Biology Reference
In-Depth Information
Figure 2. The relationship between residence time of EPO, or any other erythropoietic agent, reticu-
locyte response and hemoglobin response. The disproportionate effect on hemoglobin from elevated
amounts of an erythropoietic agent. The duration A is controlled largely by three factors: the dose, the
route of injection which controls the gradient of the upward slope, and the rate of clearance which
controls the gradient of the downward slope. The half-life of rHuEPO is approximately eight hours
(see Chapter 6 by Heatherington). The duration B of the reticulocyte response is determined by the
duration of A - the time when serum levels of the erythropoietic agent are above baseline. Once serum
levels of the erythropoietic agent return to baseline, reticulocyte numbers will begin to decline at a
rate proportional to their half-life in the circulation. Reticulocyte life-span is of the order of five days.
The duration C is controlled again by the duration B. During the time supranormal levels of reticulo-
cytes are being produced the rate of production of hemoglobin exceeds the rate of loss, so hemoglo-
bin will be increasing. When reticulocyte numbers return to baseline, the hemoglobin curve will
inflect and hemoglobin will be lost at a rate proportional to the life-span of erythrocytes. Normal ery-
throcyte life-span in humans is around 120 days. Overall, an erythropoietic agent with a half-life
measured in hours can influence hemoglobin levels on a timescale measured in months. Thus changes
in the duration A, influenced by dose, route of administration and rate of clearance, will have a dis-
proportionate effect on the duration C. See Chapter 15 by Elliott, for exploitation of this paradigm in
the evolution of improved erythropoietic agents.
Biologic basis for the use of EPO in various diseases
Anemia
Anemia of renal failure
As the kidney represents the major site of EPO production in the adult, the pro-
gressive destruction of this organ might be intuitively linked to anemia of an
EPO-limited nature. Indeed,since shortly after the gene was cloned in 1983
