Also known as: SCD, HbSS, sickle cell anemia, sickle cell disease
Overview
Group of inherited hemoglobinopathies caused by a point mutation in the beta-globin gene (Glu→Val at position 6). Homozygous HbSS produces sickle cell anemia; HbSC and HbS/beta-thalassemia are clinically related compound heterozygous states. Sickle cell trait (HbAS) is generally asymptomatic.
Epidemiology
Most common hemoglobinopathy in the US; ~100,000 affected, predominantly Black/African ancestry (~1 in 365 Black births). HbS trait carriers ~8% of US Black population. Geographic distribution overlaps with historical malaria endemicity (heterozygote advantage).
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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
Symptoms
Vaso-occlusive pain crises — deep bony pain in back, chest, extremities; lasts hours to days
Fatigue, dyspnea from chronic anemia (baseline Hb 6-9 g/dL)
Dactylitis (hand-foot syndrome) — first manifestation in infants 6-12 months
Recurrent infections (encapsulated organisms: pneumococcus, H. flu, meningococcus, Salmonella)
Splenomegaly in young children, autosplenectomy by ~5 years
Bone tenderness over affected areas during crisis
Retinopathy on fundoscopy (especially HbSC)
Cardiomegaly, systolic flow murmur
Classic findings
African-American child with dactylitis at 6-12 months age and family history of sickle cell disease.
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
MRI brain for stroke evaluation; MRI of bone if osteomyelitis vs infarction unclear
Echocardiogram for pulmonary hypertension screening in adults
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]
Sickle cell disease pathophysiology — single point mutation drives both hemolytic and vaso-occlusive complications.
Treatment
First-line
Hydroxyurea — disease-modifying therapy; increases HbF and reduces sickling; indicated for all SCD patients ≥9 months; reduces vaso-occlusive crises, acute chest syndrome, transfusion need, and mortality
Penicillin prophylaxis (penicillin V 125 mg BID <3 years, 250 mg BID ages 3-5; continue to age 5 minimum) — reduces pneumococcal sepsis
Routine immunizations PLUS pneumococcal (PCV13/PCV15 + PPSV23), meningococcal (MenACWY + MenB), and annual influenza
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
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