Ring hemorrhages in the central nervous system of severely anemic cynomolgus monkeys.

Abstract

Ring hemorrhages are characteristic ring-shaped lesions in the parenchyma of the central nervous system (CNS) surrounding small blood vessels and are typically reported to occur in white matter of the brain. In humans, they are seen in various diseases, including pernicious anemia, cerebral fat embolism, and cerebral malaria. Ring hemorrhages are also sporadically seen in the CNS of animals and have been previously reported in 4 nonhuman primate (NHP) species with various forms of anemia. Here we present the results of 4 preclinical toxicity studies testing 4 drug candidates of different modalities, targets, mechanisms of action, and indications in NHPs (cynomolgus monkeys). Within each study, ring hemorrhages were observed associated with severe anemia in affected animals and were in line with those previously reported. They occurred in gray matter and occasionally white matter of the brain and spinal cord; in the brain, the thalamus, basal ganglia, and cerebellum were particularly affected. Lesions comprised a central eosinophilic core, sometimes with small blood vessels or eosinophilic to slightly basophilic amorphous material in the center, surrounded by red blood cells and/or microglial cells or microglia aggregates. Fibrin staining confirmed the presence of fibrin in the central core. No commonality in type/cause of anemia was noted; in one study, the anemia was considered a spontaneous (non-treatment-related) finding. A thorough examination of the brain is therefore recommended in the presence of anemic conditions in animals. Pathologists should be aware of this finding and its relationship with anemia when assessing associations with diseases or drug candidates.