title: Nitrated fibrinogen is a biomarker of oxidative stress in venous thromboembolism.
abstract: The pathogenesis of venous thromboembolism (VTE) is linked to inflammation and oxidant production, although specific markers for these pathways with pathological relevance to VTE have not been explored. The coagulant protein fibrinogen is posttranslationally modified by nitric oxide-derived oxidants to nitrated fibrinogen in both acute and chronic inflammatory states. Therefore, nitrated fibrinogen may serve as a marker of inflammation and oxidative stress in VTE. To test this hypothesis we enrolled subjects (n=251) presenting with suspected VTE at the University of Pennsylvania Hospital emergency department, 50 (19.9%) of whom were positive by imaging or 90-day follow-up. Mean nitrated fibrinogen was elevated in VTE-positive (62.7 nM, 95% CI 56.6-68.8) compared to VTE-negative patients (54.2 nM, 95% CI 51.4-57.1; P<0.01). Patients in the highest quartile of nitrated fibrinogen had an increased risk of VTE compared with patients in the lowest quartile (OR 3.30; 95% CI 1.25-8.68; P<0.05). This risk persisted after univariate adjustment for age, active cancer, and recent surgery, but not after multivariate adjustment. Mean fibrinogen levels measured either by the Clauss assay or by ELISA were not different between VTE-negative and VTE-positive patients. These data indicate that nitrated fibrinogen is an oxidative risk marker in VTE, providing a novel mechanistic link between oxidant production, inflammation, and VTE.
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia and Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4318, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Martinez
authors.forename: Adam
authors.initials: A
authors.lastname: Cuker
authors.forename: Angela
authors.initials: A
authors.lastname: Mills
authors.forename: Richard
authors.initials: R
authors.lastname: Lightfoot
authors.forename: Yiying
authors.initials: Y
authors.lastname: Fan
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000097:blood*; D009589:Nitrogen Oxides / Q000097:blood; D018384:Oxidative Stress; D011446:Prospective Studies; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000097:blood* / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D009566:Nitrates; D009589:Nitrogen Oxides; C036309:fibrin fragment D; D005340:Fibrinogen