Sickle cell disease
Description
- HBB point mutation, chromosome 11: glutamate -> valine at codon 6 -> haemoglobin S
- Deoxygenated HbS is poorly soluble -> polymerises -> rigid sickled cell
Genotypes
| Severity | |
|---|---|
| HbSS (sickle cell anaemia) | Most severe; ~60-70% of disease |
| HbS/beta0-thal | Equivalent to SS |
| HbSC | Milder anaemia but more retinopathy, avascular necrosis, and proliferative eye disease; larger spleen retained |
| HbS/beta+-thal | Mild-moderate |
| HbAS (trait) | *Not a disease* |
Two pathological arms
- Vaso-occlusion - adhesion, inflammation, ischaemia-reperfusion -> pain, acute chest, stroke, organ infarction
- Haemolysis - free plasma Hb scavenges NO -> endothelial dysfunction, pulmonary hypertension, priapism, leg ulcers
- Different complications track with different arms - HbSC sits at the vaso-occlusive end
Epidemiology
- ~300,000 affected births/yr worldwide; commonest severe monogenic disorder
- Sub-Saharan Africa, Middle East, India, Mediterranean, Caribbean
- HbAS trait protects against severe falciparum malaria - the selection pressure
- Australia: uncommon, concentrated in African and Middle Eastern migrant communities
- No universal newborn screening for haemoglobinopathy in most Australian jurisdictions - diagnosis is often late
Aetiopathogenesis
Polymerisation
- Determined by degree of deoxygenation, intracellular HbS concentration and HbF level
- HbF blocks polymerisation - it cannot enter the HbS polymer
- Protection depends on the proportion of cells containing HbF, per-cell HbF amount, and selective survival of HbF-containing reticulocytes
- This is why hydroxyurea works, and why disease is silent until HbF falls at 3-6 months
- Co-inherited alpha-thalassaemia is protective - dec MCHC -> less polymerisation
- But higher Hb -> more viscosity -> more retinopathy and avascular necrosis
Downstream
- Repeated sickling -> membrane damage, dehydration (Gardos channel, K-Cl cotransport) -> irreversibly sickled cells
- inc adhesion to endothelium (P-selectin, VCAM-1), neutrophil and platelet activation -> microvascular occlusion
- Chronic haemolysis (RBC survival ~10-20 days) -> NO scavenging, arginine depletion
- Autosplenectomy from repeated infarction - functionally asplenic by 5 years in HbSS
Crisis precipitants
- Hypoxia, dehydration, infection/fever, cold, acidosis, high altitude, extreme heat, pregnancy, alcohol, stress, menstruation
- Often none identifiable
Diagnosis
Screening and confirmation
- HPLC or capillary electrophoresis - quantifies HbS, HbF, HbA2, HbC
- Sickle solubility test screens but cannot distinguish trait from disease - always confirm with HPLC
- Genotyping where phenotype ambiguous; family/partner testing
Baseline steady state
- Hb 60-90 g/L (SS), reticulocytosis, inc bilirubin, inc LDH, dec haptoglobin
- Film: sickle cells, target cells, Howell-Jolly bodies (hyposplenism), nucleated RBC
- Establish each patient's steady-state Hb and reticulocyte count - acute assessment is meaningless without it
Acute chest syndrome
- New pulmonary infiltrate + at least one of: fever, chest pain, hypoxaemia, tachypnoea, wheeze, cough
- Multifactorial: infection, pulmonary infarction, fat embolism from marrow necrosis, hypoventilation from pain, atelectasis, opioid-induced hypoventilation
- *Second commonest cause of admission and the leading cause of death - deteriorates rapidly, often 24-72 h after admission for pain*
Distinguish the anaemic crises
| Reticulocytes | Spleen | Cause | |
|---|---|---|---|
| Aplastic crisis | Very low | Normal | Parvovirus B19 (also EBV, pneumococcus, Salmonella). Recovers 2-14 days |
| Splenic sequestration | High | Rapidly enlarging, tender | Infants/young children (or any age in HbSC). Hypovolaemic shock |
| Hyperhaemolytic crisis | High | Variable | Often delayed haemolytic transfusion reaction - Hb falls below pre-transfusion level |
Screening programme
- Transcranial Doppler annually from age 2-16 in HbSS/HbS-beta0 - time-averaged mean velocity >=200 cm/s = high stroke risk
- Annual retinal review (especially HbSC), urinalysis for albuminuria, echo (TRV >2.5 m/s -> further assessment), BP, DEXA, ferritin
Management
A. Acute vaso-occlusive pain
- *Analgesia within 30 minutes of arrival; reassess within 30 minutes*
- Strong opioid (IV/SC morphine or hydromorphone; PCA) + regular paracetamol + NSAID if renal function allows
- Pain is not proportional to signs. Under-treatment and pejorative labelling are the standard failures of care
- Oxygen only if hypoxic; keep warm; oral or IV maintenance fluids (avoid over-hydration - precipitates acute chest)
- Incentive spirometry every 2 hours while awake - prevents acute chest syndrome
- VTE prophylaxis; laxatives; screen for infection
- *Transfusion does NOT treat uncomplicated painful crisis*
B. Acute chest syndrome
- Oxygen, analgesia (enough to allow deep breathing, not so much as to hypoventilate), incentive spirometry, bronchodilator
- Antibiotics covering atypicals - macrolide + cephalosporin
- Transfuse: simple if mild, urgent exchange transfusion if hypoxic or deteriorating
- Escalate early to HDU/ICU
C. Other emergencies
- Acute stroke -> urgent exchange transfusion, target HbS <30% (do not wait for thrombolysis pathways)
- Splenic sequestration -> transfuse, treat shock; recurrent -> splenectomy
- Aplastic crisis -> transfuse; parvovirus serology/PCR; isolate from pregnant staff
- Priapism >4 h -> urological emergency: aspiration + irrigation +/- phenylephrine; exchange transfusion adjunctive
- Fever = medical emergency in a functionally asplenic patient -> blood cultures + immediate broad-spectrum antibiotics
- Girdle syndrome (mesenteric sickling: ileus, distension) -> exchange transfusion
D. Disease-modifying therapy
- Hydroxyurea (hydroxycarbamide) is the mainstay
- inc HbF, dec neutrophils and platelets, dec adhesion, inc NO
- Indications: >=3 vaso-occlusive episodes/yr, any acute chest syndrome, symptomatic anaemia, chronic pain - and offered to all HbSS/HbS-beta0 children from 9 months
- Titrate to maximum tolerated dose; monitor FBE 2-4 weekly during escalation
- Teratogenic - contraception; myelosuppression is the dose-limiting toxicity
- L-glutamine - modest reduction in crises
- *Voxelotor was withdrawn worldwide in September 2024 - excess vaso-occlusive crises and deaths. Do not prescribe or recommend it*
- *Crizanlizumab (anti-P-selectin) failed its confirmatory phase 3 (STAND) and was withdrawn in Europe* - at most a marginal option
- Gene therapy for severe disease
- Exagamglogene autotemcel (CRISPR of BCL11A erythroid enhancer -> reinduce HbF)
- Lovotibeglogene autotemcel (anti-sickling beta-globin gene addition)
- Busulfan myeloablation; infertility; cost and access limiting
- Allogeneic HSCT - matched sibling donor in children with severe disease; the longest-established curative option
E. Chronic transfusion programmes
- Indications: primary stroke prevention if TCD >=200 cm/s, secondary stroke prevention, recurrent acute chest syndrome despite hydroxyurea
- Extended phenotype-matched (Rh + Kell) units; target HbS <30%
- *Delayed haemolytic transfusion reaction / hyperhaemolysis is the specific hazard* - a falling Hb after transfusion is not "more crisis"
- Iron overload -> chelate (exchange transfusion loads less iron than simple transfusion)
F. Preventive care - the largest survival gain
- Penicillin V prophylaxis from 3 months to at least 5 years (lifelong after splenectomy or invasive pneumococcal disease)
- Pneumococcal, meningococcal, Hib, influenza, hepatitis B vaccination
- Folic acid; malaria prophylaxis if travelling
- ACE inhibitor for albuminuria; annual eye review; hip imaging for AVN
- Pre-operative: simple transfusion to Hb ~100 g/L before medium/high-risk surgery; avoid hypoxia, hypothermia, dehydration, tourniquets
- Pregnancy: high-risk; stop hydroxyurea, low-dose aspirin, VTE prophylaxis
G. Sickle cell trait
- Reassurance - not a disease and not a cause of anaemia
- Risks only under extremes: exertional rhabdomyolysis/sudden death, splenic infarction at altitude, renal medullary carcinoma, painless haematuria (papillary necrosis), hyposthenuria
- *HbA1c is unreliable in some assays; reproductive counselling and partner testing*
Associations
- Functional asplenia -> encapsulated organisms: S. pneumoniae, H. influenzae, N. meningitidis; also Salmonella osteomyelitis and parvovirus B19
- Pigment gallstones, cholecystitis
- Pulmonary hypertension - TRV >2.5 m/s; associated with the haemolytic phenotype and increased mortality
- Sickle nephropathy - hyperfiltration -> albuminuria -> CKD; papillary necrosis, renal medullary carcinoma (also in trait)
- Proliferative sickle retinopathy - commoner in HbSC
- Avascular necrosis of femoral/humeral head; osteomyelitis; osteoporosis
- Leg ulcers, priapism, stroke and silent cerebral infarct
- Delayed puberty, growth failure; iron overload from transfusion
- Alloimmunisation - very high rate (donor/recipient antigen mismatch)
Natural history & complications
- Untreated in low-resource settings: 50-90% mortality before age 5 (infection, sequestration)
- With comprehensive care: median survival now into the 5th-6th decade, but ~20-30 years below the general population
- Silent cerebral infarcts in ~35% by age 14 -> cognitive impairment; overt stroke ~11% by 20 without screening
Acute complications
- Vaso-occlusive pain, acute chest syndrome, stroke, splenic/hepatic sequestration, aplastic crisis, priapism, AKI, sepsis, girdle syndrome, dactylitis (often the first presentation, 6-24 months)
Chronic complications
- Chronic pain from infarction, osteonecrosis, leg ulcers - often opioid-dependent
- CNS: silent infarcts, cognitive and behavioural impairment
- Pulmonary hypertension, sleep-disordered breathing, restrictive lung disease
- CKD, hypertension, concentrating defect (hyposthenuria/nephrogenic DI)
- Diastolic dysfunction, heart failure, sudden cardiac death
- Retinopathy, erectile dysfunction, gallstones, iron overload
Causes of death
- Acute chest syndrome, sudden death, infection, stroke, chronic organ failure (renal, cardiopulmonary)
- Peak mortality in the transition from paediatric to adult services - a system failure, not a biological one
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