Thrombocytopenic c-mpl−/− mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response

Abstract

Administration of 5-fluorouracil (5-FU) to mice results in a marked increase in the level of circulating platelets in 10 days. Mice lacking Mpl, the receptor for thrombopoietin (TPO), are thrombocytopenic. To gain insight into the mechanism by which 5-FU produces such a substantial stimulation of platelet production, this study investigated whether 5-FU (150 mg/kg) produced thrombocytosis in c-mpl−/− mice, thus establishing whether TPO was required for this response. A 5- to 6-fold increase in platelet levels in c-mpl−/− mice (to approximately 1000 × 109/L) was observed on days 20 and 25 after 5-FU injection. Thus, at the peak of the response, c-mpl−/− mice had platelet levels comparable to those in normal mice. Administration of 5-FU also produced thrombocytosis in previously splenectomized c-mpl−/− mice. Comparison of the platelet response to 5-FU in young (6-12 weeks) and old (33-46 weeks) c-mpl−/− mice found that older mice produced a much more marked response than younger mice, with a mean maximum platelet level of approximately 1700 × 109/L. To determine whether this increase in circulating platelets was preceded by an increase in hematopoietic progenitors, serial cultures of bone marrow and spleen were evaluated. A considerable increase in all colony types studied was observed on days 15 and 20 in spleens of c-mpl−/− mice, but no similar elevations were detected in bone marrow. These results indicate that c-mpl−/− mice can achieve a normal level of platelets after 5-FU injection, by means of a TPO-independent mechanism, and that they respond to 5-FU myelosuppression by producing large numbers of megakaryocytic, myeloid, and erythroid progenitors.