What is sickle cell anemia?

Sickle Cell Anemia: Pathophysiology, Clinical Features, and Management

Sickle cell anemia is a genetic blood disorder characterized by the production of abnormal hemoglobin S (HbS), which causes red blood cells to become rigid and sickle-shaped when deoxygenated, leading to vaso-occlusion, hemolysis, and progressive multi-organ damage that significantly impacts morbidity, mortality, and quality of life. 1, 2

Pathophysiology

Sickle cell anemia results from a specific genetic mutation:

• A point mutation in the beta-globin gene (substitution of glutamic acid by valine at position 6) leads to the formation of abnormal hemoglobin called HbS (α₂βˢ₂) 1
• When deoxygenated, HbS molecules polymerize, causing red blood cells to deform into the characteristic sickle shape 1
• This process is cyclical - red cells sickle when deoxygenated and can return to normal shape when oxygenated, but repeated cycles cause permanent damage to the cell membrane 1
• Damaged red cells:
  • Have increased adherence to vascular endothelium
  • Are prematurely destroyed (hemolysis)
  • Cause vaso-occlusion, ischemia-reperfusion injury, and end-organ damage 1

Genetic Patterns and Disease Severity

The severity of sickle cell disease varies by genotype:

• HbSS (Sickle Cell Anemia): Homozygous for HbS - most severe form, accounts for 50-60% of cases in the UK 1
• HbSC: Compound heterozygous for HbS and HbC - moderate severity, accounts for 25-30% of cases 1
• HbS/β⁰-thalassemia: Severe phenotype similar to HbSS 1
• HbS/β⁺-thalassemia: Milder phenotype 1
• Sickle trait (HbAS): Heterozygous carrier state - generally benign 1

Fetal hemoglobin (HbF) levels above 8% can reduce HbS polymerization and lead to milder disease 1.

Clinical Features

Sickle cell anemia manifests with various acute and chronic complications:

Acute Complications

• Acute painful crises: Severe pain due to vaso-occlusion, varying by age (dactylitis in infants; pain in long bones, sternum, ribs, and back in older patients) 2
• Acute chest syndrome: New pulmonary infiltrates, fever, respiratory symptoms, decreasing hemoglobin, and hypoxemia 2
• Splenic sequestration: Massive splenomegaly, acute anemia, hypovolemic shock (common in children 5 months-2 years) 2
• Aplastic crisis: Temporary cessation of red blood cell production, often triggered by parvovirus B19 2
• Priapism: Painful, prolonged erection that may lead to impotence if untreated 2
• Fever: Temperature ≥38°C requires immediate medical attention due to high risk for septicemia and meningitis 2

Chronic Complications

• Chronic hemolytic anemia: Baseline hemoglobin typically 60-90 g/L in severe forms 1
• Stroke: Occurs in up to 10% of children; silent cerebral infarcts in 40% of adults 2
• Pulmonary complications: Obstructive sleep apnea, chronic lung disease, pulmonary hypertension 2
• Renal complications: Renal insufficiency, proteinuria, hyposthenuria 2
• Musculoskeletal complications: Avascular necrosis of the femoral head, osteomyelitis 2
• Other complications: Cholelithiasis, retinopathy, leg ulcers, erectile dysfunction 2

Diagnosis

• Newborn screening: Implemented in many countries to detect sickle cell disease early 1
• Hemoglobinopathy screen: High-performance liquid chromatography, capillary electrophoresis, mass spectrometry, or gel electrophoresis can detect homozygous or heterozygous states 1
• Sickle solubility test: Can detect presence of HbS but cannot differentiate between heterozygous, compound heterozygous, or homozygous states 1

Management

Acute Management

• Pain management: Prompt administration of opioid analgesics using scheduled dosing or patient-controlled analgesia 2
• Hydration: IV crystalloid fluids (5% dextrose in 0.25% normal saline) while avoiding excessive fluid administration 2
• Oxygen therapy: Supplemental oxygen to maintain SpO2 >95% 2
• Antibiotics: Immediate broad-spectrum antibiotics for fever or suspected infection 2
• Transfusion therapy: Exchange transfusion for severe acute chest syndrome; simple or exchange transfusion for moderate cases 2

Disease-Modifying Therapies

• Hydroxyurea: First-line therapy that increases fetal hemoglobin and reduces red cell sickling 3
• L-glutamine: Reduces hospitalization rates and length of stay 3
• Crizanlizumab: Reduces frequency of pain crises 3
• Voxelotor: Increases hemoglobin levels 3
• Hematopoietic stem cell transplant: Only curative therapy, best results in children with matched sibling donors 3

Preventive Measures

• Hydration: Maintaining adequate hydration
• Temperature management: Avoiding extreme temperatures
• Vaccinations: Pneumococcal vaccination to reduce infection risk
• Prophylactic antibiotics: To prevent bacterial infections
• Regular screening: Transcranial Doppler for stroke risk assessment 2

Prognosis

With optimal multidisciplinary care, patients can survive into the 7th decade, though life expectancy remains approximately 20 years less than the general population 2, 3. Mortality risk increases during transition from pediatric to adult healthcare systems 3.

Important Considerations

• Despite chronic pain, patients with sickle cell disease are not more likely to develop addiction to pain medications than the general population 3
• Perioperative care requires meticulous attention to avoid factors that precipitate sickling (dehydration, hypoxia, acidosis, hypothermia, pain) 2
• Routine surgery should be avoided during febrile episodes or painful crises 2