title: Active PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays.
abstract: BACKGROUND
  Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the pathophysiology of Venous ThromboEmbolism (VTE). Whether increased TAFI and/or PAI-1 concentrations are associated with VTE is unclear.
  
  
  OBJECTIVE
  To study an association of impaired fibrinolysis and VTE using a comprehensive panel of in-house developed assays measuring intact TAFI, activation peptide of TAFI (AP-TAFI), PAI-1 antigen, endogenous PAI-1:t-PA complex (PAI-1:t-PA) and active PAI-1 levels in 102 VTE patients and in 113 healthy controls (HC).
  
  
  RESULTS
  Active PAI-1 was significantly higher in VTE patients compared to HC (20.9 [9.6-37.8] ng/ml vs. 6.2 [3.5-9.7] ng/ml, respectively). Active PAI-1 was the best discriminator with an area under the ROC curve and 95% confidence interval (AUROC [95%CI]) of 0.84 [0.79-0.90] compared to 0.75 [0.68-0.72] for PAI-1:t-PA, 0.65 [0.58-0.73] for PAI-1 antigen, 0.62 [0.54-0.69] for AP-TAFI and 0.51 [0.44-0.59] for intact TAFI. Using ROC analysis, we defined an optimal cut-off of 12.8 ng/ml for active PAI-1, with corresponding sensitivity of 71 [61-79] % and specificity of 89 [82-94] %. A lack of association with the time between VTE event and sample collection or with the intake of anticoagulant treatment suggests that active PAI-1 levels are sustainable high in VTE patients.
  
  
  CONCLUSIONS
  This case-control study emphasizes the clinical importance of measuring active PAI-1 instead of PAI-1 antigen and identifies active PAI-1 as a potential marker of VTE. Prognostic studies will need to address the clinical significance of active PAI-1 as biomarker.
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Lize
authors.initials: L
authors.lastname: Bollen
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, UZ Leuven, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: Peetermans
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Miet
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Systems and Modeling Unit, Montefiore Institute, University of Liège, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, UZ Leuven, Belgium.
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, UZ Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium. Electronic address: ann.gils@pharm.kuleuven.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D025901:Carboxypeptidase B2 / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D054556:Venous Thromboembolism / Q000097:blood* / Q000175:diagnosis* / Q000378:metabolism; D055815:Young Adult
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D025901:Carboxypeptidase B2
keywords: Fibrinolysis; PAI-1; Sensitivity and specificity; TAFI; Venous Thromboembolism