Cytokines Associated with Increased Erythropoiesis in Sprague-Dawley Rats Administered a Novel Hyperglycosylated Analog of Recombinant Human Erythropoietin. (April 2014)

• Record Type: Journal Article
• Authors: Andrews, Dina A.; Hamadeh, Hisham K.; He, Yudong D.; Boren, Babette M.; Turk, James R.; Boyce, Rogely W.; Mytych, Daniel T.; Barger, Troy E.; Salimi-Moosavi, Hossein; Sloey, Bethlyn; Elliott, Steve; McElroy, Patricia; Sinclair, Angus M.; Shimamoto, Grant; Pyrah, Ian T. G.; Lightfoot-Dunn, Ruth M.
• Is Part Of: Toxicologic pathology. Volume 42:Number 3(2014:Apr.)
• Page Start: 540
• Page End: 554
• Publication Date: 2014-04
• Subjects: erythropoiesis -- rat -- cytokine -- polycythemia -- thrombosis -- inflammation -- coagulation.; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623313486318
• Languages: English
• ISSNs: 0192-6233

Abstract

We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 high-dose group, but not in lower dose groups with a similar high HCT.