Sickle Cell Anaemia

Inheritance and Variants

• Homozygosity for HbS (HbSS) leads to sickle cell anaemia, the most severe clinical form.
• Compound heterozygosity for HbS and another abnormal β-globin variant leads to milder or variant forms of SCD:
  • HbSC disease: HbS inherited from one parent and HbC (lysine substituted for glutamic acid at the same position) from the other. Common in West Africa and may present with retinal complications and fewer painful crises.
  • HbS/β-thalassaemia: Coinheritance of HbS with a β-thalassaemia mutation (either β⁰ or β⁺). HbS/β⁰ thalassaemia closely mimics HbSS disease, whereas HbS/β⁺ thalassaemia often presents more mildly.

Sickle Cell Trait (HbAS)

Clinical Implications of Subtypes

• HbSS: Severe haemolytic anaemia, frequent pain crises, high risk of complications (e.g. stroke, ACS)
• HbSC: Milder anaemia but higher risk for proliferative retinopathy
• HbS/β⁰ thalassaemia: Clinically severe, resembling HbSS
• HbS/β⁺ thalassaemia: Milder anaemia with fewer complications
• HbAS (trait): Usually benign but with noted susceptibility to specific stress-induced complications

Molecular Mechanism

• The fundamental defect in sickle cell disease is a single nucleotide substitution in the β-globin gene (GAG → GTG), resulting in the replacement of glutamic acid with valine at the sixth position of the β-globin chain.
• This substitution creates a hydrophobic patch on the haemoglobin molecule.
• Under low oxygen conditions, haemoglobin S (HbS) molecules aggregate into polymers, distorting red blood cells (RBCs) into a rigid, sickle shape.
• These sickled cells have impaired deformability, reduced lifespan, and increased tendency to occlude small vessels.

Normal and Abnormal Haemoglobin Subtypes

• Adult haemoglobin composition includes:
  • HbA1 (α₂β₂) – ~95% of normal adult haemoglobin.
  • HbA2 (α₂δ₂) – <4% of total haemoglobin.
  • HbF (α₂γ₂) – Dominant in fetal life; persists at low levels in adults.
• Elevated HbF levels are associated with reduced disease severity due to its ability to inhibit HbS polymerisation.

Genetic Inheritance and Clinical Variants

HbSS (Sickle Cell Anaemia)

• Homozygous for the HbS mutation.
• Most severe form of the disease.
• Characterised by chronic haemolytic anaemia, frequent vaso-occlusive crises, and progressive multi-organ damage.

HbAS (Sickle Cell Trait)

• Heterozygous for HbS and normal HbA.
• Generally asymptomatic but may develop complications under stress (e.g. hypoxia, dehydration, extreme exertion).

HbSC Disease

• Compound heterozygosity for HbS and HbC (substitution of lysine for glutamic acid at the same β-globin site).
• No HbA present.
• Clinical features include milder anaemia but heightened risk of complications such as proliferative retinopathy and avascular necrosis.

HbS/β-thalassaemia

• Involves co-inheritance of HbS with a β-thalassaemia allele.
  • HbS/β⁰-thalassaemia: No β-globin production; phenotype similar to HbSS.
  • HbS/β⁺-thalassaemia: Some β-globin production; results in a typically milder clinical picture.

Pathophysiological Implications

Reversibility of Sickling

• Initially, sickling is reversible with reoxygenation.
• With chronic deoxygenation and repeated sickling cycles, RBCs undergo irreversible membrane damage, leading to persistent sickled forms.

Haemolysis and Vascular Occlusion

• Sickled RBCs are fragile and undergo intravascular haemolysis.
• They also adhere to vascular endothelium, causing microvascular obstruction, ischaemia, and pain crises.

Inflammation and Systemic Effects

• These mechanisms promote chronic anaemia, systemic inflammation, and progressive organ dysfunction.

Modulating Factors

• Coinheritance of alpha thalassaemia may reduce mean corpuscular haemoglobin concentration, limiting HbS polymerisation.

HbS Polymerisation and Red Cell Deformation

• The core event in SCD pathophysiology is the polymerisation of deoxygenated HbS, which distorts red blood cells into a rigid, crescent (sickle) shape.
• Triggers for polymerisation include hypoxia, acidosis, dehydration, and increased HbS concentration.
• The sickling is initially reversible but becomes permanent with repeated deoxygenation-reoxygenation cycles, leading to persistent membrane damage and reduced RBC deformability.

Vaso-Occlusion and Endothelial Interaction

• Sickled RBCs adhere to the vascular endothelium through upregulated adhesion molecules, contributing to microvascular occlusion.
• Neutrophils, platelets, free haemoglobin, and reactive oxygen species (ROS) also interact with endothelial surfaces, amplifying inflammation and thrombosis.
• Repeated episodes of vaso-occlusion result in tissue ischaemia, pain crises, and progressive organ damage.

Oxidative Stress and Nitric Oxide Dysregulation

• Oxidative injury stems from auto-oxidation of HbS and heightened ROS production due to altered expression of xanthine dehydrogenase/oxidase and diminished NADPH oxidase activity.
• Lysis of RBCs releases cell-free haemoglobin and arginase-1 into the circulation. Haemoglobin scavenges nitric oxide (NO), while arginase competes with nitric oxide synthase for L-arginine.
• The resulting NO deficiency impairs vasodilation, increases vascular tone, and predisposes to pulmonary hypertension and endothelial dysfunction.

Chronic Haemolysis

• Haemolysis is both intravascular and extravascular, contributing to chronic anaemia.
• Persistent anaemia increases cardiac output, potentially causing cardiomegaly and high-output cardiac failure, especially in severe cases or during crises like splenic sequestration or aplastic episodes.

Inflammatory State

• SCD represents a chronic inflammatory state, with heightened activation of granulocytes and monocytes.
• Inflammatory mediators further exacerbate endothelial damage and promote vaso-occlusive events.
• Triggers for crises include infections, acidosis, cold exposure, physical exertion, and psychological stress.

Splenic and Immune Dysfunction

• Early-life vascular occlusion in the spleen leads to progressive infarction and functional asplenia.
• This significantly compromises immunity, particularly against encapsulated bacteria, thereby increasing susceptibility to life-threatening infections.

Clinical Variability and Genetic Modifiers

• Clinical expression is highly variable and influenced by:
  • HbF levels: Higher concentrations inhibit HbS polymerisation and ameliorate disease severity.
  • Coinheritance of alpha-thalassaemia: Reduces intracellular HbS concentration and lowers the frequency of sickling.
• Some individuals may remain asymptomatic into adolescence, especially those with protective genetic modifiers.

Sickle Cell Trait (HbAS)

• Individuals with sickle cell trait usually remain clinically unaffected but are at increased risk of complications such as:
  • Pulmonary embolism
  • Exertional rhabdomyolysis
  • Renal complications including haematuria, proteinuria, and progression to chronic kidney disease and end-stage renal failure.

Global and Regional Distribution

• Sub-Saharan Africa bears the overwhelming majority of the global burden. As of 2010, it was estimated that approximately 230,000 children were born with sickle cell anaemia (SCA) and more than 3.5 million with HbAS in this region, accounting for over 75% of global SCD births.
• West Africa has particularly high rates of HbSC disease.
• In India, Saudi Arabia, the Middle East, and the Mediterranean, specific ethnic populations exhibit high SCD prevalence due to similar selective pressures.
• Migration patterns, including the trans-Atlantic slave trade, have distributed the haemoglobin S gene widely across the Americas and Europe.

Trends in Disease Burden

• Global estimates indicate a 13.7% increase in annual births with SCD from 2000 to 2021, reaching approximately 515,000.
• The total number of people living with SCD grew by 41.4% over the same period, with an estimated 7.74 million people affected globally in 2021.
• Specific-cause mortality directly attributed to SCD was estimated at 34,400 deaths in 2021, but the broader mortality burden (including indirect causes) reached approximately 376,000 deaths, most of which occurred in children under five years of age.

Country-Specific Data

United States

• Around 100,000 individuals live with SCD, with the vast majority being of African-American descent.
• SCD affects 1 in 365 African-American births.
• Sickle cell trait (HbAS) is present in about 1 in 13 African-American infants.
• HbSC disease accounts for roughly 30% of SCD cases.
• Approximately 40% of the affected population comprises children and adolescents.
• Incidence and distribution vary by region due to internal migration and immigration.

United Kingdom

• Estimated 14,000 individuals live with SCD.
• In England, more than 1 in 2,000 live births are affected.

Brazil and other parts of South America

• Genetic studies link the origin of affected individuals to the West African slave trade (especially from the Mina Coast and Angola).

Impact of Socioeconomic Disparities

• In high-income countries, advances in newborn screening, prophylactic interventions (e.g., penicillin, pneumococcal vaccination), and disease-modifying therapies have dramatically reduced childhood mortality. A 68% reduction in SCD mortality in children aged 0–4 years was observed between 1999 and 2002 compared to 1983–1986.
• Low-income countries still face extremely high childhood mortality rates, with 50–90% of children with SCD dying before the age of five due to lack of early diagnosis, supportive care, and infection control measures.
• Even in wealthier countries, life expectancy for individuals with SCD lags significantly behind the general population. For example, projected life expectancy in SCD is about 54 years compared to 76 years in matched non-SCD individuals, with a quality-adjusted life expectancy of 33 versus 67 years.

Onset and Phenotypic Variation

• Delayed clinical onset: Patients with homozygous HbSS typically remain asymptomatic for the first 6–9 months of life due to the protective effects of fetal haemoglobin (HbF).
• Phenotypic diversity: SCD manifestations vary considerably, influenced by levels of HbF and co-inheritance of genetic modifiers such as alpha thalassaemia.

Clinical Subphenotypes to Elicit from History

Vaso-occlusive (VOC) subphenotype

• History of frequent painful crises.
• Usually associated with higher haematocrit, leading to increased blood viscosity.
• Common sites include extremities, chest, back, and abdomen.

Haemolysis–vascular subphenotype

• Features include more severe anaemia, jaundice, dark urine, and prior diagnoses of gallstones or pulmonary hypertension.
• Risk of priapism, stroke, and nephropathy should be explored.
• Patients often have elevated bilirubin and lactate dehydrogenase (LDH) levels.

High HbF subphenotype

• May correlate with fewer crises and milder disease.
• Ask about baseline HbF levels if known, or whether the disease has remained mild.

Pain-sensitive phenotype

• Some patients have a heightened pain response despite similar haematological parameters.
• Important to understand the patient’s personal pain experience, prior pain episodes, and baseline coping mechanisms.

Key Elements to Include in the History

Frequency and pattern of pain crises

• Earliest onset of VOC (e.g. dactylitis before age 2).
• Recent pain episodes, their locations, duration, triggers, and treatments.
• Number of hospitalisations for pain in the past year.

Pain management history

• Regular or as-needed analgesic use.
• Opioid and non-opioid use, including dose, timing of last dose, and efficacy.
• Previous use of patient-controlled analgesia (PCA).

History of disease-modifying therapy

• Hydroxyurea, voxelotor, crizanlizumab, or L-glutamine.
• Duration of therapy, side effects, and adherence.

Transfusion history

• Frequency and indication (e.g. ACS, stroke prophylaxis, chronic anaemia).
• History of alloimmunisation or transfusion reactions.
• Iron overload concerns or current chelation therapy.

Complication history

• Prior events such as stroke, acute chest syndrome, splenic sequestration, priapism, or aplastic crises.
• History of infections, particularly pneumococcal or salmonella osteomyelitis.

Other medical and psychiatric comorbidities

• Depression, anxiety, or substance use disorders.
• Use of psychotropic medications.

Growth and development

• In children, inquire about school performance, growth delay, or pubertal development.

Surgical history

• Splenectomy, cholecystectomy, hip arthroplasty for avascular necrosis, or any surgical complications.

Family history and genetic counselling

• Parental carrier status.
• Siblings with SCD or known complications.
• Use of reproductive planning or prenatal screening.

Coordination of care

• Involvement of a haematologist or SCD clinic.
• Existence of an established care plan or emergency protocol.

Previous life-threatening episodes

• Inquire specifically about episodes of fat embolism, severe ACS, or cardiovascular collapse, especially during acute pain crises.

Relevant History Indicators of SCD Complications

• Dactylitis (hand–foot syndrome): Often the first manifestation in infancy.
• Fever: Can signal serious infections or evolving acute chest syndrome; prompt investigation is crucial.
• Bone pain or previous avascular necrosis: Common in older children and adults; assess mobility and joint pain.
• Visual disturbances: Floaters or vision changes may indicate sickle retinopathy.
• Splenic sequestration: Past episodes of pallor, lethargy, abdominal fullness, or shock.
• Chronic symptoms: Fatigue, failure to thrive, pallor, jaundice, and breathlessness.
• Signs of organ dysfunction: History of renal impairment, proteinuria, or priapism.

General

Vital signs

• Fever (>38.5°C) may indicate infection or acute chest syndrome (ACS).
• Tachypnoea and hypoxia may suggest ACS or severe anaemia.
• Tachycardia, hypotension, and lethargy can reflect haemolysis, splenic sequestration, or impending shock.

General appearance

• Pallor is a sign of anaemia or sequestration.
• Jaundice suggests ongoing haemolysis.
• Failure to thrive or growth delay may be noted in infants and children with chronic anaemia and hypermetabolism.

System-Specific Findings

Musculoskeletal

• Dactylitis (hand-foot syndrome):
  • Swelling of the dorsal surfaces of hands and feet, often the first clinical manifestation in infants, typically seen from six months of age.
  • Associated with worse prognosis when onset occurs early.
• Bone tenderness or joint limitation:
  • Suggests bone infarction or avascular necrosis (particularly femoral head).
  • Present in up to 40% of adults with HbSS or HbSC genotypes.

Respiratory

• Chest examination:
  • Crackles or reduced breath sounds may indicate ACS.
  • Rapid respiratory rate and use of accessory muscles may signify respiratory distress.

Cardiovascular

• Systolic flow murmur:
  • Common in infants and children due to hyperdynamic circulation from anaemia.
• Signs of heart failure:
  • Especially in those with chronic anaemia or cardiomegaly; look for displaced apex beat, gallop rhythm, or peripheral oedema.

Abdominal

• Hepatosplenomegaly:
  • A rapidly enlarging spleen in children may suggest acute splenic sequestration.
  • Protuberant abdomen with splenic or hepatic enlargement is common in infants.
• Tender right upper quadrant:
  • May indicate hepatic sequestration or gallbladder disease (e.g., cholelithiasis).

Neurological

• Altered consciousness, slurred speech, or unilateral weakness:
  • Red flags for acute ischaemic stroke.
• Visual disturbances:
  • Ask about and examine for visual floaters; fundoscopy may reveal proliferative retinopathy or retinal haemorrhage.

Head and Neck

• Maxillary hypertrophy with dental overbite:
  • Seen in children with chronic marrow expansion due to ineffective erythropoiesis.

Skin

• Leg ulcers
  • More common in adolescents and adults; chronic and often located near the malleoli.

Red Flags Suggestive of Acute Life-Threatening Events

• Signs of shock (cold extremities, low BP, delayed capillary refill): Suspect splenic sequestration or fat embolism.
• Sudden respiratory deterioration: Suggests ACS.
• Neurological deficit: Needs urgent evaluation for stroke.
• Visual loss or proptosis: May indicate orbital infarction or retinal complications.

Phenotypic Clues on Examination

• High haematocrit patients (VOC subtype):
  • May exhibit more pain crises without signs of severe anaemia.
• Low haematocrit patients (haemolysis-vascular subtype):
  • Likely to show pallor, jaundice, gallbladder tenderness, and signs of pulmonary hypertension or priapism.
• High HbF subtype:
  • Often minimal findings on physical exam despite known diagnosis.

Diagnostic Confirmation

Newborn Screening and Early Detection

• Haemoglobin isoelectric focusing (Hb IEF) and high-performance liquid chromatography (HPLC) are routinely used in newborn screening.
  • HbF predominates in neonates; HbS levels increase as HbF declines by age 2.
  • No HbA is found in HbSS disease.
• Solubility testing is a preliminary screen in older children/adults but cannot distinguish trait from disease and is unreliable in infants under 6 months.
• Cellulose acetate electrophoresis at alkaline pH helps classify haemoglobin types in older children and adults.

Molecular Techniques

• DNA-based assays confirm ambiguous results or are used for antenatal diagnosis.
  • Detects mutations and differentiates compound heterozygous states (e.g., HbS/β-thalassaemia).
  • Superior reliability compared to protein-based assays in complex cases.

Peripheral Blood Analysis

Peripheral blood smear

• Identifies characteristic features: sickle cells, nucleated RBCs, Howell-Jolly bodies.
• Target cells seen in HbSC; may also show polychromasia, anisopoikilocytosis.

Full blood count (FBC) and reticulocyte count

• Baseline anaemia common; reticulocyte count usually elevated unless bone marrow suppression occurs (e.g., aplastic crisis).
• Reticulocytopenia (<1%) strongly suggests parvovirus B19-induced aplasia.

Iron studies

• Distinguish between haemolytic and iron-deficiency anaemia.
• Elevated serum ferritin and transferrin saturation suggest iron overload, often due to chronic transfusion.

Acute Complication Evaluation

Acute Chest Syndrome (ACS)

• Clinical features: cough, dyspnoea, chest pain ± fever.
• Investigations:
  • Chest X-ray: new infiltrates (defining feature).
  • Pulse oximetry: detects hypoxia; desaturation may precede radiographic changes.
  • Blood cultures, sputum cultures, and inflammatory markers to rule out infection.

Splenic/Hepatic Sequestration

• Sudden organ enlargement with anaemia.
• FBC: marked drop in haemoglobin (>2 g/dL), elevated reticulocytes, nucleated RBCs.
• Clinical exam confirms hepatosplenomegaly; no routine imaging needed unless ruling out abscess.

Stroke

• Transcranial Doppler (TCD): screening tool in children to detect elevated cerebral flow velocities.
• MRI/MRA and CT head: for acute stroke diagnosis in symptomatic patients.

Aplastic Crisis

• Sudden severe anaemia with low reticulocyte count.
• Bone marrow biopsy (if unclear): arrest at pro-normoblast stage.

Infections

• Blood, urine, and stool cultures are essential in febrile patients.
• Consider Salmonella and Staphylococcus aureus in suspected osteomyelitis.
• Plain X-rays: assess for bone infarction vs. infection.

Ocular Events

• CT orbit: useful in orbital infarction.
• MRI orbit: indicated for orbital apex syndrome.
• Tonometry: for raised intraocular pressure in hyphema.
• Ophthalmologic review is essential in suspected central retinal artery occlusion (CRAO) or retinal neovascularisation.

Evaluation of Chronic Complications

Iron Overload

• Serum ferritin, liver iron concentration (LIC) via MRI or biopsy.
• Iron overload commonly affects the liver, heart, and endocrine organs.

Avascular Necrosis (AVN)

• MRI is the most sensitive imaging for early AVN.
• X-ray: may show late-stage joint collapse.

Pulmonary Hypertension

• Echocardiography to estimate tricuspid regurgitant velocity (TRV).
• NT-proBNP levels correlate with severity.
• Right heart catheterisation for definitive diagnosis.

Renal Function

• Microalbuminuria (30–300 mg/24 h): early CKD marker.
• Serum creatinine is an unreliable early marker due to tubular hypersecretion.
• Urine dipstick or 24-hour collection preferred for proteinuria evaluation.

Ophthalmologic Screening

• Annual eye exams to monitor for proliferative sickle retinopathy.
• Fundoscopy, slit-lamp biomicroscopy, and fluorescein angiography may be indicated.
• Laser photocoagulation considered in proliferative disease.

Haemoglobinopathies Mimicking or Coexisting with SCD

• HbS/β⁰-thalassaemia: Phenotypically indistinguishable from sickle cell anaemia (HbSS); confirmed via haemoglobin analysis and DNA-based testing.
• HbSC disease: A milder genotype of SCD that can still result in serious complications (e.g. retinopathy, AVN).
• HbS/β⁺-thalassaemia: Milder than HbSS; patients typically retain some haemoglobin A (HbA).
• Other rare haemoglobin variants (when co-inherited with HbS):
  • Hb D-Punjab, Hb O-Arab, Hb E
  • Hb Jamaica-Plain, Hb Quebec-Chori
     These can cause sickling under stress conditions and require electrophoretic or molecular confirmation.

Alternative Causes of Haemolysis

Autoimmune haemolytic anaemia

• Distinguished by a positive direct Coombs test.
• Can be warm (IgG-mediated) or cold (IgM-mediated).

Paroxysmal nocturnal haemoglobinuria (PNH)

• Characterised by intravascular haemolysis, thrombosis, and pancytopenia.
• Diagnosed with flow cytometry detecting GPI-anchored protein deficiencies.

RBC membrane disorders

• Hereditary spherocytosis, elliptocytosis: Detected on peripheral smear, confirmed with osmotic fragility or EMA binding tests.

Enzyme deficiencies

• G6PD deficiency or pyruvate kinase deficiency: Suspected with haemolysis triggered by drugs, infections, or fava beans; confirmed by enzyme activity assays.

Microangiopathic haemolytic anaemia

• Includes thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS).
• Diagnosed by the presence of schistocytes on smear, thrombocytopenia, and organ dysfunction.

Infectious haemolysis

• Caused by malaria, babesiosis, rickettsial infections, Clostridium, or Bartonella.
• Diagnosed with blood smears, PCR, or serological tests.

Musculoskeletal and Joint Disorders

Osteomyelitis

• Commonly affects long bones in SCD; difficult to distinguish from bone infarction.
• Favour osteomyelitis if pain is localised and febrile, with positive blood cultures (Salmonella, Staphylococcus aureus).
• MRI or bone scans may aid diagnosis.

Avascular necrosis (AVN)

• Chronic joint pain, especially in the hip or shoulder.
• MRI reveals characteristic findings but cannot differentiate SCD-related AVN from other causes.

Gout

• Can occur secondary to renal impairment in SCD.
• Confirmed with joint aspiration (monosodium urate crystals).

Septic arthritis

• Suspected with fever and monoarthritis; confirmed with purulent joint aspirate and culture.

Connective tissue diseases

• Systemic lupus erythematosus (SLE) and rheumatoid arthritis may mimic joint symptoms of SCD.
• Diagnosed with serological markers (ANA, RF).

Legg-Calvé-Perthes disease

• Osteonecrosis of femoral head in children aged 4–10.
• Differentiated from sickle-related AVN via clinical context and imaging.

Abdominal and Systemic Conditions

Acute abdomen

• Vaso-occlusive crises may mimic cholecystitis or pancreatitis.
• Ultrasound and lipase/amylase levels help differentiate true surgical causes.

Iron deficiency anaemia

• May coexist with SCD.
• Identified by low serum ferritin, transferrin saturation, and microcytic indices.

Parvovirus B19 infection

• May trigger aplastic crisis in SCD patients.
• Presents with low haemoglobin and reticulocyte count, and characteristic "slapped cheek" rash.

Trauma

• Pain may mimic sickle crises; imaging is necessary, especially in non-verbal children.

Ocular and Neurological Conditions

Orbital infarction vs orbital cellulitis

• Orbital pain, proptosis, reduced motility; differentiated via CT scan.

Retinal artery/vein occlusion

• Sudden vision loss due to sickling in retinal vasculature; requires fundoscopic evaluation.

Central nervous system events

• Stroke in SCD must be distinguished from other causes (e.g., vasculitis, CNS infection, thrombophilia).

Core Management Principles

General Framework

• Paediatric focus: Prevent early mortality through infection control.
• Adult focus: Manage chronic complications and reduce morbidity.
• Holistic care: Includes education, psychosocial support, and trigger avoidance (e.g. dehydration, cold exposure, high altitudes, and overexertion).

Key Treatment Objectives

• Infection prevention (vaccination, prophylactic antibiotics).
• Reduction in pain crises.
• Prevention and management of organ damage (renal, pulmonary, hepatic).
• Stroke prevention.
• Genetic counselling and nutritional guidance.
• Use of disease-modifying and curative therapies.

Pharmacological Interventions

Hydroxycarbamide (Hydroxyurea)

• Recommended from age ≥2 years in HbSS or HbS/β⁰-thalassaemia.
• Increases fetal haemoglobin (HbF), reducing crisis frequency, transfusion need, ACS episodes, and stroke risk.
• Most common complication: neutropenia.
• Safe in paediatric populations for growth and development; however, long-term safety remains under review.
• Limited evidence for use in HbSC disease.

L-Glutamine

• Indicated for patients ≥5 years intolerant to or uncontrolled on hydroxycarbamide.
• Reduces oxidative stress in sickled RBCs.
• Decreases crisis frequency and hospitalisation rates.
• Avoid in hepatic or renal impairment; not licensed in all regions.

Crizanlizumab

• A monoclonal antibody targeting P-selectin to reduce VOC frequency.
• Approved for patients ≥16 years; used alone or with hydroxycarbamide.
• Effective across genotypes including HbSC.
• EMA authorisation withdrawn pending further trial results.
• Common side effects: arthralgia, gastrointestinal upset, chest pain.

Voxelotor

• First-in-class HbS polymerisation inhibitor.
• Withdrawn in 2024 due to safety concerns.

Blood Transfusion Strategies

• Indications: Stroke prevention, ACS, severe anaemia, surgery, pregnancy complications.
• Chronic transfusions: Maintain HbS <30%.
• Preoperative transfusion: Effective at Hb ≥100 g/L; exchange transfusions may be required for HbSC.
• Stroke prevention: Chronic transfusion reduces first stroke risk by 90%.
• Alloimmunisation prevention:
  • Use ABO, D, CcEe, and K-matched RBCs.
  • Extended antigen matching recommended for patients with alloantibodies.

Special Considerations

Pregnancy

• Prophylactic transfusions not routine but may benefit high-risk pregnancies.
• Indications: severe anaemia, prior obstetric complications, multiple gestation.
• Transfusion associated with reduced maternal and perinatal morbidity.

Haematopoietic Stem Cell Transplant (HSCT)

• Currently the only curative treatment.
• Indicated in: stroke history, recurrent ACS, or severe VOC despite standard care.
• Matched sibling donors preferred; alternative donors under investigation in trials.
• Outcomes improve when performed at younger ages.
• Conditioning regimens vary: myeloablative preferred in children; non-myeloablative in adults.
• Long-term data are limited; risks include graft rejection and treatment-related toxicity.

Management of Acute Events

Vaso-Occlusive Crisis (VOC)

• Pain management: Paracetamol/NSAIDs for mild pain; opioids for moderate to severe pain.
  • Patient-controlled analgesia (PCA) can be effective.
  • Avoid delay; reassess every 30–60 minutes.
• Hydration: Correct dehydration with oral or IV fluids; adjust for cardiac comorbidities.
• Oxygen: For hypoxaemic patients (O₂ saturation <95% or PaO₂ <70 mmHg).
• Antibiotics: If infection suspected.

Acute Chest Syndrome (ACS)

• Defined by new infiltrate plus symptoms such as fever, cough, or hypoxia.
• Treatment:
  • Oxygen therapy
  • Broad-spectrum IV antibiotics (typical + atypical coverage)
  • Simple or exchange transfusion (indicated in low PaO₂ or multi-lobar pneumonia)
  • Incentive spirometry and pain control to prevent atelectasis
  • ICU admission in severe cases

Chronic Pain and Supportive Measures

• Chronic daily pain: Affects many adults; requires individualised pain plans.
  • Referral to pain specialists encouraged.
  • Consider non-opioid strategies (psychological support, physiotherapy).
• Psychosocial interventions: Address stigma, mental health, and adherence barriers.

Historical and Current Survival Estimates

• The Cooperative Study of Sickle Cell Disease (CSSCD), conducted between 1978–1988, reported median survival ages of 42 years for women and 48 years for men with sickle cell anaemia (HbSS).
• More recent data from US public health insurance registries (2008–2016) estimated a life expectancy of 52.6 years at birth for individuals with SCD. Women had longer life expectancy (55.0 years) than men (49.3 years), and non-Black individuals had marginally higher survival than Black individuals.
• In Africa, where access to early screening and comprehensive care is limited, 50% to 90% of children with SCD die before the age of five.

Influence of Genotype on Prognosis

• HbSS (sickle cell anaemia) is associated with the most severe disease and shortest survival. A 2014 US-based study reported median survival of 58 years.
• HbSC disease, though milder, is not benign; it was associated with median survival of 66 years in the same study.
• Individuals with HbS/β⁺-thalassaemia tend to have longer life expectancy compared to those with HbSS or HbS/β⁰-thalassaemia.

Prognostic Factors for Mortality

• Acute complications: Acute chest syndrome (ACS), seizures, and stroke.
• Chronic complications: Renal failure, pulmonary hypertension, and chronic haemolysis.
• Cardiopulmonary parameters:
  • Elevated tricuspid regurgitant jet velocity (TRV ≥2.5 m/s) on echocardiogram.
  • Raised N-terminal pro-brain natriuretic peptide (NT-proBNP).
  • Prolonged QTc interval on ECG.
• Hematological markers:
  • High leukocyte count.
  • Low fetal haemoglobin (HbF) levels.
  • Increased reticulocyte count as a marker of marrow stress.
• History of asthma or wheezing.
• End-stage renal disease requiring dialysis.

Impact of Modern Therapeutics

• Approval and use of hydroxycarbamide, crizanlizumab, and L-glutamine have reduced the frequency of vaso-occlusive crises, acute chest syndrome, and hospitalisations.
• Hematopoietic stem cell transplantation (HSCT) has emerged as a curative option for select patients.
• Gene therapy and gene editing technologies are under investigation and hold promise for long-term disease control or cure.
• With these advancements, a continued increase in both survival and quality of life is expected, particularly in high-resource settings.

Global Disparities in Prognosis

• In high-income countries, more than 90% of patients survive beyond 20 years of age, and an increasing number reach age 50 or older.
• In contrast, the mortality burden remains highest in sub-Saharan Africa, where neonatal screening, vaccination, prophylactic antibiotics, and access to hydroxycarbamide are limited.

Acute Complications

Acute Chest Syndrome (ACS)

• Leading cause of mortality.
• Presents with fever, chest pain, hypoxia, and new pulmonary infiltrates.

Splenic or Hepatic Sequestration

• Sudden pooling of blood in spleen or liver, leading to acute anaemia.
• More frequent in young children.

Fat Embolism Syndrome

• Rare but often fatal.
• Characterised by respiratory distress, neurological signs, and multiorgan failure.

Bone Infarction/Necrosis

• Severe pain episodes affecting long bones.
• Clinically resembles osteomyelitis, making differentiation challenging.

Stroke and CNS Events

• Includes both overt stroke and silent cerebral infarctions.
• More common in children with HbSS; silent infarcts increase cognitive morbidity.

Coagulopathy and Thromboembolism

• Increased risk of arterial and venous events, including myocardial infarction and pulmonary embolism.

Aplastic Crisis

• Often triggered by parvovirus B19.
• Results in profound anaemia with reticulocytopenia.

Papillary Necrosis

• Infarction of renal papillae, presenting with painless haematuria.

Ocular Vaso-Occlusion

• Can cause retinal artery/vein occlusion, vitreous haemorrhage, and retinal detachment.

Chronic Complications

Growth and Development

• Delayed growth and puberty, especially in males.
• Due to chronic anaemia and elevated metabolic demands.

Cardiopulmonary

• Cardiomegaly, arrhythmias, and heart failure from chronic high-output states.
• Pulmonary hypertension associated with elevated tricuspid regurgitant velocity (TRV); linked to reduced exercise tolerance and early mortality.
• Pulmonary oedema and sickle cell lung disease may result from repeated ACS and interstitial fibrosis.

Hepatobiliary

• Hepatomegaly, intrahepatic cholestasis, and viral hepatitis are common.
• Cholelithiasis occurs in up to 70% due to chronic haemolysis.
• Laparoscopic cholecystectomy is a safe and effective intervention.

Splenic

• Splenomegaly in early childhood, progressing to autosplenectomy due to repeated infarction.
• Splenectomised individuals are at high risk for overwhelming pneumococcal infection.

Renal

• Hypoesthenuria: Reduced ability to concentrate urine, leading to polyuria and nocturia.
• Proteinuria and chronic kidney disease (CKD): Annual urine albumin screening recommended.
• ACE inhibitors help reduce proteinuria.
• Renal medullary carcinoma: Rare but aggressive; more common in patients with HbSC or sickle cell trait.

Musculoskeletal

• Avascular necrosis (AVN): Common in hips and shoulders; causes chronic pain and disability.
• Osteomyelitis: Frequently caused by Salmonella or Staphylococcus aureus.
• Osteopenia and osteoporosis: Related to chronic inflammation and corticosteroid exposure.

Neurologic

• Silent cerebral infarcts: Most frequent neurological injury; increases stroke risk and cognitive decline.
• Cognitive impairment: More evident in adults with severe anaemia and prior infarcts.

Ophthalmic

• Proliferative sickle retinopathy: Neovascularisation leads to vitreous haemorrhage and blindness.
• Annual eye exams starting at age 10 are advised.
• Laser photocoagulation is indicated for proliferative lesions.

Endocrine

• Primary hypogonadism, hypothalamic dysfunction, and pituitary insufficiency.
• May result in delayed puberty and infertility.

Iron Overload

• Caused by recurrent transfusions and chronic haemolysis.
• Screening: Ferritin levels, liver MRI, and echocardiography.
• Chelation therapy: Options include Desferrioxamine (IV), Deferiprone, and Deferasirox (oral).

Leg Ulcers

• Affect ~2.5% of older children and adults.
• Chronic, painful, and prone to secondary infection.

Priapism

• Occurs in ~90% of males aged 12–20.
• Episodes lasting >4 hours require urgent intervention.
• Managed with hydration, analgesia, and urological procedures for decompression.

Opioid Use Disorder

• Long-term opioid therapy for chronic pain can lead to dependence, tolerance, and psychosocial burden.

Less Common but Important Complications

Transient Red Cell Aplasia

• Often due to viral infection (e.g. parvovirus B19).
• Causes acute anaemia with low reticulocyte count.

Invasive Pneumococcal Disease

• Risk reduced with vaccination and penicillin prophylaxis, especially in young children.

Rhabdomyolysis

• Reported in sickle trait carriers after extreme exertion or heat exposure.

Malaria

• Protective advantage in sickle cell trait.
• When infection occurs, it may present more severely in patients with sickle cell disease.

1. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of haematologic malignancies. Blood. 2013;121(18):3563–3572.
2. Aizawa S, Kanakura Y, Shibayama H, et al. Characteristics of polycythemia vera and essential thrombocythemia in Japanese patients: a retrospective study. Int J Hematol. 2008;88(2):212–218.
3. Alvarez-Larrán A, Cervantes F, Pereira A, et al. Observation versus cytoreductive therapy in polycythemia vera: thrombosis risk in 265 patients. Blood. 2006;108(10):3302–3307.
4. Alvarez-Larrán A, Pereira A, Guglielmelli P, et al. Risk factors for thrombosis in polycythemia vera. Leukemia. 2016;30(1):170–173.
5. Anía BJ, Suman VJ, Sobell JL, et al. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935–1989. Am J Hematol. 1994;47(2):89–93.
6. Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, et al. Increased platelet and leukocyte activation in primary myelofibrosis. Ann Hematol. 2006;85(12):888–893.
7. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations. J Clin Oncol. 2011;29(6):761–770.
8. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647–3656.
9. Ballas SK, Lieff S, Benjamin LJ, et al. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol. 2010;85(1):6–13.
10. Ballas SK, Marcolina MJ. Hypercoagulability and thrombosis in hemoglobinopathies. Hematol Oncol Clin North Am. 2005;19(5):939–956.
11. Centers for Disease Control and Prevention (CDC). Sickle Cell Disease (SCD). https://www.cdc.gov/ncbddd/sicklecell/index.html
12. Collaborators GBD Sickle Cell. Global, regional, and national burden of sickle cell anaemia, 2000–2021, and projections to 2050: a systematic analysis. Lancet Haematol. 2023;10(3):e173–e185.
13. Davies SC, Oni L. Management of sickle cell disease. BMJ. 1997;315(7109):656–660.
14. Eaton WA. Linus Pauling and sickle cell disease. Biophys Chem. 2003;100(1-3):109–116.
15. Elliott MA, Tefferi A. Pathogenesis, clinical features, and management of essential thrombocythemia. Hematol Oncol Clin North Am. 2003;17(6):177–188.
16. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350(9):886–895.
17. Grinfeld J, Nangalia J, Baxter EJ, et al. Classification and personalised prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379(15):1416–1430.
18. Grunwald MR, Makam S, Griffith ML, et al. National practice patterns of polycythemia vera treatment in the United States. Am J Hematol. 2021;96(7):792–800.
19. Hasselbalch HC, Bjørn ME. MPNs as inflammatory diseases: the evidence, consequences, and perspectives. Mediat Inflamm. 2015;2015:102476.
20. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–1148.
21. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
22. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22–33.
23. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders. Haematologica. 2007;92(12):1701–1702.
24. Michiels JJ, Berneman ZN, Schroyens WA, et al. Pathogenesis and diagnosis of erythromelalgia in thrombocythemia. Ann Hematol. 2004;83(7):395–402.
25. Naoum PC. Sickle cell disease: from the beginning until it was recognised as a public health disease. Rev Bras Hematol Hemoter. 2011;33(1):7–9.
26. Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601–612.
27. Passamonti F, Griesshammer M, Palandri F, et al. Comparing symptoms and quality of life in patients with polycythemia vera: results from the CYTO-PV and RESPONSE trials. Haematologica. 2020;105(1):91–100.
28. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease—life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639–1644.
29. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018–2031.
30. Rosenthal DS, Stoddard L, Galperin I, et al. Clinical burden and quality of life in patients with polycythemia vera. J Med Econ. 2019;22(12):1279–1287.
31. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013;3(10):a011783.
32. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100(13):4272–4290.
33. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874–1881.
34. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667–679.
35. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med. 2000;342(25):1855–1865.