What is Hemoglobin S (HbS)?
Hemoglobin S is an abnormal hemoglobin variant caused by a single point mutation in the beta-globin gene where valine replaces glutamic acid at position 6 of the beta chain, resulting in hemoglobin that polymerizes under low oxygen conditions and causes red blood cells to sickle. 1
Molecular Basis
The genetic defect is a C to A substitution at codon 6 of the beta globin gene, producing an abnormal beta globin chain (βs) that combines with normal alpha chains to form HbS (α2βs2) instead of normal adult hemoglobin HbA (α2β2). 1
This single nucleotide substitution places valine where glutamic acid should be at codon 6 of the β-globin chain. 2
Pathophysiology
HbS is an insoluble hemoglobin that crystallizes and polymerizes when deoxygenated or under other precipitating conditions (such as dehydration, acidosis, or temperature changes), leading to rigid, sickle-shaped red blood cells. 2
These sickled cells are inflexible and stick to vessel walls, causing vaso-occlusion that blocks blood flow and prevents oxygen delivery to tissues. 3
HbS is a low-affinity hemoglobin that delivers oxygen at lower partial pressures compared to normal HbA, though this paradoxically can be somewhat protective by releasing oxygen more readily to tissues. 2
Clinical Significance by Genotype
Homozygous HbSS (sickle cell anemia): The most severe form with 80-95% HbS and no normal HbA present, causing severe anemia (hemoglobin 60-90 g/L), early painful crises, and highest risk of stroke, acute chest syndrome, and end-organ damage. 4
Compound heterozygous states: HbSC disease and HbSβ-thalassemia have different proportions of HbS mixed with other abnormal hemoglobins, generally resulting in milder disease with higher baseline hemoglobin levels. 4
Heterozygous HbAS (sickle cell trait): Contains 30-40% HbS with 55-65% normal HbA, representing a mostly benign carrier state that only becomes problematic at extremes of physiology such as severe dehydration, high altitude, or intense exertion. 1, 5
Disease Consequences
The sickling process causes chronic hemolytic anemia, painful vaso-occlusive crises, and progressive acute and chronic end-organ damage affecting the brain, spleen, eyes, lungs, liver, kidneys, and bones. 1, 3
Intravascular hemolysis releases free hemoglobin and heme into plasma, which act as danger-associated molecular patterns (DAMPs) that trigger chronic inflammation, decrease nitric oxide bioavailability, and generate reactive oxygen species. 6
This creates a vicious cycle where inflammation further damages red blood cells, worsening their rheological properties and adhesiveness to vessel walls. 6