Unfortunately, some athletes abuse recombinant EPO—
particularly professional bike racers and marathon runners
seeking increased stamina and performance. However, the con-
sequences can be deadly. By injecting EPO, healthy athletes in-
crease their normal hematocrit from 45% to as much as 65%.
Ten, with the dehydration that occurs in a long race, the blood
concentrates even further, becoming a thick, sticky “sludge” that
can cause clotting, stroke, and heart failure.
Te male sex hormone
also enhances the kidneys’
production of EPO. Because female sex hormones do not have
similar stimulatory eﬀects, testosterone may be at least partially
responsible for the higher RBC counts and hemoglobin levels
seen in males. Also, a wide variety of chemicals released by leu-
kocytes, platelets, and even reticular cells stimulates bursts of
Te raw materials required for eryth-
ropoiesis include the usual nutrients and structural materials—
amino acids, lipids, and carbohydrates. Iron is essential for hemo-
globin synthesis. Iron is available from the diet, and intestinal cells
precisely control its absorption into the bloodstream in response
to changing body stores of iron.
Approximately 65% of the body’s iron supply (about 4000
mg) is in hemoglobin. Most of the remainder is stored in the
liver, spleen, and (to a much lesser extent) bone marrow. Free
iron ions (Fe
) are toxic, so iron is stored inside cells as
protein-iron complexes such as
er-in). In blood, iron is transported loosely
bound to a transport protein called
, and develop-
ing erythrocytes take up iron as needed to form hemoglobin
. Small amounts of iron are lost each day in feces,
urine, and perspiration. Te average daily loss of iron is 1.7 mg
in women and 0.9 mg in men. In women, the menstrual ﬂow
accounts for the additional losses.
(oxygen deﬁcient), oxygen-sensitive enzymes are unable
to carry out their normal functions of degrading an intracel-
lular signaling molecule called hypoxia-inducible factor (HIF).
As HIF accumulates, it accelerates the synthesis and release of
Te drop in normal blood oxygen levels that triggers EPO
formation can result from
Reduced numbers of red blood cells due to hemorrhage
(bleeding) or excessive RBC destruction
Insuﬃcient hemoglobin per RBC (as in iron deﬁciency)
Reduced availability of oxygen, as might occur at high alti-
tudes or during pneumonia
Conversely, too many erythrocytes or excessive oxygen in
the bloodstream depresses erythropoietin production. Note
that it is not the number of erythrocytes in blood that controls
the rate of erythropoiesis. Instead, control is based on their abil-
ity to transport enough oxygen to meet tissue demands.
Bloodborne erythropoietin stimulates red marrow cells that
are already committed
to becoming erythrocytes, causing them
to mature more rapidly. One to two days a±er erythropoietin
levels rise in the blood, the rate of reticulocyte release and the
reticulocyte count rise markedly. Notice that hypoxia does not
activate the bone marrow directly. Instead it stimulates the kid-
neys, which in turn provide the hormonal stimulus that acti-
vates the bone marrow.
Renal dialysis patients whose kidneys have failed produce too
little EPO to support normal erythropoiesis. Consequently,
they routinely have red blood cell counts less than half those of
healthy individuals. Genetically engineered (recombinant) EPO
has helped these patients immeasurably.
Kidney (and liver to
a smaller extent)
increases RBC count.
ability of blood
Normal blood oxygen levels
delivery) due to
availability of O
Erythropoietin mechanism for regulating erythropoiesis.