease-modifying therapy, up to one third of children report distress, loss of trust when leaving familiar develop silent infarcts, often present at first MRI, paediatric providers, and insufficient preparation for underscoring the need for earlier and intensified autonomy.146 Globally, no consensus exists on age cutoffs interventions.139–141 Strategies under evaluation include or care models, despite unique developmental needs. systematic extracranial carotid assessment, earlier use of Transition of care is not a simple transfer of records, but a hydroxyurea, and combining transcranial Doppler longitudinal process requiring readiness assessments, screening with magnetic resonance angiography to multidisciplinary collaboration, and health-system refine transfusion decisions. Yet, infarcts still occur on accountability.146,147 Successful examples from quality hydroxyurea, transfusion remains most effective for networks show that structured approaches can improve vasculopathy, and transplantation can be curative in outcomes (eg, joint transition clinics, detailed pathways, selected cases. Prevention remains controversial, and and adequate education of adolescents, young adults, and broader neurovascular screening and international trials families), but implementation remains uneven. As sickle are essential to reduce the lifelong cognitive burden. cell disease shifts from a paediatric to a lifelong condition, Ensuring adequate access to screening of neurovascular building equitable and sustainable care transition disease with broad screening coverage and participation pathways is an urgent global priority.7 into clinical trials of children with cerebral vasculopathy are essential to move forward. Conclusion Recent decades have seen considerable advances in sickle Management of HbSC and HbS–β+ disease cell disease management, from universal newborn Non-HbSS genotypes of sickle cell disease once screening to transformative gene therapy. However, global traditionally regarded as mild, such as HbSC and HbS– inequities and fragmented care models persist. As sickle β+-thalassemia, are increasingly recognised as clinically cell disease becomes a lifelong condition, coordinated, heterogeneous conditions associated with considerable multidisciplinary care is crucial. Future clinical trials morbidity. Recent large registry and cohort studies show should incorporate patient-reported outcomes and quality- that adults with HbSC disease frequently develop of-life measures co-developed with patients with sickle cell complications, such as retinopathy, splenomegaly, disease, allowing interventions to address what truly avascular necrosis, pulmonary embolism, and acute matters to those living with the condition. Implementation chest syndrome, with acute care use similar to those with science should guide the scaling of proven interventions to HbSS.142,143 Yet, patients with HbSC remain under- across diverse health systems, bridging discovery–delivery represented in clinical trials, restricting evidence for the gaps and informing context-specific strategies that ensure efficacy and safety of disease-modifying therapies. equitable uptake and sustained integration of effective Similarly, HbS–β+-thalassemia shows a variable therapies, such as hydroxyurea.30,31,148–151 While progress is phenotype strongly influenced by the underlying celebrated, the sickle cell disease community should β+ mutation. Individuals carrying the IVS-I-110 mutation continue advocating for research funding and improved often have vaso-occlusive crises, splenic sequestration, global access. The next frontier extends beyond curative and stroke, and require transfusion support that therapies to embedding equity, personalisation, and resembles HbSS in severity, while those with promoter integration at every care level. Seminar Contributors 15 Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral All authors designed the Seminar and wrote the first draft of the penicillin in children with sickle cell anemia. A randomized trial. manuscript, including the figures and tables. All authors participated in N Engl J Med 1986; 314: 1593–99. the editing of the manuscript and approved the final version, and all 16 Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on fulfil the authorship requirements as outlined in the International the frequency of painful crises in sickle cell anemia. N Engl J Med Committee of Medical Journal Editors recommendations. 1995; 332: 1317–22. 17 Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very Declaration of interests young children with sickle-cell anaemia: a multicentre, randomised, RC received grants or contracts from Vertex and Agios (to institution); controlled trial (BABY HUG). Lancet 2011; 377: 1663–72. payment or honoraria from Global Blood Therapeutics; support for 18 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by attending meetings and travel from the Physicians’ Education Resource; transfusions in children with sickle cell anemia and abnormal and participated on advisory boards for Vertex, Pfizer, Novo Nordisk, results on transcranial Doppler ultrasonography. N Engl J Med 1998; Forma Therapeutics, Global Blood Therapeutics, AddMedica, and Agios. 339: 5–11. WJ participated on advisory boards for Vertex and Pfizer. JM received 19 Adams RJ, Brambilla D, and the Optimizing Primary Stroke grants or contracts from the National Institutes of Health, Gates Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Foundation, Novartis Institutes for BioMedical Research, European & Discontinuing prophylactic transfusions used to prevent stroke in Developing Countries Clinical Trials Partnership, University of Chicago, sickle cell disease. N Engl J Med 2005; 353: 2769–78. and Imperial College London; consulting fees from Pfizer and Tanzania 20 Abboud MR. Standard management of sickle cell disease Health Promotion Support; payment or honoraria from Teaching complications. Hematol Oncol Stem Cell Ther 2020; 13: 85–90. Hematology and the American Society of Hematology; and support for 21 Lubeck D, Agodoa I, Bhakta N, et al. Estimated life expectancy and attending meetings and travel from Annual Reviews Genomics and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Netw Open 2019; 2: e1915374. Human Genetics, Baylor Tanzania at Texas Children’s Hospital, Harvard Medical School, WHO Afro, and Novo Nordisk. 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