title: Persistent high factor VIII activity leading to increased thrombin generation - a prospective cohort study.
abstract: BACKGROUND
  A persistently elevated level of factor VIII (FVIII) is an independent risk factor for venous thromboembolism (VTE). Although the pathophysiology of VTE is unclear, the involvement of thrombin generation (TG) has been postulated. Consequently this study was designed to (i) investigate the relationships between FVIII, Thrombin generation test (TGT) parameters and D-dimer in VTE patients, (ii) determine whether elevated levels of FVIII and increased TG in these patients are transient or sustained.
  
  
  METHODS
  After an initial period of anticoagulation had been completed 91 VTE patients and 52 healthy controls were recruited. FVIII levels were determined by one-stage clotting (FVIII:C) and chromogenic (FVIII:Ch) assays. The potential to generate thrombin was measured using the Calibrated Automated Thrombogram (CAT) and D-Dimer was by immuno-turbidometric assay.
  
  
  RESULTS
  Patients' FVIII:C levels and FVIII:Ch, exhibited good agreement (rs=0.94; p<0.0001), although FVIII:C exhibited a mean bias of -6%. FVIII:Ch show a significant correlation with TGT Peak Thrombin (rs=0.30; p=0.004) and Peak Thrombin was found to be significantly higher (p=0.04) in patients with FVIII>200 iu/dL. Furthermore elevated levels of FVIII and increased thrombin generation parameters appeared to be consistent over time.
  
  
  CONCLUSIONS
  Our data suggests that high FVIII leading to increased TG confers a significant risk of recurrent VTE and therefore we speculate that these patients may benefit from prolonged anticoagulation therapy.
authors.affiliation: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Ryland
authors.forename: A S
authors.initials: AS
authors.lastname: Lawrie
authors.forename: I J
authors.initials: IJ
authors.lastname: Mackie
authors.forename: S J
authors.initials: SJ
authors.lastname: Machin
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005169:Factor VIII / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013917:Thrombin / Q000032:analysis*; D006113:United Kingdom / Q000453:epidemiology; D054556:Venous Thromboembolism / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D005169:Factor VIII; D013917:Thrombin