What is Sickle Cell HbSS (Hemoglobin SS) or Sickle Cell Anemia?

What is Sickle Cell HbSS (Sickle Cell Anemia)?

Sickle cell HbSS, also called sickle cell anemia, is the most severe form of sickle cell disease where patients inherit two abnormal beta globin genes (one from each parent), resulting in 80-95% hemoglobin S with no normal adult hemoglobin (HbA) present. 1, 2

Genetic and Molecular Basis

The fundamental defect is a single nucleotide substitution (C to A at codon 6) in the beta globin gene that replaces glutamic acid with valine, creating abnormal hemoglobin S (α2βs2) instead of normal hemoglobin A (α2β2). 1, 3

• When deoxygenated, HbS molecules polymerize and form rigid polymers that distort red blood cells into the characteristic sickle shape 1, 4
• This polymerization is reversible with oxygenation, creating continuous cycles of sickling and un-sickling as cells travel through the circulation 1
• Extensive polymerization damages the red cell membrane irreversibly, leading to hemolysis and removal by the reticuloendothelial system 1

Clinical Severity and Characteristics

HbSS disease represents the most severe phenotype among all sickle cell disease variants, characterized by: 1, 2

• Severe chronic hemolytic anemia with typical hemoglobin levels of 60-90 g/L (6-9 g/dL) 1, 2
• Early onset of painful vaso-occlusive crises beginning in childhood 1, 2
• No protective normal hemoglobin A (0% HbA), unlike milder variants like HbSC disease 1
• Highest risk of complications including stroke, acute chest syndrome, priapism, pulmonary hypertension, and multiorgan damage 1, 2

Pathophysiology and Clinical Consequences

The disease causes three main pathological processes: 1, 4

• Chronic hemolytic anemia from premature red cell destruction, causing fatigue and requiring the body to compensate with increased red cell production 1, 5
• Vaso-occlusion from sickled cells adhering to vascular endothelium and blocking small blood vessels, causing acute painful crises and tissue ischemia 1, 5
• Progressive end-organ damage from repeated cycles of ischemia-reperfusion injury, inflammation, and nitric oxide depletion affecting brain, lungs, kidneys, liver, spleen, and bones 1, 5

Important Clinical Distinctions

Always distinguish HbSS from other sickle cell variants, as management intensity differs significantly: 2

• HbSS (sickle cell anemia): Most severe, 80-95% HbS, 0% HbA, hemoglobin 60-90 g/L 1
• HbSC disease: Moderate severity, 50-55% HbS, 40-45% HbC, higher baseline hemoglobin 1
• HbS β0-thalassemia: Severe like HbSS, 80-90% HbS, 0% HbA 1
• HbS β+-thalassemia: Mild, 70-80% HbS, 10-25% HbA present 1
• HbAS (sickle cell trait): Benign carrier state, 30-40% HbS, 55-65% HbA, not a disease 1

Modifying Factors

Fetal hemoglobin (HbF) levels significantly impact disease severity in HbSS patients: 1

• HbF reduces HbS polymerization and provides protection against sickling 1
• Patients with HbF levels >8% typically have milder symptoms and fewer crises 1
• Hydroxycarbamide (hydroxyurea) is now standard therapy to raise HbF levels and reduce complications 1, 6

Epidemiology

HbSS disease predominantly affects individuals of African, Caribbean, Middle Eastern, Indian, and Mediterranean descent, with approximately 50-60% of UK sickle cell disease patients having the HbSS genotype. 1