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 (HbS) that causes red blood cells to become sickle-shaped when deoxygenated, leading to chronic hemolytic anemia, vaso-occlusive crises, and progressive multi-organ damage. 1, 2

Pathophysiology

Sickle cell anemia results from a specific genetic mutation:

• A single nucleotide substitution (C to A) at codon 6 of the beta-globin gene, replacing glutamic acid with valine 1
• This creates abnormal hemoglobin S (HbS) that polymerizes when deoxygenated 1, 3
• When deoxygenated, HbS molecules form long chains (polymers) that distort red blood cells into the characteristic sickle shape 1, 3
• This process is reversible initially, but repeated cycles lead to irreversibly sickled cells 1

The consequences of this abnormal hemoglobin include:

• Damaged red cell membrane and cytoskeleton leading to hemolysis 1
• Increased red cell adhesion to vascular endothelium 1, 3
• Vaso-occlusion causing ischemia-reperfusion injury 1
• Nitric oxide depletion from intravascular hemolysis 1
• Chronic inflammation and oxidative stress 3

Genetic Variants and Disease Severity

The severity of sickle cell disease varies by genotype:

• HbSS (Sickle Cell Anemia): Most severe form, with hemoglobin levels typically 60-90 g/L 1
• HbSC: Moderate severity, higher baseline hemoglobin 1
• HbS/β⁰-thalassemia: Severe phenotype similar to HbSS 1
• HbS/β⁺-thalassemia: Milder phenotype 1
• Sickle Cell Trait (HbAS): Generally benign carrier state 1

Protective factors that reduce disease severity:

• Higher fetal hemoglobin (HbF) levels (>8%) are associated with milder disease 1, 4
• Hydroxycarbamide (hydroxyurea) therapy increases HbF levels 1, 2

Clinical Features

Sickle cell anemia manifests through several key clinical features:

Acute Complications

• Vaso-occlusive painful crises: Severe pain in bones, chest, abdomen; most common complication 5, 2
• Acute chest syndrome: New pulmonary infiltrates, fever, respiratory symptoms, decreasing hemoglobin 1, 5
• Splenic sequestration: Massive splenomegaly, acute anemia, hypovolemic shock 5
• Aplastic crisis: Temporary cessation of red cell production, often triggered by parvovirus B19 5
• Stroke: Occurs in up to 10% of children 5, 2
• Priapism: Painful, prolonged erection that may lead to impotence if untreated 5
• Fever/Infection: High risk for septicemia and meningitis, particularly with encapsulated bacteria 5

Chronic Complications

• Chronic hemolytic anemia: Fatigue, exercise intolerance, jaundice 5, 2
• Pulmonary hypertension: Associated with increased mortality 5
• Renal insufficiency: Proteinuria, hyposthenuria 5
• Avascular necrosis: Particularly affecting the femoral head 5
• Retinopathy: Progressive visual impairment 5, 2
• Leg ulcers: Chronic, painful wounds 5, 2
• Cognitive impairment: Due to silent cerebral infarcts in up to 40% of adults 5

Management

Management focuses on preventing complications and treating acute events:

Preventive Measures

• Regular follow-up with hematology specialists 5
• Hydroxyurea: First-line disease-modifying therapy that increases HbF and reduces sickling 2
• Pneumococcal vaccination and prophylactic antibiotics to prevent infections 5
• Regular transcranial Doppler screening for stroke risk assessment 5
• Adequate hydration and avoiding extreme temperatures 5

Acute Crisis Management

• Pain management: Prompt administration of opioid analgesics using scheduled dosing or patient-controlled analgesia 5
• Hydration: IV crystalloid fluids while avoiding overhydration 5
• Oxygen therapy: Maintain SpO2 >95% 5
• Antibiotics: Immediate broad-spectrum antibiotics for fever or suspected infection 5
• Blood transfusion: Simple or exchange transfusion for severe anemia or acute chest syndrome 5

Newer Therapies

• L-glutamine: Reduces hospitalization rates 2
• Crizanlizumab: Reduces frequency of pain crises 2
• Voxelotor: Increases hemoglobin levels 2
• Hematopoietic stem cell transplant: Only curative therapy, best results in children with matched sibling donors 2

Prognosis

With optimal multidisciplinary care, survival into the 7th decade can now be expected 1, 5. However, life expectancy remains approximately 20 years less than the general population 5, 2. Mortality risk increases during the transition from pediatric to adult healthcare systems 2.

Important Considerations

• Patients are not more likely to develop addiction to pain medications than the general population 2
• Fever ≥38°C (≥100.4°F) requires immediate medical attention 5
• Perioperative care requires meticulous attention to avoid factors that precipitate sickling (dehydration, hypoxia, acidosis, hypothermia) 5
• Regular screening for end-organ damage is essential for early intervention 5