title: Propagation of thrombosis by neutrophils and extracellular nucleosome networks.
abstract: Neutrophils, early mediators of the innate immune defense, are recruited to developing thrombi in different types of thrombosis. They amplify intravascular coagulation by stimulating the tissue factor-dependent extrinsic pathway via inactivation of endogenous anticoagulants, enhancing factor XII activation or decreasing plasmin generation. Neutrophil-dependent prothrombotic mechanisms are supported by the externalization of decondensed nucleosomes and granule proteins that together form neutrophil extracellular traps. These traps, either in intact or fragmented form, are causally involved in various forms of experimental thrombosis as first indicated by their role in the enhancement of both microvascular thrombosis during bacterial infection and carotid artery thrombosis. Neutrophil extracellular traps can be induced by interactions of neutrophils with activated platelets; vice versa, these traps enhance adhesion of platelets via von Willebrand factor. Neutrophil-induced microvascular thrombus formation can restrict the dissemination and survival of blood-borne bacteria and thereby sustain intravascular immunity. Dysregulation of this innate immune pathway may support sepsis-associated coagulopathies. Notably, neutrophils and extracellular nucleosomes, together with platelets, critically promote fibrin formation during flow restriction-induced deep vein thrombosis. Neutrophil extracellular traps/extracellular nucleosomes are increased in thrombi and in the blood of patients with different vaso-occlusive pathologies and could be therapeutically targeted for the prevention of thrombosis. Thus, during infections and in response to blood vessel damage, neutrophils and externalized nucleosomes are major promoters of intravascular blood coagulation and thrombosis.
authors.affiliation: Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, Germany Susanne.Pfeiler@med.uni-muenchen.de Konstantin.Stark@med.uni-muenchen.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiler
authors.affiliation: Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany Susanne.Pfeiler@med.uni-muenchen.de Konstantin.Stark@med.uni-muenchen.de.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stark
authors.affiliation: Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.affiliation: Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Engelmann
mesh_terms: D000818:Animals; D015415:Biomarkers; D001777:Blood Coagulation; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D015539:Platelet Activation; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D002843:Chromatin; D009707:Nucleosomes; D005337:Fibrin