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Prolonged thrombocytosis in mice after 5-fluorouracil results from failure
to down-regulate megakaryocyte concentration. An experimental model that
dissociates regulation of megakaryocyte size and DNA content from
megakaryocyte concentration
PJ Chenaille, SA Steward, RA Ashmun and CW Jackson
Department of Hematology/Oncology, St Jude Children's Research Hospital,
Memphis, TN 38101.
Rodents treated with 150 mg/kg of 5-fluorouracil (5-FU) exhibit a marked
and prolonged rebound thrombocytosis, suggesting that feedback control of
one or more megakaryocyte characteristics (size, polyploidy, or
concentration) is altered. To determine the changes in megakaryocytes that
lead to such a profound thrombocytosis, C3H mice were injected with 150
mg/kg 5-FU, and platelet and megakaryocyte responses were examined at
frequent intervals from days 1 through 25. After 5-FU injection, all
megakaryocyte indices decreased, as did platelet number. However, the
decrease in platelets to one third of control was greater than the
decreases in megakaryocyte indices, suggesting that thrombocytopoiesis was
ineffective from days 3 through 7 post 5-FU. Megakaryocyte size began to
recover on day 4, followed by polyploid DNA content on day 5, and
megakaryocyte concentration and platelets at 7.5 days. Megakaryocyte size
peaked on days 6 through 8 (1.25 x normal), followed by megakaryocyte
polyploid DNA content on day 8, megakaryocyte concentration on days 9
through 12 (2 1/2 to 3x normal), and platelets on days 12 through 15 (2x
normal). Platelet levels are thought to be important in the feedback
regulation of megakaryocytes; however, only polyploid DNA content
distributions showed a close inverse relationship to platelet counts during
both the recovery and rebound thrombocytosis phases after 5-FU. In
contrast, megakaryocyte size peaked before platelet recovery commenced,
while megakaryocyte concentration increased in parallel with platelets from
7.5 to 10 days post 5-FU and continued to be maintained at 2 to 3 times
normal through day 13, despite platelet levels that were more than twice
normal. Both megakaryocyte size and polyploid DNA content distributions
shifted toward lower values in response to the rebound thrombocytosis (DNA
content on day 10 and size on days 12 and 13). Splenectomy did not
substantially alter the pattern of post 5-FU rebound thrombocytosis or
megakaryocyte response from that seen in intact mice, indicating that
splenic megakaryocytes are not responsible for the prolonged thrombocytosis
seen after this drug. In summary, the prolonged thrombocytosis after 5-FU
administration results from failure to down-regulate the number of
precursors entering the differentiating megakaryocyte compartment. These
data indicate that megakaryocyte size and DNA content are responsive to
different feedback controls than megakaryocyte concentration in this model
system.
Volume 76,
Issue 3,
pp. 508-515,
08/01/1990
Copyright © 1990 by The American Society of Hematology
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