Heparin Prevents Histone-Induced Thrombocytopenia and Mortality

Abstract 2106

Histones and DNA are released from activated neutrophils to form extracellular traps (NETs) which bind and kill bacteria. Histones contribute to this antimicrobial activity, but they are a double-edged sword because they are a major mediator of death in sepsis. Histones are cytotoxic and intravenous infusion of histones into mice can lead to death. Recently we have shown that NETs provide a scaffold supporting platelet adhesion, activation and thrombus formation. NETs and histones were found in deep vein thrombi. Here we show that platelets in blood are preferentially targeted by histones. Histone binding to platelets induces calcium influx, recruits fibrinogen and causes platelet aggregation which depends on the interaction of histones, fibrinogen and αIIβ3-integrins. Mice challenged intravenously with histones at sublethal concentrations developed a rapid and profound thrombocytopenia reflecting platelet aggregation in vivo. Heparin administration abolished histone interaction with platelets and prevented thrombocytopenia. Heparin also prevented histone induced cytotoxicity towards endothelial cells and rescued mice after a challenge with a lethal dose of histones. The biological function of heparin stored in granules of mast cells is not known. We propose that it may be to counteract histone-mediated thrombosis and injury during innate immune response.