What is sickle cell disease?

Sickle Cell Disease: A Genetic Blood Disorder

Sickle cell disease (SCD) is an autosomal recessive genetic disorder characterized by the presence of abnormal hemoglobin S, causing red blood cells to become sickle-shaped, leading to vaso-occlusion, hemolysis, and progressive multiorgan damage. 1

Pathophysiology

Sickle cell disease results from a specific genetic mutation:

• A single amino acid change (glutamic acid replaced by valine) in the beta globin gene causes polymerization of deoxygenated hemoglobin, leading to sickle or crescent-shaped red blood cells 2
• When hemoglobin S deoxygenates, it forms polymers that distort red blood cells into the characteristic sickle shape 2
• These sickled cells:
  • Become rigid and sticky
  • Block small blood vessels causing tissue ischemia
  • Are damaged and prematurely destroyed (hemolysis)
  • Lead to chronic anemia and episodic vaso-occlusive crises 2, 1

Types of Sickle Cell Disease

SCD encompasses several genotypes with varying severity:

Genotype	Description	Severity	Prevalence in UK
HbSS (Sickle cell anemia)	No HbA, 80-95% HbS	Severe	50-60%
HbSC	No HbA, 50-55% HbS, 40-45% HbC	Moderate	25-30%
HbS β⁰-thalassemia	No HbA, 80-90% HbS	Severe	1-3%
HbS β⁺-thalassemia	10-25% HbA, 70-80% HbS	Mild	5-10%
Other sickle variants	Variable	Variable	1-2%

Note: Sickle cell trait (HbAS) is not a disease but a carrier state that is generally benign. 2

Clinical Manifestations

SCD affects multiple organ systems with both acute and chronic complications:

Acute Complications

• Vaso-occlusive pain crisis: Most common manifestation, causing severe pain in bones, chest, abdomen
• Acute chest syndrome: Chest pain, fever, respiratory symptoms, pulmonary infiltrates
• Stroke: Can cause hemiparesis, aphasia, seizures, or coma
• Splenic sequestration: Rapid enlargement of spleen with severe anemia
• Aplastic crisis: Severe worsening of anemia with decreased reticulocytes
• Priapism: Prolonged painful erection lasting >4 hours 2, 1

Chronic Complications

• Chronic hemolytic anemia
• Progressive organ damage (kidneys, lungs, heart)
• Avascular necrosis of bones (especially hips)
• Pulmonary hypertension
• Retinopathy
• Leg ulcers
• Gallstones
• Growth and developmental delays in children 2, 3

Diagnosis

• Newborn screening: All 50 US states and many countries screen for SCD at birth 2
• Hemoglobin electrophoresis: Definitive test that identifies specific hemoglobin types
• Complete blood count: Shows anemia, often with elevated reticulocyte count
• Peripheral blood smear: Shows sickled red blood cells 2

Management

Management focuses on preventing complications and treating acute events:

Preventive Care

• Infection prevention:

  • Penicillin prophylaxis in children
  • Pneumococcal, meningococcal, and Haemophilus influenzae type b vaccines 1

• Disease-modifying therapies:

  • Hydroxyurea: First-line therapy that increases fetal hemoglobin and reduces sickling 3
  • L-glutamine: Reduces hospitalization rates
  • Crizanlizumab: Reduces frequency of pain crises
  • Voxelotor: Increases hemoglobin levels 3

• Comprehensive care:

  • Regular follow-up with hematology specialists
  • Screening for organ damage
  • Patient education on hydration, avoiding temperature extremes 1

Acute Crisis Management

• Pain crisis:

  • Prompt analgesia following tiered approach
  • Mild pain: Acetaminophen or NSAIDs
  • Moderate-severe pain: Opioids
  • Adequate hydration 1

• Acute chest syndrome:

  • Oxygen therapy
  • Broad-spectrum antibiotics
  • Blood transfusion when indicated 1

• Stroke:

  • Immediate medical attention
  • Exchange transfusion to reduce HbS percentage
  • Secondary prevention with chronic transfusion program 1

Curative Options

• Hematopoietic stem cell transplantation: Currently the only established cure, limited by donor availability and transplant-related risks 3, 4
• Gene therapy: Emerging curative options including CRISPR-based approaches like Casgevy 5

Prognosis

• Life expectancy for individuals with SCD has improved significantly but remains approximately 20 years less than the general population 3
• Mortality risk increases during transition from pediatric to adult care 3, 4
• Early diagnosis and comprehensive care significantly improve outcomes 2

Important Considerations

• SCD primarily affects individuals of African, Mediterranean, Middle Eastern, and South Asian descent 6
• Patient education is crucial for recognizing emergencies like fever, respiratory symptoms, and worsening pain 1
• Despite experiencing chronic pain, patients with SCD are not more likely to develop addiction to pain medications than the general population 3
• Comprehensive care should ideally include comanagement by primary care providers and SCD specialists 2