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874 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 875

Erythropoietin Receptor

PO4 JAK PO4 JAK
STAT5
STAT5 HCP
Negative HCP HCP
regulatory
domain

Figure 57–1. Left panel: Erythropoietin binding to a normal erythropoietin receptor (EPOR) results in interaction of a protein kinase (JAK) with the
receptor. The interaction leads to phosphorylation of the receptor and initiates a cascade of signaling that ultimately results in erythroid progenitor
proliferation and differentiation. This process is self-regulatory. Activated signal transduction molecules, hematopoietic cell phosphatase (HCP) binds
to the C-terminal of the EPOR, which is a negative regulatory domain. This interaction dephosphorylates the receptor and turns off the signaling
resulting in cessation of erythroid progenitor proliferation. Right panel: Patients with mutated gain-of-function EPOR gene lack the C-terminal portion
of the receptor that contains the negative regulatory domain. Erythropoietin binds and the signal transduction pathway is activated by change of
configuration of erythropoietin receptor dimer, but because there is there is no structure for HCP to bind on the activated EPOR dimer, the receptor
is left in the activated position resulting in unbridled erythroid proliferation and an elevated red cell mass. PO4, phosphate; STAT, signal transducer
and activator of transcription.

SECONDARY POLYCYTHEMIAS vapor pressure are constant and acclimatized individuals do not ven-
The morbidity of primary polycythemias, such as polycythemia vera tilate excessively, the normal sea level gradient of about 60 torr is only
reduced to approximately 40 torr at 4540 m (14,900 ft) above sea level.
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(Chap. 84), is largely the result of increased activated neutrophils and, Further reduction can be achieved, and at the top of Mount Everest,
perhaps, attendant pathologic platelet–endothelial interactions, whereas extreme hyperventilation reduces the gradient to less than 10 torr. A
in secondary polycythemias it is presumably related to an increase in shift in the oxygen dissociation curve to the right, which represents
53
blood viscosity and, in part, to the resulting increased cardiac work. decreased affinity of hemoglobin for oxygen, may be of benefit for
In most instances, the etiology of morbidity or mortality, such as associ- short-term high-altitude acclimatization, but its usefulness for chronic
56
54
ated with congenital disorders of hypoxia sensing, is largely unknown. acclimatization has probably been exaggerated. In the unacclimatized
57
The effect of blood viscosity on oxygen delivery is often oversimplified subject exposed acutely to high altitude, hyperventilation alkalosis leads
and the emphasis on the hematocrit alone may lead to ill-advised thera- initially to a shift of the oxygen dissociation curve to the left, represent-
peutic interventions. In the normovolemic state, viscosity increases in a ing an increased affinity of hemoglobin for oxygen, further worsening
log-linear fashion as hematocrit increases, and the effect is particularly already present tissue hypoxia. The alkalosis and the hypoxia will, in
pronounced when the hematocrit rises above 50 percent. The prediction turn, promote red cell synthesis of 2,3-BPG and cause the oxygen dis-
is that oxygen delivery decreases as hematocrit rises significantly above sociation curve to shift back to a normal or even right-shifted position
50, as the greatly increased viscosity reduces blood flow, overshadowing
the increased oxygen-carrying capacity of blood with a higher concen-
tration of hemoglobin. However, polycythemia is not a normovolemic
state, but is accompanied by an increase in blood volume, which, in Tracheal Alveolar Arterial Mean Mixed
turn, enlarges the vascular bed and decreases peripheral resistance air air blood capillary venous
blood
blood
(Chap. 34). Thus, hypervolemia can increase oxygen transport, and the Lima
optimum for oxygen transport occurs at higher hematocrit values than 140
in normovolemic states. Consequently, despite the attendant increase
in viscosity, an increase in hematocrit may generally be of benefit in 120
appropriate secondary polycythemias. However, at some point, the high 100
viscosity causes an increase in the work of the heart and a reduction Morococha
in blood flow to most tissues and may be responsible for cerebral and 80
cardiovascular impairment. PO 2 torr 60

APPROPRIATE POLYCYTHEMIAS 40
High Altitude Polycythemia 20
Adaptive adjustments of humans living at high altitude involve a series
of steps that reduce the steepness of the oxygen gradient between the 0
atmosphere and mitochondria (Fig. 57–2). The initial oxygen gra- Figure 57–2. The oxygen gradient from atmospheric air to the tissues
55
dient between atmospheric and alveolar air can be reduced by an in individuals living at sea level (Lima, Peru) and in Morococha, Peru, at
increase in respiratory rate and volume. Because dead space and water 4540 m (14,900 ft) above sea level.

Kaushansky_chapter 57_p0871-0888.indd 874 9/18/15 9:36 AM