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Dose-response effects of pegylated human megakaryocyte growth and
development factor on platelet production and function in nonhuman primates
LA Harker, UM Marzec, P Hunt, AB Kelly, A Tomer, E Cheung, SR Hanson and RB Stead
Division of Hematology and Oncology, Yerkes Regional Primate Research
Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Thrombopoietin (TPO) is the physiologic Mpl-ligand regulating platelet
production. Pegylated human recombinant megakaryocyte growth and
development factor (PEG-rHuMGDF), a truncated polypeptide Mpl-ligand
derivitized with poly-(ethylene glycol), induces megakaryocyte
endoreduplication and proliferation in vitro and in vivo. In the present
study, the dose-response effects of PEG-rHuMGDF on pharmacokinetics,
megakaryocytopoiesis, platelet production, and platelet function were
characterized for dosing 0.05, 0.10, 0.50, or 2.5 micrograms/kg/d in 22
baboons for 28 days. Daily subcutaneous injections of PEG-rHuMGDF produced
linear log-dose responses in (1) steady-state trough plasma levels of
PEG-HuMGDF (P < 10(-3)); (2) marrow megakaryocyte volume (P <
10(-3)), ploidy (P < 10(-4)), and number (P < .01); and (3)
peripheral platelet concentrations (P < 10(- 4)) and platelet mass
turnover (P < 10(-3)). Platelet morphology, life span, and recovery were
normal, and peripheral leukocyte, neutrophil, and erythrocyte counts were
not significantly affected by PEG-rHuMGDF (P > .1 in all cases).
PEG-rHuMGDF at 0.5 micrograms/kg/d produced similar blood concentrations of
Mpl-ligand and platelets as 10 times the dose of rHu-MGDF (5.0
micrograms/kg/d), reflecting the extended plasma half-life achieved through
pegylation. Whereas PEG-rHuMGDF did not induce platelet aggregation in
vitro, platelet aggregatory responsiveness induced by thrombin receptor
agonist peptide (TRAP1-6) and collagen was transiently enhanced ex vivo
during the initial few days of PEG-rHuMGDF administration. However,
adenosine diphosphate (ADP)-induced platelet aggregation was not enhanced
ex vivo by PEG- rHuMGDF therapy. 111In-platelet deposition on segments of
homologous endarterectomized aorta (EA) and vascular graft (VG) interposed
in arteriovenous femoral shunts increased in direct proportion to the
circulating platelet concentration (P < 10(-4) for both EA and VG);
125l-fibrin accumulation was not affected by PEG-rHuMGDF-induced increases
in peripheral platelet counts. Changes in platelet production and function
produced by PEG-rHuMGDF returned to baseline within 2 weeks after
discontinuing treatment. Thus, in nonhuman primates, PEG- rHuMGDF increases
platelet production in a linear log-dose-dependent manner by stimulating
megakaryocyte endoreduplication and new megakaryocyte formation from marrow
hematopoietic progenitors. These findings suggest that appropriate dosing
of PEG-rHuMGDF therapy during periods of chemotherapy-induced marrow
suppression may maintain hemostatic concentrations of peripheral platelets
without increasing the risk of thrombosis.
Volume 88,
Issue 2,
pp. 511-521,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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