title: Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers.
abstract: 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 microg/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 x 10(3)/microL to 522 +/- 90 x 10(3)/microL (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 (111)In-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 x 10(3) platelets/microL/d (baseline) to 101 +/- 27.6 x 10(3) platelets/microL/d (P =.0009), and marrow megakaryocyte mass expanded from 37.4 +/- 18.5 fL/kg to 62 +/- 17 x 10(10) 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. (Blood. 2000;95:2514-2522)
authors.affiliation: Division of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Harker
authors.forename: L K
authors.initials: LK
authors.lastname: Roskos
authors.forename: U M
authors.initials: UM
authors.lastname: Marzec
authors.forename: R A
authors.initials: RA
authors.lastname: Carter
authors.forename: J K
authors.initials: JK
authors.lastname: Cherry
authors.forename: B
authors.initials: B
authors.lastname: Sundell
authors.forename: E N
authors.initials: EN
authors.lastname: Cheung
authors.forename: D
authors.initials: D
authors.lastname: Terry
authors.forename: W
authors.initials: W
authors.lastname: Sheridan
mesh_terms: D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin