COMPENSATORY MECHANISMS IN PLATELET PRODUCTION - LACK OF A PARACRINE RESPONSE IN W W-V MICE TREATED WITH 5-FLUOROURACIL/

W/W-v mice maintain normal platelet levels despite having a reduced fu nctional stem cell pool, indicating that platelet production in these mice is compensated by altered megakaryocytopoiesis. In this study the effect of 5-fluorouracil (5-FU) treatment on platelet production in W /W-v mice and their congenic normal littermates was assessed. Recovery of circulating platelet levels occurred 11 days after 5-FU administra tion in W/W-v mice and subsequently did not increase above control val ues. In contrast, normal littermates showed an increased platelet coun t by day 8 and significant thrombocytosis between days 11 and 14. Inve stigation of bone marrow megakaryocytopoiesis in W/W-v mice showed the re was no recovery in the number of megakaryocyte progenitors (CFU-Meg ) per femur between days 3 and 5, but control values were reached by d ay 10. In addition, by day 8 the number of mature megakaryocytes per u nit volume of bone marrow in these mice had not returned to control va lues, although the megakaryocytes were of an increased size. In compar ison, the number of CFU-Meg per femur in normal mice treated with 5-FU began to recover after day 3, returned to control values by day 8 and increased to supranormal levels by day 14. Bone marrow megakaryocyte concentration was increased 2-fold over the control by day 8 and an in crease in mean megakaryocyte size was also observed. The data suggest that platelet production in mice is dependent on the rate of establish ment of both the progenitor cell and megakaryocyte pools. The inabilit y of W/W-v mice to enhance and accelerate progenitor cell levels led t o a reduced bone marrow response and failure to produce a marked throm bocytosis.