Sickle Cell Anemia

Definition & Genetics

• Homozygous HbSS = sickle cell anemia (most severe)
• HbSC, HbSβ+ thalassemia = milder variants
• HbSβ0 thalassemia = severity similar to HbSS
• HbAS (sickle trait) = heterozygous carrier; generally asymptomatic

Pathogenesis

1. HbS polymerization: On deoxygenation, the abnormal valine residue allows intermolecular contacts that form rigid polymers. These distort the red cell into an elongated, crescentic "sickle" shape.
2. Reversible vs. irreversible sickling: Early sickling is reversible on re-oxygenation. However, repeated sickling cycles cause calcium influx, loss of potassium and water, and membrane skeleton damage - eventually creating irreversibly sickled cells (ISCs) prone to hemolysis.
3. Three key factors that determine whether clinically significant sickling occurs:
   • Intracellular HbS concentration - HbA and HbF retard polymerization; HbF explains why neonates are protected until ~5-6 months of age; α-thalassemia coexistence reduces Hb concentration and decreases sickling
   • Red cell dehydration - increases intracellular Hb concentration, promoting polymerization
   • Microvascular transit time - slow blood flow (spleen, bone marrow, inflamed tissues) allows polymerization to occur before cells re-oxygenate
4. Vaso-occlusion mechanism: Beyond simple physical blockage, sickle cells adhere abnormally to endothelium via P-selectin and other adhesion molecules. Leukocytes and platelets are co-recruited. Intravascular hemolysis releases free hemoglobin that scavenges nitric oxide (NO), impairing vasodilation and promoting a pro-thrombotic, pro-inflammatory vascular state.
5. Two major pathologic consequences:
   • Hemolytic anemia - RBC lifespan only ~20 days (vs. normal 120 days)
   • Vaso-occlusive ischemia - causes pain crises and end-organ damage

Peripheral Blood Smear

Morphology & Organ Pathology

Clinical Features

Vaso-occlusive Crises

• Pain crisis (most common) - precipitated by infection, dehydration, cold, hypoxia, acidosis
• Hand-foot syndrome (dactylitis) - most common presenting symptom in young children; infarction of metacarpal/metatarsal bones
• Acute chest syndrome (ACS) - fever, chest pain, hypoxemia, pulmonary infiltrates; triggered by infection or fat emboli from infarcted bone; vicious cycle of worsening pulmonary and systemic hypoxemia
• Stroke - both ischemic and hemorrhagic; the two leading causes of ischemia-related death are ACS and stroke
• Aplastic crisis - sudden drop in red cell production, typically from parvovirus B19 infection of erythroblasts; self-limited
• Splenic sequestration crisis (mainly in young children before autosplenectomy) - massive pooling of blood in spleen → rapid anemia + hypovolemia

Chronic Complications

• Chronic kidney disease / sickle cell nephropathy
• Pulmonary hypertension
• Leg ulcers
• Gallstones (pigmented; from chronic hemolysis)
• Avascular necrosis
• Retinopathy

Infections

Diagnosis

• Newborn screening: Mandatory in the US - hemoglobin electrophoresis/HPLC from heel-stick blood
• Peripheral smear: Sickle cells, target cells, Howell-Jolly bodies (post-autosplenectomy)
• Hemoglobin electrophoresis / HPLC: Gold standard - quantifies HbS, HbA, HbF, HbA2
• Sickle preparation / Sickledex: Rapid screening; positive in all sickle hemoglobinopathies (not specific for HbSS; false-negatives in neonates with high HbF)
• Prenatal diagnosis: Fetal DNA from amniocentesis or chorionic villus sampling

Genotype-Severity Table

Treatment

Disease-Modifying Therapies

Curative Options

• Hematopoietic stem cell transplantation (HSCT): Potentially curative; best outcomes with HLA-matched sibling donor; significant morbidity/mortality risk
• Gene therapy: Now approved for clinical use (as of 2023-2025) - includes lentiviral gene addition (betibeglogene, lovotibeglogene) and CRISPR-based gene editing (exa-cel/Casgevy); represents a major advance

Transfusion Therapy

• Simple transfusion: For symptomatic anemia, aplastic crisis, splenic sequestration
• Exchange transfusion (RBC exchange): Indicated for stroke, rapidly progressive ACS, multi-organ failure, priapism unresponsive to other treatment, and pre-operative preparation. Goal: HbS <30-40%, Hct <30% (to avoid hyperviscosity)
• Chronic transfusion: Children with prior stroke or transcranial Doppler (TCD) velocity >200 cm/sec

Acute Pain Crisis Management

1. Aggressive hydration (IV or oral)
2. Analgesia - NSAIDs + opioids (escalate as needed); patient-controlled analgesia (PCA) for severe crises
3. Supplemental oxygen (if hypoxic)
4. Incentive spirometry (reduces pulmonary complications)
5. Treat precipitating factors (infection, dehydration)

Preventive Care

• Penicillin prophylaxis: From 2 months of age through at least age 5 (prevents pneumococcal sepsis)
• Vaccinations: Pneumococcal (PCV + PPSV23), meningococcal, Hib, influenza, hepatitis B
• Folic acid supplementation: Daily, to support erythropoiesis
• TCD screening: Annual in children 2-16 years to identify stroke risk
• Ophthalmology: Annual retinal exams from adolescence
• Hydroxyurea: Start consideration from infancy (≥9 months per current guidelines)

Pregnancy

• Hydroxyurea is contraindicated (teratogenic)
• NSAIDs avoided after 30 weeks
• Regional anesthesia preferred over general
• Prophylactic transfusions considered to reduce pain crises and maternal mortality
• Sixfold increased risk of maternal death compared to unaffected controls

Prognosis

• Robbins & Kumar Basic Pathology (Robbins Pathology), pp. 386-388
• Goldman-Cecil Medicine International Edition (Cecil), pp. 1717-1722
• Harriet Lane Handbook, 23rd ed., p. 479
• Colombatti R et al., Sickle cell disease. Lancet 2026 - comprehensive 2026 update confirming gene therapies now approved and ongoing optimization of hydroxyurea protocols [PMID: 41831848]