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.
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.
Centre for Developmental Cancer Therapeutics, Melbourne, Victoria, Australia.
C J
CJ
O'Malley
J E
JE
Rasko
R L
RL
Basser
K M
KM
McGrath
J
J
Cebon
A P
AP
Grigg
W
W
Hopkins
B
B
Cohen
J
J
O'Byrne
M D
MD
Green
R M
RM
Fox
M C
MC
Berndt
C G
CG
Begley
D015331:Cohort Studies; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010976:Platelet Count / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000008:administration & dosage; D013926:Thrombopoietin / Q000008:administration & dosage*
D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; C023592:glycocalicin; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D005340:Fibrinogen; D013926:Thrombopoietin