What are the evidence‑based long‑term management recommendations for sickle cell disease, including hydroxyurea dosing, immunizations, prophylactic penicillin, transfusion protocols, organ complication screening, and alternative disease‑modifying therapies?

Long-Term Management of Sickle Cell Disease

Disease-Modifying Therapy: Hydroxyurea

Hydroxyurea remains the gold standard first-line disease-modifying therapy for sickle cell disease and should be offered to all patients regardless of symptom severity. 1, 2

Dosing and Initiation

• Start hydroxyurea at 15-35 mg/kg/day with dose titration based on myelosuppressive effects and patient compliance 3
• For infants, children, and adolescents: offer hydroxyurea treatment without regard to presence of symptoms (moderate strength recommendation) 4
• For adults: strongly recommend hydroxyurea if any of the following:
  • 3 or more severe vaso-occlusive crises during any 12-month period 4
  • SCD pain or chronic anemia interfering with daily activities 4
  • Severe or recurrent episodes of acute chest syndrome 4
  • Increased mortality risk (TRV >2.5 m/s, NT-pro-BNP >160 pg/ml, or RHC-confirmed pulmonary hypertension) 5

Monitoring Hydroxyurea Therapy

• Efficacy depends on dose and patient adherence—monitor compliance closely 3
• Expect mild to moderate neutropenia (absolute neutrophil count 500-1,249/mm³) in approximately 47% of patients, which may require dose reduction but is rarely complicated by infection 5
• Hydroxyurea takes months to reach optimal fetal hemoglobin levels, unlike transfusion therapy which works within hours to weeks 5

Prophylactic Antimicrobial Therapy

All children with sickle cell disease must receive daily oral prophylactic penicillin from diagnosis through age 5 years (strong recommendation) 4

Immunization Protocol

Annual transcranial Doppler examinations are mandatory for children ages 2-16 years with sickle cell anemia to screen for stroke risk (strong recommendation) 4

Transfusion Therapy

Chronic Transfusion Indications

Long-term transfusion therapy is strongly recommended for:

• Children with abnormal transcranial Doppler velocity (≥200 cm/s) to prevent stroke 4
• Cerebral and end-organ damage protection 3
• Second-line prevention of recurrent vaso-occlusive events after hydroxyurea failure 3

Transfusion Targets

• Preoperative transfusion: increase hemoglobin to 10 g/dL (strong recommendation) 4
• During long-term transfusion: maintain sickle hemoglobin <30% prior to next transfusion (moderate strength recommendation) 4
• Goal hemoglobin concentration: 10-12 g/dL is typically attainable via chronic transfusion 5

Iron Overload Management

• Assess iron overload regularly in all patients receiving chronic transfusions (strong recommendation) 4
• Begin iron chelation therapy when indicated (moderate strength recommendation) 4
• Critical pitfall: Never provide iron supplementation unless biochemically proven iron deficiency exists, as repeated transfusions create iron overload risk 6

Organ Complication Screening

Renal Screening and Management

• For patients with worsening anemia associated with chronic kidney disease: use combination therapy with hydroxyurea and erythropoiesis-stimulating agents (conditional recommendation) 5
• When using erythropoiesis-stimulating agents: do not exceed hemoglobin threshold of 10 g/dL (hematocrit 30%) to reduce risk of vaso-occlusion, stroke, and VTE 5
• For end-stage renal disease: renal transplant is justified over dialysis despite very low certainty evidence, given the high burden of dialysis and comparable outcomes to diabetic patients 5
• Aggressive hydration is crucial as patients have impaired urinary concentrating ability and dehydrate easily 7

Pulmonary Screening

• Do not perform routine screening echocardiography in asymptomatic patients (conditional recommendation) 5
• However, maintain low threshold for echocardiography based on comprehensive history and review of systems 5
• For proliferative sickle cell retinopathy: refer to expert specialists for consideration of laser photocoagulation (strong recommendation) 4

Cardiovascular Monitoring

• Perform echocardiography to evaluate signs of pulmonary hypertension when clinically indicated (strong recommendation) 4

Alternative Disease-Modifying Therapies

Newer FDA-Approved Agents (Adjunctive or Second-Line)

• L-glutamine (approved 2017): reduces hospitalization rates by 33% and mean length of stay from 11 to 7 days 2, 8
• Crizanlizumab (approved 2019): reduces pain crises from 2.98 to 1.63 per year 2, 8
• Voxelotor (approved 2019): increases hemoglobin by ≥1 g/dL in 51% vs 7% with placebo 2, 8
• Gene therapies (approved 2023): exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) 8

Hematopoietic Stem Cell Transplantation

• For HbSβ0-thalassemia with HLA-matched sibling donor: strongly consider early HSCT given 95% disease-free survival 6
• Perform transplantation before organ damage develops as event-free survival is significantly better 6
• HSCT is the only curative therapy but limited by donor availability, with best results in children with matched sibling donors 2

Acute Complication Management

Vaso-Occlusive Crisis

• Rapidly initiate opioids for severe pain (strong recommendation) 4
• Use incentive spirometry in all hospitalized patients (strong recommendation) 4
• Provide aggressive IV hydration with close fluid balance monitoring 6
• Use PCA with hydromorphone for severe pain requiring parenteral opioids 6

Acute Chest Syndrome

• Maintain oxygen therapy to keep SpO2 above baseline or 96% (whichever is higher) 7

Perioperative Management

Preoperative Planning

• A nominated lead hematologist must be involved in all surgical planning 6
• Avoid routine surgery if patient is febrile or having active painful crisis 6

Transfusion Strategy by Surgical Risk

• High-risk surgery: exchange transfusion targeting Hb 100 g/L 6
• Low/medium-risk surgery with baseline Hb <90 g/L: top-up transfusion to Hb 100 g/L 6

Intraoperative Care

• Maintain normothermia as hypothermia causes shivering and peripheral stasis, increasing sickling 7
• Meticulous attention to hydration, oxygenation, thermoregulation, and acid-base balance 5

Special Populations

Pregnancy

• Manage pregnant patients in obstetric units with special interest in SCD given 1-3% maternal mortality risk 6
• Epidural analgesia is ideal for labor, particularly with opioid tolerance or lower body sickle pain 6
• Regional anesthesia is strongly preferred over general anesthesia for cesarean section 6

Critical Pitfalls to Avoid

• Never assume patients are at higher risk for opioid addiction—they are not more likely to develop addiction than the general population 2
• Never delay opioid initiation for severe pain due to unfounded addiction concerns 4
• Never provide iron supplementation without biochemically proven deficiency 6
• Never perform surgery during active crisis or fever 6
• Never exceed hemoglobin 10 g/dL when using erythropoiesis-stimulating agents 5