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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2514-2522
Effects of megakaryocyte growth and development factor on
platelet production, platelet life span, and platelet function in
healthy human volunteers
Laurence A. Harker,
Lorin K. Roskos,
Ulla
M. Marzec,
Richard A. Carter,
Judith K. Cherry,
Birgitta Sundell,
Ellen N. Cheung,
Dixon Terry, and
William Sheridan
From the Division of Hematology and Oncology, Emory University
School of Medicine, Atlanta, GA; and Amgen Inc, Thousand Oaks, CA.
The effects of thrombopoietic stimulation on megakaryocytopoiesis,
platelet production, and platelet viability and function were examined
in normal volunteers randomized to receive single bolus subcutaneous
injections of 3 µg/kg pegylated recombinant megakaryocyte growth and
development factor (PEG-rHuMGDF) or placebo in a 3:1 ratio. PEG-rHuMGDF
transiently doubled circulating platelet counts, from 237 ± 41 × 103/µL to 522 ± 90 × 103/µL (P < .0001), peaking on day 12. Baseline and day-12 samples showed no
differences in responsiveness of platelets to adenosine diphosphate or
thrombin receptor agonist peptide (P > .4 in all cases);
expression of platelet ligand-induced binding sites or annexin V
binding sites (P > .6 in both cases); or density of platelet
TPO-receptors (P > .5). Platelet counts normalized by day 28. The life span of autologous 111In-labeled platelets
increased from 205 ± 18 hours (baseline) to 226 ± 22 hours
(P < .01) on day 8. Platelet life span decreased from 226 ± 22 hours (day 8) to 178 ± 53 hours (P < .05) on day 18. The
theoretical basis for senescent changes in mean platelet life span was
illustrated by biomathematical modeling. Platelet turnover increased
from 43.9 ± 11.9 × 103 platelets/µL/d (baseline) to
101 ± 27.6 × 103 platelets/µL/d (P = .0009), and marrow megakaryocyte mass expanded from 37.4 ± 18.5 fL/kg to 62 ± 17 × 1010 fL/kg (P = .015). Although PEG-rHuMGDF initially increased megakaryocyte volume
and ploidy, subsequently ploidy showed a transient reciprocal decrease
when the platelet counts exceeded placebo values. In healthy human
volunteers PEG-rHuMGDF transiently increases megakaryocytopoiesis 2-fold. Additionally, peripheral platelets expand correspondingly and
exhibit normal function and viability during the ensuing 10 days. The
induced perturbation in steady state thrombopoiesis resolves by 4 weeks.
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