The Red Cell
In order to carry haemoglobin into close contact with the tissues and for successful gaseous exchange, the red cell, 8 μm in diameter, must be able: to pass repeatedly through the microcirculation whose minimum diameter is 3.5 μm, to maintain haemoglobin in a reduced (ferrous) state and to maintain osmotic equilibrium despite the high concentration of protein (haemoglobin) in the cell. A single journey round the body takes 20 seconds and its total journey throughout its 120‐day lifespan has been estimated to be 480 km (300 miles). To fulfil these functions, the cell is a flexible biconcave disc with an ability to generate energy as adenosine triphosphate (ATP) by the anaerobic glycolytic (Embden–Meyerhof ) pathway (Fig. 2.11) and to generate reducing power as nicotinamide adenine dinucleotide (NADH) by this pathway and as reduced nicotinamide adenine dinucleotide phosphate (NADPH) by the hexose monophosphate shunt (see Fig. 6.6).
Red cell metabolism
In this series of biochemical reactions, glucose that enters the red cell from plasma by facilitated transfer is metabolized to lactate (Fig. 2.11). For each molecule of glucose used, two molecules of ATP and thus two high‐energy phosphate bonds are generated. This ATP provides energy for maintenance of red cell volume, shape and flexibility.
The Embden–Meyerhof pathway also generates NADH, which is needed by the enzyme methaemoglobin reductase to reduce functionally dead methaemoglobin containing ferric iron (produced by oxidation of approximately 3% of haemoglobin each day) to functionally active, reduced haemoglobin containing ferrous ions. The Luebering–Rapoport shunt, or side arm, of this pathway (Fig. 2.11) generates 2,3‐DPG, important in the regulation of haemoglobin’s oxygen affinity (Fig. 2.9).
Hexose monophosphate (pentose phosphate) shunt
Approximately 10% of glycolysis occurs by this oxidative pathway in which glucose‐6‐phosphate is converted to 6‐ phosphogluconate and so to ribulose‐5‐phosphate (see Fig. 6.6). NADPH is generated and is linked with glutathione which maintains sulphydril (SH) groups intact in the cell, including those in haemoglobin and the red cell membrane. In one of the most common inherited abnormalities of red cells, glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, the red cells are extremely susceptible to oxidant stress (see p. 66).
Red cell membrane
The red cell membrane comprises a lipid bilayer, integral membrane proteins and a membrane skeleton (Fig. 2.12). Approximately 50% of the membrane is protein, 20% phospholipids, 20% cholesterol molecules and up to 10% is carbohydrate. Carbohydrates occur only on the external surface while proteins are either peripheral or integral, penetrating the lipid bilayer. Several red cell proteins have been numbered according to their mobility on polyacrylamide gel electrophoresis (PAGE), e.g. band 3, proteins 4.1, 4.2 (Fig. 2.12).
The membrane skeleton is formed by structural proteins that include α and β spectrin, ankyrin, protein 4.1 and actin. These proteins form a horizontal lattice on the internal side of the red cell membrane and are important in maintaining the biconcave shape. Spectrin is the most abundant and consists of two chains, α and β, wound around each other to form heterodimers which then self‐associate head‐to‐head to form tetramers. These tetramers are linked at the tail end to actin and are attached to protein band 4.1. At the head end, the β spectrin chains attach to ankyrin which connects to band 3, the transmembrane protein that acts as an anion channel (‘vertical connections’) (Fig. 2.12). Protein 4.2 enhances this interaction.
Defects of the membrane proteins explain some of the abnormalities of shape of the red cell membrane (e.g. hereditary spherocytosis and elliptocytosis) (see Chapter 6), while alterations in lipid composition because of congenital or acquired abnormalities in plasma cholesterol or phospholipid may be associated with other membrane abnormalities (see Fig. 2.16).