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Thrombocytopenia in dogs induced by granulocyte-macrophage colony-
stimulating factor: increased destruction of circulating platelets
RA Nash, SA Burstein, R Storb, W Yang, K Abrams, FR Appelbaum, T Boone, HJ Deeg, LD Durack and FG Schuening
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Administration of recombinant canine granulocyte-macrophage colony-
stimulating factor (rcGM-CSF) to normal dogs in previous studies induced an
increase in peripheral blood neutrophils and a dose- dependent decrease in
platelet counts. In six dogs that received the highest tested dose of
rcGM-CSF (50 micrograms/kg/d) for a minimum of 12 days, the mean nadir of
the platelet count was 46,000/microL (range, 4,000 to 91,000/microL) on day
9 +/- 1.1 after starting therapy, compared with a mean baseline platelet
count of 398,000/microL (range, 240,000 to 555,000/microL). In three dogs,
survival of autologous 111In- labeled platelets was reduced from a mean of
4.9 days to 1.3 days during the administration of rcGM-CSF. Biodistribution
studies with gamma camera imaging indicated that there was an increase in
mean hepatic uptake during the administration of rcGM-CSF, from 15% to 44%
of the total injected 111In-labeled platelets at 2 hours, whereas splenic
uptake was not significantly changed. In contrast, in two evaluable dogs
who were recipients of 111In-labeled platelets from matched allogeneic
donors receiving rcGM-CSF, platelet survival was not reduced and no
increased hepatic uptake was noted. A third dog became alloimmunized to the
matched donor platelets and was not evaluable. Immunohistologic studies of
liver and spleen were performed with monoclonal antibodies specific for
canine gpIIb/IIIa and P-selectin in dogs treated with rcGM-CSF and compared
with untreated controls. On treatment, a marked reduction of platelets in
the red pulp of the spleen was evident, and in general, the presence of
platelet antigen in the liver was unchanged. Therefore, platelets were not
being sequestered, but destroyed in the liver and spleen. The platelet
antigens, P-selectin and gpIIb/IIIa, were identified in association with
Kupffer cells in the liver, but no difference in the number of distribution
of these Kupffer cells was found between controls and rcGM- CSF-treated
dogs. In the spleen during rcGM-CSF treatment, most platelet antigens were
associated with large mononuclear cells in the marginal zone. During
administration of rcGM-CSF, CD1c and CD11c expression was increased on
Kupffer cells. Platelet P-selectin expression and binding of leukocytes to
circulating platelets were unchanged from baseline studies with rcGM-CSF
treatment. In conclusion, during the administration of rcGM-CSF to dogs, a
local process in the liver and spleen is induced resulting in
thrombocytopenia.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 86,
Issue 5,
pp. 1765-1775,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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