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C H A P T E R 33

PATHOBIOLOGY OF THE HUMAN ERYTHROCYTE AND

ITS HEMOGLOBINS

Martin H. Steinberg, Edward J. Benz, Jr., Adeboye H. Adewoye,
and Benjamin L. Ebert

Anemia, polycythemia, and functional derangements of the human Intermediate progenitor cells arising during differentiation have
erythrocyte together represent a common group of human disorders been characterized experimentally, including the burst-forming unit-
with a significant impact on public health. Sickle cell disease, hemo- erythroid (BFU-E) and the colony-forming unit-erythroid (CFU-E)
globin E (HbE)–associated disorders, and the thalassemias are stages. BFU-Es are progenitor cells that in culture produce bursts or
humankind’s most common single-gene diseases, but the relevance of clusters of erythroid colonies, are relatively less sensitive to erythropoi-
red blood cell (RBC) disorders to general medicine extends even etin, and are more plastic with respect to important gene expression
beyond their individual clinical severities or the number of patients parameters, such as the synthesis of adult or fetal Hb (HbF) by their
affected. A critical added dimension of erythrocyte disorders is the descendants. CFU-Es produce single colonies, exhibit considerably
extraordinarily detailed knowledge available about the basic biochem- higher sensitivity to erythropoietin, and appear to be more fixed
istry, physiology, and molecular biology of the human RBC and its in their potential to express a particular subset of globin genes.
membrane, metabolism, and major component, Hb. RBCs are CFU-Es appear to give rise to the first morphologically recognizable
especially abundant, relatively simple, and readily accessible for erythroid cells, the proerythroblasts. At this “primitive” morphologic
repeated testing in individual patients. These features have facilitated stage, the program of erythroid cell expression has already been
rapid application of the techniques of cellular and molecular biology essentially predetermined. The cell is predestined to undergo only a
to studies of the RBC, its component molecules and structures, and limited additional number of cell divisions, culminating in formation
syndromes resulting from abnormalities of these entities. Taken as a of the enucleate reticulocyte. The terminal maturation stages are
group, erythrocyte disorders are better understood at the molecular morphologically recognizable as erythroblasts exhibiting progressive
and cellular levels than disorders of any other cell or tissue. It is for hemoglobinization of the cytoplasm, condensation and eventual ejec-
this reason that these conditions merit particularly careful scrutiny tion of the nucleus, and remodeling of the plasma membrane. Actual
by students of hematology. expression of the preprogrammed genes occurs during the 5- to 7-day
This chapter reviews the concepts about normal RBC homeostasis period of erythroblast maturation.
that form the essential knowledge base for understanding anemias, As discussed in Chapters 9 and 26, the actual reconfiguration of
polycythemias, and functional erythrocyte disorders. The primary chromatin for activation of the genes and activation itself appear to
focus and the object for detailed discussion within this chapter is Hb, require the concerted and complex interaction of a diverse but limited
the major component, both quantitatively and qualitatively, of the group of transcription factors and associated epigenetic regulators. These
erythrocyte. Hb molecules dominate the pathophysiology of many regulatory proteins recognize a specific array of promoter and enhancer
RBC disorders and modulate most of the others, in part because of sequences that are embedded as recurrent motifs in and around the
their sheer quantitative predominance in RBC cytoplasm. The other appropriate target genes. Even though an enormous amount of infor-
major relevant aspects of human RBCs—the membrane, the enzymes mation has been gathered about sequences such as the GATA enhancers
used for intermediary metabolism, differentiation and development, and their cognate transcription factors (e.g., GATA, FOG, ETS), the
and the process of destruction—are discussed in detail in the intro- precise means by which these sequences and factors cause erythroid
ductory portions of other chapters. This chapter surveys these areas differentiation remains mysterious. At this time, this information is
only briefly. Detailed descriptions of the RBC membrane can be of limited clinical relevance to anemias or polycythemias. The orderly
found in Chapter 45. RBC enzymes and enzymopathies are described 14- to 21-day sequence of differentiation and maturation becomes
in Chapter 44; differentiation and development are described in progressively influenced by the levels of erythropoietin available to the
Chapters 9 and 26; regulation of the RBC mass by erythropoietin is progenitor cells, possibly because of increasing density and affinity of
discussed in Chapter 22; and the necessary aspects of RBC destruc- erythropoietin receptors on their cell surfaces. Within 24 hours after
tion are considered in Chapters 43, 46, and 47. enucleation, the reticulocyte traverses the bone marrow–blood barrier
membrane and enters the circulation as an immature erythrocyte.
ESSENTIAL FEATURES OF RED BLOOD These cells retain remnants of nucleated precursors in the form of
a relatively small number of polyribosomes actively translating mes-
CELL HOMEOSTASIS senger ribonucleic acid (RNA) (>90% of which is globin messenger
RNA), a cell membrane that retains some molecules and structures
As discussed in Chapter 26, the mature RBC is the product of a reminiscent of its earlier stages of differentiation, and the complement
complex and orderly set of differentiation and maturation steps of enzymes, phospholipids, and cytoskeletal proteins that the cell will
beginning with the pluripotent stem cell. By incompletely understood possess throughout its remaining life span.
mechanisms involving hierarchic networks of cytokines, a portion of During its first 24 hours in the circulation, the reticulocyte spends
these cells becomes committed to differentiate along the erythroid considerable amounts of time in the spleen, during which its mem-
pathway. Commitment to erythropoiesis provokes a progressively brane is “polished.” This is a poorly understood remodeling process
increasing sensitivity to the stimulatory actions of the hormone by which some lipids and proteins, including adhesive molecules such
erythropoietin. As differentiation proceeds, there is preprogramming as fibronectin, are removed. The content of polyribosomes and other
of certain genes whose expression at high levels will be required nucleic acids progressively declines so that stainability with methylene
during the maturation phase of erythropoiesis. Genes coding for blue is lost by the end of the first day. At this time, the RBC is
molecules defining the RBC phenotype (e.g., globin) are poised for regarded as a mature erythrocyte, and it circulates largely unchanged
activation at later maturation steps. for the remainder of its 120-day life span.

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