Chapter 20: Sickle Cell

Historical Background

  • 1910: First medical description of SCA (Walter Noel; Herrick & Irons) – introduced the term “sickle.”
  • 1920-30s: Sydenstricker coined “crisis,” Hahn & Gillespie linked sickling to de-O2; Harris visualised intracellular tactoids.
  • 1940s: Hb electrophoresis separated HbS from HbA.
  • 1949: J.V. Neel proved Mendelian inheritance – differentiated HbAS (trait) vs HbSS (disease).
  • 1950s-70s: Structure of normal & variant Hbs, β6 Glu→Val pinpointed; polymer ultrastructure (7 paired double filaments, 21 nm diameter) elucidated.
  • 1970s-present: CSSCD & international cohorts defined natural history, risk factors, screening, preventive therapies.

Pathophysiology

Hemoglobin S Mutation & Haplotypes

  • Single-base substitution in β-globin gene (GAG→GTG) ⇒ β6 Glu→Val (βS).
  • Hydrophobic Val exposed only in deoxy conformation → abnormal lateral contact → polymer seed.
  • Five independent origins (Senegal, Benin, CAR/Bantu, Cameroon, Arab-Indian); haplotype influences HbF level & severity (Senegal/Arab-Indian milder, CAR severe).
  • Distribution parallels historic malaria – heterozygote advantage (impaired parasite growth, enhanced clearance, altered cyto-adherence).

Polymer Formation (“Double Nucleation”)

  • Homogeneous nucleus: spontaneous 30-tetramer critical fiber.
  • Heterogeneous nucleus: growth on pre-existing fiber; reaction becomes autocatalytic.
  • Delay time 1/t<em>d=K (C/C</em>s)301/t<em>d=K\,(C/C</em>s)^{30} – 30th-power dependence ⇒ tiny [Hb]Δ hugely alters kinetics.
  • Kinetics modulated by pO₂, pH, T, ionic strength, 2,3-DPG.
  • Slow de-O₂ ⇒ long aligned polymers; fast capillary transit (<1 s) can outrun polymerisation.

Interaction with HbA & HbF

  • HbA or HbF dilute HbS and raise solubility; HbF far more potent.
    • 15-30 % HbA → delay ↑×10² ; 20-30 % HbF → delay ↑×10⁴ ; 60 % HbA (trait) → delay ↑×10⁶.
  • HbF hardly enters polymer (α₂β^Sγ asymmetric hybrids excluded) vs HbA hybrids incorporated.

Membrane & Ionic Damage

  • HbS binds membrane > HbA; auto-oxidation → ROS → band-3 clustering, IgG opsonisation, Heinz bodies, ankyrin/spectrin damage.
  • Gardos channel (KCa, KCNN4) & K⁺/Cl⁻ cotransporter dehydrating loops: Ca²⁺ influx → K⁺Cl⁻ efflux → water loss → ↑MCHC.
  • Pathologic variants: ↑Ca²⁺, ↓Mg²⁺ activate channels. Inhibitors: clotrimazole, senicapoc (failed phase III); oral Mg²⁺ (mixed results).
  • ISC: MCHC >44 g dL⁻¹, membrane ‘locked’ by oxidised β-actin & non-ubiquitinated α-spectrin; survive days; correlate with hemolysis, splenomegaly.

External Interactions & Hyper-adhesion

  • Reticulocytes display VLA-4, CD47, Lu/BCAM → bind VCAM-1, thrombospondin, laminin, fibronectin.
  • Endothelial activation (TNF-α, IL-18) ↑VCAM-1/ICAM-1/E-,P-selectin.
  • PS externalisation flips during sickling; pro-coagulant surface accelerates thrombin (↑F1.2, TAT, D-dimer).

Hemolysis & NO Depletion

  • 1⁄3 intravascular hemolysis releases free Hb that scavenges NO.
  • ↓NO → vasoconstriction, platelet activation, endothelial dysfunction; proposed link to PHT, priapism, leg ulcers.
  • Alternative PHT path: marrow hyperplasia → placental growth factor → endothelin-1.

Inflammation

  • Baseline leukocytosis, CRP, vWF, fibrinogen; neutrophil/endothelial adhesion via P-selectin.
  • iNKT cells & mast-cell activation contribute to ACS & pain (A2A agonist regadenoson; imatinib in mice).
  • Chronic vasculopathy → organ damage independent of acute crises.

Genetic Modifiers

  • α-thalassemia (–α/αα or –α/–α) ↓MCHC, ↓hemolysis, ↓stroke but ↑pain/AVN (↑viscosity).
  • HbF regulators: large HPFH deletions (HbS/HPFH pancellular, benign); XmnI (–158 C→T); trans-acting loci HBS1L-MYB (6q23) & BCL11A (2p15) explain ≈30 % HbF variance.
  • UGT1A1 promoter (TA)₇ → hyperbilirubinaemia & gallstones.
  • Few validated phenotype modifiers beyond these.

Diagnosis

Fetal/Pre-implantation

  • PCR or sequencing of chorionic villus (8-10 wk), amnio (≥15 wk), PGD on blastomere.
  • Non-invasive cell-free fetal DNA under study.

Newborn Screening

  • Universal US screening (IEF or HPLC on dried-blood spot). Cord blood/transfusion may yield false-neg.

Older Children Baseline Labs

  • Progressive anemia (Hb 6–9 g dL⁻¹), retic ↑ to >10\% , HbF declines slowly; morphology evolves from targets→ISCs.

Clinical Manifestations

Vaso-occlusive Crises

  • Pain (bones, back, chest); dactylitis in <5 y.
    • Risk ↑ with HbF<8.6 %, WBC↑, prior dactylitis, low baseline Hb.
  • Osteomyelitis vs infarct: Salmonella, Staph, Gr-ve bacilli; MRI, culture definitive.

Acute Chest Syndrome (ACS)

  • New infiltrate + fever/tachypnoea/hypoxia.
  • Etiologies: fat embolus, bacteria (Strep, Staph), atypical (Mycoplasma, Chlamydia), viruses.
  • Management: broad ABx (incl. macrolide), O₂, bronchodilator, incentive spirometry, simple Tx → Hb≈10 g dL⁻¹ (exchange if refractory).

CNS Events

  • Ischemic stroke incidence 0.7 % yr⁻¹; peak 5–10 y.
  • TCD: TAMV ≥200 cm s⁻¹ predicts stroke; STOP showed 92 % risk reduction with chronic transfusion.
  • Secondary prevention: indefinite transfusion (HbS<30 %) better than hydroxyurea+phlebotomy (SWiTCH).
  • Silent cerebral infarcts ≥25 % prevalence → cognitive deficits.

Splenic Sequestration

  • Rapid splenomegaly, Hb↓≥2 g dL⁻¹, thrombocytopenia. Treat with urgent transfusion. Consider elective splenectomy after ≥1 episode.

Aplastic Crisis

  • Parvovirus B19 → retic 0 %, Hb↓ rapidly; supportive transfusion.

Priapism

  • Stuttering (

Acute Abdomen

  • Rule-out cholecystitis, hepatic sequestration, splenic infarct. US & labs, cautious opioids, surgical consultation.

Infection

  • Encapsulated bacteria (Strep pneumo, H. flu, Salmonella). Functional asplenia by 2 y; give PCV13, PPV23 (>2 y), Hib, MenACWY, annual flu; penicillin 125 mg BID ≤3 y then 250 mg BID until 5 y (longer if splenectomy/ sepsis).
  • Febrile child (≥38.5 °C): cultures, ceftriaxone 50–75 mg kg⁻¹ ASAP; admit if toxic, Hb

Chronic Organ Damage

  • Cardio: chamber dilation, high output; TR jet velocity >2.5 m s⁻¹ signals PHT & ↑mortality.
  • Renal: hyposthenuria, micro-/macro-albuminuria (screen ≥10 y yearly); ACE-I if persistent; papillary necrosis ⇒ hematuria.
  • Hepatobiliary: pigmented stones (40 % teens), cholecystectomy if symptomatic; intrahepatic cholestasis (high direct bili).
  • Eye: proliferative sickle retinopathy (stages I-V); annual dilated exam ≥10 y; consider laser.
  • Skin: chronic malleolar ulcers – compression, wound care, transfusion/hydroxyurea if refractory.
  • Bone: AVN of femoral/humeral heads (incidence rises with age, α-thal); treat with PT, analgesia, core decompression, arthroplasty.
  • Growth/puberty: delayed height/weight; catch-up by adulthood; menarche linked to weight; monitor zinc, vitamins.

Mortality

  • Childhood deaths ↓ with penicillin & vaccines; current survival to 18 y ≈94 %.
  • Adult median survival HbSS 42 y (♂) /48 y (♀); HbSC 60/68 y.
  • Early death risks: HbF <8-9 %, WBC↑, pain/ACS frequency, Hb<7 g dL⁻¹ <2 y, ↑BP, low SpO₂.

Therapeutic Approaches

Health Maintenance

  • Visits q3 mo (infant) then q6 mo; record vitals, spleen, labs.
  • Education: fever action plan, hydration, pain plan, inheritance, transition.

Pain Management

  • Home: fluids, heat, NSAIDs/opioids.
  • Hospital: IV fluids 1-1.25× maintenance; rapid parenteral opioids (avoid meperidine); NSAID (ketorolac), PCA preferred; monitor for hypoventilation (incentive spirometry q2 h).

HbF Induction

  • Hydroxyurea PO daily; start ≥9 mo; escalate q8 wk to MTD (ANC 2–4×10⁹/L).
  • Benefits: ↓pain, ACS, transfusion, mortality; preserves spleen/kidney; safe long-term.
  • Other agents: decitabine, 5-azacytidine, butyrate (IV/oral), in trials.

Lower HbS Concentration / Dehydration Blockade

  • Gardos inhibitor senicapoc improved MCHC but no crisis reduction.
  • Oral Mg²⁺ blocks KCC; mixed data.

Polymer Solubility / Direct Anti-sickling

  • Covalent modifiers (cyanate) neuro-toxic; Voxelotor (Hb–O₂ affinity modulator) in trials.

Reduce Dwell Time / Adhesion

  • Poloxamer 188 (rheo-modifier) – ongoing study.
  • Selectin blockers (e.g., crizanlizumab, rivipansel) in phase II/III.
  • Inhaled NO