title: Cytokines associated with increased erythropoiesis in Sprague-Dawley rats administered a novel hyperglycosylated analog of recombinant human erythropoietin.
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.
authors.affiliation: 1Comparative Biology Safety Sciences, Pathology, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Dina A
authors.initials: DA
authors.lastname: Andrews
authors.forename: Hisham K
authors.initials: HK
authors.lastname: Hamadeh
authors.forename: Yudong D
authors.initials: YD
authors.lastname: He
authors.forename: Babette M
authors.initials: BM
authors.lastname: Boren
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.forename: Rogely W
authors.initials: RW
authors.lastname: Boyce
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Mytych
authors.forename: Troy E
authors.initials: TE
authors.lastname: Barger
authors.forename: Hossein
authors.initials: H
authors.lastname: Salimi-Moosavi
authors.forename: Bethlyn
authors.initials: B
authors.lastname: Sloey
authors.forename: Steve
authors.initials: S
authors.lastname: Elliott
authors.forename: Patricia
authors.initials: P
authors.lastname: McElroy
authors.forename: Angus M
authors.initials: AM
authors.lastname: Sinclair
authors.forename: Grant
authors.initials: G
authors.lastname: Shimamoto
authors.forename: Ian T G
authors.initials: IT
authors.lastname: Pyrah
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Lightfoot-Dunn
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood* / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000737:chemistry / Q000494:pharmacology*; D006400:Hematocrit; D006801:Humans; D008297:Male; D011086:Polycythemia; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology*; D012156:Reticulocytes; D013927:Thrombosis
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D004921:Erythropoietin
keywords: coagulation.; cytokine; erythropoiesis; inflammation; polycythemia; rat; thrombosis