Page 1225 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 68

THE POLYCYTHEMIAS

Marina Kremyanskaya, Vesna Najfeld, John Mascarenhas, and
Ronald Hoffman

Under normal conditions, the red blood cell (RBC) mass in humans delivery to tissues. Regulation of oxygen homeostasis is critical to
is tightly controlled and remains relatively constant in a given indi- survival. In humans, oxygen sensing occurs at many levels, leading to
vidual. The numbers of senescent RBCs lost daily are replaced by both acute and chronic adaptation. The acute reduction of the avail-
newly formed ones by a carefully controlled network of growth ability of oxygen leads to the initiation of a cascade of adaptive events
factors and progenitor cells. Erythropoiesis can be augmented by a that sets in place compensatory events to correct the lack of oxygen
variety of stimuli that increase the delivery of oxygen to tissues. This supply. Low oxygen levels, or hypoxia (60 mmHg), in humans cause
delicate balance can be disturbed by various pathologic conditions oxygen-sensing chemosensory cells to undergo rapid membrane
and can result in either reduced numbers of RBCs (anemia) or depolarization within seconds, leading to the production of action
excessive numbers of RBCs (polycythemia). Hematocrit values over potentials, influx of calcium ions, and release of the neurotransmitters
49% in males and 48% in females are abnormal and require further that result in stimulation of the brain stem that controls the respira-
evaluation to determine if the patient has an absolute increase in their tory and cardiovascular systems. These chemosensory cells are found
RBC mass and if investigation of its cause should be pursued. The within the glomus cells of the carotid body located at the bifurcation
RBC mass is increased if it is greater than 125% above that expected of the internal and external carotid arteries. The released neurotrans-
for sex and body mass. The measurement of the RBC mass is a mitters activate the nerve endings of the carotid body sensory nerve
diagnostic study that is now available at a dwindling number of to convey to the CNS signals that command ventilation to fight
tertiary care centers, making other diagnostic studies pivotal in evalu- hypoxia, resulting in an increase of the lung ventilation rate and
ating patients with elevated hematocrit levels. Polycythemic states can restoration of normal oxygen tension to vital organs. In addition,
be caused by a variety of disorders that can be attributed to several there are changes in blood pressure and heart rate to maximize oxygen
pathophysiologic mechanisms. Determination of the etiology of an delivery. The carotid body is the organ with the greatest blood flow
individual’s polycythemia is a critical step in defining the patient’s within the body. Activation of the carotid body results in the sensa-
appropriate prognosis and treatment plan. Primary polycythemias are tion of breathlessness experienced by individuals at high altitudes.
the result of innate abnormalities involving hematopoietic progeni- During chronic hypoxia when the carotid body is permanently active,
tors and stem cells that lead to constitutive overproduction of RBCs, there is marked enlargement of the carotid body because of an
which are accompanied by low erythropoietin (EPO) levels. By increase in capillaries and a marked reduction in the mean distance
contrast, secondary polycythemias are the consequence of a number from the capillaries to the edge of the chemoreceptor cells.
of conditions that lead to increased EPO production, which acts on In response to chronic hypoxia, multiple compensatory mecha-
normal progenitors to overproduce RBCs. In a small number of nisms come into play over several days within the kidneys, the major
patients, the cause of erythrocytosis cannot be determined; these site of EPO production. Hypoxic stimulation results in production
patients are classified as having idiopathic erythrocytosis. of hypoxia-inducible factor-1 (HIF-1), the major factor responsible
1
for transcriptional activation of the EPO gene. The HIF transcrip-
tional system is a master regulator of the hypoxic response controlling
ERYTHROPOIESIS a large number of genes in multiple cell types. HIF-1 is a heterodi-
meric protein consisting of HIF-1α and HIF-1β, which is required
RBC production can be influenced by numerous factors, including for normal development of the heart, blood vessels, and blood cells.
nutrients, growth factors, numbers and function of bone marrow The levels of HIF-1α increase exponentially as the oxygen concentra-
(BM) progenitor and precursor cells, and cellular receptors and tran- tion declines. As the key mediator of cellular oxygen maintenance,
scription factors. EPO is considered to be the physiologic regulator of HIF-1 facilitates body oxygen delivery and responses to oxygen
the terminal phases of erythropoiesis. Alterations in its production are deprivation by regulating the expression of gene products that
followed by adjustments in the rate of formation of RBCs. In humans, are involved in cellular energy metabolism and glucose transport,
EPO production is controlled by the relative supply of oxygen to the angiogenesis, erythropoiesis and iron metabolism, pH regulation,
kidneys, the major site of EPO production. In states of severe hypoxia, apoptosis, cell proliferation, and cell–cell and cell–matrix interactions.
EPO production can be increased up to 1000-fold. In a healthy person Classic HIF target genes include phosphoglycerate kinase, glucose
after phlebotomy, EPO excretion increases, and an inverse logarithmic transporter-1, vascular endothelial growth factor (VEGF), and EPO.
relationship between hematocrit and EPO excretion rates exists. The HIF proteins are members of the Per–ARNT–Sim family of
Patients with secondary erythrocytosis caused by chronic hypoxia have heterodimeric basic helix–loop–helix transcription factors (Fig. 68.1).
either normal or increased basal EPO values, but they also have In contrast to the constitutively expressed, HIF-1β subunits,
increased values after reduction of the hematocrit to normal levels by HIF-1α is an oxygen-labile protein that becomes stabilized in
phlebotomy. By contrast, EPO excretion is invariably subnormal in response to hypoxia. HIF-1α mRNA and protein levels are induced
patients with polycythemia vera (PV), which demonstrates that this by hypoxia, and HIF-1α protein levels decay rapidly with return to
disorder is not a result of excessive EPO production. normoxia. The posttranslational regulation of HIF-1α protein
accounts for the majority of the regulation of this gene. Normoxia-
ERYTHROPOIETIN, OXYGEN SENSING, AND induced, ubiquitin-mediated degradation of the HIF-1α protein is
the major regulator of HIF-1α levels, thereby reducing the stimulus
HYPOXIA-INDUCIBLE FACTOR for additional EPO production. The targeting and subsequent polyu-
biquitination of HIF-1α require the von Hippel-Lindau (VHL)
Under normal conditions, EPO production is mediated by a reduced protein, oxygen, and three different iron-requiring proline hydroxy-
oxygen content, termed hypoxemia, which leads to decreased oxygen lase (PHD) enzymes (see Fig. 68.1). The PHD proteins exist in three

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