A mild transient decrease of peripheral red blood cell counts induced by asuprapharmacological dose of pegylated human megakaryocyte growth and development factor in rats

Previous studies have shown that pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) at suprapharmacological dose in duces a mild transient decrease of red blood cell counts according to throm bopoiesis in normal mice. To unravel the mechanism underlying this mild tra nsient decrease of red blood cells, we have studied the effect of PEG-rHuMG DF on the circulating plasma and blood volume, and the serum biochemical pa rameters of anaemia and splenectomy. Also, we have performed histological s tudies of the bone marrow and the spleen of PEG-rHuMGDF-treated rats. PEG-rHuMGDF (300 mu g 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-rHu MGDF administration, the platelet counts and plateletcrit levels were signi ficantly increased, reaching peak values on day 10, and recovering to norma l by day 20. The red blood cell counts and the haematocrit levels were sign ificantly decreased on day 6 to 13. The decreases in red blood cell levels and haematocrit produced by PEG-rHuMGDF treatment were mild and had recover ed 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. T he histological examination on day 10 revealed a marked increase in megakar yocytes and a slight decrease in erythropoiesis in the bone marrow of rats that received PEG-rHuMGDF (300 mu g kg(-1)). There was also a slight increa se 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 i nduced 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 change s due to the regulation of the excess production of megakaryocytes in the m arrow and the peripheral platelets.