Sickle cell disease: molecular basis and pathophysiology

At a glance

• A single base change in HBB gives HbS (β6 Glu to Val). Deoxygenated HbS polymerises into fibres that distort and stiffen red cells.
• Polymerisation is a race: if the delay time exceeds the time a cell spends in the capillaries, it reoxygenates before it sickles. Anything that raises HbS concentration or lowers oxygen loses the race.
• Two overlapping disease processes: vaso-occlusion (pain, acute chest syndrome, avascular necrosis, stroke) and haemolysis with nitric oxide depletion (pulmonary hypertension, priapism, leg ulcers).