Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice.
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.
Ulich
T R
TR
Amgen Inc, Thousand Oaks, CA 91320, USA.
del Castillo
J
J
Senaldi
G
G
Kinstler
O
O
Yin
S
S
Kaufman
S
S
Tarpley
J
J
Choi
E
E
Kirley
T
T
Hunt
P
P
Sheridan
W P
WP
D000740:Anemia / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000737:chemistry / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D007274:Injections, Intraperitoneal; D008533:Megakaryocytes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage; D055728:Primary Myelofibrosis / Q000139:chemically induced* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000633:toxicity; D011994:Recombinant Proteins; D012155:Reticulin / Q000032:analysis; D013163:Splenomegaly / Q000139:chemically induced* / Q000473:pathology; D013922:Thrombocytosis / Q000139:chemically induced* / Q000473:pathology; D013926:Thrombopoietin / Q000008:administration & dosage / Q000235:genetics / Q000633:toxicity*
D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012155:Reticulin; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin