A Mild Transient Decrease of Peripheral Red Blood Cell Counts Induced by a Suprapharmacological Dose of Pegylated Human Megakaryocyte Growth and Development Factor in Rats

• Published in: Journal of pharmacy and pharmacology Vol. 51; no. 7; pp. 841 - 846
• Main Authors: Harada, Katsuhiko, Ide, Youichi, Tazunoki, Yoshiko, Imai, Atsuko, Yanagida, Makoto, Kikuchi, Yasuko, Imai, Atsushi, Ishii, Hiromo, Kawahara, Jun-Ichi, Izumi, Hideakira, Kusaka, Masaru, Tokiwa, Tomonobu
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-1999; Pharmaceutical Press
• Subjects: Anemia - blood; Anemia - chemically induced; Anemia - physiopathology; Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Dose-Response Relationship, Drug; Erythrocyte Count - drug effects; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Hematocrit; Humans; Medical sciences; Megakaryocytes - cytology; Megakaryocytes - drug effects; Pharmacology. Drug treatments; Plasma Volume - drug effects; Platelet Count - drug effects; Polyethylene Glycols - adverse effects; Polyethylene Glycols - pharmacology; Rats; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacology; Spleen - cytology; Spleen - drug effects; Splenectomy; Thrombopoietin - adverse effects; Thrombopoietin - pharmacology; Erythropoiesis; Megakaryocytopoiesis; Thrombopoiesis; Pathophysiology; Rat; Anemia; Rodentia; Cytokine; Red blood cell; Megakaryocyte; Hemopathy; Thrombopoietin; Vertebrata; Mammalia; Hematopoiesis; Analog; Animal; High dose; Growth factor
• DOI: 10.1211/0022357991773041
• EISSN: 2042-7158
• ISSN: 0022-3573

Previous studies have shown that pegylated recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF) at suprapharmacological dose induces a mild transient decrease of red blood cell counts according to thrombopoiesis in normal mice. To unravel the mechanism underlying this mild transient decrease of red blood cells, we have studied the effect of PEG‐rHuMGDF on the circulating plasma and blood volume, and the serum biochemical parameters of anaemia and splenectomy. Also, we have performed histological studies of the bone marrow and the spleen of PEG‐rHuMGDF‐treated rats.
PEG‐rHuMGDF (300 μg kg−1) or vehicle was subcutaneously administered to rats once a day for up to five days. From day 6 after the start of PEG‐rHuMGDF administration, the platelet counts and plateletcrit levels were significantly increased, reaching peak values on day 10, and recovering to normal by day 20. The red blood cell counts and the haematocrit levels were significantly decreased on day 6 to 13. The decreases in red blood cell levels and haematocrit produced by PEG‐rHuMGDF treatment were mild and had recovered by day 15. The plasma and blood volumes were significantly increased on day 10 in PEG‐rHuMGDF‐treated rats. No alteration of the serum biochemical parameters for anaemia, iron or total bilirubin, were observed on day 10. The histological examination on day 10 revealed a marked increase in megakaryocytes and a slight decrease in erythropoiesis in the bone marrow of rats that received PEG‐rHuMGDF (300 μg kg−1). There was also a slight increase in splenic megakaryocytes and erythropoiesis. The decrease of red blood cells by PEG‐rHuMGDF was not affected by splenectomy.
These results suggest that the mild transient decrease of red blood cells induced by PEG‐rHuMGDF treatment for up to five days is based mainly on the increases in the plasma and blood volume. These events are secondary changes due to the regulation of the excess production of megakaryocytes in the marrow and the peripheral platelets.