title: Drug-induced hemolytic anemia and thrombocytopenia associated with alterations of cell membrane lipids and acanthocyte formation.
abstract: CXCR3 is a chemokine receptor, upregulated upon activation of T cells and expressed on nearly 100% of T cells in sites of inflammation. SCH 900875 is a selective CXCR3 receptor antagonist. Thrombocytopenia and severe hemolytic anemia with acanthocytosis occurred in rats at doses of 75, 100, and 150 mg/kg/day. Massively enlarged spleens corresponded histologically to extramedullary hematopoiesis, macrophages, and hemosiderin pigment and sinus congestion. Phagocytosed erythrocytes and platelets were within splenic macrophages. IgG and/or IgM were not detected on erythrocyte and platelet membranes. Ex vivo increased osmotic fragility of RBCs was observed. Lipid analysis of the RBC membrane revealed modifications in phosphatidylcholine, overall cholesterol, and/or sphingomyelin. Platelets exhibited slender filiform processes on their plasma membranes, analogous to those of acanthocytes. The presence of similar morphological abnormalities in acanthocytes and platelets suggests that possibly similar alterations in the lipid composition of the plasma membrane have taken place in both cell types. This phenotype correlated with alterations in plasma lipids (hypercholesterolemia and low triglycerides) that occurred after SCH 900875 administration, although other factors cannot be excluded. The increased cell destruction was considered triggered by alterations in the lipid profile of the plasma membranes of erythrocytes and platelets, as reflected morphologically.
authors.affiliation: Merck Research Laboratories, Lafayette, NJ 07848, USA. frederique.poulet@spcorp.com
authors.forename: Frederique M
authors.initials: FM
authors.lastname: Poulet
authors.forename: Kelley
authors.initials: K
authors.lastname: Penraat
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Collins
authors.forename: Ellen
authors.initials: E
authors.lastname: Evans
authors.forename: Evan
authors.initials: E
authors.lastname: Thackaberry
authors.forename: Denise
authors.initials: D
authors.lastname: Manfra
authors.forename: Laura
authors.initials: L
authors.lastname: Engstrom
authors.forename: Richard
authors.initials: R
authors.lastname: Geissler
authors.forename: Maria
authors.initials: M
authors.lastname: Geraci-Erck
authors.forename: Carlos
authors.initials: C
authors.lastname: Frugone
authors.forename: Malaz
authors.initials: M
authors.lastname: Abutarif
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: Brianna L
authors.initials: BL
authors.lastname: Peterson
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cummings
authors.forename: Robert C
authors.initials: RC
authors.lastname: Johnson
mesh_terms: D000050:Acanthocytes / Q000378:metabolism* / Q000473:pathology; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000378:metabolism; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects*; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced; D008563:Membrane Lipids / Q000378:metabolism*; D009996:Osmotic Fragility; D010713:Phosphatidylcholines / Q000378:metabolism; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013109:Sphingomyelins / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000097:blood
chemical_list: D008563:Membrane Lipids; D010713:Phosphatidylcholines; D054367:Receptors, CXCR3; D013109:Sphingomyelins; D014280:Triglycerides; D002784:Cholesterol