What Causes Red Blood Cell Sickling in Sickle Cell Disease
Sickling occurs when abnormal hemoglobin S (HbS) polymerizes under deoxygenated conditions, causing red blood cells to deform into a sickle or crescent shape. 1
The Molecular Defect
The fundamental cause is a single point mutation in the beta-globin gene:
A C to A substitution at codon 6 of the beta-globin gene replaces glutamic acid with valine (βGlu6Val), creating the abnormal beta-globin gene (βs) and resulting in hemoglobin S (α2βs2) instead of normal adult hemoglobin A (α2β2). 1
This single amino acid change—from a hydrophilic glutamic acid to a hydrophobic valine—fundamentally alters the hemoglobin molecule's behavior. 2
The Polymerization Process
The pathologic sickling process occurs through specific molecular interactions:
When HbS is deoxygenated, the valine at position 6 (βVal6) creates hydrophobic interactions with a pocket formed by βAla70, βPhe85, and βLeu88 amino acid residues on adjacent hemoglobin tetramers. 2
These noncovalent interactions between the side chain of βVal6 and the hydrophobic grooves of other tetramers cause hemoglobin molecules to associate and form elongated polymers. 2
The polymerization and precipitation of these elongated polymers physically distorts the red blood cell membrane, creating the characteristic sickle or crescent shape. 1, 2
Critical Physiologic Context
The sickling process is reversible and dependent on oxygen tension:
Polymerization occurs primarily in the deoxygenated (T-state) of HbS, not when oxygen is bound. 2
The oxygenated form of HbS inhibits polymerization, which is why sickling is intermittent and triggered by conditions causing deoxygenation. 2
Normal interactions that facilitate oxygen binding and release in HbA are not as effective in HbS, making abnormal polymerization more likely. 1
Clinical Consequences of Sickling
The sickled red blood cells cause disease through two primary mechanisms:
Hemolysis: The abnormally shaped cells are fragile and undergo premature destruction, causing chronic anemia with typical hemoglobin levels of 60-90 g/L in severe disease. 1, 3
Vaso-occlusion: Sickled cells obstruct blood flow in small vessels, causing tissue ischemia that leads to acute painful crises and progressive organ damage. 1
Important Clinical Pitfall
The severity of sickling and clinical disease varies significantly even with the same genetic mutation:
HbSS (homozygous), HbSβ0-thalassemia, and HbSD are associated with severe disease, early painful crises, and severe anemia. 1
HbSC and HbSβ+-thalassemia typically cause milder disease, though marked variability exists within each genotype. 1
This unpredictable clinical variability occurs despite the same underlying molecular defect, likely due to genetic modifiers and other factors. 4