Drug-induced hemolytic anemia and thrombocytopenia associated with alterations of cell membrane lipids and acanthocyte formation.
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.
Poulet
Frederique M
FM
Merck Research Laboratories, Lafayette, NJ 07848, USA. frederique.poulet@spcorp.com
Penraat
Kelley
K
Collins
Nathaniel
N
Evans
Ellen
E
Thackaberry
Evan
E
Manfra
Denise
D
Engstrom
Laura
L
Geissler
Richard
R
Geraci-Erck
Maria
M
Frugone
Carlos
C
Abutarif
Malaz
M
Fine
Jay S
JS
Peterson
Brianna L
BL
Cummings
Brian S
BS
Johnson
Robert C
RC
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
D008563:Membrane Lipids; D010713:Phosphatidylcholines; D054367:Receptors, CXCR3; D013109:Sphingomyelins; D014280:Triglycerides; D002784:Cholesterol