Sickle Cell Disease (SCD) refers to a group of inherited hemoglobinopathies characterized by the presence of hemoglobin S (HbS), which polymerizes under low oxygen tension, causing red blood cells (RBCs) to assume a sickle shape. This was first reported in 1910 by James Herrick.
Genetics and Inheritance
- Causative mutation: A single nucleotide substitution (GAG → GTG) in the HBB gene (β-globin gene) located on chromosome 11.
- Amino acid change: Glutamic acid → Valine at the 6th position of the β-globin chain.
- Inheritance: Autosomal codominant.
- Homozygous (SS) → Sickle Cell Anemia (severe disease).
- Heterozygous (AS) → Sickle Cell Trait (usually asymptomatic).
- Compound heterozygous states:
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HbS/β-thalassemia
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HbSC disease (one β-globin gene carries the S mutation, the other the C mutation).
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Structure and Types of Hemoglobin
- Hemoglobin A (HbA): 2 α + 2 β chains.
- HbS: 2 α + 2 β<sub>S</sub> chains.
- HbF (fetal hemoglobin): 2 α + 2 γ chains (protective against sickling).
- HbC: Glutamic acid is replaced by lysine at position 6.
Pathophysiology
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Polymerization of HbS occurs in hypoxic, acidic, and dehydrated environments → sickling of RBCs.
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Sickled RBCs:
- Are rigid and adhere to endothelium → vaso-occlusion.
- Undergo hemolysis → release free hemoglobin, depleting nitric oxide → vasoconstriction and endothelial dysfunction.
- Induce inflammation via adenosine pathways.
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Vaso-occlusion + Hemolysis = Tissue ischemia, organ dysfunction, chronic anemia.
Triggers of Sickling
- Hypoxia, acidosis, dehydration
- Infections, cold exposure, stress
- Presence of HbC (promotes sickling); HbF (protective)
Clinical Manifestations
Onset:
- Usually after 6 months of age when HbF declines.
1. Anemia-related symptoms:
- Pallor, fatigue, jaundice, gallstones
2. Vaso-occlusive events:
- Pain crises ("sickle cell crisis"): bones, chest, abdomen
- Dactylitis (Hand-Foot Syndrome) in infants
- Acute chest syndrome: cough, chest pain, fever, hypoxia
- Stroke (especially in children)
3. Organ damage:
- Spleen: functional asplenia → recurrent infections
- Liver: hepatomegaly, biliary stones
- Kidney: hematuria, hyposthenuria, papillary necrosis
- Heart: cardiomegaly, murmurs, high-output failure
- Eyes: proliferative retinopathy
- Bones: avascular necrosis (femoral head), osteomyelitis
- Skin: chronic leg ulcers
- Priapism
Types of Crises
| Crisis Type | Description |
|---|---|
| Vaso-occlusive | Most common; triggered by stress, dehydration; severe pain |
| Aplastic | Often due to parvovirus B19; reticulocytopenia |
| Splenic Sequestration | Sudden pooling of blood in spleen; hypovolemic shock (usually in children <2 years) |
| Hemolytic | Sudden increase in hemolysis; may occur with G6PD deficiency |
| Megaloblastic | Folate deficiency due to increased erythropoiesis |
Diagnostic Evaluation
- CBC:
- Chronic anemia (Hb 6–10 g/dL), ↑ Reticulocytes
- Leukocytosis, thrombocytosis
- Peripheral Smear:
- Sickled cells, target cells, Howell-Jolly bodies, nucleated RBCs
- Hemoglobin Electrophoresis:
- Confirms diagnosis
- HbS >90% in homozygotes; no HbA
- Variable HbF levels
- Bilirubin:
- Elevated indirect bilirubin
- Sickling Test: Qualitative test with sodium metabisulfite
- Chest X-ray: Acute chest syndrome
- Transcranial Doppler: Screening for stroke risk in children
Management
Acute Management
- Hydration, oxygen, analgesia (opioids, NSAIDs)
- Treat infections aggressively
- Blood transfusions (esp. for severe anemia or stroke)
- Hydroxyurea: Increases HbF, decreases crises (first-line in severe disease)
Chronic Management
- Folic acid supplementation
- Prophylactic Penicillin V (from age 2 months to 5 years)
- Vaccinations:
- Pneumococcal (PCV13 + PPSV23)
- Meningococcal, Hib, Hepatitis B, Influenza
- Regular monitoring: CBC, liver/renal function, TCD scans (children)
- Psychosocial support
- Bone marrow transplantation: Potentially curative in children with matched donor
- Gene therapy: Promising future approach
Complications by System
| System | Complication |
|---|---|
| CVS | Myocardial infarction, cardiomyopathy |
| Respiratory | Acute chest syndrome, pulmonary hypertension |
| CNS | Stroke, TIA, hemorrhage |
| Hepatobiliary | Gallstones, hepatic crisis |
| Renal | Hematuria, nephropathy, renal failure |
| Ocular | Retinopathy, blindness |
| Musculoskeletal | AVN, osteomyelitis |
| Reproductive | IUGR, infertility, miscarriage |
Prenatal & Genetic Considerations
- Prenatal diagnosis via chorionic villus sampling (CVS) or amniocentesis
- Genetic counseling essential for carriers (HbAS)
