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Megakaryocyte Differentiation and Platelet Formation from Human Cord Blood-derived CD34+ Cells
Published on: December 27, 2017
Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet
L A Harker1, L K Roskos, U M Marzec
1Division of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
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)
Insights
Pegylated recombinant megakaryocyte growth and development factor (PEG-rHuMGDF) temporarily doubled platelet counts in healthy volunteers. Platelet function and viability remained normal, with thrombopoiesis returning to baseline within four weeks.
Area of Science:
- Hematology
- Pharmacology
Background:
- Thrombopoiesis is regulated by megakaryocyte growth and development factor (MGDF).
- PEG-rHuMGDF is a thrombopoietic agent designed to stimulate platelet production.
Purpose of the Study:
- To evaluate the effects of PEG-rHuMGDF on megakaryocytopoiesis, platelet production, and platelet function in healthy individuals.
Main Methods:
- Randomized, placebo-controlled study involving subcutaneous injections of PEG-rHuMGDF.
- Monitoring of platelet counts, function (ADP and TRAP stimulation), viability (Annexin V binding), and TPO-receptor expression.
- Assessment of platelet lifespan using (111)In-labeled platelets and biomathematical modeling.
- Measurement of platelet turnover and megakaryocyte mass in bone marrow.
Main Results:
- PEG-rHuMGDF transiently doubled circulating platelet counts, peaking at day 12 and normalizing by day 28.
- Platelet function, viability, and TPO-receptor expression remained unchanged.
- Platelet lifespan initially increased but subsequently decreased, consistent with senescent changes.
- Platelet turnover and megakaryocyte mass significantly increased post-treatment.
Conclusions:
- PEG-rHuMGDF effectively stimulates megakaryocytopoiesis and platelet production in healthy humans.
- Induced platelets exhibit normal function and viability.
- The thrombopoietic perturbation is transient and resolves within four weeks.
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