title: Association of increased fibrinogen concentration with impaired activation of anticoagulant protein C.
abstract: BACKGROUND
  Low levels of activated protein C (APC) are a risk factor for venous thrombosis. The mechanisms leading to interindividual differences in APC are not totally elucidated. Protein C is activated by the thrombin-thrombomodulin complex. As thrombin binds to fibrinogen and thrombomodulin through a common region, it is conceivable that fibrinogen influences the activation of protein C. This would help to explain the association between high levels of fibrinogen and an increased thrombotic risk.
  
  
  METHODS
  We analyzed the association between circulating APC levels and fibrinogen concentration in 382 healthy subjects. Subsequently, we studied the effect of increasing fibrinogen concentrations on the APC generation on cultured endothelial cells.
  
  
  RESULTS
  An independent inverse association between circulating APC levels and fibrinogen was found [betacoefficient, -0.16; 95% confidence interval (95% CI) -0.26, -0.06; P = 0.001]. For each 100 mg dL(-1) increase in fibrinogen, the independent risk of having low APC levels (<0.7 ng mL(-1)) was almost three times higher (OR 2.8; 95% CI 1.1, 7.2; P = 0.04). Accordingly, a notable association between increasing fibrinogen concentrations and the reduction in the thrombin-thrombomodulin dependent activation of protein C on endothelial cells was found (r = -0.57; P = 0.002).
  
  
  CONCLUSIONS
  We present evidence of an inverse association between circulating APC and fibrinogen levels. According to this finding together with the results of our in vitro experiments, we propose that the impairment in the generation of APC on endothelial cells constitutes a new prothrombotic mechanism of fibrinogen.
authors.affiliation: Department of Haematology, Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Clínica Universitaria/School of Medicine, Centre for Applied Medical Research, Pamplona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Díez
authors.forename: R
authors.initials: R
authors.lastname: Montes
authors.forename: A
authors.initials: A
authors.lastname: Alonso
authors.forename: P
authors.initials: P
authors.lastname: Medina
authors.forename: S
authors.initials: S
authors.lastname: Navarro
authors.forename: F
authors.initials: F
authors.lastname: España
authors.forename: J
authors.initials: J
authors.lastname: Hermida
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism*; D012016:Reference Values; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood / Q000209:etiology
chemical_list: D000925:Anticoagulants; D011486:Protein C; D005340:Fibrinogen