What is the recommended treatment plan for a patient with sickle cell disease?

Recommended Treatment Plan for Sickle Cell Disease

All patients with HbSS or Sβ⁰-thalassemia should be offered hydroxyurea starting at 9 months of age, even without clinical symptoms, as this is the first-line disease-modifying therapy that reduces vaso-occlusive complications, hospitalizations, and mortality. 1

Disease-Modifying Therapies

Hydroxyurea (First-Line Therapy)

• Initiate hydroxyurea at 9 months of age for all children with HbSS or Sβ⁰-thalassemia, regardless of symptom status 1
• Hydroxyurea increases fetal hemoglobin, reduces red blood cell sickling, and decreases vaso-occlusive complications including painful episodes and acute chest syndrome 1, 2
• The medication reduces hospitalizations and transfusion requirements with no unique adverse effects when started in early infancy 1
• Dosing: Taken once daily orally as capsule, fast-dissolving tablet, or compounded liquid 1
• Monitoring: CBC and reticulocyte count every 1-3 months to assess for myelosuppression 1
• Hydroxyurea has demonstrated positive impact on health-related quality of life 1

L-Glutamine (Adjunctive Therapy)

• FDA-approved for patients 5 years and older to reduce acute complications of sickle cell disease 3
• L-glutamine decreases oxidative stress and hemolysis, reducing the number of pain events 1, 4
• Dosing by weight: 3
  • <30 kg: 5 grams twice daily (10 grams/day)
  • 30-65 kg: 10 grams twice daily (20 grams/day)

  • 65 kg: 15 grams twice daily (30 grams/day)

• Mix immediately before ingestion with 8 oz of cold/room temperature beverage or 4-6 oz of food 3
• Does not require laboratory monitoring 1
• In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days 2

Additional Disease-Modifying Agents

• Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo 2
• Voxelotor increased hemoglobin by at least 1 g/dL in 51% vs 7% with placebo 2
• These agents serve as adjunctive or second-line therapies 2

Preventive Care

Infection Prophylaxis

• Penicillin V potassium prophylaxis: 1
  • Start by 2 months of age: 125 mg orally twice daily
  • Increase at 3 years: 250 mg orally twice daily
  • Continue until age 5 years or completion of pneumococcal vaccine series
  • Consider continuation after age 5 for patients with history of invasive pneumococcal infection or surgical splenectomy
• Alternative for penicillin allergy: Erythromycin 1
• Routine penicillin prophylaxis is NOT recommended for HbSC or Sβ⁺-thalassemia unless surgical splenectomy performed 1

Immunizations

• Pneumococcal vaccination: Complete series per recommendations for children with functional asplenia 1
• Meningococcal vaccination: Against serotypes A, C, W, Y at appropriate age; serotype B after age 10 years 1
• Administer all vaccines according to current recommendations for children with functional asplenia 1

Screening and Monitoring

• Blood pressure goal: ≤130/80 mm Hg (not ≤140/90 mm Hg) for adults with SCD 1
• Screen for iron overload: Use MRI for liver iron content (R2, T2*, or R2* methods) rather than ferritin alone in patients receiving chronic transfusion therapy 5
• Renal monitoring: Assess for chronic kidney disease and proteinuria 1
• Ophthalmologic screening: Monitor for retinopathy 2

Transfusion Support

Red Cell Antigen Matching (Critical for Preventing Alloimmunization)

• Obtain extended red cell antigen profile by genotype or serology before first transfusion 1, 5
• Genotyping is preferred over serology as it provides additional antigen information and increased accuracy 1, 5
• Mandatory matching: Rh (C, E or C/c, E/e) and K antigens for ALL transfusions (strong recommendation) 1, 5
• Extended matching recommended: Jka/Jkb, Fya/Fyb, S/s provides further protection from alloimmunization 1, 5

Chronic Transfusion Therapy Indications

• Primary or secondary stroke prophylaxis (most common indication) 1
• Recurrent complications not responding to other disease-modifying therapies 1
• Goal: Suppress bone marrow and decrease HbS percentage 1
• Monitoring: Screen for iron overload by MRI when ferritin ≥1000 ng/mL or after 12-20 transfusions 1, 5

Perioperative Transfusion

• Recommend preoperative transfusion for surgeries requiring general anesthesia lasting >1 hour 5
• Target: Total hemoglobin >9 g/dL before surgery 5
• Schedule patients early on operating list to avoid prolonged starvation 1
• Avoid last-minute cancellations, particularly if patient received preparatory transfusion 1

Management of Acute Complications

Acute Chest Syndrome

• Emergency transfer to acute care setting for patients with acute chest pain 6
• Respiratory support: Maintain SpO2 above baseline or 96% (whichever higher) 6
• Incentive spirometry: Every 2 hours to prevent atelectasis 6
• Aggressive pain control: Parenteral opioids with PCA using scheduled around-the-clock dosing 6
• Hydration: Aggressive but monitor carefully to prevent overhydration 6
• Antibiotics: Initiate if temperature ≥38.0°C or signs of sepsis 6
• For severe ACS with bilateral infiltrates: Automated or manual red cell exchange transfusion immediately to reduce HbS <30% (ideally <20%) 6, 5
• ICU admission criteria: Rapidly progressive disease despite initial interventions or consideration of exchange transfusion 6

Vaso-Occlusive Pain Crisis

• Effective analgesia is crucial for treating painful crises 7
• Provide aggressive pain control with parenteral opioids for moderate to severe pain 6
• Use PCA with scheduled around-the-clock dosing rather than as-needed dosing 6
• Hydration: 5% dextrose solution or 5% dextrose in 25% normal saline (avoid normal saline due to hyposthenuria) 7
• Patients with SCD are NOT more likely to develop addiction to pain medications than general population 2

Venous Thromboembolism

• First unprovoked VTE: Indefinite anticoagulation over defined periods 1
• First provoked VTE: Defined periods of anticoagulation (3-6 months) over indefinite 1
• Recurrent provoked VTE: Indefinite anticoagulation over shorter periods 1
• Thromboprophylaxis: For post-pubertal patients due to increased DVT risk 6

Curative Therapy

Hematopoietic Stem Cell Transplant

• Only curative therapy currently available 2, 4
• Best results in children with matched sibling donor 2
• Limited by donor availability—less than 25% of patients have suitable donor 8, 4
• Barriers: Immunologic rejection, long-term adverse effects, prognostic uncertainty, poor end-organ function in older patients 4
• Standard care for severe disease with matched sibling donor 2

Gene Therapy

• Under investigation to correct the βs point mutation 4
• Represents potential future curative modality 4

Perioperative Management

Preoperative Preparation

• Anesthesia should ideally be undertaken in centers with experience in SCD 1
• Review in pre-assessment clinic with input from nominated lead hematologist 1
• Notify acute pain team in advance for major surgery, especially if history of chronic pain 1
• Avoid routine surgery if patient is febrile or having painful crisis 1

Intraoperative Care

• Meticulous care to avoid sickling triggers: 1
  • Dehydration
  • Hypoxia
  • Acidosis
  • Hypothermia
  • Pain
• Maintain normothermia as hypothermia causes shivering and peripheral stasis 6

Postoperative Monitoring

• Majority of complications occur postoperatively 1
• Low threshold to admit to high dependency or intensive care 1
• Monitor for acute chest syndrome, pain, acute renal insufficiency, stroke, sepsis, and VTE 1

Special Populations

Pregnancy

• Pregnancy confers increased risk for patients with SCD 1
• Manage by multidisciplinary team in hospitals able to manage high-risk pregnancies and SCD complications 1
• Either prophylactic transfusion at regular intervals or standard care may be used (evidence equivocal) 5

Chronic Kidney Disease

• Combination therapy with hydroxyurea and erythropoiesis-stimulating agents for worsening anemia associated with CKD 1
• Conservative hemoglobin threshold advised—do not exceed 10 g/dL (hematocrit 30%) to reduce risk of vaso-occlusion, stroke, and VTE 1

Critical Pitfalls to Avoid

• Do not delay hydroxyurea initiation—start at 9 months regardless of symptoms 1
• Do not use simple transfusion for severe acute chest syndrome with bilateral infiltrates—use exchange transfusion 6, 5
• Do not transfuse patients with delayed hemolytic transfusion reaction unless life-threatening anemia—additional transfusions may worsen hemolysis 5
• Do not apply SCD monitoring protocols to sickle cell trait patients—this is a benign carrier state 9
• Do not use normal saline for hydration—use 5% dextrose or 5% dextrose in 25% normal saline due to hyposthenuria 7
• Do not withhold pain medication due to addiction concerns—SCD patients have same addiction risk as general population 2