title: Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behçet Disease.
abstract: BACKGROUND
  Behçet disease (BD) is a systemic vasculitis with a broad range of organ involvement, characterized by a multisystemic, immune-inflammatory disorder involving vessels of all sizes and often complicated by thrombosis. Systemic redox imbalance and circulating neutrophil hyperactivation have been observed in BD patients and are thought to be responsible for impaired coagulation. We here focused on the pathogenetic mechanisms potentially linking immune cell activation and thrombosis, and specifically examined whether neutrophil activation can affect fibrinogen modifications and consequently elicit thrombosis.
  
  
  RESULTS
  Blood samples were collected from 98 consecutive BD patients attending our dedicated Center and from 70 age- and sex-matched healthy controls; in all patients fibrinogen function and structure, fibrin susceptibility to plasmin-lysis, plasma redox status, leukocyte oxidative stress markers, and possible reactive oxygen species sources were examined. Thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis were significantly impaired in BD patients (P<0.001). These findings were associated with increased plasma oxidative stress markers (P<0.001) and with a marked carbonylation of fibrinogen (P<0.001), whose secondary structure appeared deeply modified. Neutrophils displayed an enhanced NADPH oxidase activity and increased reactive oxygen species production (P<0.001), which significantly correlated with fibrinogen carbonylation level (r(2)=0.33, P<0.0001), residual β-band intensity (r(2)=0.07, P<0.01), and fibrinogen clotting ability (r(2)=0.073, P<0.01) CONCLUSIONS: In BD patients, altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production whose primary source is represented by neutrophil NADPH oxidase.
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Becatti
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Giacomo
authors.initials: G
authors.lastname: Emmi
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Elena
authors.initials: E
authors.lastname: Silvestri
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Giulia
authors.initials: G
authors.lastname: Bruschi
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciucciarelli
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Danilo
authors.initials: D
authors.lastname: Squatrito
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Niccolò
authors.initials: N
authors.lastname: Taddei
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Emmi
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.). claudia.fiorillo@unifi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorillo
authors.affiliation: From Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (M.B., G.B., N.T., C.F.) and Department of Experimental and Clinical Medicine (G.E., E.S., L.C., D.S., R.A., D.P.), University of Florence, Italy; Nephrology Unit, University Hospital of Parma, Italy (A.V.); Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy (L.E., D.P.); and Department of Clinical and Experimental Medicine, University Medical School and University Hospital of Parma, Italy (M.G.).
authors.forename: Domenico
authors.initials: D
authors.lastname: Prisco
mesh_terms: D001528:Behcet Syndrome / Q000097:blood* / Q000175:diagnosis*; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D018375:Neutrophil Activation / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000175:diagnosis*
chemical_list: D017382:Reactive Oxygen Species; D005340:Fibrinogen
keywords: fibrinogen; neutrophils; oxidative stress; thrombosis