Thrombocytopenia in Dogs Induced by Granulocyte-Macrophage Colony-Stimulating Factor: Increased Destruction of Circulating Platelets

Richard A. Nash, Samuel A. Burstein, Rainer Storb, Woojin Yang, Kraig Abrams, Frederick R. Appelbaum, Tom Boone, H. Joachim Deeg, Lawrence D. Durack, Friedrich G. Schuening, Sean McDonough, Peter Moore, Wil B. Nelp, Sherrill Slichter

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Abstract

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 μg/kg/d) for a minimum of 12 days, the mean nadir of the platelet count was 46,000/μL (range, 4,000 to 91,000/μL) on day 9 ± 1.1 after starting therapy, compared with a mean baseline platelet count of 398,000/μL (range, 240,000 to 555,000/μL). 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 111ln-labeled platelets at 2 hours, whereas splenic uptake was not significantly changed. In contrast, in two evaluable dogs who were recipients of 111ln-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 or 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. Because rcGM-CSF reproducibly induces thrombocytopenia in dogs, this may be an important animal model for further studies to identify a non-autoimmune mechanism by which an activated monocyte-macrophage system can increase the rate of platelet removal.

Original languageEnglish (US)
Pages (from-to)1765-1775
Number of pages11
JournalBlood
Volume86
Issue number5
StatePublished - Sep 1 1995

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ASJC Scopus subject areas

  • Hematology

Cite this

Nash, R. A., Burstein, S. A., Storb, R., Yang, W., Abrams, K., Appelbaum, F. R., Boone, T., Deeg, H. J., Durack, L. D., Schuening, F. G., McDonough, S., Moore, P., Nelp, W. B., & Slichter, S. (1995). Thrombocytopenia in Dogs Induced by Granulocyte-Macrophage Colony-Stimulating Factor: Increased Destruction of Circulating Platelets. Blood, 86(5), 1765-1775.