THROMBOCYTOPENIA IN DOGS INDUCED BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR - INCREASED DESTRUCTION OF CIRCULATING PLATELETS

Administration of recombinant canine granulocyte-macrophage colony-sti mulating factor (rcGM-CSF) to normal dogs in previous studies induced an increase in peripheral blood neutrophils and a dose dependent decre ase in platelet counts. In six dogs that received the highest tested d ose of rcGM-CSF (50 mu g/kg/d) for a minimum of 12 days, the mean nadi r of the platelet count was 46,000/mu L (range, 4,000 to 91,000/mu L) on day 9 +/- 1.1 after starting therapy, compared with a mean baseline platelet count of 398,000/mu L (range, 240,000 to 555,000/mu L). In t hree dogs, survival of autologous In-111-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 administratio n of rcGM-CSF, from 15% to 44% of the total injected In-111-labeled pl atelets at 2 hours, whereas splenic uptake was not significantly chang ed. In contrast, in two evaluable dogs who were recipients of In-111-l abeled platelets from matched allogeneic donors receiving rcGM-CSF, pl atelet survival was not reduced and no increased hepatic uptake was no ted. A third dog became alloimmunized to the matched donor platelets a nd was not evaluable. Immunohistologic studies of liver and spleen wer e performed with monoclonal antibodies specific for canine gpIIb/IIIa and P-selectin in dogs treated with rcGM-CSF and compared with untreat ed controls. On treatment, a marked reduction of platelets in the red pulp of the spleen was evident, and in general, the presence of platel et antigen in the liver was unchanged. Therefore, platelets were not b eing sequestered, but destroyed in the liver and spleen. The platelet antigens, P-selectin and gpIIb/IIIa, were identified in association wi th Kupffer cells in the liver, but no difference in the number or dist ribution of these Kupffer cells was found between controls and rcGM-CS F-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 wa s increased on Kupffer cells. Platelet P-selectin expression and bindi ng of leukocytes to circulating platelets were unchanged from baseline studies with rcGM-CSF treatment. In conclusion, during the administra tion of rcGM-CSF to dogs, a local process in the liver and spleen is i nduced resulting in thrombocytopenia. Because rcGM-CSF reproducibly in duces thrombocytopenia in dogs, this may be an important animal model for further studies to identify a nonautoimmune mechanism by which an activated monocyte-macrophage system can increase the rate of platelet removal. (C) 1995 by The American Society of Hematology.