Effect on erythrocytes

Red cells acquire the sickle or elongated shape upon deoxy-genation as a result of intracellular polymerization of HbS, a phenomenon that is reversible upon reoxygenation. Even in the normally shaped red cells, however, the presence of HbS polymer reduces deformability, with consequent increase in blood viscosity. Repeated or prolonged sickling progressively damages the red cell membrane, which is a phenomenon of primary importance in the pathophysiology of SCD. Membrane damage causes movement of potassium ions and water out of the cell by the Gardos pathway and potassium-chloride co-transport, leading to dehydration of red cells. The intracel-lular haemoglobin concentration rises (producing dense cells), which shortens the delay time to sickle polymer formation. A

Figure 7.1 Induction of red cell sickling. As red cells traverse the microcirculation, oxygen is released from oxy-HbS (red circles), generating deoxy-HbS (purple circles). Conformational change exposes a hydrophobic patch at the site of the P6-valine replacement, shown as a projection (left column), which can bind to a complementary hydrophobic site on a subunit of another haemoglobin tetramer, shown as an indentation. Only one of the two P6-valine sites in each HbS tetramer makes this contact. The middle column shows the assembly of deoxy-HbS into a helical 14-strand fibre, shown as a twisted rope-like structure. The delay time is inversely proportional to the intracellular haemoglobin concentration raised to the 15th power. As deoxy-HbS polymerizes and fibres align, the red cell is distorted into an elongated banana or 'sickle' shape (right column) (from Bunn, HF, 1997, New England Journal of Medicine 337: 762, with permission).

a

ß

a

ß

Oxygenated HbS

Deoxygenated HbS

Polymerized HbS

a ß HbS molecules

Sickle polymer

Red cell a ß HbS molecules

Oxygenated HbS

Deoxygenated HbS

Polymerized HbS

Sickle polymer

Red cell second key consequence of membrane damage is alteration of the chemistry of the red cell membrane. Perturbation of lipid organization causes negatively charged phosphatidylserine to appear on the red cell surface instead of its normal location in the inner monolayer. In addition, the red cells become abnormally adherent to the vascular endothelium through vascular cell adhesion molecule 1 (VCAM-1), thrombospondin and fibronectin.

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