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Administration of pegylated recombinant human megakaryocyte growth and
development factor to humans stimulates the production of functional
platelets that show no evidence of in vivo activation
CJ O'Malley, JE Rasko, RL Basser, KM McGrath, J Cebon, AP Grigg, W Hopkins, B Cohen, J O'Byrne, MD Green, RM Fox, MC Berndt and CG Begley
Centre for Developmental Cancer Therapeutics, Melbourne, Victoria,
Australia.
This report describes the effect of pegylated recombinant human
megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet
production and platelet function in humans. Subjects with advanced solid
tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase
in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day
12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold
median increase (maximum 10-fold) in platelet count by day 16. The
platelets produced in vivo in response to PEG-rHuMGDF showed unchanged
aggregation and adenosine triphosphate (ATP)-release responses in in vitro
assays. Tests included aggregation and release of ATP in response to
adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2
micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and
ristocetin (1.5 mg/mL). Administration of aspirin to an individual with
platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced
ablation of the normal aggregation and ATP-release response to stimulation
with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25
mumol/L). There was no change in the expression of the platelet-surface
activation marker CD62P (P-selectin) nor induction of the fibrinogen
binding site on glycoprotein IIb/IIIa as reported by the monoclonal
antibody, D3GP3. An elevation of reticulated platelets was evident after 3
days of treatment with PEG-rHuMGDF and preceded the increase in circulating
platelet count by 5 to 8 days; this reflected the production of new
platelets in response to PEG-rHuMGDF. At later time points, the mean
platelet volume (MPV) decreased in a manner inversely proportional to the
platelet count. Levels of plasma glycocalicin, a measure of platelet
turnover, rose 3 days after the initial increase in the peripheral platelet
count. The level of plasma glycocalicin was proportional to the total
platelet mass, suggesting that platelets generated in response to
PEG-rHuMGDF were not more actively destroyed. Thus, the administration of
PEG-rHuMGDF, to humans, increased the circulating platelet count and
resulted in fully functional platelets, which showed no detectable increase
in reactivity nor alteration in activation status.
Volume 88,
Issue 9,
pp. 3288-3298,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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