Extracellular histones induce erythrocyte fragility and anemia

Abstract

Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity towards nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histones on erythrocyte function. We demonstrate here that histones promote erythrocyte aggregation, sedimentation and, using a novel in vitro shear stress model, induce erythrocyte fragility and lysis in a concentration dependent manner. Furthermore, histones impair erythrocyte deformability based on reduced passage of erythrocytes through an artificial spleen. These in vitro results were mirrored in vivo with the injection of histones inducing anemia, within minutes of administration, with a concomitant increase in splenic hemoglobin content. Thrombocytopenia and leukopenia were also observed. These findings suggest that histones binding to erythrocytes may contribute to the elevated erythrocyte sedimentation rates (ESR) observed in inflammatory conditions. Furthermore, histone-induced increases in RBC lysis and splenic clearance may be a significant factor in the unexplained anemias seen in critically ill patients. Show more