Recombinant human macrophage colony-stimulating factor-induced thrombocytopenia in dogs

Authors


Richard A. Nash, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, PO Box 19024, Seattle, WA 98109–1024, USA. E-mail: rnash@fhcrc.org

Abstract

Summary. To characterize recombinant human macrophage-colony stimulating factor (rhM-CSF)-associated thrombocytopenia (TCP), in vivo studies were performed in dogs, including the biodistributions and recoveries of radiolabelled autologous and allogeneic platelets. rhM-CSF induced a reversible, dose-dependent decrease in platelet counts. The number of megakaryocytes in spleen and marrow of rhM-CSF-treated dogs was increased two to threefold. Recoveries of allogeneic platelets transfused from rhM-CSF-treated donors into tolerized recipients (n = 3) were not significantly different from allogeneic baseline studies (93 ± 10% of baseline values at 24 h and 90 ± 1% at 40 h), whereas autologous platelets infused back into rhM-CSF-treated donors had decreased recoveries (45 ± 2% of baseline values at 24 h, P = 0·03 and 20 ± 4% at 40 h, P = 0·001). Platelet biodistribution studies showed increased accumulation of radiolabelled platelets over the spleens and livers of rhM-CSF-treated dogs. Histochemistry showed increased levels of platelet-specific antigen (CD41; glycoprotein IIb) associated with Kupffer cells. The sensitivity of platelets from rhM-CSF-treated dogs to activation from thrombin, as measured by expression of P-selectin (CD62P), was not significantly different when compared with baseline studies (P = 0·18; n = 4). These results support the concept that rhM-CSF induces an activation of the monocyte–macrophage system (MMS), which causes a reversible TCP in a dog model.

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