Page 533 - Hematology_ Basic Principles and Practice ( PDFDrive )

448 Part V Red Blood Cells

Perhaps the most remarkable feature of the human RBC is its As described in Chapter 46, the complex structure of the mem-
durability, given that it is an enucleated cell devoid of organelles that brane is exquisitely sensitive to perturbations impinging on any of its
appear to be critical for the survival and function of most other cell components. In particular, the membrane cytoskeleton and phospho-
types. The RBC has no mitochondria available for efficient oxidative lipid structures are each highly susceptible to oxidation, particularly
metabolism; no ribosomes for regeneration of lost or damaged pro- by partially proteolyzed molecules of Hb, which denature to form
teins; a very limited metabolic repertoire that largely precludes de novo highly toxic compounds called hemopyrroles. This interaction of
synthesis of lipids; and no nucleus to direct regenerative processes, denatured Hb with the RBC membrane is clinically important, as
adaptation to circulatory stresses, or cell division to replenish itself. illustrated by its impact on the pathophysiology of sickle cell anemia
Given these handicaps, the 120-day survival of these cells is even more (see Chapter 42) or of oxidized and precipitated globin inclusion
striking considering the multiple and often exceedingly hostile envi- bodies in thalassemia (Chapter 41). In this chapter, it is sufficient to
ronments they must traverse. Mechanical stresses of the circulation note that alterations of proteins of the RBC membrane can contribute
include high hydrostatic pressure and turbulence and the shear stresses to shortening the life span of the RBC. Damage can result from direct
inherent in a microcirculation networked with many capillaries having defects in the cytoskeletal proteins themselves or from susceptibility
diameters only one-third to one-half that of the normal RBC. Bio- of these proteins to direct oxidation or attack by oxidized or denatured
chemical stresses include osmotic and redox fluxes associated with Hb molecules. Readers are referred to chapters 43 through 47 for
travel through the collecting system of the kidney; the sluggish vascular detailed descriptions of the relevant phenomena.
beds of the spleen, muscle, and bone; and the rapid changes in ambient
oxygen pressures occurring in the lungs. All conspire to damage RBCs.
Their 4-month survival is truly remarkable. ENZYMES OF RED BLOOD CELL INTERMEDIARY
The ability of the RBC to persist in the circulation depends on
its simple but exquisitely adaptive membrane structures; its pathways Metabolism
of intermediary energy metabolism and redox regulation; and its
ability to maintain its largest cytoplasmic component, Hb, in a Mammalian erythrocytes possess a highly specialized but remarkably
soluble and nonoxidized state. The membrane and enzymes of the simplified set of metabolic pathways. As discussed in Chapter 44,
RBC appear to be exquisitely crafted to protect the cell from the there are essentially three relevant sets of pathways. The first two are
external ravages of the circulation and the potential internal assaults interconnected by the enzyme glucose-6-phosphate dehydrogenase
of the massive amount of iron-rich and potentially oxidizing protein (G6PD). Glucose entering the RBC is metabolized by an anaerobic
represented by its complement of Hb molecules. For these reasons, a pathway, the Embden-Meyerhof pathway, which terminates with the
few basic features of these membrane and enzyme systems merit enzyme lactic dehydrogenase, forming lactate. Despite its inefficiency
comment before considering the Hb molecule itself. (a net of only two adenosine triphosphate [ATP]/glucose molecule),
this pathway is the sole source of usable ATP in the cell. Moreover,
MAJOR FEATURES OF THE RED BLOOD the pathway generates reduced nicotinamide adenine dinucleotide
(NADH), a molecule necessary for driving the reduction of methe-
CELL MEMBRANE moglobin to Hb (see Chapters 44 and 47). A shunt within this
pathway, the Rapoport-Luebering shunt, generates the compound
Chapter 45 describes the RBC membrane in considerable detail. 2,3-bisphosphoglycerate (bis[phosphoglyceric acid]) (2,3-BPG), an
Only a few major aspects of that discussion bear repeating for the important cofactor that, when bound to Hb, reduces the affinity of
purposes of this chapter. The RBC membrane and its underlying Hb for oxygen (see Hemoglobin Function). The ATP generated is
cytoskeleton have evolved to provide mechanical strength and the necessary for kinase reactions controlling phosphorylation of mem-
necessary pliability and resilience to withstand the mechanical, brane and signaling components, for fueling ion pumps and channels,
osmotic, and chemical stresses of the circulation. Because the lipid and for maintaining phospholipid levels.
bilayer membrane essentially has the physical properties of a soap The anaerobic metabolic pathway generates, as one of its inter-
bubble, it would rapidly be emulsified in the circulation. Strength mediates, glucose-6 phosphate, which is the substrate for G6PD.
and order are provided to the lipid bilayer by the hexagonal arrays of G6PD appears to be the rate-limiting enzyme for a linked pathway
the highly helical protein spectrin, which forms a latticework under- called the oxidative hexose monophosphate shunt. This pathway involves
lying the membrane. a cascade of reactions culminating in the reduction of oxidized glu-
The spectrin meshwork is held together by adaptor molecules, tathione to reduced glutathione. Reduced glutathione is used
such as protein 4.1, adducin, p55, and ankyrin, arrayed at defined to reverse oxidation of critical structures, including Hb, cytoskeletal
points along the highly coiled, rod-like structure of the spectrin proteins, and membrane lipids. Anaerobic glycolysis generates
oligomers. These protein–protein interactions appear to be critical NADH for methemoglobin reduction, 2,3-BPG for modulation of
for holding the latticework together in what has been described as Hb oxygen affinity, and ATP for metabolic energy requirements. Its
the “horizontal” dimension that permits resistance to shear stress. The end product is lactate. The oxidative hexose monophosphate shunt
involvement of intermediate-length actin fibers and the variability of generates NADH phosphate (NADPH) and reduced glutathione for
binding affinities by phosphorylation state appear to provide some use as the major erythrocyte antioxidant.
flexibility and pliability at these points of interaction. Strength in the During the past decade, most of the enzymes (or at least the
“vertical” dimension is provided by additional molecules or additional erythroid isoforms of these enzymes) involved in RBC intermediary
binding functions of the same molecule, whereby the latticework is metabolism have been characterized at the molecular level by cloning
attached to the lipid bilayer. For the most part, the physiologically of their cDNAs, genomic loci, or both. Some of the more relevant
important attachments appear to be indirect. Linkage is mediated information arising from this progress is discussed in Chapter 44.
through the interaction of the adaptor proteins, such as ankyrin and The erythrocyte possesses membrane-based signaling receptors and
protein 4.1, with the cytoplasmic domains of abundant transmem- cytoplasmic signal transduction elements similar, although perhaps
brane proteins. These proteins traverse and are embedded in the lipid less elaborate, than those of nucleated cells. The relevance of these
bilayer, providing a firm anchor. The two most critical of these systems to the pathophysiology of RBC disorders is just becoming
molecules appear to be band 3 (i.e., the anion transport channel) and apparent.
a glycophorin, probably glycophorin C/D. A possible additional
stabilizing role for the Rh protein complex has been suggested. The
construction of these attachments by multiple “hinge” or coupling RED BLOOD CELL SENESCENCE AND DESTRUCTION
molecules appears to provide for the flexibility and distensibility of
the RBC membrane, a property essential to its ability to flow through Erythrocytes, despite their impressive adaptations to circulatory
small capillaries. stresses, eventually wear out and are destroyed. RBC survival in