title: Histones induce rapid and profound thrombocytopenia in mice.
abstract: Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage.
authors.affiliation: Immune Disease Institute, Boston, MA, USA.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Bhandari
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000378:metabolism; D006657:Histones / Q000009:adverse effects* / Q000494:pharmacology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism / Q000502:physiology; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D006657:Histones; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen