12.1 Sickle Cell Disease: Vaso-occlusive Crises & Disease-Modifying Therapies

12.1 Sickle Cell Disease: Vaso-occlusive Crises & Disease-Modifying Therapies

Sickle cell disease (SCD) is a group of inherited autosomal recessive hemoglobinopathies characterized by the production of abnormal sickle hemoglobin (HbS). In the United States, SCD affects approximately 1 in 365 Black or African American births and 1 in 16,300 Hispanic American births. The underlying molecular pathology arises from a single-point mutation in the $\beta$-globin gene (HBB) on chromosome 11, wherein adenine is substituted for thymine (GAG $\rightarrow$ GTG), resulting in the replacement of hydrophilic glutamic acid with hydrophobic valine at the sixth position of the $\beta$-globin polypeptide chain ($\beta^6\text{Glu}\rightarrow\text{Val}$).

Under conditions of hypoxia, acidosis, cellular dehydration, or cold exposure, deoxygenated HbS molecules undergo conformational alterations that expose hydrophobic valine contact points. These abnormal tetramers polymerize into long, insoluble intracellular paracrystalline fibers (tactoids). Polymerization distorts the normally pliable, biconcave erythrocyte into a rigid, fragile, crescent- or "sickle"-shaped cell. The consequences are two-fold: continuous intravascular and extravascular hemolysis resulting in severe chronic hemolytic anemia, and microvascular vaso-occlusion causing ischemia, excruciating pain, end-organ infarction, and premature mortality.

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Genotypes & Clinical Severity Spectrum

The clinical severity of sickle cell disease varies widely according to the specific genotype inherited:

• HbSS (Sickle Cell Anemia): Homozygous inheritance of two $\beta^S$ alleles. Represents approximately 65% of SCD in North America. This is the most severe classical phenotype, characterized by high rates of vaso-occlusive pain episodes, acute chest syndrome, chronic hemolytic anemia, splenic autoinfarction, and stroke.
• HbS/$\beta^0$-Thalassemia: Compound heterozygosity for $\beta^S$ and a null mutation ($\beta^0$) yielding zero normal $\beta$-globin synthesis. The clinical severity, hematologic profile (severe microcytic anemia), and complication rates mirror homozygous HbSS.
• HbSC Disease: Compound heterozygosity for $\beta^S$ and $\beta^C$ (lysine substituted for glutamic acid at codon 6). Patients exhibit moderate hemolytic anemia, higher baseline hemoglobin levels (10–12 g/dL), elevated whole blood viscosity, and pronounced risks for proliferative retinopathy, avascular necrosis of the femoral head, and thromboembolism.
• HbS/$\beta^+$-Thalassemia: Compound heterozygosity with a mutation permitting reduced synthesis of normal $\beta$-globin. Produces a milder clinical phenotype with mild microcytic anemia, modest hemolysis, and fewer acute vaso-occlusive events.

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Splenic Autoinfarction & Functional Asplenia

The red pulp of the spleen is particularly vulnerable to sickling due to its sluggish microcirculation, low oxygen tension, and acidic environment. Within the first months of life, repeated cycles of sickling, sinusoidal obstruction, and tissue hypoxia produce micro-infarctions and progressive splenic scarring. While infants frequently present with splenomegaly during the first two years of life, recurrent subclinical tissue necrosis leads to progressive fibrosis, organ shrinkage, and splenic autoinfarction.

Splenic Pathophysiological Cascade:

HbS Polymerization in Sinusoids 
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Microvascular Sinusoidal Vaso-occlusion 
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Repeated Tissue Hypoxia & Reticuloendothelial Necrosis 
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Functional Asplenia (Loss of Phagocytic & Opsonization Function by 6–12 months) 
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Fibrotic Organ Atrophy & Anatomical Autoinfarction (Complete by 3–5 years of age)

Functional asplenia—the functional loss of splenic macrophage clearance, bacterial filtration, and splenic IgM memory B-cell production—develops well before anatomical atrophy is complete. It can be documented in infants as young as 6 to 12 months by the presence of Howell-Jolly bodies (nuclear remnants normally pitted out by functional splenic macrophages) on peripheral blood smears or absent uptake on technetium-99m sulfur colloid spleen scintigraphy. Over 90% of children with HbSS exhibit complete functional asplenia by 3 to 5 years of age.

Encapsulated Bacterial Sepsis Vulnerability

Loss of splenic filtering capacity and deficient alternative complement pathway opsonization expose infants and young children with SCD to a 300- to 600-fold increased risk of fulminant, fatal septicemia and meningitis caused by polysaccharide-encapsulated organisms:

• Streptococcus pneumoniae (Pneumococcus): The leading historical cause of bacteremia and mortality in children under 5 years with SCD.
• Haemophilus influenzae type b (Hib): High risk of invasive meningitis and epiglottitis without immunization.
• Neisseria meningitidis (Meningococcus): Causes rapid purpura fulminans, shock, and Waterhouse-Friderichsen syndrome.
• Salmonella enterica serotypes: Common cause of pediatric osteomyelitis in necrotic bone infarcts (exceeding Staphylococcus aureus incidence in SCD).

Prophylactic Penicillin Protocol

Routine universal newborn screening detects abnormal hemoglobins at birth, allowing immediate intervention before functional asplenia develops. The seminal multicenter PROPS (Prophylactic Penicillin Study) trial demonstrated an 84% reduction in the incidence of invasive pneumococcal infections in children receiving oral penicillin prophylaxis compared to placebo.

[!IMPORTANT] BCPPS Protocol Standard for Penicillin Prophylaxis:

• Initiation: Initiate at confirmation of diagnosis, no later than 2 months of age.
• Infants < 3 years of age: Penicillin VK 125 mg orally twice daily (or oral amoxicillin 20 mg/kg/day divided twice daily if penicillin VK liquid is unavailable).
• Children 3 to 5 years of age: Penicillin VK 250 mg orally twice daily.
• Duration: Continue uninterrupted until at least the fifth birthday (age 5).
• Discontinuation criteria at age 5: Discontinuation is permissible ONLY IF the child has received all recommended pneumococcal immunizations (including conjugate series and 23-valent polysaccharide booster) AND has never suffered an invasive pneumococcal infection or undergone surgical splenectomy. Many hematologists continue prophylaxis indefinitely in high-risk patients.
• Severe Penicillin Allergy (Type 1 / IgE-mediated): Administer Erythromycin ethylsuccinate 20 mg/kg/day orally divided twice daily (or azithromycin 5 mg/kg once daily).

Immunization Schedules for Functional Asplenia

Children with SCD require an intensified immunization schedule combining protein-conjugated and pure polysaccharide vaccines:

1. Pneumococcal Vaccines:
   • Primary Series: 20-valent pneumococcal conjugate vaccine (PCV20) at ages 2, 4, 6, and 12–15 months. (If PCV15 was utilized for the primary series, administer 23-valent pneumococcal polysaccharide vaccine [PPSV23] at least 8 weeks after the last conjugate dose at $\ge 2$ years of age, followed by a second PPSV23 dose 5 years later).
2. Meningococcal Vaccines:
   • MenACWY (Conjugate): Menveo initiated at 2 months of age (4-dose infant series: 2, 4, 6, and 12 months) OR MenQuadfi initiated at $\ge 2$ years of age. A booster dose is administered every 3 to 5 years throughout life.
   • MenB (Serogroup B): MenB-4C (Bexsero, 2-dose series at 0 and 1–6 months) or MenB-FHbp (Trumenba, 3-dose series at 0, 1–2, and 6 months) initiated at 10 years of age with boosters every 2 to 3 years if ongoing risk persists.
3. Annual Influenza & Routine Childhood Vaccines: Inactivated influenza annually; avoid live-attenuated intranasal influenza vaccine.

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Vaso-occlusive Crisis (VOC) Pain Management

Vaso-occlusive crises (pain episodes) represent the most frequent acute complication of SCD and the leading cause of emergency department (ED) visits and hospitalizations. Ischemia induced by sickled erythrocyte microvascular occlusion triggers an intense inflammatory cascade, peripheral nociceptive activation, and central sensitization.

Acute Analgesic Titration Protocols

Consensus guidelines from the National Heart, Lung, and Blood Institute (NHLBI) and American Society of Hematology (ASH) establish rigorous benchmarks for pediatric VOC analgesia:

• Target Door-to-Needle Time: Parenteral opioid analgesia must be administered within 30 to 60 minutes of triage or within 30 minutes of physician assessment.
• Rapid Parenteral Titration: Use rapid-acting intravenous opioids titrated every 15 to 30 minutes until pain intensity decreases significantly on validated pediatric pain scales (e.g., Wong-Baker FACES or Numeric Rating Scale).
• First-Line Opioid Selection & Doses:
  • IV Morphine: 0.05 to 0.1 mg/kg per dose (typical maximum starting dose 5–10 mg) IV every 15–30 minutes until pain is controlled.
  • IV Hydromorphone: 0.015 to 0.02 mg/kg per dose (typical maximum starting dose 1–2 mg) IV every 15–30 minutes until pain is controlled.
  • Intranasal Fentanyl: 1.5 to 2 mcg/kg (maximum 100 mcg) administered via mucosal atomization device while intravenous access is being established.
• Maintenance Regimen: Once pain is stabilized, convert to scheduled intermittent IV boluses (every 2–3 hours) or Patient-Controlled Analgesia (PCA) with a basal infusion and demand boluses for opioid-tolerant children. Never prescribe PRN-only opioids for acute hospitalized VOC, as this produces fluctuating plasma concentrations, inadequate analgesia, and breakthrough pain.

[!WARNING] Strict Avoidance of Meperidine: Meperidine is strictly contraindicated for pediatric VOC. Its active metabolite, normeperidine, has a prolonged elimination half-life (15–30 hours) and accumulates rapidly, especially with renal insufficiency. Normeperidine causes severe central nervous system excitation, tremors, hyperreflexia, myoclonus, and fatal generalized seizures.

Multimodal Non-Opioid Adjuvant Pharmacotherapy

To enhance analgesia, reduce total opioid requirements, and mitigate opioid-related adverse events (sedation, respiratory depression, constipation, pruritus):

• Intravenous Ketorolac: Highly effective cyclooxygenase (COX-1/COX-2) inhibitor that reduces inflammatory prostaglandin production in ischemic bone marrow. Dose: 0.5 mg/kg IV every 6 hours (maximum single dose 30 mg). To prevent acute kidney injury, gastrointestinal ulceration, and platelet dysfunction, ketorolac must be limited to a strict maximum duration of 5 consecutive days. Monitor baseline serum creatinine, urine output, and hydration state.
• Oral NSAIDs: Ibuprofen (10 mg/kg orally every 6 hours, max 800 mg/dose) or naproxen (5–7.5 mg/kg orally every 12 hours) once transitioned to oral therapy.
• Acetaminophen: 10 to 15 mg/kg IV or PO every 4 to 6 hours (maximum 75 mg/kg/day or 4,000 mg/day) as a continuous baseline antipyretic/analgesic.
• Judicious Hydration: Hypotonic or isotonic fluids (e.g., $D_5$ 0.45% NaCl) at maintenance rates (1.0 to 1.5 times maintenance). Avoid aggressive overhydration (>1.5 times maintenance), which induces hemodilution, increases cardiac preload, and precipitates pulmonary edema and acute chest syndrome.
• Bowel Regimen: Scheduled stimulant laxative (senna) plus stool softener (docusate) or osmotic agent (polyethylene glycol 3350) initiated concurrently with opioids.

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Acute Chest Syndrome (ACS)

Acute chest syndrome is the second most common cause of hospitalization in SCD and the leading cause of ICU admission and premature mortality. It is defined as a new pulmonary infiltrate on chest radiography involving at least one complete lung segment, combined with fever ($\ge 38.5^\circ\text{C}$) and at least one acute respiratory symptom:

• Tachypnea and increased work of breathing (retractions, nasal flaring)
• Cough
• Chest pain
• Hypoxemia (drop in baseline oxygen saturation $SpO_2 > 3%\text{--}4%$ or $SpO_2 < 92\text{--}95%$ on room air)
• Wheezing, rales, or bronchial breath sounds

ACS Etiology & Pathophysiological Triad

The pathogenesis of ACS involves a complex interplay among pulmonary microvascular vaso-occlusion, fat embolism from infarcted bone marrow, and respiratory infection (identified in up to 50% of pediatric cases):

• Atypical Pathogens: Mycoplasma pneumoniae and Chlamydia pneumoniae account for up to 30% of infectious ACS cases in children.
• Bacterial Pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and non-typeable H. influenzae.
• Viral Pathogens: Respiratory syncytial virus (RSV), human metapneumovirus, influenza, and rhinovirus.

Pathophysiological Cascade in Acute Chest Syndrome:

Bone Marrow Infarction / Infection / Atelectasis 
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Release of Free Fatty Acids / Endothelial Activation / Local Hypoxia 
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Intrapulmonary HbS Polymerization & Erythrocyte Sickling 
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Microvascular Thrombosis & Pulmonary Arterial Hypertension 
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Severe V/Q Mismatch, Progressive Hypoxemia & Respiratory Failure

Multimodal Treatment Protocol for ACS

1. Empiric Antimicrobial Therapy:
   • Intravenous Beta-Lactam: Ceftriaxone 50 to 75 mg/kg/day IV every 24 hours (maximum 2,000 mg/day) OR Cefotaxime 150 to 200 mg/kg/day IV divided every 6 to 8 hours for coverage of encapsulated S. pneumoniae.
   • PLUS Macrolide (Atypical Coverage): Azithromycin 10 mg/kg IV/PO on day 1 (maximum 500 mg), followed by 5 mg/kg/day (maximum 250 mg) on days 2 through 5, to eradicate Mycoplasma and Chlamydia.
   • If MRSA is suspected (severe necrosis, hemodynamic instability), add Vancomycin 15 mg/kg IV every 6 to 8 hours.
2. Respiratory Support & Atelectasis Prevention:
   • Incentive Spirometry: 10 breaths every 2 hours while awake. The landmark Charache study demonstrated that incentive spirometry reduces the development of ACS by over 50% in children hospitalized with chest or back VOC pain.
   • Supplemental Oxygen: Titrate to maintain $SpO_2 \ge 95%$ (or at baseline). Hypoxemia strongly accelerates HbS polymer formation.
   • Bronchodilators: Nebulized albuterol (2.5 mg) every 4 hours if wheezing, airway reactivity, or history of asthma is present.
3. Blood Transfusion Strategies (Simple vs. Exchange):
   • Simple Blood Transfusion (10 mL/kg packed red blood cells [PRBCs]): Indicated for mild-to-moderate ACS when baseline hemoglobin is significantly decreased ($>1.5\text{--}2.0\text{ g/dL}$ below baseline) and total hemoglobin is $\le 9.0\text{ g/dL}$. Infuse slowly over 3 to 4 hours.
   • Exchange Transfusion (Erythrocytapheresis or Manual Exchange): Indicated for severe, rapidly progressive ACS manifested by multi-lobar infiltrates, arterial hypoxemia ($PaO_2 < 60\text{ mmHg}$ or $SpO_2 < 90%$ despite high-flow oxygen), mechanical ventilation requirement, or when baseline hemoglobin is already $\ge 9.0\text{ g/dL}$.

[!CAUTION] Hyperviscosity Risk: Never transfuse PRBCs to a target hemoglobin exceeding 10.0 to 11.0 g/dL. In the presence of circulating HbS, whole blood viscosity rises exponentially at hemoglobin concentrations above 10–11 g/dL, dramatically worsening microvascular sludging, precipitating stroke, and accelerating vaso-occlusion.

• Simple Transfusion Target: Hemoglobin 9.0 to 10.0 g/dL.
• Exchange Transfusion Target: Hemoglobin 10.0 g/dL with an HbS fraction < 30%.

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Disease-Modifying Pharmacotherapies

Three oral or intravenous disease-modifying agents remain commercially available for the chronic outpatient management of pediatric sickle cell disease, each addressing a distinct point along the pathophysiological pathway. A fourth agent, voxelotor, was withdrawn worldwide in 2024 and is covered below because candidates still encounter it in older review material.

Therapeutic Targets in Sickle Cell Disease:

           [Hydroxyurea]
                 │ Induces HbF (α2γ2)
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   Inhibits HbS Polymerization ◄── [Voxelotor] (WITHDRAWN 2024)
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        Erythrocyte Sickling
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                 ├──────────────────► [L-Glutamine] (Reduces Oxidative Stress)
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  Endothelial & Platelet Adhesion ◄── [Crizanlizumab] (Blocks P-Selectin)
                 │
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       Microvascular VOC

1. Hydroxyurea (Hydroxycarbamide)

Hydroxyurea is the cornerstone disease-modifying therapy for SCD. The pediatric BABY HUG and MSH trials established its efficacy in reducing vaso-occlusive pain episodes, acute chest syndrome crises, transfusion requirements, and all-cause mortality.

• Mechanism of Action: Inhibits the enzyme ribonucleotide reductase, depleting intracellular deoxynucleoside triphosphate (dNTP) pools and arresting cells in the S-phase of the cell cycle. This induces cellular stress that stimulates the reactivation of $\gamma$-globin gene transcription. Elevated $\gamma$-globin chains pair with $\alpha$-globin chains to assemble fetal hemoglobin ($HbF, \alpha_2\gamma_2$). Because HbF cannot incorporate into the deoxy-HbS polymer and physically impedes polymer elongation, intracellular sickling is markedly suppressed. Hydroxyurea also decreases circulating neutrophil, monocyte, and reticulocyte counts (reducing cellular adhesion), increases erythrocyte mean corpuscular volume (MCV), and enhances nitric oxide-mediated vasodilation.
• BCPPS Dosing & Titration Protocol:
  • Initial Dose: 15 to 20 mg/kg/day orally as a single daily dose (available as capsules or compounded oral liquid).
  • Titration: Evaluate CBC and reticulocyte count every 4 weeks during initiation. Titrate dose by 5 mg/kg/day every 8 to 12 weeks until reaching the Maximum Tolerated Dose (MTD), up to a ceiling of 35 mg/kg/day, provided bone marrow function remains adequate.
  • Monitoring: CBC with differential, reticulocytes, and renal/hepatic panel every 4 weeks during titration, extending to every 8 to 12 weeks once a stable MTD is achieved. Monitor HbF percentage annually (target HbF $>20%$).
• Hematologic Toxicity Hold Thresholds:
  • Absolute Neutrophil Count (ANC): $< 2,000/\text{mcL}$ (or $< 1,250/\text{mcL}$ in some protocols)
  • Platelet Count: $< 80,000/\text{mcL}$
  • Hemoglobin Concentration: $< 5.0\text{ g/dL}$ OR a $>20%$ acute drop in baseline reticulocytes when hemoglobin is $< 7.0\text{ g/dL}$
  • Action upon Toxicity: Hold hydroxyurea immediately. Monitor CBC weekly. Once bone marrow recovers above threshold values, resume therapy at a dose 5 mg/kg/day lower than the toxic dose.
• Safety & Reproductive Toxicology: Hydroxyurea is a teratogen (pregnancy category D) and mutagen. Effective non-hormonal or hormonal contraception is mandatory during therapy and for at least 6 months (females) or 1 year (males) post-discontinuation.

2. Crizanlizumab (Adakveo)

• Mechanism: Humanized monoclonal IgG2$\kappa$ antibody that selectively binds to P-selectin on activated vascular endothelial cells and platelets. By blocking the interaction between P-selectin and its ligand (PSGL-1) on leukocytes, reticulocytes, and sickled erythrocytes, crizanlizumab prevents cellular rolling, adhesion, and microvascular vaso-occlusion.
• FDA Indication & Age: Indicated to reduce the frequency of VOC in patients with SCD aged $\ge 16$ years.
• Dosing: 5 mg/kg IV administered over 30 minutes at weeks 0 and 2 (loading), followed by 5 mg/kg IV every 4 weeks thereafter as maintenance.
• Adverse Effects: Infusion-related reactions (fever, chills, flushing), arthralgias, nausea, diarrhea, and transient laboratory interference with automated platelet counts (platelet clumping in EDTA tubes).

3. Voxelotor (Oxbryta) — Withdrawn from the Market (September 2024)

[!WARNING] Voxelotor is no longer available. On September 25, 2024, Pfizer voluntarily withdrew all lots of Oxbryta (voxelotor) from every market in which it was approved and simultaneously discontinued all active voxelotor clinical trials and expanded-access programs worldwide. The FDA issued a public alert the following day. The decision rested on the totality of post-marketing and trial data, which showed an imbalance in vaso-occlusive crises and in fatal events such that the overall benefit no longer outweighed the risk. Any BCPPS answer option that selects voxelotor as current therapy is wrong; any patient still holding supply should be transitioned to an available disease-modifying agent.

• Historical Mechanism: Voxelotor was a hemoglobin S polymerization inhibitor that reversibly bound via Schiff base formation to the N-terminal valine of the $\alpha$-chain of hemoglobin, shifting the oxygen-hemoglobin dissociation curve to the left, increasing oxygen affinity, and stabilizing the oxygenated (R) state of HbS. Because only deoxygenated (T state) HbS polymerizes, the drug reduced hemolysis and raised steady-state hemoglobin.
• Former Indication: Previously approved for SCD in patients aged $\ge 4$ years, with weight-tiered oral dosing (600 mg daily for 10 to <20 kg; 900 mg daily for 20 to <40 kg; 1,500 mg daily at $\ge 40$ kg).
• Why the Hemoglobin Rise Was Misleading: Voxelotor raised total hemoglobin by $>1.0\text{ g/dL}$ in the majority of patients and lowered indirect bilirubin and reticulocytes, but the left-shifted dissociation curve also meant that oxygen was released less readily to tissue, and pulse oximetry overestimated true arterial oxygenation. The laboratory improvement in hemoglobin never translated into a reduction in vaso-occlusive events — a recurring exam theme about surrogate endpoints that do not track clinical outcomes.

3b. Gene and Cell Therapies for Severe SCD

Two one-time autologous cell therapies were approved in December 2023 for patients aged $\ge 12$ years with SCD and recurrent vaso-occlusive events. Both require myeloablative busulfan conditioning, with the attendant infertility, prolonged cytopenia, and infection risks.

• Exagamglogene autotemcel (exa-cel, Casgevy): A CRISPR-Cas9 therapy that disrupts the BCL11A erythroid enhancer, de-repressing $\gamma$-globin transcription and raising fetal hemoglobin. It is the first CRISPR-based therapy approved in the United States.
• Lovotibeglogene autotemcel (lovo-cel, Lyfgenia): A lentiviral vector gene-addition therapy that inserts a modified $\beta^{A-T87Q}$-globin gene, producing an anti-sickling hemoglobin. Its label carries a boxed warning for hematologic malignancy, and lifelong monitoring is required.
• Pharmacist Role: Confirm hydroxyurea washout before mobilization, manage plerixafor-based stem-cell mobilization (granulocyte colony-stimulating factor is contraindicated in SCD because it precipitates severe vaso-occlusive crises), and coordinate red-cell exchange to lower HbS before conditioning.

4. L-Glutamine (Endari)

• Mechanism: L-glutamine is an essential amino acid required for the de novo synthesis of nicotinamide adenine dinucleotide (NAD/NADH). Sickled erythrocytes experience severe continuous oxidative stress that exhausts intracellular NADH. Exogenous L-glutamine replenishes the erythrocyte NADH pool, restoring cellular redox balance, neutralizing reactive oxygen species, and improving red cell deformability.
• FDA Indication & Age: Approved to reduce acute complications in patients aged $\ge 5$ years with SCD.
• Weight-Based Dosing (Powder mixed into room-temperature food or liquid):
  • Body Weight < 30 kg: 5 grams orally twice daily.
  • Body Weight 30 to 65 kg: 10 grams orally twice daily.
  • Body Weight > 65 kg: 15 grams orally twice daily.
• Adverse Effects: Constipation, nausea, abdominal pain, cough, and musculoskeletal chest pain.

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Comparison of Disease-Modifying Agents in Pediatric SCD

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Practice Pearls & BCPPS Exam Traps

• Exam Trap 1: Never recommend fluid restriction for pediatric VOC pain; however, do not prescribe indiscriminate hyperhydration ($>1.5\times$ maintenance) because volume overload directly precipitates pulmonary edema and transforms an uncomplicated VOC into life-threatening acute chest syndrome.
• Exam Trap 2: Do not confuse the simple transfusion target with the exchange transfusion target. Simple transfusion should never push the hematocrit $>30%$ or hemoglobin $>10\text{ g/dL}$ due to exponential whole-blood hyperviscosity. Automated exchange transfusion uniquely lowers HbS fraction below 30% while maintaining total hemoglobin at approximately 10 g/dL.
• Exam Trap 3: Never discontinue prophylactic penicillin at age 5 if the child has experienced prior invasive pneumococcal disease or has undergone surgical splenectomy. These high-risk children require lifelong or prolonged prophylaxis.
• Exam Trap 4: Review questions written before late 2024 still list voxelotor among first-line disease-modifying options. Since the September 2024 worldwide withdrawal, the available disease-modifying agents in pediatric SCD are hydroxyurea (from age 9 months), L-glutamine (from age 5 years), and crizanlizumab (from age 16 years), with exa-cel and lovo-cel reserved for severe disease from age 12 years.
• Board Rule: If a child on hydroxyurea presents with an ANC of 1,800/mcL and platelets of 70,000/mcL, the only correct immediate action is to temporarily withhold hydroxyurea and repeat the CBC weekly until counts recover; never continue the current dose or titrate upward in the face of myelosuppression.