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Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice
T R Ulich1, J del Castillo, G Senaldi
1Amgen Inc, Thousand Oaks, CA 91320, USA.
Abstract:
PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.
Insights
Pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rHuMGDF) increases platelet production in mice. While generally reversible, high doses can cause myelofibrosis-like pathology, but low doses treat thrombocytopenia without these effects.
Area of Science:
- Hematology
- Pharmacology
- Regenerative Medicine
Background:
- Thrombopoiesis, the production of platelets, is regulated by growth factors.
- Megakaryocyte growth and differentiation factor (MGDF) stimulates megakaryocyte proliferation and platelet production.
- PEG-rHuMGDF is a modified form of MGDF designed for therapeutic use.
Purpose of the Study:
- To investigate the dose-dependent effects of PEG-rHuMGDF on platelet production and related hematologic parameters in mice.
- To assess the potential for PEG-rHuMGDF to induce myelofibrosis-like pathology and its reversibility.
- To evaluate the efficacy of PEG-rHuMGDF in ameliorating chemotherapy-induced thrombocytopenia.
Main Methods:
- Daily subcutaneous injections of varying doses of PEG-rHuMGDF in normal mice.
- Monitoring of platelet counts, mean platelet volume (MPV), and platelet distribution width (PDW).
- Hematologic and bone marrow analyses, including assessment of reticulin fiber deposition and extramedullary hematopoiesis.
- Evaluation of PEG-rHuMGDF's effect on carboplatin-induced thrombocytopenia.
Main Results:
- PEG-rHuMGDF induced a rapid, dose-dependent increase in megakaryocytes and platelets.
- Low doses decreased MPV and PDW; intermediate doses caused transient increases; high doses increased MPV and PDW.
- High doses led to transient anemia, bone marrow hyperplasia (megakaryocytic, myeloid), hypoplasia (erythroid, lymphoid), reticulin deposition, splenomegaly, and extramedullary hematopoiesis, resembling myelofibrosis.
- These hematopathologies were completely reversible upon cessation of PEG-rHuMGDF administration.
- Low-dose PEG-rHuMGDF effectively ameliorated carboplatin-induced thrombocytopenia without causing myelofibrosis-like pathology.
Conclusions:
- PEG-rHuMGDF is a potent stimulator of thrombopoiesis.
- Dose and duration of PEG-rHuMGDF administration influence platelet indices and can induce reversible myelofibrosis-like changes.
- Low-dose PEG-rHuMGDF offers a potential therapeutic strategy for thrombocytopenia without significant adverse hematologic effects.