Acute sickle cell crisis in the ICU · ICU Topics

ICU bedside scene of a sickle-cell patient with a cardiac monitor showing tachycardia, a peripheral blood smear with sickled erythrocytes, an oxygen mask, IV hydration running, and a chest X-ray revealing a new infiltrate, clinical-blue lighting — FigureSickle-cell crisis — the single HBB point mutation drives HbS polymerisation, vaso-occlusion and haemolysis. Acute chest syndrome (new infiltrate + hypoxia) is the leading cause of death: oxygen, hydration, opioid PCA, and exchange transfusion (HbS <30%, total Hb <110 to avoid hyperviscosity).

Pathophysiology — the molecular basis

From a single base change to multi-organ vasculopathy

1. The mutation (HBB c.20A>T; p.Glu6Val)

A single-nucleotide substitution (GAG→GTG) in codon 6 of the β-globin gene (HBB on chromosome 11p15.4) replaces the polar, negatively charged **glutamic acid with the hydrophobic valine at position 6** of the β-chain. This is autosomal recessive: homozygous HbSS = sickle cell anaemia (disease); heterozygous HbAS = sickle cell trait (usually asymptomatic). HbS proportion determines severity (HbSS > HbSβ⁰-thal > HbSC > HbSβ⁺-thal).

2. Deoxygenation → HbS polymerisation

Deoxygenated HbS (α₂β₂ where the β6 Val creates a hydrophobic patch) polymerises via longitudinal contact into **14-strand helical fibres** that distort the red cell. Polymerisation kinetics follow a **delay time** inversely related to HbS concentration²⁰–³⁰, so anything that increases deoxygenation, lowers pH, raises 2,3-DPG or concentrates HbS (dehydration) shortens delay time and accelerates sickling. **HbF inhibits polymerisation** (γ-chain lacks β6 Val) — the rationale for hydroxyurea and BCL11A-editing gene therapy.

3. Sickling → deformed, rigid, dehydrated erythrocyte

Repeated sickling–unsickling damages the membrane: activation of Gardos and K-Cl cotransport channels → **K⁺ and water loss → intracellular dehydration** (raises MCHC, the single most powerful driver of polymerisation). The cell becomes irreversibly sickled (ISC), rigid and adhesive. This reduces deformability → microvascular obstruction.

4. Haemolysis — the haemolytic phenotype

Intravascular and extravascular haemolysis releases free haemoglobin and arginase → **scavenges nitric oxide (NO)** and depletes arginine → endothelial dysfunction, pulmonary hypertension, priapism, leg ulcers, stroke. Markers of haemolysis: low/normal Hb, high reticulocytes, high LDH, indirect bilirubin, low haptoglobin, high plasma free Hb. A low haemoglobin phenotype (co-existence of α-thalassaemia trait, high HbF) shifts the picture towards a milder "viscosity" phenotype.

5. Endothelial activation + leucocyte/platelet adhesion

Sickled reticulocytes adhere (via VLA-4/α4β1, CD36, LW) to endothelium upregulated by cytokines/hypoxia (VCAM-1, ICAM-1, selectins). **P-selectin** on endothelium and platelets drives heterotypic aggregates — the target of crizanlizumab. Neutrophil trapping, platelet activation and complement activation generate the vaso-occlusive plug.

6. Vaso-occlusion → ischaemia–reperfusion

Microvascular occlusion in bone marrow, spleen, lung, brain and renal medulla produces **ischaemia–reperfusion injury**, oxidative stress and a sterile inflammatory response (IL-1β, IL-6, TNF-α). This is the final common pathway of the painful crisis, acute chest syndrome, splenic infarction, papillary necrosis and avascular necrosis.

7. Chronic vasculopathy

Cumulative injury produces functional asplenia (infarction by age 5–7 in HbSS), pulmonary hypertension (TRV >2.5 m/s, risk of death), sickle nephropathy (hyperfiltration → albuminuria → CKD), retinopathy (HbSC > HbSS), moyamoya (collaterals after cerebral infarction), and a shortened lifespan — median ~45–55 years, improving with comprehensive care.

[1] [3] [4] [13]

Types of crisis

Vaso-occlusive (VOC)

Pain crisis — most common

Sickled RBCs occlude microvasculature → ischaemia → pain
Common sites: long bones (femur, humerus), spine, chest, abdomen
Triggers: infection, dehydration, cold, hypoxia, stress, altitude
Treatment: oxygen, hydration, opioid analgesia (morphine PCA), warmth

Acute chest syndrome (ACS)

#1 cause of death

New pulmonary infiltrate + respiratory symptoms (fever, cough, dyspnoea, chest pain) in SCD patient
Causes: infection (pneumonia), fat embolism (from bone marrow infarction), pulmonary infarction
Treatment: antibiotics (ceftriaxone + azithromycin), oxygen, hydration, incentive spirometry, transfusion, bronchodilators
Severe: exchange transfusion (reduce HbS <30%)

Other crises

Organ-specific

Stroke: cerebral infarction (especially children). Urgent exchange transfusion.
Splenic sequestration: sudden splenic enlargement + Hb drop (children). Transfuse.
Aplastic crisis: parvovirus B19 → temporary RBC aplasia. Hb drops rapidly. Transfuse.
Priapism: painful persistent erection. Aspiration + phenylephrine. Exchange transfusion if severe.

[1] [2]

Crisis types in detail

Acute painful (VOC) crisis

~90% of admissions; #1 reason for ICU

Mechanism: vaso-occlusion in bone marrow/skeletal muscle → ischaemic nociceptive pain + secondary inflammatory pain
Pain often diffuse; classic dactylitis ("hand-foot syndrome") in infants. Back, chest, long bones, abdomen.
Severe VOC driving ACS: new infiltrate within 24–72 h of admission — 50% of "ACS" events are triggered by rib infarction + hypoventilation from opioid analgesia
Differentials to actively exclude: osteomyelitis, septic arthritis, intra-abdominal pathology, ACS, PE, acute abdomen

Acute chest syndrome (ACS)

#1 cause of death; ~10% of episodes

Definition: **new pulmonary infiltrate on CXR + ≥1 of fever, chest pain, tachypnoea, wheeze, cough, hypoxia (SpO2 drop >2% from baseline), increased work of breathing**
Aetiology (Vichinsky NASCSSG): infection ~30% (Chlamydia, Mycoplasma, RSV, S. pneumoniae), fat embolism ~10% (bone marrow infarction → fat emboli → POI + neurologic symptoms), infarction/occlusion, hypoventilation/atelectasis (rib infarction, opioid analgesia)
Risk factors: HbSS, low HbF, high steady-state Hb, recent VOC, postoperative, young adult, winter
Mortality 1–10% adults; recurrence ~50% → chronic lung disease, pulmonary hypertension

Stroke

Ischaemic in children; haemorrhagic in adults

Ischaemic stroke: ~11% of HbSS by age 20 — one of the highest childhood stroke rates of any disease. Driven by large-vessel vasculopathy of the distal ICA/MCA/ACA → moyamoya.
Primary screening: **annual transcranial Doppler (TCD)** ages 2–16. Abnormal (≥200 cm/s) → chronic transfusion (STOP trial).
Acute management: **urgent exchange transfusion** (target HbS <30%, Hb ≤110 g/L) — do NOT delay for MRI if clearly lateralising deficit. Standard thrombolysis is NOT indicated for the vaso-occlusive mechanism.
Secondary prevention: chronic transfusion for ≥1 year (STOP II / SWiTCH), transition to hydroxyurea after ~3 years if low-risk (TWiTCH).

Splenic sequestration

Children <5; functional asplenia later

Acute pooling of blood in an enlarged spleen → sudden Hb drop ≥20 g/L + reticulocytosis + palpable spleen >2 cm. Can progress to hypovolaemic shock within hours.
Major type: Hb <60 g/L + reticulocyte response; minor type: less severe. Triggered by viral infection.
Treatment: **isovolaemic transfusion** (avoid over-transfusion — splenic release causes rebound Hb rise). Fluid resuscitation for shock.
Recurrence rate high (~50%) → elective splenectomy after recovery. Chronic transfusion in younger children to delay splenectomy.

Aplastic crisis

Parvovirus B19 — self-limiting

Parvovirus B19 infects erythroid progenitor cells (P-antigen/globoside) → transient red-cell aplasia (~7–10 days). With a RBC lifespan of only ~10–20 days in SCD, Hb falls precipitously.
Hallmark: **very low reticulocytes** (<1% — distinguishes from sequestration/haemolysis), Hb 30–60 g/L, no rise in bilirubin/LDH. Serology: parvovirus B19 IgM+/PCR+.
Management: **transfusion** until marrow recovers; isolate (parvovirus is contagious to pregnant staff/contacts — hydrops fetalis). IVIG for immunocompromised / persistent infection.

Priapism

Ischaemic emergency — salvage window 24 h

Stuttering (recurrent, <4 h, often nocturnal) vs prolonged (>4 h, ischaemic). Sickling in corpora cavernosa → venous occlusion.
Prolonged priapism = **urological emergency**: risk of permanent ED >50% if >24 h.
Management: corporal aspiration + intracavernosal **phenylephrine** (α-agonist), ice, analgesia; **exchange transfusion** if refractory or recurrent; shunt surgery last resort. Pseudoephedrine/etafenone for stuttering prophylaxis.

Other organ-specific

Multi-organ & misc

Hepatic sequestration / intrahepatic cholestasis: RUQ pain, jaundice, transaminitis, extreme bilirubin. Exchange transfusion.
Renal: papillary necrosis (painless gross haematuria), sickle nephropathy (albuminuria, hyperkalaemia, type IV RTA).
Dactylitis (hand–foot) in infants; avascular necrosis of femoral head; retinal artery occlusion; fat embolism syndrome.
Acute multi-organ failure syndrome: sudden organ failure (lung, liver, kidney) + fever + falling platelets; **urgent exchange transfusion** — mimics sepsis/TTP.

[1] [2] [12] [15] [7] [14]

Management

Sickle cell crisis ICU management

Oxygen + hydration

Supplemental oxygen (target SpO2 >95% — prevents further sickling). IV hydration: normal saline or Hartmann at 1-1.5x maintenance rate (promotes haemodilution, reduces blood viscosity, prevents further sickling). Do NOT over-hydrate (risk of pulmonary oedema, especially in ACS).

Analgesia — treat pain aggressively

Severe pain is the hallmark of VOC. Do NOT undertreat. Morphine PCA (1 mg bolus, 6 min lockout) or continuous infusion (1-5 mg/h). Add paracetamol + NSAIDs (if no renal impairment). Assess pain with VAS/NRS every 2h. Patient-controlled analgesia preferred — patients know their pain.

Investigate and treat triggers

Infection: blood/urine/sputum cultures, start empiric antibiotics (ACS: ceftriaxone + azithromycin). Dehydration: correct electrolytes, assess volume status. Check: FBC (Hb trend, reticulocyte count), LDH (haemolysis), bilirubin, lactate. CXR for ACS.

Transfusion — SIMPLE or EXCHANGE

Simple transfusion: if Hb <70 (or drop >20 from baseline). Target Hb 100-110 (do NOT exceed — hyperviscosity worsens sickling above Hb 110). Exchange transfusion: for severe complications (stroke, severe ACS, multi-organ failure, severe refractory pain). Goal: reduce HbS to <30%, maintain Hb 100-110. Automated erythrocytapheresis preferred (removes HbS-rich cells and replaces with normal HbA cells).

Acute chest syndrome specific management

Antibiotics (ceftriaxone + azithromycin — cover community pathogens + atypicals). Incentive spirometry (prevent atelectasis — major contributor to ACS). Bronchodilators (if wheeze). Simple transfusion if Hb <90 or PaO2 <70 despite oxygen. Exchange transfusion if deteriorating (worsening hypoxia, increasing infiltrates, respiratory failure). Consider ECMO if refractory.

Prevention of recurrence

Hydroxyurea (increases HbF — reduces sickling). Prophylactic penicillin (children — functional asplenia). Vaccination (pneumococcal, Haemophilus, meningococcal). Stem cell transplant (curative — for severe cases). CRISPR gene therapy (Casgevy — FDA approved Dec 2023 — edits BCL11A to increase HbF).

[1] [2]

ICU bundle for the acute admission

First 6 hours of any sickle cell admission

0. Recognise the crisis & stratify severity

ABCDE. Is this ACS, stroke, sequestration, aplastic, priapism, or "simple" VOC? Sepsis screen for every febrile patient (functional asplenia). Early warning scores (NEWS2/MEWS) — SCD patients decompensate fast. Two large-bore cannulae; group & save + crossmatch; extended RBC phenotype (C, c, E, e, Kell) to reduce alloimmunisation.

1. Oxygen + monitoring

Target SpO2 ≥94% (or within 2% of patient baseline). Continuous SpO2, serial ABG if any respiratory signs. Escalate SpO2 fall >2% from baseline as evolving ACS.

2. Hydration — isotonic, controlled

Crystalloid (0.9% saline or Hartmann) at **1–1.5× maintenance** (~3–4 L/day adult; ~5 mL/kg/h). Avoid hypotonic dextrose-only (worsens hyponatraemia). Caution in CKD, cardiac disease, ACS (over-hydration precipitates pulmonary oedema). Reassess volume every 4 h.

3. Analgesia — rapid, titrated, opioid-first

Severe pain: morphine 0.1 mg/kg IV q10–20 min until controlled, then PCA/infusion. Avoid pethidine (meperidine) — norpethidine neurotoxicity, seizures. Adjuncts: paracetamol, NSAID (if eGFR ok), gabapentin for neuropathic component. Pain reassessment q15 min during titration, then q2 h. Naloxone available; antiemetic + laxative co-prescribed.

4. Investigate triggers

FBC + reticulocytes, U&E, LFTs, LDH, bilirubin, haptoglobin, CRP, lactate, group & screen, coagulation. Cultures (blood ×2, urine, sputum, throat). CXR (every febrile patient and any respiratory sign). Parvovirus PCR if reticulocytes low. Lipase, urinalysis, peripheral film. Venous Doppler if limb pain/swelling.

5. Empiric antibiotics

Fever in SCD = medical emergency. Ceftriaxone 2 g IV (cover encapsulated organisms — pneumococcus, meningococcus, H. influenzae). Add macrolide (azithromycin) if ACS suspected. Add antipseudomonal cover if line infection/known colonisation. Add oseltamivir in influenza season.

6. Incentive spirometry + VTE prophylaxis

Incentive spirometry q2 h while awake — halves ACS in patients with chest/back pain (Bellet trial principle). VTE prophylaxis (LMWH) for immobilised patients — SCD is prothrombotic.

[2] [4]

Acute chest syndrome — the killer complication

ACS recognition, monitoring & escalation

Recognise early (any one is enough)

New infiltrate on CXR PLUS any of: T >38.5°C, RR increased, SpO2 drop >2% from baseline or <92%, chest pain, cough, wheeze, increased work of breathing. Beware: CXR may lag symptoms by 12–24 h — trend clinically and repeat CXR daily.

Bundle: antibiotics + respiratory support

Ceftriaxone 2 g IV + azithromycin 500 mg IV (cover S. pneumoniae, Chlamydia, Mycoplasma, H. influenzae, viruses). Oxygen to SpO2 ≥94%. Incentive spirometry q2 h. Bronchodilators if wheeze. Consider steroids if asthma overlap (short course; rebound VOC risk).

Simple transfusion — early

If Hb <90 g/L or falls >10 g/L from baseline, or PaO2/FiO2 <300 → simple/top-up transfusion to Hb ~100–110 g/L. Reduces HbS fraction by dilution.

Exchange transfusion — deteriorating

Indications: rapid progression (new multilobar infiltrate, rising O2 requirement, PaO2 <60 mmHg on FiO2 ≥0.5), fall in Hb >20 g/L, platelets falling, multi-organ failure. Target **HbS <30%, Hb ≤110 g/L**. Automated erythrocytapheresis preferred (isovolaemic, removes HbS-rich cells); manual exchange if not available.

Advanced respiratory support

HFNC/bipap to avoid intubation if possible (positive pressure reduces venous return, can worsen). If intubated: lung-protective ventilation (Vt 6 mL/kg, Pplat <30), permissive hypercapnia, PEEP titrated. **Inhaled nitric oxide** or epoprostenol for severe hypoxaemia. ECMO (V-V) for refractory hypoxaemia — centre-specific.

Disposition & follow-on

ICU for: rising FiO2, organ failure, exchange transfusion, unstable physiology. After recovery: initiate/optimise hydroxyurea, transfusion programme, plan vaccination, iron studies if transfused.

[12] [15]

Transfusion strategies

Simple (top-up) transfusion

Raising Hb

Indication: symptomatic anaemia (Hb <70, or <90 with ACS, or drop >20 from baseline). Aplastic crisis, sequestration (cautiously), pre-op in selected.
Goal: Hb 100–110 g/L. NEVER exceed 110–120 (hyperviscosity worsens sickling, stroke risk).
Phenotype-matched units (C, c, E, e, Kell) to reduce alloimmunisation (~30% of multi-transfused SCD patients form antibodies — anti-C, anti-E, anti-Kell common).

Exchange transfusion

Lowering HbS

Indications: **acute stroke, severe/progressive ACS, multi-organ failure syndrome, severe refractory VOC, severe priapism, hepatic sequestration, fat embolism, pre-op major surgery**.
Goal: HbS <30% (acute stroke, severe ACS) or <40% (elective), Hb ≤110 g/L. One volume exchange removes ~60% of HbS.
Automated erythrocytapheresis isovolaemic (preferred — removes HbS-rich cells precisely); manual 2-volume exchange if apheresis unavailable. Central venous access often required; large FFP/blood demand.

Chronic transfusion programme

Stroke prevention

Indications: secondary stroke prevention, primary prevention if abnormal TCD (STOP), severe/recurrent ACS, pregnancy in selected.
Goal: keep HbS <30% every 3–4 weeks. Iron overload monitoring (ferritin, MRI T2* liver/heart). Chelation (deferasirox first-line).
Transition to hydroxyurea after ~3 years if low risk (TWiTCH) — non-inferior with less iron overload.

[1] [2] [9]

Disease-modifying & preventive therapy

Hydroxyurea (hydroxycarbamide)

First-line; ↑HbF

Mechanism: ribonucleotide reductase inhibition → myelosuppression + **raises HbF** (γ-chain lacks β6 Val → no polymerisation); also ↓reticulocytes, ↓WBC, ↑NO.
Indications: ≥3 VOC/year, recurrent ACS, HbSS/HbSβ⁰-thal, from age 9 months (BABY HUG showed safety).
Dose: start 15–20 mg/kg/day (adult max 35 mg/kg/day), titrate to max tolerated dose (neutrophils ≥2.0, platelets ≥80). Monitor FBC q4–6 weeks. Cytopenia is dose-limiting and reversible.

Crizanlizumab (anti-P-selectin)

Adjuvant VOC prevention

Humanised monoclonal anti-P-selectin → blocks leucocyte/platelet–endothelium adhesion (SUSTAIN trial).
Indication: ≥2 VOC/year despite hydroxyurea (or contraindication). IV infusion 5 mg/kg q4 weeks.
Reduces crisis rate by ~45% (median 1.6 vs 3.0 crises/year). Not for acute treatment. Thrombocytopenia, infusion reactions.

Voxelotor (HbS polymerisation inhibitor)

Raises Hb, ↓haemolysis

Allosteric modifier of HbS — increases oxygen affinity → stabilises oxy-state → **inhibits polymerisation** (HOPE trial).
Indication: haemolytic anaemia phenotype; raises Hb by ~10 g/L. Oral 1500 mg daily.
Note: voluntary withdrawal from US market 2023 (PH-adjusted safety review; vaso-occlusive events signal) — check local availability. Avoid in pregnancy.

L-glutamine (endorcel)

Adjunct

Reduces oxidative stress (NAD⁺/NADH). Approved ; modest reduction in crisis/hospitalisation. Oral powder BID. Limited by GI side-effects and adherence.

Curative: HSCT

Myeloablative / RIC

Matched-sibling allogeneic HSCT: >90% overall / ~85% event-free survival; only ~15% have a matched sibling donor. Haploidentimal & unrelated donor protocols expanding.
Indications: severe phenotype (stroke, recurrent ACS, refractory VOC) especially children.

Curative: gene therapy (Casgevy)

FDA/MHRA-approved Dec 2023

CRISPR/Cas9 ex-vivo edit of the **BCL11A erythroid enhancer** in autologous CD34⁺ cells → reactivates γ-globin → high HbF → no polymerisation.
CLIMB-121: ~94% voxel-free from severe VOC for ≥12 months after exagamglogene autotemcel.
Other platforms: lovo-cel (lentiviral βA-T87Q) — Bluebird; beti-cel (Lyfgenia, FDA 2023). Cost (~US$2M), myeloablative busulfan conditioning, fertility/secondary malignancy considerations.

[8] [16] [17] [6]

Landmark trials & evidence

MSH (Charache 1995) — hydroxyurea in sickle cell anaemia

PMID 7715639

RCT, double-blind, 299 adults with ≥3 painful crises/year; hydroxyurea vs placebo

Key finding

Hydroxyurea reduced median crisis rate from 4.5 → 2.5/year, halved ACS episodes (25 vs 51), and reduced transfusions. Stopped early for efficacy. Foundation of hydroxyurea therapy.

STOP (Adams 1998–2000) — primary stroke prevention by transfusion

PMID 10830201

RCT, 130 children with abnormal TCD (≥200 cm/s); chronic transfusion vs observation

Key finding

Chronic transfusion reduced first stroke by ~90% (from 10%/year to <1%/year). Established TCD screening + transfusion for primary stroke prevention. Stopped early for overwhelming benefit.

TWiTCH (Ware 2016) — hydroxyurea non-inferior to transfusion

PMID 26670617

RCT non-inferiority, 121 children with abnormal TCD normalised after ≥1 year transfusion; switched to hydroxyurea vs continued transfusion

Key finding

Hydroxyurea non-inferior for maintaining normal TCD over 3 years. Allowed discontinuation of chronic transfusion and avoidance of iron overload in selected children.

SWiTCH (Ware 2012) — transfusion vs hydroxyurea for secondary stroke prevention

PMID 22318199

RCT, 133 children with prior stroke + iron overload; hydroxyurea + phlebotomy vs chronic transfusion + chelation

Key finding

Stopped early for futility (stroke recurrence 7% transfusion vs 10% hydroxyurea, NS, but failed non-inferiority). Demonstrated chronic transfusion remains standard for secondary stroke prevention; led to TWiTCH.

SUSTAIN (Ataga 2017) — crizanlizumab for VOC prevention

PMID 27959701

RCT, 198 patients ≥2 VOC/year; crizanlizumab high-dose vs low-dose vs placebo

Key finding

High-dose crizanlizumab increased crisis-free survival (median 4.07 vs 1.38 months) and reduced annual crisis rate (1.63 vs 2.98). First targeted anti-adhesion therapy.

HOPE (Vichinsky 2019) — voxelotor in SCD

PMID 31199090

RCT, 274 patients; voxelotor 1500 mg, 900 mg vs placebo

Key finding

Voxelotor 1500 mg raised Hb >10 g/L in 51% vs 6% placebo, reduced haemolysis markers. Approved for haemolytic anaemia (later withdrawn in US 2023 pending safety review).

[1]

Vichinsky 2000 — NASCSSG ACS aetiology study

PMID 10861320

Prospective, 671 episodes / 538 patients; comprehensive microbiology + imaging

Key finding

Identified infection (Chlamydia, Mycoplasma, viruses, bacteria), fat embolism and infarction as causes; ~50% had no pathogen isolated. Defined diagnostic criteria, severity predictors and outcomes (mortality 3% adults).

CLIMB-121 / Casgevy (Frangoul 2024) — CRISPR gene therapy

PMID 38661449

Phase 1–3, single-arm, 44 patients with severe SCD; exagamglogene autotemcel (BCL11A enhancer edit)

Key finding

~94% were voxel-free (no severe VOC) for ≥12 consecutive months during 24-month follow-up. First CRISPR therapy approved (FDA/MHRA Dec 2023). Curative intent; long-term follow-up ongoing.

Acute stroke in SCD

Stroke in SCD — recognise and act in minutes

Recognise

Sudden focal deficit, altered mental status, seizure, headache. Children: BE-FAST / paediatric stroke signs (hemiparesis, aphasia, visual change). High index of suspicion — SCD has one of the highest childhood stroke rates of any disease.

Image immediately

Non-contrast CT to exclude haemorrhage. MRI/MRA for infarct territory and large-vessel vasculopathy (distal ICA/MCA). **Do NOT delay exchange transfusion** for MRI if clearly lateralising ischaemic stroke.

Urgent exchange transfusion

Goal: HbS <30%, Hb ≤110 g/L (avoid hyperviscosity). Automated erythrocytapheresis preferred. Standard IV thrombolysis/thrombectomy NOT routinely indicated (mechanism is vaso-occlusive + vasculopathy, not cardio/atheroembolic) unless clear additional indication.

Secondary prevention

Chronic transfusion programme (every 3–4 weeks to HbS <30%) for ≥1 year. After ~3 years, transition to hydroxyurea (max tolerated dose) if low-risk (TWiTCH); lifelong in some. Control BP, hydration, fever.

Long-term

Repeat TCD/MRA surveillance (moyamoya risk). Consider revascularisation surgery (EDAS/pial synangiosis) for progressive moyamoya. Antiplatelet (aspirin) per stroke guidelines.

[5] [9] [10]

Splenic sequestration & aplastic crisis — paediatric emergencies

Splenic sequestration

Hypovolaemic shock risk

Sudden pooling of blood in enlarging spleen → Hb drop ≥20 g/L (often <60) + reticulocytosis + palpable spleen >2 cm. Mostly children <5 (HbSS), but adults with HbSC retain splenic function longer.
Treatment: **isovolaemic transfusion** (cautious — spleen releases trapped blood → rebound polycythaemia; target Hb ~80, recheck). IV fluids for shock.
Recurrence ~50% → splenectomy (after age ~2) or chronic transfusion to delay surgery. Parent education in palpating the spleen.

Aplastic crisis

Parvovirus B19

Parvovirus B19 infects erythroid precursors → transient RBC aplasia (~7–10 days). With shortened RBC lifespan, Hb falls to 30–60 g/L.
Hallmark: **reticulocytes <1%** (vs high in sequestration), no rise in bilirubin/LDH. Parvovirus IgM+/PCR+.
Treatment: transfuse until marrow recovery. **Isolate** (contagious — risk to pregnant contacts: hydrops fetalis). IVIG if persistent infection.

[14]

Priapism — urological emergency

Prolonged priapism (>4 h) management

Recognise

Prolonged, painful erection not resolved by ejaculation/urination. Stuttering (<4 h, often nocturnal) vs prolonged (>4 h, ischaemic). Corpora cavernosa rigid, glans spongy.

Analgesia + urology referral

Opioid analgesia (pain is severe). Urgent urology review — salvage window ~24 h before irreversible ED (>50% risk).

Corporal aspiration + phenylephrine

Aspirate 30–60 mL from corpora (send for gas — acidic, low glucose confirms ischaemic). Instil **intracavernosal phenylephrine** 100–500 µg q5–10 min (dilute 1:1,000,000; cardiac monitoring — α-agonist, hypertension/arrhythmia risk).

Exchange transfusion if refractory

If no detumescence after aspiration/phenylephrine or recurrent within 24 h → exchange transfusion (HbS <30%). Beware ASPEN syndrome (afibrinogenaemia, sudden severe thrombocytopenia) after exchange for priapism — rare but fatal.

Surgical shunt

Last resort — Winter/T-shunt / Ebbehoj. Distal glans–cavernosal shunt. High ED rate.

Prevent recurrence

Stuttering prophylaxis: pseudoephedrine 30–60 mg PO q6 h or etafenone; self-tamponade (squatting/exercise); hydroxyurea; chronic transfusion; beta-agonists (terbutaline). Consider oestrogen in adolescents.

[7]

Differential diagnosis of acute pain in SCD

VOC vs infection

Painful crisis vs osteomyelitis/septic arthritis

VOC: usually multifocal, symmetric, no systemic toxicity (initially). Often no fever or low-grade.
Osteomyelitis: unifocal, persistent, localised warmth/swelling, high fever, raised inflammatory markers, positive blood culture. Salmonella & S. aureus classic. MRI distinguishes.
Septic arthritis: hot swollen joint, restricted movement; aspirate joint fluid.

Abdominal pain

Mesenteric vs surgical

VOC of mesentery/abdominal organs: common, usually no peritonism. Often improves with hydration/analgesia.
Exclude: appendicitis, cholecystitis (pigment stones — almost universal by adulthood), splenic/ hepatic sequestration, pancreatitis, mesenteric adenitis, ectopic, AAA in older adults.
Worrying signs: peritonism, guarding, rising lactate, progressive organ dysfunction → surgical review.

Chest pain / dyspnoea

ACS vs PE/pneumonia

ACS: new infiltrate on CXR. PE: SCD is prothrombotic; D-dimer unhelpful (always raised). CTPA if suspicion.
Myocardial ischaemia (rare, young, but coronary vasculopathy + anaemia possible). Fat embolism (bone marrow infarction → triad of hypoxia, neuro signs, thrombocytopenia, petechiae).
Aortic dissection, pneumothorax (especially with pneumonia/ventilation) — bedside ultrasound.

[1] [4]

Anaesthesia & perioperative considerations

Perioperative management of SCD

Pre-op

Stratify phenotype (HbSS highest risk). Optimise Hb, hydrate, ensure transfusion history (alloantibodies). Pre-op transfusion for moderate/high-risk surgery (target Hb 90–100). Aggressive prophylaxis not needed for low-risk procedures (TAPS trial).

Intra-op

Avoid hypoxia, hypothermia, dehydration, acidosis, hypotension, venous stasis/tourniquets. Warm fluids, humidified gases, monitor SpO2 + end-tidal CO2. Adequate depth of anaesthesia. Regional anaesthesia excellent (epidural for thoracic/abdominal).

Post-op

Oxygen to SpO2 ≥94%, generous hydration, multimodal analgesia (regional where possible), **incentive spirometry q2 h** (prevents ACS), early mobilisation, VTE prophylaxis. Highest ACS risk 24–72 h post-op — monitor closely.

High-risk surgery

Major (cardiac, neuro, prolonged): pre-op exchange transfusion to HbS <30%, Hb 100–110.

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Complications of transfusion

Alloimmunisation

~30% multi-transfused

Anti-C, anti-E, anti-Kell most common. Mitigate with **extended phenotype-matched units** (Rh + Kell). Risk of delayed haemolytic transfusion reaction (DHTR) days–weeks later.

Iron overload

Chronic transfusion

Each unit ~200 mg iron; no physiological excretion. Monitor ferritin + MRI T2* (liver, heart). Chelation: deferasirox (first-line), deferiprone, deferoxamine. Cardiac iron → cardiomyopathy/arrhythmia.

Acute transfusion reactions

AHTR, TACO, TRALI, allergic

Acute haemolytic (ABO mismatch, alloantibody) — stop transfusion, supportive. TACO (circulatory overload). TRALI (within 6 h, hypoxia + bilateral infiltrates, no raised LA pressure).

Infection

Historical & residual

HBV, HCV, HIV (now very low risk). Bacterial contamination (rare but high mortality). Parvovirus B19 (pure red cell aplasia). Prion (theoretical).

[2]

Exam practice

SAQ — Acute chest syndrome and exchange transfusion

10 minutes · 10 marks

A 26-year-old woman with HbSS sickle cell anaemia is admitted with a painful vaso-occlusive crisis. On day 2 she develops a fever (38.9°C), pleuritic chest pain, tachypnoea (RR 30) and new oxygen requirement (SpO2 91% on air). Chest X-ray shows a new right lower-lobe infiltrate. Hb has fallen from 82 to 64 g/L.

[1]

SAQ — Splenic sequestration and the acute anaemia crises

10 minutes · 10 marks

A 3-year-old boy with HbSS disease presents with sudden-onset pallor, lethargy, tachycardia and abdominal fullness. Hb 42 g/L (baseline 78), reticulocytes 18%, platelets 60 × 10⁹/L, and a palpable, tender spleen 6 cm below the costal margin. He is tachypnoeic but normotensive.

[1]

Clinical pearls

High-yield sickle cell crisis points for the CICM/FFICM exam

Acute chest syndrome = new infiltrate + respiratory symptoms = #1 cause of death.[1]
Exchange transfusion for stroke, severe ACS, multi-organ failure. Target HbS <30%.[2]
Do NOT over-transfuse — target Hb 100-110. Hyperviscosity above 110 worsens sickling.[1]
Treat pain aggressively — opioids (morphine PCA). Do NOT undertreat.[2]
Hydration (1-1.5x maintenance) — reduces viscosity, prevents sickling.[2]
Stroke in SCD: urgent exchange transfusion (reduce HbS <30%).[1]
Triggers: infection (#1), dehydration, cold, hypoxia, altitude, stress.[2]
Functional asplenia — prophylactic penicillin, vaccination (encapsulated organisms).[1]
Parvovirus B19 → aplastic crisis (temporary bone marrow suppression). Transfuse.[1]
Priapism: prolonged erection. Aspiration + phenylephrine ± exchange transfusion.[2]
Hydroxyurea: increases HbF → reduces sickling and crisis frequency.[2]
CRISPR gene therapy (Casgevy): FDA-approved Dec 2023 — edits BCL11A gene to reactivate fetal haemoglobin.[2]
SCD is autosomal recessive — HbS inherited from BOTH parents (homozygous HbSS = sickle cell disease). Heterozygous (HbAS) = sickle cell trait (usually asymptomatic).[1]
Mortality: median survival ~45-55 years (improving with modern care).[1]

Examiner-favourite molecular & pathophysiology pearls

The molecular lesion is a single point mutation: GAG→GTG in codon 6 of HBB → glutamic acid replaced by valine at position 6 of the β-chain (β6 Glu→Val). One base, one amino acid, one disease.[1]
HbF inhibits polymerisation because the γ-chain (fetal) lacks the β6 Val contact site — the entire rationale for hydroxyurea (↑HbF) and Casgevy gene therapy (edits BCL11A to switch HbF back on).[3]
Polymerisation has a delay time inversely related to [HbS]²⁰–³⁰ — hence small reductions in HbS (transfusion) or concentration (hydration) cause large kinetic slowing, and why a cell that traverses the pulmonary capillary before polymerising does NOT sickle (kinetics, not just equilibrium).[3]
MCHC is the master variable: RBC dehydration (Gardos/K-Cl cotransport) raises MCHC and shortens delay time — the driest cells sickle first. Acidosis, hypoxia and 2,3-DPG all accelerate polymerisation.[13]
Two clinical phenotypes: a haemolysis–endothelial dysfunction phenotype (low Hb, high LDH/retic; pulmonary hypertension, priapism, leg ulcers, stroke, renal disease — NO depletion) vs a viscosity–vaso-occlusion phenotype (higher Hb, lower retic; painful crisis, ACS, osteonecrosis). Predicts complications and therapy response.[13]
Free haemoglobin scavenges nitric oxide + arginase depletes arginine → the unifying mechanism of SCD vasculopathy (pulmonary HTN, priapism, stroke).[13]
Sickle cell trait (HbAS) is usually asymptomatic but: exertional rhabdomyolysis/sudden death (athletes), renal papillary necrosis (haematuria), splenic infarction at altitude, and a small but real VTE risk.[1]
α-thalassaemia trait co-inheritance ameliorates HbSS (lowers MCHC, fewer ISCs) — a classic modifier. High HbF (BCL11A/XmnI polymorphisms) is another.[3]
Functional asplenia develops by age 5–7 in HbSS (autoinfarction); HbSC/HbSβ⁺ retain splenic function longer → higher sequestration risk in adulthood.[1]
Pigment gallstones are almost universal by adulthood in HbSS — consider cholecystitis in any RUQ pain.[4]

Acute chest syndrome pearls — the highest-yield ICU content

ACS is the leading cause of death in SCD and the commonest reason for ICU admission; ~50% of ACS episodes arise during a VOC admission (rib/marrow infarction → splinting → atelectasis, plus opioid-induced hypoventilation).[15]
Incentive spirometry q2 h in any patient with chest/back/rib pain halves the risk of ACS (Bellet) — a cheap, evidence-based intervention often forgotten.[15]
Fat embolism syndrome (bone marrow infarction → fat in pulmonary circulation): triad of sudden hypoxia + neurologic signs (confusion, seizures) + falling platelets/petechiae. Mimics ACS/TTP/DIC — exchange transfusion is the treatment.[15]
The classic microbiology (NASCSSG): Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory viruses (RSV, influenza), and S. pneumoniae / H. influenzae — hence the ceftriaxone + macrolide combination, not just beta-lactam.[15]
Steroids (prednisone 2 mg/kg) speed recovery but rebound VOC/bleeding when stopped — use short course only, not routine.[12]
Escalation thresholds for exchange transfusion: new multilobar infiltrate, PaO2 <60 mmHg on FiO2 ≥0.5, Hb fall >20 g/L, platelet fall, or any multi-organ failure.[12]
Inhaled nitric oxide / epoprostenol for refractory hypoxaemia; V-V ECMO as last resort at specialist centres.[12]
~50% of patients who have one ACS episode will have another → chronic lung disease, pulmonary hypertension. Initiate hydroxyurea / chronic transfusion after recovery.[1]

Transfusion & exchange transfusion pearls

Simple top-up transfusion: target Hb 100–110 g/L. NEVER exceed 110–120 — hyperviscosity worsens sickling, ↑stroke risk. Caution in sequestration (spleen releases blood → rebound).[1]
Exchange transfusion for acute stroke: HbS <30%, Hb ≤110 g/L. One volume exchange removes ~60% of HbS; 1.5–2 volumes removes ~80%. Automated erythrocytapheresis is isovolaemic and preferred.[2]
Always phenotype-match units (Rh C/c/E/e + Kell) — alloimmunisation in ~30% of multi-transfused SCD patients; anti-Kell, anti-C, anti-E dominate. DHTR can masquerade as a "pain crisis" days–weeks later.[2]
TCD screening (annual, ages 2–16) detects abnormal flow (≥200 cm/s) → chronic transfusion prevents ~90% of first strokes (STOP). Non-inferiority of hydroxyurea after ≥1 year of transfusion (TWiTCH) allows safer transition.[5]
Iron overload with chronic transfusion — monitor ferritin + MRI T2* (liver, heart); deferasirox first-line chelation. Cardiac iron → arrhythmia/cardiomyopathy, a leading late cause of death.[9]
Beware ASPEN syndrome (afibrinogenaemia + sudden severe thrombocytopenia) after exchange transfusion for priapism — rare but fatal. Check fibrinogen post-procedure.[7]

Pharmacology pearls — disease-modifying therapy

Hydroxyurea (hydroxycarbamide): inhibits ribonucleotide reductase → ↑HbF, ↓WBC/reticulocytes, ↑NO. MSH (1995) halved crisis + ACS rates. Start 15–20 mg/kg/day, titrate to max tolerated (neutrophils ≥2.0). Reversible cytopenia. First-line for nearly all HbSS from age 9 months.[8]
Crizanlizumab: anti-P-selectin mAb; SUSTAIN (2017) raised crisis-free survival (4.07 vs 1.38 months). Adjunct for ≥2 VOC/year despite hydroxyurea. IV q4 weeks. Adjuvant, not rescue.[16]
Voxelotor: allosteric HbS modifier — ↑O2 affinity → inhibits polymerisation; HOPE (2019) raised Hb & ↓haemolysis. Voluntarily withdrawn in the US (2023) pending a PH-adjusted safety review (vaso-occlusive signal) — check local availability; avoid in pregnancy.[17]
L-glutamine (endorcel): oral, modest effect, ↓oxidative stress. Adjunct; GI side-effects, adherence issues.[4]
Casgevy (exagamglogene autotemcel): CRISPR/Cas9 edit of BCL11A erythroid enhancer → γ-globin/HbF re-expression. CLIMB-121: ~94% voxel-free from severe VOC ≥12 months. FDA/MHRA-approved Dec 2023. Myeloablative busulfan conditioning — fertility, secondary malignancy considerations; ~US$2M cost.[6]
HSCT (matched sibling >90% OS, ~85% EFS) remains the original curative option — only ~15% have a matched sibling; haploidentical/unrelated donor protocols expanding.[4]
Penicillin V prophylaxis (children, <5 years or post-splenectomy) + vaccination (pneumococcal PCV13 + PPSV23, Hib, meningococcal ACWY + B, influenza annual, hepatitis B) against encapsulated organisms.[1]

Prognosis, epidemiology & long-term pearls

Global burden rising: SCD is the most common monogenic disease worldwide; ~300,000 babies born with HbSS annually, mostly in sub-Saharan Africa, India, Mediterranean, Middle East. The Lancet Haematology Commission (2023) prioritises newborn screening, penicillin, hydroxyurea access.[11]
Median survival ~45–55 years in high-income settings (longer with comprehensive care); childhood mortality >50–90% in low-resource settings without newborn screening.[11]
Pulmonary hypertension (TRV >2.5 m/s on echo) is an independent predictor of death; screen with echo + NT-proBNP. NO-depletion phenotype.[13]
Sickle nephropathy: hyperfiltration → microalbuminuria → proteinuria → CKD/ESKF. ACE-inhibitor/ARB for albuminuria. Type IV RTA (hyperkalaemia, acidosis) common — avoid NSAIDs where possible.[4]
Retinopathy more common in HbSC than HbSS (higher viscosity) — proliferative sickle retinopathy → vitreous haemorrhage, retinal detachment; annual ophthalmology review.[1]
Avascular necrosis of the femoral humeral head — common cause of chronic pain and disability; core decompression / arthroplasty.[1]
Pregnancy: increased risk of VOC, ACS, pre-eclampsia, fetal growth restriction, sepsis, death. Prophylactic low-dose aspirin; LMWH prophylaxis; transfuse if symptomatic anaemia or history of poor outcome. Hydroxyurea contraindicated in pregnancy — stop pre-conception.[2]

Red flags

Escalation triggers — when to call for help

Falling SpO2 / new infiltrate / rising O2 requirement → evolving ACS: escalate oxygen, antibiotics, bronchodilators, transfusion, consider exchange.[12]
Falling Hb >20 g/L or Hb <70 → check reticulocytes (sequestration = high; aplasia = low), transfuse matched units; sequestration → cautious isovolaemic transfusion.[1]
New neurologic deficit / seizure / severe headache → stroke/SAH: image, urgent exchange transfusion; do NOT delay for MRI.[5]
Fever >38.5°C in a child or unwell adult → sepsis protocol: cultures + empiric IV ceftriaxone within 1 h (functional asplenia). Add macrolide if ACS features.[2]
Priapism >4 h → urology now; corporal aspiration + phenylephrine; exchange transfusion if refractory.[7]
Multi-organ failure (lung + liver + kidney + falling platelets) → fat embolism / acute multi-organ failure syndrome → urgent exchange transfusion.[15]
Acute severe anaemia with reticulocytes <1% → parvovirus B19 aplastic crisis → transfuse + isolate (pregnancy risk).[14]

Pitfalls & avoidable deaths

Pethidine (meperidine) → norpethidine neurotoxicity (seizures, especially renal impairment). Avoid — use morphine/fentanyl.[2]
Over-hydration (especially in ACS, CKD, cardiac disease) → pulmonary oedema, worsening hypoxia. Titrate, reassess.[12]
Over-transfusion (Hb >110–120) → hyperviscosity, stroke, ACS worsening. Cap simple transfusion at Hb ~110.[1]
Withholding opioids for fear of dependence/resp. depression → undertreated pain, splinting, atelectasis, ACS. PCA is safe and effective.[2]
Forgetting phenotype matching → alloimmunisation, DHTR, difficulty finding future units.[2]
Missing pregnancy / renal potassium with NSAIDs → AKI / fetal harm. Check before each dose.[2]
Assuming trait = disease: HbAS patients are usually asymptomatic — but counsel about altitude, exertional collapse, microhaematuria, anaesthetic risk.[1]

Comparison of crisis types at a glance

Feature

Pain (VOC)
Acute chest
Stroke
Splenic sequestration
Aplastic
Priapism

Frequency

Most common (~90%)
~10% of admissions
~11% by age 20 (HbSS)
Children <5
Any age (epidemic)
Adult males ~35%

Key feature

Severe ischaemic pain
New infiltrate + resp symptoms
Focal deficit / TCD ≥200
Spleen + Hb drop + retics↑
Reticulocytes <1%
Painful erection >4 h

First treatment

O2 + fluids + opioid PCA
Abx + O2 + IS + transfusion
Urgent EXCHANGE transfusion
Cautious transfusion + fluids
Transfuse + isolate
Aspiration + phenylephrine

Definitive / specific

Hydroxyurea prevention
Exchange if worsening
Chronic transfusion → HU
Splenectomy (recurrence)
Self-limiting (7–10 d)
Exchange if refractory

[1] [2]

Key points to take to the exam

Twenty-second summary — the must-say points

One mutation (β6 Glu→Val, HBB codon 6, GAG→GTG) → HbS polymerises when deoxygenated → sickling, haemolysis, vaso-occlusion, multi-organ vasculopathy.[1]
Crisis types: vaso-occlusive (pain, #1 admission cause), acute chest syndrome (#1 death cause), stroke, splenic sequestration, aplastic (parvovirus B19), priapism.[4]
Management: oxygen, isotonic hydration 1–1.5× maintenance, opioid PCA (morphine), treat triggers, incentive spirometry, empiric antibiotics (ceftriaxone ± macrolide).[2]
Simple transfusion if Hb <70–90 (target 100–110, never >120); exchange transfusion for stroke / severe ACS / MOF / refractory (HbS <30%).[1]
Prevention/modification: hydroxyurea (↑HbF, first-line), crizanlizumab (anti-P-selectin), voxelotor (polymerisation inhibitor — withdrawn US), L-glutamine; curative = HSCT and CRISPR gene therapy (Casgevy, 2023).[8][6]
Fever = sepsis until proven otherwise (functional asplenia) — penicillin prophylaxis + vaccines.[1]

References

[1]Rees DC, Williams TN, Gladwin MT. Sickle-cell disease Lancet, 2010.PMID 21131035
[2]Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members JAMA, 2014.PMID 25203083
[3]Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease Nat Rev Dis Primers, 2018.PMID 29542687
[4]Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review JAMA, 2022.PMID 35788790
[5]Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study J Child Neurol, 2000.PMID 10830201
[6]Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease N Engl J Med, 2024.PMID 38661449
[7]Kato GJ. Priapism in sickle-cell disease: a hematologist's perspective J Sex Med, 2012.PMID 21554552
[8]Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia N Engl J Med, 1995.PMID 7715639
[9]Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial Lancet, 2016.PMID 26670617
[10]Ware RE, Helms RW, SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Blood, 2012.PMID 22318199
[11]Piel FB, Tewari S, Brousse V, et al. Defining global strategies to improve outcomes in sickle cell disease: a Lancet Haematology Commission Lancet Haematol, 2023.PMID 37451304
[12]Bhasin N, Sarode R. Acute Chest Syndrome in Sickle Cell Disease Transfus Med Rev, 2023.PMID 37741793
[13]Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease J Clin Invest, 2017.PMID 28248201
[14]Serjeant GR, Mason K, Topley JM, et al. Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent Lancet, 1981.PMID 6116082
[15]Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group N Engl J Med, 2000.PMID 10861320
[16]Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease N Engl J Med, 2017.PMID 27959701
[17]Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease N Engl J Med, 2019.PMID 31199090

[1]

Pathophysiology — the molecular basis

From a single base change to multi-organ vasculopathy

1. The mutation (HBB c.20A>T; p.Glu6Val)

2. Deoxygenation → HbS polymerisation

3. Sickling → deformed, rigid, dehydrated erythrocyte

4. Haemolysis — the haemolytic phenotype

5. Endothelial activation + leucocyte/platelet adhesion

6. Vaso-occlusion → ischaemia–reperfusion

7. Chronic vasculopathy

[1] [3] [4] [13]

Types of crisis

Vaso-occlusive (VOC)

Pain crisis — most common

Sickled RBCs occlude microvasculature → ischaemia → pain
Common sites: long bones (femur, humerus), spine, chest, abdomen
Triggers: infection, dehydration, cold, hypoxia, stress, altitude
Treatment: oxygen, hydration, opioid analgesia (morphine PCA), warmth

Acute chest syndrome (ACS)

#1 cause of death

New pulmonary infiltrate + respiratory symptoms (fever, cough, dyspnoea, chest pain) in SCD patient
Causes: infection (pneumonia), fat embolism (from bone marrow infarction), pulmonary infarction
Treatment: antibiotics (ceftriaxone + azithromycin), oxygen, hydration, incentive spirometry, transfusion, bronchodilators
Severe: exchange transfusion (reduce HbS <30%)

Other crises

Organ-specific

Stroke: cerebral infarction (especially children). Urgent exchange transfusion.
Splenic sequestration: sudden splenic enlargement + Hb drop (children). Transfuse.
Aplastic crisis: parvovirus B19 → temporary RBC aplasia. Hb drops rapidly. Transfuse.
Priapism: painful persistent erection. Aspiration + phenylephrine. Exchange transfusion if severe.

[1] [2]

Crisis types in detail

Acute painful (VOC) crisis

~90% of admissions; #1 reason for ICU

Mechanism: vaso-occlusion in bone marrow/skeletal muscle → ischaemic nociceptive pain + secondary inflammatory pain
Pain often diffuse; classic dactylitis ("hand-foot syndrome") in infants. Back, chest, long bones, abdomen.
Severe VOC driving ACS: new infiltrate within 24–72 h of admission — 50% of "ACS" events are triggered by rib infarction + hypoventilation from opioid analgesia
Differentials to actively exclude: osteomyelitis, septic arthritis, intra-abdominal pathology, ACS, PE, acute abdomen

Acute chest syndrome (ACS)

#1 cause of death; ~10% of episodes

Definition: **new pulmonary infiltrate on CXR + ≥1 of fever, chest pain, tachypnoea, wheeze, cough, hypoxia (SpO2 drop >2% from baseline), increased work of breathing**
Aetiology (Vichinsky NASCSSG): infection ~30% (Chlamydia, Mycoplasma, RSV, S. pneumoniae), fat embolism ~10% (bone marrow infarction → fat emboli → POI + neurologic symptoms), infarction/occlusion, hypoventilation/atelectasis (rib infarction, opioid analgesia)
Risk factors: HbSS, low HbF, high steady-state Hb, recent VOC, postoperative, young adult, winter
Mortality 1–10% adults; recurrence ~50% → chronic lung disease, pulmonary hypertension

Stroke

Ischaemic in children; haemorrhagic in adults

Ischaemic stroke: ~11% of HbSS by age 20 — one of the highest childhood stroke rates of any disease. Driven by large-vessel vasculopathy of the distal ICA/MCA/ACA → moyamoya.
Primary screening: **annual transcranial Doppler (TCD)** ages 2–16. Abnormal (≥200 cm/s) → chronic transfusion (STOP trial).
Acute management: **urgent exchange transfusion** (target HbS <30%, Hb ≤110 g/L) — do NOT delay for MRI if clearly lateralising deficit. Standard thrombolysis is NOT indicated for the vaso-occlusive mechanism.
Secondary prevention: chronic transfusion for ≥1 year (STOP II / SWiTCH), transition to hydroxyurea after ~3 years if low-risk (TWiTCH).

Splenic sequestration

Children <5; functional asplenia later

Acute pooling of blood in an enlarged spleen → sudden Hb drop ≥20 g/L + reticulocytosis + palpable spleen >2 cm. Can progress to hypovolaemic shock within hours.
Major type: Hb <60 g/L + reticulocyte response; minor type: less severe. Triggered by viral infection.
Treatment: **isovolaemic transfusion** (avoid over-transfusion — splenic release causes rebound Hb rise). Fluid resuscitation for shock.
Recurrence rate high (~50%) → elective splenectomy after recovery. Chronic transfusion in younger children to delay splenectomy.

Aplastic crisis

Parvovirus B19 — self-limiting

Parvovirus B19 infects erythroid progenitor cells (P-antigen/globoside) → transient red-cell aplasia (~7–10 days). With a RBC lifespan of only ~10–20 days in SCD, Hb falls precipitously.
Hallmark: **very low reticulocytes** (<1% — distinguishes from sequestration/haemolysis), Hb 30–60 g/L, no rise in bilirubin/LDH. Serology: parvovirus B19 IgM+/PCR+.
Management: **transfusion** until marrow recovers; isolate (parvovirus is contagious to pregnant staff/contacts — hydrops fetalis). IVIG for immunocompromised / persistent infection.

Priapism

Ischaemic emergency — salvage window 24 h

Stuttering (recurrent, <4 h, often nocturnal) vs prolonged (>4 h, ischaemic). Sickling in corpora cavernosa → venous occlusion.
Prolonged priapism = **urological emergency**: risk of permanent ED >50% if >24 h.
Management: corporal aspiration + intracavernosal **phenylephrine** (α-agonist), ice, analgesia; **exchange transfusion** if refractory or recurrent; shunt surgery last resort. Pseudoephedrine/etafenone for stuttering prophylaxis.

Other organ-specific

Multi-organ & misc

Hepatic sequestration / intrahepatic cholestasis: RUQ pain, jaundice, transaminitis, extreme bilirubin. Exchange transfusion.
Renal: papillary necrosis (painless gross haematuria), sickle nephropathy (albuminuria, hyperkalaemia, type IV RTA).
Dactylitis (hand–foot) in infants; avascular necrosis of femoral head; retinal artery occlusion; fat embolism syndrome.
Acute multi-organ failure syndrome: sudden organ failure (lung, liver, kidney) + fever + falling platelets; **urgent exchange transfusion** — mimics sepsis/TTP.

[1] [2] [12] [15] [7] [14]

Management

Sickle cell crisis ICU management

Oxygen + hydration

Analgesia — treat pain aggressively

Investigate and treat triggers

Transfusion — SIMPLE or EXCHANGE

Acute chest syndrome specific management

Prevention of recurrence

[1] [2]

ICU bundle for the acute admission

First 6 hours of any sickle cell admission

0. Recognise the crisis & stratify severity

1. Oxygen + monitoring

Target SpO2 ≥94% (or within 2% of patient baseline). Continuous SpO2, serial ABG if any respiratory signs. Escalate SpO2 fall >2% from baseline as evolving ACS.

2. Hydration — isotonic, controlled

3. Analgesia — rapid, titrated, opioid-first

4. Investigate triggers

5. Empiric antibiotics

6. Incentive spirometry + VTE prophylaxis

Incentive spirometry q2 h while awake — halves ACS in patients with chest/back pain (Bellet trial principle). VTE prophylaxis (LMWH) for immobilised patients — SCD is prothrombotic.

[2] [4]

Acute chest syndrome — the killer complication

ACS recognition, monitoring & escalation

Recognise early (any one is enough)

Bundle: antibiotics + respiratory support

Simple transfusion — early

If Hb <90 g/L or falls >10 g/L from baseline, or PaO2/FiO2 <300 → simple/top-up transfusion to Hb ~100–110 g/L. Reduces HbS fraction by dilution.

Exchange transfusion — deteriorating

Advanced respiratory support

Disposition & follow-on

ICU for: rising FiO2, organ failure, exchange transfusion, unstable physiology. After recovery: initiate/optimise hydroxyurea, transfusion programme, plan vaccination, iron studies if transfused.

[12] [15]

Transfusion strategies

Simple (top-up) transfusion

Raising Hb

Indication: symptomatic anaemia (Hb <70, or <90 with ACS, or drop >20 from baseline). Aplastic crisis, sequestration (cautiously), pre-op in selected.
Goal: Hb 100–110 g/L. NEVER exceed 110–120 (hyperviscosity worsens sickling, stroke risk).
Phenotype-matched units (C, c, E, e, Kell) to reduce alloimmunisation (~30% of multi-transfused SCD patients form antibodies — anti-C, anti-E, anti-Kell common).

Exchange transfusion

Lowering HbS

Indications: **acute stroke, severe/progressive ACS, multi-organ failure syndrome, severe refractory VOC, severe priapism, hepatic sequestration, fat embolism, pre-op major surgery**.
Goal: HbS <30% (acute stroke, severe ACS) or <40% (elective), Hb ≤110 g/L. One volume exchange removes ~60% of HbS.
Automated erythrocytapheresis isovolaemic (preferred — removes HbS-rich cells precisely); manual 2-volume exchange if apheresis unavailable. Central venous access often required; large FFP/blood demand.

Chronic transfusion programme

Stroke prevention

Indications: secondary stroke prevention, primary prevention if abnormal TCD (STOP), severe/recurrent ACS, pregnancy in selected.
Goal: keep HbS <30% every 3–4 weeks. Iron overload monitoring (ferritin, MRI T2* liver/heart). Chelation (deferasirox first-line).
Transition to hydroxyurea after ~3 years if low risk (TWiTCH) — non-inferior with less iron overload.

[1] [2] [9]

Disease-modifying & preventive therapy

Hydroxyurea (hydroxycarbamide)

First-line; ↑HbF

Mechanism: ribonucleotide reductase inhibition → myelosuppression + **raises HbF** (γ-chain lacks β6 Val → no polymerisation); also ↓reticulocytes, ↓WBC, ↑NO.
Indications: ≥3 VOC/year, recurrent ACS, HbSS/HbSβ⁰-thal, from age 9 months (BABY HUG showed safety).
Dose: start 15–20 mg/kg/day (adult max 35 mg/kg/day), titrate to max tolerated dose (neutrophils ≥2.0, platelets ≥80). Monitor FBC q4–6 weeks. Cytopenia is dose-limiting and reversible.

Crizanlizumab (anti-P-selectin)

Adjuvant VOC prevention

Humanised monoclonal anti-P-selectin → blocks leucocyte/platelet–endothelium adhesion (SUSTAIN trial).
Indication: ≥2 VOC/year despite hydroxyurea (or contraindication). IV infusion 5 mg/kg q4 weeks.
Reduces crisis rate by ~45% (median 1.6 vs 3.0 crises/year). Not for acute treatment. Thrombocytopenia, infusion reactions.

Voxelotor (HbS polymerisation inhibitor)

Raises Hb, ↓haemolysis

Allosteric modifier of HbS — increases oxygen affinity → stabilises oxy-state → **inhibits polymerisation** (HOPE trial).
Indication: haemolytic anaemia phenotype; raises Hb by ~10 g/L. Oral 1500 mg daily.
Note: voluntary withdrawal from US market 2023 (PH-adjusted safety review; vaso-occlusive events signal) — check local availability. Avoid in pregnancy.

L-glutamine (endorcel)

Adjunct

Reduces oxidative stress (NAD⁺/NADH). Approved ; modest reduction in crisis/hospitalisation. Oral powder BID. Limited by GI side-effects and adherence.

Curative: HSCT

Myeloablative / RIC

Matched-sibling allogeneic HSCT: >90% overall / ~85% event-free survival; only ~15% have a matched sibling donor. Haploidentimal & unrelated donor protocols expanding.
Indications: severe phenotype (stroke, recurrent ACS, refractory VOC) especially children.

Curative: gene therapy (Casgevy)

FDA/MHRA-approved Dec 2023

CRISPR/Cas9 ex-vivo edit of the **BCL11A erythroid enhancer** in autologous CD34⁺ cells → reactivates γ-globin → high HbF → no polymerisation.
CLIMB-121: ~94% voxel-free from severe VOC for ≥12 months after exagamglogene autotemcel.
Other platforms: lovo-cel (lentiviral βA-T87Q) — Bluebird; beti-cel (Lyfgenia, FDA 2023). Cost (~US$2M), myeloablative busulfan conditioning, fertility/secondary malignancy considerations.

[8] [16] [17] [6]

Landmark trials & evidence

MSH (Charache 1995) — hydroxyurea in sickle cell anaemia

PMID 7715639

RCT, double-blind, 299 adults with ≥3 painful crises/year; hydroxyurea vs placebo

Key finding

Hydroxyurea reduced median crisis rate from 4.5 → 2.5/year, halved ACS episodes (25 vs 51), and reduced transfusions. Stopped early for efficacy. Foundation of hydroxyurea therapy.

STOP (Adams 1998–2000) — primary stroke prevention by transfusion

PMID 10830201

RCT, 130 children with abnormal TCD (≥200 cm/s); chronic transfusion vs observation

Key finding

Chronic transfusion reduced first stroke by ~90% (from 10%/year to <1%/year). Established TCD screening + transfusion for primary stroke prevention. Stopped early for overwhelming benefit.

TWiTCH (Ware 2016) — hydroxyurea non-inferior to transfusion

PMID 26670617

RCT non-inferiority, 121 children with abnormal TCD normalised after ≥1 year transfusion; switched to hydroxyurea vs continued transfusion

Key finding

Hydroxyurea non-inferior for maintaining normal TCD over 3 years. Allowed discontinuation of chronic transfusion and avoidance of iron overload in selected children.

SWiTCH (Ware 2012) — transfusion vs hydroxyurea for secondary stroke prevention

PMID 22318199

RCT, 133 children with prior stroke + iron overload; hydroxyurea + phlebotomy vs chronic transfusion + chelation

Key finding

SUSTAIN (Ataga 2017) — crizanlizumab for VOC prevention

PMID 27959701

RCT, 198 patients ≥2 VOC/year; crizanlizumab high-dose vs low-dose vs placebo

Key finding

High-dose crizanlizumab increased crisis-free survival (median 4.07 vs 1.38 months) and reduced annual crisis rate (1.63 vs 2.98). First targeted anti-adhesion therapy.

HOPE (Vichinsky 2019) — voxelotor in SCD

PMID 31199090

RCT, 274 patients; voxelotor 1500 mg, 900 mg vs placebo

Key finding

Voxelotor 1500 mg raised Hb >10 g/L in 51% vs 6% placebo, reduced haemolysis markers. Approved for haemolytic anaemia (later withdrawn in US 2023 pending safety review).

[1]

Vichinsky 2000 — NASCSSG ACS aetiology study

PMID 10861320

Prospective, 671 episodes / 538 patients; comprehensive microbiology + imaging

Key finding

CLIMB-121 / Casgevy (Frangoul 2024) — CRISPR gene therapy

PMID 38661449

Phase 1–3, single-arm, 44 patients with severe SCD; exagamglogene autotemcel (BCL11A enhancer edit)

Key finding

~94% were voxel-free (no severe VOC) for ≥12 consecutive months during 24-month follow-up. First CRISPR therapy approved (FDA/MHRA Dec 2023). Curative intent; long-term follow-up ongoing.

Acute stroke in SCD

Stroke in SCD — recognise and act in minutes

Recognise

Image immediately

Urgent exchange transfusion

Secondary prevention

Long-term

Repeat TCD/MRA surveillance (moyamoya risk). Consider revascularisation surgery (EDAS/pial synangiosis) for progressive moyamoya. Antiplatelet (aspirin) per stroke guidelines.

[5] [9] [10]

Splenic sequestration & aplastic crisis — paediatric emergencies

Splenic sequestration

Hypovolaemic shock risk

Sudden pooling of blood in enlarging spleen → Hb drop ≥20 g/L (often <60) + reticulocytosis + palpable spleen >2 cm. Mostly children <5 (HbSS), but adults with HbSC retain splenic function longer.
Treatment: **isovolaemic transfusion** (cautious — spleen releases trapped blood → rebound polycythaemia; target Hb ~80, recheck). IV fluids for shock.
Recurrence ~50% → splenectomy (after age ~2) or chronic transfusion to delay surgery. Parent education in palpating the spleen.

Aplastic crisis

Parvovirus B19

Parvovirus B19 infects erythroid precursors → transient RBC aplasia (~7–10 days). With shortened RBC lifespan, Hb falls to 30–60 g/L.
Hallmark: **reticulocytes <1%** (vs high in sequestration), no rise in bilirubin/LDH. Parvovirus IgM+/PCR+.
Treatment: transfuse until marrow recovery. **Isolate** (contagious — risk to pregnant contacts: hydrops fetalis). IVIG if persistent infection.

[14]

Priapism — urological emergency

Prolonged priapism (>4 h) management

Recognise

Prolonged, painful erection not resolved by ejaculation/urination. Stuttering (<4 h, often nocturnal) vs prolonged (>4 h, ischaemic). Corpora cavernosa rigid, glans spongy.

Analgesia + urology referral

Opioid analgesia (pain is severe). Urgent urology review — salvage window ~24 h before irreversible ED (>50% risk).

Corporal aspiration + phenylephrine

Exchange transfusion if refractory

Surgical shunt

Last resort — Winter/T-shunt / Ebbehoj. Distal glans–cavernosal shunt. High ED rate.

Prevent recurrence

[7]

Differential diagnosis of acute pain in SCD

VOC vs infection

Painful crisis vs osteomyelitis/septic arthritis

VOC: usually multifocal, symmetric, no systemic toxicity (initially). Often no fever or low-grade.
Osteomyelitis: unifocal, persistent, localised warmth/swelling, high fever, raised inflammatory markers, positive blood culture. Salmonella & S. aureus classic. MRI distinguishes.
Septic arthritis: hot swollen joint, restricted movement; aspirate joint fluid.

Abdominal pain

Mesenteric vs surgical

VOC of mesentery/abdominal organs: common, usually no peritonism. Often improves with hydration/analgesia.
Exclude: appendicitis, cholecystitis (pigment stones — almost universal by adulthood), splenic/ hepatic sequestration, pancreatitis, mesenteric adenitis, ectopic, AAA in older adults.
Worrying signs: peritonism, guarding, rising lactate, progressive organ dysfunction → surgical review.

Chest pain / dyspnoea

ACS vs PE/pneumonia

ACS: new infiltrate on CXR. PE: SCD is prothrombotic; D-dimer unhelpful (always raised). CTPA if suspicion.
Myocardial ischaemia (rare, young, but coronary vasculopathy + anaemia possible). Fat embolism (bone marrow infarction → triad of hypoxia, neuro signs, thrombocytopenia, petechiae).
Aortic dissection, pneumothorax (especially with pneumonia/ventilation) — bedside ultrasound.

[1] [4]

Anaesthesia & perioperative considerations

Perioperative management of SCD

Pre-op

Intra-op

Post-op

High-risk surgery

Major (cardiac, neuro, prolonged): pre-op exchange transfusion to HbS <30%, Hb 100–110.

[2]

Complications of transfusion

Alloimmunisation

~30% multi-transfused

Anti-C, anti-E, anti-Kell most common. Mitigate with **extended phenotype-matched units** (Rh + Kell). Risk of delayed haemolytic transfusion reaction (DHTR) days–weeks later.

Iron overload

Chronic transfusion

Each unit ~200 mg iron; no physiological excretion. Monitor ferritin + MRI T2* (liver, heart). Chelation: deferasirox (first-line), deferiprone, deferoxamine. Cardiac iron → cardiomyopathy/arrhythmia.

Acute transfusion reactions

AHTR, TACO, TRALI, allergic

Acute haemolytic (ABO mismatch, alloantibody) — stop transfusion, supportive. TACO (circulatory overload). TRALI (within 6 h, hypoxia + bilateral infiltrates, no raised LA pressure).

Infection

Historical & residual

HBV, HCV, HIV (now very low risk). Bacterial contamination (rare but high mortality). Parvovirus B19 (pure red cell aplasia). Prion (theoretical).

[2]

Exam practice

SAQ — Acute chest syndrome and exchange transfusion

10 minutes · 10 marks

[1]

SAQ — Splenic sequestration and the acute anaemia crises

10 minutes · 10 marks

[1]

Clinical pearls

High-yield sickle cell crisis points for the CICM/FFICM exam

Acute chest syndrome = new infiltrate + respiratory symptoms = #1 cause of death.[1]
Exchange transfusion for stroke, severe ACS, multi-organ failure. Target HbS <30%.[2]
Do NOT over-transfuse — target Hb 100-110. Hyperviscosity above 110 worsens sickling.[1]
Treat pain aggressively — opioids (morphine PCA). Do NOT undertreat.[2]
Hydration (1-1.5x maintenance) — reduces viscosity, prevents sickling.[2]
Stroke in SCD: urgent exchange transfusion (reduce HbS <30%).[1]
Triggers: infection (#1), dehydration, cold, hypoxia, altitude, stress.[2]
Functional asplenia — prophylactic penicillin, vaccination (encapsulated organisms).[1]
Parvovirus B19 → aplastic crisis (temporary bone marrow suppression). Transfuse.[1]
Priapism: prolonged erection. Aspiration + phenylephrine ± exchange transfusion.[2]
Hydroxyurea: increases HbF → reduces sickling and crisis frequency.[2]
CRISPR gene therapy (Casgevy): FDA-approved Dec 2023 — edits BCL11A gene to reactivate fetal haemoglobin.[2]
SCD is autosomal recessive — HbS inherited from BOTH parents (homozygous HbSS = sickle cell disease). Heterozygous (HbAS) = sickle cell trait (usually asymptomatic).[1]
Mortality: median survival ~45-55 years (improving with modern care).[1]

Examiner-favourite molecular & pathophysiology pearls

The molecular lesion is a single point mutation: GAG→GTG in codon 6 of HBB → glutamic acid replaced by valine at position 6 of the β-chain (β6 Glu→Val). One base, one amino acid, one disease.[1]
HbF inhibits polymerisation because the γ-chain (fetal) lacks the β6 Val contact site — the entire rationale for hydroxyurea (↑HbF) and Casgevy gene therapy (edits BCL11A to switch HbF back on).[3]
Polymerisation has a delay time inversely related to [HbS]²⁰–³⁰ — hence small reductions in HbS (transfusion) or concentration (hydration) cause large kinetic slowing, and why a cell that traverses the pulmonary capillary before polymerising does NOT sickle (kinetics, not just equilibrium).[3]
MCHC is the master variable: RBC dehydration (Gardos/K-Cl cotransport) raises MCHC and shortens delay time — the driest cells sickle first. Acidosis, hypoxia and 2,3-DPG all accelerate polymerisation.[13]
Two clinical phenotypes: a haemolysis–endothelial dysfunction phenotype (low Hb, high LDH/retic; pulmonary hypertension, priapism, leg ulcers, stroke, renal disease — NO depletion) vs a viscosity–vaso-occlusion phenotype (higher Hb, lower retic; painful crisis, ACS, osteonecrosis). Predicts complications and therapy response.[13]
Free haemoglobin scavenges nitric oxide + arginase depletes arginine → the unifying mechanism of SCD vasculopathy (pulmonary HTN, priapism, stroke).[13]
Sickle cell trait (HbAS) is usually asymptomatic but: exertional rhabdomyolysis/sudden death (athletes), renal papillary necrosis (haematuria), splenic infarction at altitude, and a small but real VTE risk.[1]
α-thalassaemia trait co-inheritance ameliorates HbSS (lowers MCHC, fewer ISCs) — a classic modifier. High HbF (BCL11A/XmnI polymorphisms) is another.[3]
Functional asplenia develops by age 5–7 in HbSS (autoinfarction); HbSC/HbSβ⁺ retain splenic function longer → higher sequestration risk in adulthood.[1]
Pigment gallstones are almost universal by adulthood in HbSS — consider cholecystitis in any RUQ pain.[4]

Acute chest syndrome pearls — the highest-yield ICU content

ACS is the leading cause of death in SCD and the commonest reason for ICU admission; ~50% of ACS episodes arise during a VOC admission (rib/marrow infarction → splinting → atelectasis, plus opioid-induced hypoventilation).[15]
Incentive spirometry q2 h in any patient with chest/back/rib pain halves the risk of ACS (Bellet) — a cheap, evidence-based intervention often forgotten.[15]
Fat embolism syndrome (bone marrow infarction → fat in pulmonary circulation): triad of sudden hypoxia + neurologic signs (confusion, seizures) + falling platelets/petechiae. Mimics ACS/TTP/DIC — exchange transfusion is the treatment.[15]
The classic microbiology (NASCSSG): Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory viruses (RSV, influenza), and S. pneumoniae / H. influenzae — hence the ceftriaxone + macrolide combination, not just beta-lactam.[15]
Steroids (prednisone 2 mg/kg) speed recovery but rebound VOC/bleeding when stopped — use short course only, not routine.[12]
Escalation thresholds for exchange transfusion: new multilobar infiltrate, PaO2 <60 mmHg on FiO2 ≥0.5, Hb fall >20 g/L, platelet fall, or any multi-organ failure.[12]
Inhaled nitric oxide / epoprostenol for refractory hypoxaemia; V-V ECMO as last resort at specialist centres.[12]
~50% of patients who have one ACS episode will have another → chronic lung disease, pulmonary hypertension. Initiate hydroxyurea / chronic transfusion after recovery.[1]

Transfusion & exchange transfusion pearls

Simple top-up transfusion: target Hb 100–110 g/L. NEVER exceed 110–120 — hyperviscosity worsens sickling, ↑stroke risk. Caution in sequestration (spleen releases blood → rebound).[1]
Exchange transfusion for acute stroke: HbS <30%, Hb ≤110 g/L. One volume exchange removes ~60% of HbS; 1.5–2 volumes removes ~80%. Automated erythrocytapheresis is isovolaemic and preferred.[2]
Always phenotype-match units (Rh C/c/E/e + Kell) — alloimmunisation in ~30% of multi-transfused SCD patients; anti-Kell, anti-C, anti-E dominate. DHTR can masquerade as a "pain crisis" days–weeks later.[2]
TCD screening (annual, ages 2–16) detects abnormal flow (≥200 cm/s) → chronic transfusion prevents ~90% of first strokes (STOP). Non-inferiority of hydroxyurea after ≥1 year of transfusion (TWiTCH) allows safer transition.[5]
Iron overload with chronic transfusion — monitor ferritin + MRI T2* (liver, heart); deferasirox first-line chelation. Cardiac iron → arrhythmia/cardiomyopathy, a leading late cause of death.[9]
Beware ASPEN syndrome (afibrinogenaemia + sudden severe thrombocytopenia) after exchange transfusion for priapism — rare but fatal. Check fibrinogen post-procedure.[7]

Pharmacology pearls — disease-modifying therapy

Hydroxyurea (hydroxycarbamide): inhibits ribonucleotide reductase → ↑HbF, ↓WBC/reticulocytes, ↑NO. MSH (1995) halved crisis + ACS rates. Start 15–20 mg/kg/day, titrate to max tolerated (neutrophils ≥2.0). Reversible cytopenia. First-line for nearly all HbSS from age 9 months.[8]
Crizanlizumab: anti-P-selectin mAb; SUSTAIN (2017) raised crisis-free survival (4.07 vs 1.38 months). Adjunct for ≥2 VOC/year despite hydroxyurea. IV q4 weeks. Adjuvant, not rescue.[16]
Voxelotor: allosteric HbS modifier — ↑O2 affinity → inhibits polymerisation; HOPE (2019) raised Hb & ↓haemolysis. Voluntarily withdrawn in the US (2023) pending a PH-adjusted safety review (vaso-occlusive signal) — check local availability; avoid in pregnancy.[17]
L-glutamine (endorcel): oral, modest effect, ↓oxidative stress. Adjunct; GI side-effects, adherence issues.[4]
Casgevy (exagamglogene autotemcel): CRISPR/Cas9 edit of BCL11A erythroid enhancer → γ-globin/HbF re-expression. CLIMB-121: ~94% voxel-free from severe VOC ≥12 months. FDA/MHRA-approved Dec 2023. Myeloablative busulfan conditioning — fertility, secondary malignancy considerations; ~US$2M cost.[6]
HSCT (matched sibling >90% OS, ~85% EFS) remains the original curative option — only ~15% have a matched sibling; haploidentical/unrelated donor protocols expanding.[4]
Penicillin V prophylaxis (children, <5 years or post-splenectomy) + vaccination (pneumococcal PCV13 + PPSV23, Hib, meningococcal ACWY + B, influenza annual, hepatitis B) against encapsulated organisms.[1]

Prognosis, epidemiology & long-term pearls

Global burden rising: SCD is the most common monogenic disease worldwide; ~300,000 babies born with HbSS annually, mostly in sub-Saharan Africa, India, Mediterranean, Middle East. The Lancet Haematology Commission (2023) prioritises newborn screening, penicillin, hydroxyurea access.[11]
Median survival ~45–55 years in high-income settings (longer with comprehensive care); childhood mortality >50–90% in low-resource settings without newborn screening.[11]
Pulmonary hypertension (TRV >2.5 m/s on echo) is an independent predictor of death; screen with echo + NT-proBNP. NO-depletion phenotype.[13]
Sickle nephropathy: hyperfiltration → microalbuminuria → proteinuria → CKD/ESKF. ACE-inhibitor/ARB for albuminuria. Type IV RTA (hyperkalaemia, acidosis) common — avoid NSAIDs where possible.[4]
Retinopathy more common in HbSC than HbSS (higher viscosity) — proliferative sickle retinopathy → vitreous haemorrhage, retinal detachment; annual ophthalmology review.[1]
Avascular necrosis of the femoral humeral head — common cause of chronic pain and disability; core decompression / arthroplasty.[1]
Pregnancy: increased risk of VOC, ACS, pre-eclampsia, fetal growth restriction, sepsis, death. Prophylactic low-dose aspirin; LMWH prophylaxis; transfuse if symptomatic anaemia or history of poor outcome. Hydroxyurea contraindicated in pregnancy — stop pre-conception.[2]

Red flags

Escalation triggers — when to call for help

Falling SpO2 / new infiltrate / rising O2 requirement → evolving ACS: escalate oxygen, antibiotics, bronchodilators, transfusion, consider exchange.[12]
Falling Hb >20 g/L or Hb <70 → check reticulocytes (sequestration = high; aplasia = low), transfuse matched units; sequestration → cautious isovolaemic transfusion.[1]
New neurologic deficit / seizure / severe headache → stroke/SAH: image, urgent exchange transfusion; do NOT delay for MRI.[5]
Fever >38.5°C in a child or unwell adult → sepsis protocol: cultures + empiric IV ceftriaxone within 1 h (functional asplenia). Add macrolide if ACS features.[2]
Priapism >4 h → urology now; corporal aspiration + phenylephrine; exchange transfusion if refractory.[7]
Multi-organ failure (lung + liver + kidney + falling platelets) → fat embolism / acute multi-organ failure syndrome → urgent exchange transfusion.[15]
Acute severe anaemia with reticulocytes <1% → parvovirus B19 aplastic crisis → transfuse + isolate (pregnancy risk).[14]

Pitfalls & avoidable deaths

Pethidine (meperidine) → norpethidine neurotoxicity (seizures, especially renal impairment). Avoid — use morphine/fentanyl.[2]
Over-hydration (especially in ACS, CKD, cardiac disease) → pulmonary oedema, worsening hypoxia. Titrate, reassess.[12]
Over-transfusion (Hb >110–120) → hyperviscosity, stroke, ACS worsening. Cap simple transfusion at Hb ~110.[1]
Withholding opioids for fear of dependence/resp. depression → undertreated pain, splinting, atelectasis, ACS. PCA is safe and effective.[2]
Forgetting phenotype matching → alloimmunisation, DHTR, difficulty finding future units.[2]
Missing pregnancy / renal potassium with NSAIDs → AKI / fetal harm. Check before each dose.[2]
Assuming trait = disease: HbAS patients are usually asymptomatic — but counsel about altitude, exertional collapse, microhaematuria, anaesthetic risk.[1]

Comparison of crisis types at a glance

Feature

Pain (VOC)
Acute chest
Stroke
Splenic sequestration
Aplastic
Priapism

Frequency

Most common (~90%)
~10% of admissions
~11% by age 20 (HbSS)
Children <5
Any age (epidemic)
Adult males ~35%

Key feature

Severe ischaemic pain
New infiltrate + resp symptoms
Focal deficit / TCD ≥200
Spleen + Hb drop + retics↑
Reticulocytes <1%
Painful erection >4 h

First treatment

O2 + fluids + opioid PCA
Abx + O2 + IS + transfusion
Urgent EXCHANGE transfusion
Cautious transfusion + fluids
Transfuse + isolate
Aspiration + phenylephrine

Definitive / specific

Hydroxyurea prevention
Exchange if worsening
Chronic transfusion → HU
Splenectomy (recurrence)
Self-limiting (7–10 d)
Exchange if refractory

[1] [2]

Key points to take to the exam

Twenty-second summary — the must-say points

One mutation (β6 Glu→Val, HBB codon 6, GAG→GTG) → HbS polymerises when deoxygenated → sickling, haemolysis, vaso-occlusion, multi-organ vasculopathy.[1]
Crisis types: vaso-occlusive (pain, #1 admission cause), acute chest syndrome (#1 death cause), stroke, splenic sequestration, aplastic (parvovirus B19), priapism.[4]
Management: oxygen, isotonic hydration 1–1.5× maintenance, opioid PCA (morphine), treat triggers, incentive spirometry, empiric antibiotics (ceftriaxone ± macrolide).[2]
Simple transfusion if Hb <70–90 (target 100–110, never >120); exchange transfusion for stroke / severe ACS / MOF / refractory (HbS <30%).[1]
Prevention/modification: hydroxyurea (↑HbF, first-line), crizanlizumab (anti-P-selectin), voxelotor (polymerisation inhibitor — withdrawn US), L-glutamine; curative = HSCT and CRISPR gene therapy (Casgevy, 2023).[8][6]
Fever = sepsis until proven otherwise (functional asplenia) — penicillin prophylaxis + vaccines.[1]

References

[1]Rees DC, Williams TN, Gladwin MT. Sickle-cell disease Lancet, 2010.PMID 21131035
[2]Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members JAMA, 2014.PMID 25203083
[3]Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease Nat Rev Dis Primers, 2018.PMID 29542687
[4]Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review JAMA, 2022.PMID 35788790
[5]Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study J Child Neurol, 2000.PMID 10830201
[6]Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease N Engl J Med, 2024.PMID 38661449
[7]Kato GJ. Priapism in sickle-cell disease: a hematologist's perspective J Sex Med, 2012.PMID 21554552
[8]Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia N Engl J Med, 1995.PMID 7715639
[9]Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial Lancet, 2016.PMID 26670617
[10]Ware RE, Helms RW, SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Blood, 2012.PMID 22318199
[11]Piel FB, Tewari S, Brousse V, et al. Defining global strategies to improve outcomes in sickle cell disease: a Lancet Haematology Commission Lancet Haematol, 2023.PMID 37451304
[12]Bhasin N, Sarode R. Acute Chest Syndrome in Sickle Cell Disease Transfus Med Rev, 2023.PMID 37741793
[13]Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease J Clin Invest, 2017.PMID 28248201
[14]Serjeant GR, Mason K, Topley JM, et al. Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent Lancet, 1981.PMID 6116082
[15]Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group N Engl J Med, 2000.PMID 10861320
[16]Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease N Engl J Med, 2017.PMID 27959701
[17]Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease N Engl J Med, 2019.PMID 31199090

Your progress

Pathophysiology — the molecular basis

1. The mutation (HBB c.20A>T; p.Glu6Val)

2. Deoxygenation → HbS polymerisation

3. Sickling → deformed, rigid, dehydrated erythrocyte

4. Haemolysis — the haemolytic phenotype

5. Endothelial activation + leucocyte/platelet adhesion

6. Vaso-occlusion → ischaemia–reperfusion

7. Chronic vasculopathy

Types of crisis

Vaso-occlusive (VOC)

Acute chest syndrome (ACS)

Other crises

Crisis types in detail

Acute painful (VOC) crisis

Acute chest syndrome (ACS)

Stroke

Splenic sequestration

Aplastic crisis

Priapism

Other organ-specific

Management

Oxygen + hydration

Analgesia — treat pain aggressively

Investigate and treat triggers

Transfusion — SIMPLE or EXCHANGE

Acute chest syndrome specific management

Prevention of recurrence

ICU bundle for the acute admission

0. Recognise the crisis & stratify severity

1. Oxygen + monitoring

2. Hydration — isotonic, controlled

3. Analgesia — rapid, titrated, opioid-first

4. Investigate triggers

5. Empiric antibiotics

6. Incentive spirometry + VTE prophylaxis

Acute chest syndrome — the killer complication

Recognise early (any one is enough)

Bundle: antibiotics + respiratory support

Simple transfusion — early

Exchange transfusion — deteriorating

Advanced respiratory support

Disposition & follow-on

Transfusion strategies

Simple (top-up) transfusion

Exchange transfusion

Chronic transfusion programme

Disease-modifying & preventive therapy

Hydroxyurea (hydroxycarbamide)

Crizanlizumab (anti-P-selectin)

Voxelotor (HbS polymerisation inhibitor)

L-glutamine (endorcel)

Curative: HSCT

Curative: gene therapy (Casgevy)

Landmark trials & evidence

MSH (Charache 1995) — hydroxyurea in sickle cell anaemia

STOP (Adams 1998–2000) — primary stroke prevention by transfusion

TWiTCH (Ware 2016) — hydroxyurea non-inferior to transfusion

SWiTCH (Ware 2012) — transfusion vs hydroxyurea for secondary stroke prevention

SUSTAIN (Ataga 2017) — crizanlizumab for VOC prevention

HOPE (Vichinsky 2019) — voxelotor in SCD

Vichinsky 2000 — NASCSSG ACS aetiology study

CLIMB-121 / Casgevy (Frangoul 2024) — CRISPR gene therapy

Acute stroke in SCD

Recognise

Image immediately

Urgent exchange transfusion

Secondary prevention

Long-term

Splenic sequestration & aplastic crisis — paediatric emergencies

Splenic sequestration

Aplastic crisis

Priapism — urological emergency

Recognise

Analgesia + urology referral

Corporal aspiration + phenylephrine

Exchange transfusion if refractory

Surgical shunt

Prevent recurrence

Differential diagnosis of acute pain in SCD