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CHAPTER 34 erythroid progenitors and, thus, red cell production, e.g., clonal expansion of

CLINICAL MANIFESTATIONS a multipotential hematopoietic cell (polycythemia vera) or gain-of-function
mutations of the EPO receptor (EPOR) on red cell progenitors—or secondary,
AND CLASSIFICATION OF caused by increased levels of circulating erythropoiesis-stimulating factors,
usually EPO, as a result of tissue hypoxia (e.g., chronic pulmonary disease,
ERYTHROCYTE DISORDERS high oxygen-affinity hemoglobin mutants, cobalt poisoning). Some poly-
cythemias have hypersensitive erythroid progenitors, as well as increased
levels of EPO, and thus share features of both primary and secondary poly-
cythemia; these include Chuvash polycythemia and some other congenital
Josef T. Prchal disorders of hypoxia sensing. Persons with relative (spurious) polycythemia
have an increased hematocrit as a result of a decreased plasma volume but a
normal red cell mass.
SUMMARY

Anemias are characterized by a decrease and polycythemias by an increase
of the red cell mass. In most clinical situations, changes in red cell mass are ANEMIA
inferred from the hemoglobin concentration or hematocrit. Some red cell dis-
orders are associated with compensated hemolysis without or with only slight PATHOPHYSIOLOGY AND MANIFESTATIONS
anemia. Their clinical manifestations are evident not by the effects of anemia Effects on Oxygen Transport
but by changes associated with catabolism of hemoglobin such as an increase The clinical manifestations of anemia are a function of the degree of
in serum bilirubin and, if sustained, cholelithiasis, decreased haptoglobin, and tissue hypoxia and the etiology and pathogenesis of the specific anemia
usually chronic reticulocytosis. Some red cells disorders are only showcased by (e.g., splenomegaly characteristic of hereditary spherocytosis, neuro-
morphologic abnormalities as exemplified by hereditary elliptocytosis unac- logic degeneration, or gastric atrophy of pernicious anemia). Decreased
companied by hemolysis or anemia. oxygen-carrying capacity mobilizes compensatory mechanisms
designed to prevent or ameliorate tissue hypoxia. Red cells also trans-
The anemias have their principal effect by decreasing the oxygen-carrying port carbon dioxide from tissues to the lungs and help distribute nitric
capacity of blood and their severity is best considered in terms of blood hemo- oxide throughout the body (Chap. 50), but transport of these gases does
globin concentration. Anemia may cause symptoms because of tissue hypoxia not appear to be dependent on the concentration of red cells in the
(e.g., fatigue, dyspnea on exertion). Some manifestations are also caused by blood and is normal in anemic patients. Tissue hypoxia occurs when
compensatory attempts to ameliorate hypoxia (e.g., hyperventilation, tachy- the pressure of oxygen in the capillaries is too low to provide cells with
cardia, and increased cardiac output). These manifestations are a function of enough oxygen for cell metabolic needs. In an average person, the
the severity and rapidity of onset of the anemia. Tissue hypoxia sensing is red cell mass must provide the total body tissues with approximately
ubiquitous and is signaled by an increased level of hypoxia-inducible tran- 250 mL/min of oxygen to support life. The oxygen-carrying capacity
scription factors (HIFs)-1 and -2. HIFs upregulate transcription of many genes, of normal blood is 1.34 mL per gram of hemoglobin (approximately
in addition to the principal erythropoietic factor erythropoietin (EPO), that are 200 mL/L of normal blood) and cardiac output is approximately
involved in erythropoiesis, but also in angiogenesis, energy metabolism, and 5000 mL/min; thus, 1000 mL/min of oxygen is available at the tis-
sue level. Extraction of one-fourth of this amount reduces the oxygen
iron balance. The classification of anemia should take into account new kinetic tension of 100 torr in the arterial end of the capillary to 40 torr in the
and molecular findings. venous end. This partial extraction ensures the presence of sufficient
The polycythemias (erythrocytoses) are best expressed in terms of the diffusion pressure throughout the capillaries to provide all cells with
packed red cell volume (hematocrit), as their clinical manifestations are pri- enough oxygen for the cell’s metabolic needs (Fig. 34–1). In anemia,
marily related to the expanded red cell mass and resulting increased viscosity extraction of the same amount of oxygen leads to greater hemoglobin
of blood, and other specific features related to the pathophysiology stemming desaturation and lower oxygen tension at the venous end of the capil-
from a molecular causative defect (e.g., thrombosis in polycythemia vera, lary. The resulting hypoxia in the immediate vicinity initiates a number
cyanosis in congenital methemoglobinemia). The polycythemias may be pri- of compensatory, and frequently symptomatic, adjustments in the sup-
mary, caused by somatic or germline mutation(s) dysregulating expansion of ply of blood and oxygen.
Hypoxia-Inducible Transcription Factors Hypoxia-inducible
transcription factor (HIF)-1 and its homologue with tissue-restricted
expression, HIF-2, play a central role in the body’s response to hypoxia
(Chaps. 32 and 57). HIF-1 was first identified as a factor regulating the
transcriptional activity of the erythropoietin (EPO) gene (Chap. 32).
1
Acronyms and Abbreviations: EGLN1, a gene encoding PHD2 protein; EPAS1, The essential role of this transcriptional factor in global regulation of
a gene encoding hypoxia-inducible factor-2α; EPO, erythropoietin; EPOR, protection against hypoxia soon became clear. Its actions include respi-
ratory control, transcriptional regulation of glycolytic enzyme genes,
erythropoietin receptor; HIF, hypoxia-inducible factor; MCHC, mean cor- angiogenesis, and energy metabolism. The prediction that degrada-
2–4
puscular hemoglobin concentration; MCV, mean corpuscular volume; PFCP, tion of the hypoxia-regulated subunit of HIF-1 (HIF-1α) is controlled
primary familial and congenital polycythemia; PHD2, prolyl hydroxylase by an enzyme sensitive to the presence or absence of oxygen proved to
5
domain-containing protein 2; VHL, a gene encoding von Hippel-Lindau be prescient. Thus, HIF’s downregulation is mediated by two principal
tumor suppressor. negative regulators: von Hippel-Lindau tumor suppressor (VHL) and
prolyl hydroxylase domain-containing protein 2 (PHD2). Chapter 32

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