11  Sickle Cell Disease

Key Points
  • SCD: autosomal recessive hemoglobinopathy w/ 2 abnormal HBB genes; HbSS, HbSC, HbSβ-thalassemia most common US genotypes
  • Pathophysiology: HbS polymerization → hemolysis, endothelial injury, inflammation, hypercoagulability, vaso-occlusion
  • Epidemiology: ~100,000 US patients; near-universal childhood survival in high-resource settings; significant mortality in low-resource areas
  • Key complications: VOC, stroke, ACS, organ damage (lung, heart, kidney, liver, bone, retina, penis, placenta)
  • TCD screening: identifies high-risk stroke; velocity ≥200 cm/s → prophylactic transfusion, ~90% risk reduction
  • 1° therapies: hydroxyurea, chronic transfusions; novel agents: crizanlizumab, voxelotor, HSCT, gene therapy
  • Curative: HSCT for children ≤13 yo w/ matched sibling; gene therapy investigational

11.1 Introduction

  • SCD prevalence: ~100,000 US; millions worldwide
  • Genetics: 2 abnormal HBB genes; ≥1 must be βS variant
  • Common genotypes: HbSS (sickle cell anemia), HbSC, HbSβ-thalassemia
  • Sickle trait (HbAS): 5% African ancestry; ~20% Saudi Arabia/Oman; >40% West Africa
    • Malaria protection → evolutionary advantage
  • Pathophysiology: HbS polymerization → hemolysis, endothelial injury, abnormal adhesion, inflammation, hypercoagulability, vaso-occlusion
  • Hemolysis effects: RBC survival ↓ to 10–20 days; ↑ LDH, ↓ haptoglobin, ↑ indirect bili, jaundice, cholelithiasis (80% by age 21)

11.2 Sickle Cell Trait

  • HbAS: heterozygous; asymptomatic normally
  • Prevalence: >20% Central Africa; ~20% Saudi Arabia/Oman; 2–3% African Americans
  • Findings: normal Hb, mild polymerization under stress, no clinical disease
  • No dactylitis: distinguishes from SCD
  • Counseling: important for genetic assessment, prenatal testing, HSCT eligibility

11.3 Pathophysiology

11.3.1 Sickling Mechanism

  • Under deoxygenation: HbS polymerizes → long fibers, crystalline structures, RBC distortion
  • Reoxygenation: reverses polymerization initially
  • Repeated cycles: → irreversible sickling, ↓ RBC deformability

11.3.2 HbS Polymerization

  • Hb structure: α₂β₂ heterotetramer
  • Mutation: β-chain Glu6Val (HBB GAG→GTG) creates hydrophobic patch
  • Triggers: deoxygenation, hypoxia, acidosis, dehydration
  • T state: deoxygenation → conformational change → polymerization via hydrophobic interactions

11.3.3 Chronic Effects

  • HbF protection: does not polymerize w/ HbS; ↑ HbF → milder disease
  • RBC changes: membrane stiffness, fragmentation, hemolysis
  • Hb concentration: intracellular density & other Hb types affect sickling propensity
  • Survival: HbSS 10–25 days; HbSC 30–40 days (vs. 120 days normal)

11.4 Laboratory Features

11.4.1 Diagnosis

  • Hemoglobin electrophoresis: isoelectric pH separates HbS, HbA, HbC, HbF
  • Citrate agar: pH 6; separates HbS from HbC; distinguishes HbSS vs HbSC
  • HPLC: gold standard; identifies HbS, HbA, HbC, HbF, HbA₂
  • Solubility test: dithionite tube; confirms HbS but not HbS zygosity

11.4.2 Initial Workup

  • CBC: Hb, hematocrit, Hb typing (HPLC preferred), reticulocyte count
  • Peripheral smear: review morphology
  • Hemoglobin levels: HbA₂, HbF (assess thalassemia inheritance)
  • Chemistry: kidney (creatinine, urine microalbumin/creatinine), liver (AST, ALT)
  • Hemolysis: LDH, haptoglobin, indirect bili
  • Baseline: eye exam
Typical findings SCD variants
Disease Severity S % F % A₂ % Hb (g/dL) MCV (fL)
HbSS Marked >90 <10 <3.5 6–9 >80
HbAS Marked endurance >80 <20 >3.5 8–12 85–95
HbSC Mild-moderate >60 <20 >3.5 10–30 <75
HbSβ⁺ Mild-moderate >60 >5 >3.5 10–30 75–85
HbSβ⁰ Asymptomatic >50 >20 <2.5 12–14 <80
HbS-HPFH Asymptomatic >70 >20 <2.5 12–14 <80

11.5 Clinical Manifestations

11.5.1 Anemia & Hemolysis

  • Baseline Hb: HbSS 6–9 g/dL; HbSC 10–12 g/dL
  • Smear findings: microcytosis, target cells, polychromasia
  • Markers: ↑ retic, ↑ LDH, ↓ haptoglobin, ↑ indirect bili → hemolysis

11.5.2 Vaso-Occlusive Crisis (VOC)

  • Most common complication: polymerization → sickling, ↓ RBC deformability, abnormal adhesion, ↑ viscosity, vaso-occlusion
  • Triggers: hypoxia, dehydration, fever, cold, infection, stress, menstruation, exercise
  • Pain location: bones (femur, tibia, humerus, pelvis, spine, jaw, ribs), joints (knee, shoulder, elbow)
  • Duration: minutes to weeks; variable severity
  • Marker of severity: frequency of painful episodes

11.5.3 Acute Splenic Sequestration

  • Age: <5 years; rare in older children/adults (autoinfarction)
  • Mechanism: RBC trapping in splenic vasculature → splenic enlargement, acute Hb ↓, hypovolemic shock
  • Urgency: rapid deterioration; requires exchange transfusion

11.5.4 Acute Chest Syndrome (ACS)

  • Definition: new chest x-ray infiltrate + respiratory sx (cough, chest pain, dyspnea, fever)
  • Incidence: ~40% adults; ~10% children
  • Mortality: ~5% now (vs. 14% historically)
  • Etiology: pulmonary infarction, pneumonia; mimics infection

11.5.5 Stroke & Silent Cerebral Infarcts

  • Overt stroke: 11% children w/ SCD
  • Silent infarcts: 27% HbSS, HbSβ⁰-thalassemia
  • TCD screening: gold standard; velocity ≥200 cm/s → high risk
  • Prophylaxis: chronic RBC transfusion → 99% risk reduction (STOP trial)

11.5.6 CNS Disease

  • Manifestations: overt & silent strokes, cognitive impairment, depression, behavioral problems, learning disabilities, seizures
  • Silent infarct effect: cumulative neurologic damage
  • Moyamoya disease: identified in substantial proportion

11.5.7 Pulmonary Disease

  • Acute: asthma exacerbation, ACS, pneumonia
  • Chronic: sickle cell lung disease (SCLD), pulmonary hypertension (PH), fibrosis
  • PH markers: TRJV ↑ (tricuspid regurgitation jet velocity)
    • ≥2.5 m/s suggests PH
    • ~30% SCD patients meet PH criteria
    • ≥2.5 m/s → elevated mortality risk; median survival <5 years

11.5.8 Renal Disease

  • Early injury: GFR ↓ early; hyperfiltration precedes decline
  • Hyposthenuria: inability to concentrate urine
  • Chronic CKD: develops; ESRD affects 5–25%
  • Common: hematuria, proteinuria
  • Transplant: indicated for ESRD

11.5.9 Cardiac Disease

  • Morbidity/mortality: significant cause
  • MI risk: ↑ despite lack conventional risk factors
  • Transfusion iron overload: common → myocardial iron deposition → impaired contractility, conduction abnormalities

11.5.10 Bone Complications

  • Avascular necrosis (AVN): femoral head, humeral head most common
  • Onset: 6–18 months life
  • Risk factors: hemolysis, inflammation, hypercoagulability
  • Imaging: MRI (early); x-ray (advanced)
  • Treatment: conservative early; joint replacement advanced
  • BMD: low; vitamin D supplementation usual

11.5.11 Ophthalmologic

  • Retinopathy: proliferative most sight-threatening
  • Non-proliferative (NP): dot/blot hemorrhages, microaneurysms
  • Proliferative: neovascularization, retinal detachment risk
  • Lesions: salmon patches, sea-fan lesions
  • Management: angiography diagnostic; laser therapy for proliferative lesions
  • Monitoring: regular eye exams essential

11.5.12 Reproductive Health & Pregnancy

  • Counseling: genetic assessment recommended
  • Partner testing: preconception partner status
  • Pregnancy risk ↑: mortality, morbidity increased
  • Complications: miscarriage, preeclampsia, thrombosis, infection, PROM, IUGR, fetal loss, neonatal death
  • Management: multidisciplinary (high-risk OB + SCD expertise)

11.5.13 Priapism

  • Ischemic (low-flow): ~40% SCD patients; veno-occlusive disease
  • Stuttering priapism: intermittent → full priapism
  • Management:
    • Conservative: hydration, analgesics, oxygen
    • Medical: α-agonists (pseudoephedrine, terbutaline), aspiration/cavernosal wash
    • Surgical: shunting, exchange transfusion
  • Timing: delayed intervention → erectile dysfunction risk
Clinical Pearls
  • TCD screening: gold standard stroke risk; velocity ≥200 cm/s → chronic transfusion, ~90% risk reduction
  • ACS mimics pneumonia: new infiltrate + respiratory sx + fever in SCD = ACS until proven otherwise; early ABX, O₂, exchange transfusion critical
  • Hydroxyurea 1st-line: ↑ HbF → ↓ VOC, ↓ ACS, ↓ mortality

11.6 Therapeutics

11.6.1 First-Line Agents

Hydroxyurea - Mechanism: ribonucleotide reductase inhibitor → ↑ HbF → ↓ HbS polymerization - Efficacy: ↓ VOC ~50%; ↓ ACS; ↓ death - Dosing: 15–35 mg/kg/day; maximize tolerated dose - Monitoring: baseline & periodic CBC, liver, kidney function - Contraindication: pregnancy

Red Cell Transfusions - Indications: stroke/TCD ≥200 cm/s, recurrent ACS, recurrent splenic sequestration, severe anemia refractory to meds, pre-op prophylaxis - Goal: HbS <30% or total Hb 10 g/dL - Risks: iron overload (chelation needed), alloimmunization, transfusion reactions

Iron Chelation - Agents: deferoxamine (IV/SC), deferasirox (oral), deferiprone (oral) - Trigger: ferritin >1000–1500 ng/mL or MRI T2* concerning - Benefit: prevents organ iron deposition (myocardial, endocrine, hepatic)

11.6.2 Emerging & Novel Therapies

Voxelotor - Mechanism: ↑ O₂ affinity Hb → ↑ O₂ delivery - Dose: 500 mg daily - Effects: ↓ hemolysis, ↓ retic, ↑ Hb ~1 g/dL

Crizanlizumab - Mechanism: P-selectin inhibitor; blocks endothelium & platelet selectin - Route: IV monthly - Efficacy: ~30% ↓ VOC rate (SUSTAIN trial)

L-Glutamine - Mechanism: antioxidant; ↓ oxidative stress - Efficacy: ~25% ↓ VOC (REBUILD trial)

HSCT - Indication: curative; children ≤13 yo w/ matched sibling (HLA-identical) - Expansion: HLA-matched unrelated donor increasingly used - Regimen: reduced-intensity preparative - Monitoring: GVHD, engraftment, cure - Outcomes: event-free survival >90% sibling donors

Gene Therapy - Approaches: - Ex vivo BCL11A knockdown (CRISPR-Cas9) - Deliver functional β-globin or γ-globin to CD34+ cells → reinfuse autologous edited cells - Status: lentiviral vector FDA-approved some centers; limited availability

11.6.3 Pain Management

Acute VOC - Assessment: rapid standardized evaluation - Opioids 1st-line: IV morphine 0.1–0.15 mg/kg or hydromorphone 0.015–0.02 mg/kg w/in 1h ED arrival - Adjuncts: NSAIDs (ketorolac if renal OK), acetaminophen, topical agents - Supportive: IV hydration, supplemental O₂, pulse oximetry - Protocols: standardized regimens, patient-controlled analgesia (PCA) effective - Individual plans: minimize undertreatment & opioid complications

Chronic Pain - Prevalence: ~50% adults; underrecognized - Risk factors: frequent VOCs, prior transfusions, older age - Approach: multimodal (opioids, antidepressants, anticonvulsants, PT, psychology) - Transition: complexity ↑ to adulthood; multidisciplinary coordination needed

11.7 Specific Complications

11.7.1 Acute Chest Syndrome

  • Definition: new radiographic infiltrate + ≥1 sx (chest pain/cough, dyspnea, fever)
  • Challenge: difficult to distinguish infection
  • Management: supplemental O₂, broad-spectrum ABX (CAP coverage), exchange transfusion if severe (↑ Hb, ↓ HbS)
  • Recurrence: repeated episodes → greater severity

11.7.2 Pulmonary Hypertension

  • Diagnosis: TRJV ≥2.5 m/s on echo indicates PH
  • Risk: high-risk group for sudden death
  • Workup: ECG (right axis deviation), right heart cath for hemodynamics
  • Prevalence: 30–40% adults
  • Outcomes: poor if TRJV ≥2.5 m/s; median follow-up 17.3 mo → median survival <5 yr
  • Pre-HSCT: evaluation recommended

11.7.3 Renal Disease

  • Early findings: hematuria, proteinuria common; hyposthenuria present
  • Progression: GFR ↓ & albuminuria → overt dysfunction
  • CKD: develops; ESRD in 5–25%
  • Treatment: kidney transplant for ESRD; ACE-I for albuminuria

11.7.4 Bone Complications

  • AVN sites: femoral head, humeral head most common
  • Timing: 6–18 months life
  • Imaging: MRI (early AVN); x-ray (advanced)
  • Management: conservative early → joint replacement advanced
  • Monitoring: bone mineral density low; vitamin D supplementation usual

11.8 Summary

  • SCD: complex multi-organ disorder; ~100,000 US
  • Pathophysiology: HbS polymerization → hemolysis, vaso-occlusion, endothelial injury
  • Severity: mild (HbSC) to severe (HbSS)
  • Key complications: VOC, ACS, stroke, organ damage (renal, cardiac, pulmonary, hepatic, bone)
  • Screening: neonatal now routine; diagnosis (hemoglobin electrophoresis, genetic testing)
  • Management: hydroxyurea 1st-line; chronic transfusions; novel agents (voxelotor, crizanlizumab)
  • Curative: HSCT children ≤13 yo w/ matched donor; gene therapy investigational
  • Prognosis: improving; median survival >50 yr (vs. <20 yr historically)
  • Future: non-chemotherapy HSCT, Direct Cas9/AAV6 gene editing, in vivo gene therapy

11.9 References

  • Amin A, La LA, Covert TH, Fackenthal S, eds. Guidelines for the Management of Hemoglobin E and Related Conditions. National Institutes of Health; 2023. https://www.nchi.nih.nih.gov/books/NBK699223/.
  • Coppellini MU, Cohen A, Porter J, et al. Guidelines for the Management of Transfusion Dependent Thalassemia. 3rd ed. Thalassemia International Federation; 2014. https://www.tif.nhi.nih.gov/books/NBK267402/.
  • Frampton H, Abdukar U. Ceppellini MU, et al. A CRISPR-Cas9 gene editing in sickle cell disease. N Engl J Med. 2021;384:252–260.
  • Kizilowski JT. Current recommendations for chelation for transfusion-dependent thalassemias. N Y-Acad Sci. 2016;1368(1):–114.
  • Li A, Wong T, Keel S, et al. The translation management of beta thalassemia in the United States. Transfusion. 2021;61(10):3027–3039.
  • Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotempcel gene therapy for non-β/β genotypes β-thalassemia. N Engl J Med. 2022;386:415–427.
  • Salita A, Musallam KM, Taher A. How I treat non-transfusion-dependent β-thalassemia. Blood. 2023;142(11):949–960.
  • Sheth S, Thein SL. Thalassemia: a disorder of globin synthesis. In: Kaushansky K, Prchal JT, Burns LJ, Lichtman MA, Levi M, Linch DC, eds. Williams Hematology. 10th ed. McGraw Hill; 2021:785–824.
  • Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia international management aiming for lower complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115(1886–1892.
  • Taher A, Musallam KM, Cappellini MD, eds. Guidelines for the Management of Non-Transfusion-Dependent β-Thalassemia (NTDT). 3rd edition. Thalassemia International Federation; 2023. https://www.nhi.nih.nih.gov/books/NBK599489/.