What is sickle cell disease?

Sickle Cell Disease

Sickle cell disease is a serious inherited genetic blood disorder characterized by abnormal hemoglobin that causes red blood cells to become sickle-shaped, leading to chronic hemolytic anemia, painful vaso-occlusive crises, and progressive multi-organ damage. 1

Pathophysiology

• Sickle cell disease results from a genetic mutation - a C to A substitution at codon 6 of the beta globin gene, replacing glutamic acid with valine, creating abnormal hemoglobin S (HbS) 1
• When deoxygenated, HbS molecules form polymers causing red blood cells to deform into the characteristic sickle shape 1
• This sickling process leads to:
  • Damaged red cell membranes and cytoskeleton
  • Irreversibly sickled cells and hemolysis
  • Increased adherence to vascular endothelium
  • Vaso-occlusion, ischemia-reperfusion injury, and end-organ damage 1
• Intravascular hemolysis causes nitric oxide depletion and free heme release, worsening vascular endothelial damage 1

Genetic Patterns and Prevalence

• SCD is one of the most common serious inherited conditions globally, diagnosed in more than 1:2000 live births in England annually 1
• Patients may have:
  • Homozygous sickle gene (HbSS - sickle cell anemia)
  • Compound heterozygous state with another abnormal hemoglobin (e.g., HbSC, HbS-β-thalassemia) 1
• The heterozygous carrier state (HbAS or sickle cell trait) is generally benign 1
• SCD predominantly affects people of African or Caribbean background (98% in UK registry), but also occurs in families from the Middle East, India, and Mediterranean regions 1
• Approximately 300,000 infants are born with SCD annually worldwide, with about 100,000 individuals living with SCD in the US 2

Clinical Manifestations

Acute Complications

• Painful vaso-occlusive crises - severe acute pain episodes 1
• Acute chest syndrome - a potentially life-threatening complication 2
• Stroke - presenting with hemiparesis, aphasia, seizures, severe headache, or altered consciousness 1
• Splenic sequestration - rapid enlargement of the spleen with trapped blood 1
• Transient aplastic crisis - exacerbation of anemia with decreased reticulocyte count, often triggered by parvovirus B19 1
• Priapism - prolonged painful erection, occurring in two forms:
  • Stuttering episodes lasting <4 hours
  • Severe acute ischemic episodes lasting ≥4 hours 1

Chronic Complications

• Chronic hemolytic anemia 1
• Progressive multi-organ damage affecting:
  • Kidneys (nephropathy)
  • Eyes (retinopathy)
  • Bones (avascular necrosis)
  • Lungs (pulmonary hypertension)
  • Skin (leg ulcers) 2
• Increased susceptibility to infections, particularly pneumococcal 1
• Neuropsychological impairment affecting school and job performance 1

Disease Severity and Variants

• Severity varies by genotype and within genotypes 1
• Severe forms include:
  • HbSS (sickle cell anemia)
  • HbSβ0-thalassemia
  • HbSD disease 1
• These severe forms typically present with:
  • Early onset of painful crises
  • Severe anemia (hemoglobin 60-90 g/L)
  • More frequent complications 1
• Milder forms like HbSC disease and HbSβ+-thalassemia generally have fewer symptoms and higher baseline hemoglobin levels 1
• Higher fetal hemoglobin (HbF) levels (>8%) are associated with milder disease phenotype 1

Management Approaches

• Hydroxyurea (hydroxycarbamide) remains first-line therapy, increasing fetal hemoglobin and reducing red cell sickling 2
• Newer therapies approved since 2017 include:
  • L-glutamine - reduced hospitalization rates by 33%
  • Crizanlizumab - reduced pain crises from 2.98 to 1.63 per year
  • Voxelotor - increased hemoglobin by at least 1 g/dL 2
• Hematopoietic stem cell transplantation is the only curative therapy, with best results in children with matched sibling donors 2
• Regular blood transfusions may be needed for certain complications, particularly stroke prevention 1

Prognosis

• With optimal multidisciplinary care, survival into the 7th decade can be expected 1
• In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population 2
• Mortality increases during transition from pediatric to adult healthcare systems 2, 3
• Death in childhood is now uncommon in the UK (1-2%) 1

Important Considerations

• Patients with SCD are at increased risk of complications during surgery and anesthesia 1
• Iron supplementation should not be given unless iron deficiency is biochemically proven, due to risk of iron overload from repeated transfusions 1
• Comprehensive care programs are well-established in pediatrics but often lacking for adults 3
• Regular screening and preventive care are essential to reduce complications and improve quality of life 1