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A Single Intravenous Dose of Murine Megakaryocyte Growth and
Development Factor Potently Stimulates Platelet Production, Challenging
the Necessity for Daily Administration
Najat C. Daw,
Julie T. Arnold,
Basel A. Abushullaih,
Paula E. Stenberg,
Melanie M. White,
Deepthi Jayawardene,
Deo Kumar
Srivastava, and
Carl W. Jackson
From the Division of Experimental Hematology, St. Jude Children's
Research Hospital, Memphis, TN; the Department of Pathology, Oregon
Health Sciences University, Portland, OR; the Division of
Hematology/Oncology, University of Tennessee, Memphis, TN; and the
Department of Biostatistics, St. Jude Children's Research Hospital,
Memphis, TN.
The thrombopoietic efficacy of recombinant forms of c-mpl
ligand is being actively investigated in preclinical studies using daily dosing schedules. However, a comprehensive kinetic study of the
thrombopoietic response to a single injection of recombinant c-mpl ligand has not been performed. Here, we present the
results of a detailed kinetic analysis of the platelet response to a
single intravenous administration of pegylated recombinant murine
megakaryocyte growth and development factor (PEG-rmMGDF) in mice. In
addition, we compare the efficacy of single versus daily dosing in
stimulating platelet production. A single intravenous injection of
PEG-rmMGDF produced a marked and dose-dependent elevation in platelet
number and a moderate increase in mean platelet volume (MPV). After
administration of 25 or 250 µg/kg of PEG-rmMGDF, platelet number was
first increased on day 3 and peaked at 2.7-fold (25 µg/kg) and
5.7-fold of normal (250 µg/kg) on day 5. Thereafter, platelet number
declined and returned to baseline by days 9 and 14, with the 25 and 250 µg/kg doses, respectively. MPV began to increase on day 2 after
PEG-rmMGDF, reaching maximum values of 1.2-fold (25 µg/kg) and
1.5-fold of normal (250 µg/kg) on day 4. Subsequently, MPV declined
and was downregulated on days 6 to 7 (25 µg/kg) and day 8 (250 µg/kg). Based on these results, we evaluated the platelet response to PEG-rmMGDF administered intravenously as a single dose versus daily for
5 days. A single administration of 100 µg/kg produced a higher
platelet number on day 5 than daily administration of 100 or 20 µg/kg
for 5 days. However, the thrombocytosis was less sustained after single
versus daily dosing. The smaller platelet number increase on day 5 after daily dosing reflected the production of larger platelets, rather
than suppression of thrombopoiesis. Our results indicate that
PEG-rmMGDF administered as a single intravenous dose potently
stimulates platelet production in mice, challenging the need for its
daily administration. Adoption of an intermittent administration
schedule of this cytokine could be more efficacious and is merited in
future clinical trials.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 466-474
© 1998 by The American Society of Hematology.
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