A novel prevention of erythrocyte fragility and anaemia induced by extracellular histones

Neutrophil extracellular traps (NETs) are released from neutrophils following activation by pathogens and/or tissue injury and exhibit anti-microbial activity. Uncontrolled formation of NETs can, however, become pathogenic, particularly via their associated histones, that can be cytotoxic in the vasculature causing endothelial cell death, systemic vascular obstruction, multiple organ failure and initiate coagulation by both activating platelets and damaging erythrocytes such that they become pro-thrombotic.
Recently we discovered an additional effect of histones on erythrocyte, which is to enhance their fragility when they are subjected to sheer stress associated with blood flow through the vasculature and spleen in particular. We have synthesised a family of small polyanions (SPAs) which have beenscreened for their ability to neutralise the pathogenic effects of histones and NETs. We have used a novel mechanically-induced sheer stress method as well as an in vitro spleenfiltration model to investigate the effects of mammalian histones ± SPAs, on RBC fragility. The in vitro findings were mirrored in vivo with the injection of histones and SPAs in mice.Our results revealed that free histones bind to erythrocytes with high affinity and render erythrocytes susceptible to lysis by shear stress in a dose-dependent manner and some SPAs could totally inhibitor reverse this phenomenon.
Based on these data we propose that erythrocytes can neutralise the damaging effects of histones in the circulation and also transport them to the spleen for disposal. Overload of this disposal system could cause the unexplained anaemia associated with sepsis, cancer and other pathological conditions.