The Use of Human Recombinant Erythropoietin for the Treatment of Nonregenerative Anemia in the Rough-Toothed Dolphin, Steno bredanensis
Erythropoietin (EPO) is a glycoprotein growth hormone that serves as both a mitogen and a survival factor for erythrocyte progenetors. EPO
is produced primarily in the kidneys. Human recombinant erythropoietin has been used to stimulate bone marrow production in humans as well as a number of domestic
A mature male rough-toothed dolphin, Steno bredanensis (158 kg), part of a mass stranding in the Florida Panhandle in December 1997,
was being rehabilitated at the Dolphin and Whale Hospital at Mote Marine Laboratory in Sarasota, Florida. The dolphin was being treated for a resistant pneumonia
and enterocolitis and was found to exhibit a persistent hematuria and proteinuria that was eventually diagnosed as chronic glomerulonephritis. During treatment,
the animal developed a gradually dropping hematocrit, erythrocyte count, and hemoglobin concentration with no concurrent increase in absolute nucleated
erythrocytes, absolute reticulocytes, or immature reticulocytes. It was assumed that the blood loss was from both the gastrointestinal tract and the kidneys. It
is known that any inflammation of the kidneys can decrease endogenous erythropoietin production and it was felt that this might have been the cause of the lack of
response of the bone marrow to the anemia. The dolphin was given two doses of human recombinant erythropoietin (epoietin alfa, Procrit, Amgen, Inc.) at a dosage
of 63 U/kg intramuscularly 48 hours apart. By the time the second dosage was given, nucleated erythrocytes had begun to appear in the peripheral circulation and
their levels peaked five days later at 115 per 100 WBCs.
Reticulocyte maturity may be categorized by the relative nucleic acid content. High fluorescent ratio (HFR) reticulocytes are the most
immature form of reticulocytes. The HFR, which had been at 0.0% on the day of the first dosage, reached 29.1% 72 hours later. Total reticulocytes did not increase
until 96 hours after the initiation of treatment, peaked six days later (at 14.17% or 427.9 x103/mm3), then decreased for six more days, and
peaked again 22 days after the beginning of treatment. During this second peak (11.33%), there was no significant increase in peripheral nucleated erythrocytes. A
significant increase in hematocrit did not occur until the second peak with the increase continuing for 18 days following the second peak (40 days after the
initiation of treatment). It is assumed that the first peak was due to the exogenous hormone and that the second peak was due to the stimulation of endogenous
production by the kidneys.
Endogenous erythropoietin concentrations were determined retrospectively using an ELISA for both this dolphin and a mature male conspecific
from the same stranding. It was found that the treated dolphin had somewhat lower basal levels of erythropoietin but these levels did increase as the anemia
developed. The other dolphin (untreated) developed a transient regenerative anemia during its rehabilitation and its erythropoietin concentrations increased to
about the same level as those of the treated dolphin. It is assumed that there was a certain degree of bone marrow suppression in the treated dolphin that may
have been caused by the stress of captivity and may have been exacerbated by extensive treatment for the other conditions present. Both dolphins recovered and
were released after 100 days in rehabilitation. They were monitored by satellite transmitters for an additional 112 days and were spotted together by a
recreational fisherman with a group of 10-12 other dolphins just over 5 months after release. Both animals appeared to be healthy at that time.
Given the same situation again, the authors would use only a single dose of human recombinant erythropoietin, as there have been reported
cases in humans, dogs, and horses of antibodies being produced to the recombinant hormone.