Sickle Cell Disease

Risk factors

• Autosomal recessive: both parents must carry HbS, HbC, or beta-thalassemia variant
• African, Mediterranean, Middle Eastern, Indian, and Caribbean ancestry
• Triggers for vaso-occlusion: hypoxia, dehydration, infection, acidosis, cold exposure, stress, high altitude

Pathophysiology

HbS polymerizes when deoxygenated, deforming red cells into a sickle shape. Sickled cells are rigid, adhesive to endothelium, and short-lived (lifespan 10-20 days vs normal 120). Two consequences: chronic hemolytic anemia and microvascular occlusion → ischemia/infarction of multiple organs. Repeated splenic infarction → functional asplenia by early childhood, increasing risk of encapsulated organism infections.

Clinical presentation

Differential diagnosis

• Acute chest syndrome — New pulmonary infiltrate + fever/respiratory symptoms in SCD patient — leading cause of death; treat with antibiotics, transfusion, bronchodilators, analgesia
• Vaso-occlusive crisis — Severe deep bony pain without infiltrate or other organ failure; treat with hydration, analgesia, oxygen if hypoxic
• Splenic sequestration — Pediatric SCD, acute splenomegaly, drop in Hb >2 g/dL, hypovolemia; medical emergency, transfuse
• Aplastic crisis — Sudden severe anemia with low reticulocytes, often parvovirus B19; transfusion supportive
• Hemolytic crisis — Increased baseline hemolysis (G6PD coincident, drug-induced, hyperhemolysis from transfusion)
• Osteomyelitis — Salmonella is classic in SCD; clinically overlaps with bone infarction; MRI and blood cultures discriminate
• Stroke — Up to 11% of children with SCD by age 20; TCD screening identifies high-risk; treat with exchange transfusion

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[HbSS homozygote] --> B[HbS polymerization<br/>when deoxygenated]
  B --> C[RBC sickling<br/>rigid, adhesive]
  C --> D[Chronic hemolysis<br/>Hb 6-9, retic ↑, LDH ↑]
  C --> E[Microvascular<br/>occlusion]
  E --> F[Vaso-occlusive<br/>pain crisis]
  E --> G[Acute chest<br/>syndrome]
  E --> H[Stroke]
  E --> I[Splenic infarction<br/>→ autosplenectomy]
  E --> J[Avascular necrosis]
  I --> K[Encapsulated<br/>organism infection<br/>S. pneumoniae, H. flu,<br/>Salmonella]
  D --> L[Pigment gallstones]
  D --> M[Pulmonary HTN]

Treatment

Complications

• Acute chest syndrome — leading cause of mortality in adults
• Stroke — peak ages 2-9 in children; recurrent without secondary prevention
• Pulmonary hypertension, chronic kidney disease, hyposthenuria
• Avascular necrosis of femoral/humeral head
• Retinopathy (especially HbSC), leg ulcers, priapism, cholelithiasis (pigment stones)
• Functional asplenia — pneumococcal sepsis is the historic leading cause of pediatric mortality
• Iron overload from chronic transfusion
• Alloimmunization, delayed hemolytic transfusion reaction, hyperhemolysis syndrome

PANCE pearls

• Hydroxyurea works primarily by inducing HbF (fetal hemoglobin), which does not sickle; benefits accrue over weeks to months. Monitor CBC for myelosuppression.
• Salmonella osteomyelitis is the classic SCD-associated infection; Staphylococcus aureus is still the most common organism overall.
• Parvovirus B19 causes transient aplastic crisis — severe anemia with reticulocyte count <1%.
• Howell-Jolly bodies on smear indicate functional asplenia and the need for encapsulated-organism prophylaxis.
• Avoid meperidine — accumulation of normeperidine causes seizures, especially with renal dysfunction.
• Exchange transfusion (not simple) is preferred when HbS reduction is needed quickly without volume overload — acute stroke, severe ACS.
• TCD screening starting at age 2 has dramatically reduced primary stroke incidence in SCD children (STOP trial).

References

• ASH 2020 — American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic complications
• NHLBI 2014 — Evidence-Based Management of Sickle Cell Disease: Expert Panel Report (NHLBI 2014)
• STOP Trial — Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia (Adams et al., NEJM 1998)
• MSH Trial — Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia (Charache et al., NEJM 1995)
• Frangoul et al. — Exagamglogene autotemcel for Severe Sickle Cell Disease (NEJM 2024)