title: Active site-inactivated factor VIIa prevents thrombosis without increased surgical bleeding: topical and intravenous administration in a rat model of deep arterial injury.
abstract: OBJECTIVE
  The primary event in the procoagulant response after vascular interventions is the tissue factor (TF)-factor VIIa complex formation, which occurs when TF is exposed to the circulating blood by the inflicted trauma. Human recombinant active site-inhibited coagulation factor VIIa (FFR-rFVIIa) binds well to TF but cannot initiate blood coagulation, and should thereby block thrombus formation. This hypothesis was tested with a rat model of arterial thrombosis.
  
  
  METHODS
  In a blinded randomized study, the antithrombotic and antihemostatic effects of FFR-rFVIIa and heparin were evaluated in a rat model of mechanical deep arterial injury. In one arm of the study, FFR-rFVIIa (0.2 mg in 150 microL) or vehicle alone was applied topically at the site of vascular injury. In the other arm, FFR-rFVIIa (4 mg/kg), heparin (1 mg/kg), or vehicle alone was injected intravenously.
  
  
  RESULTS
  FFR-rFVIIa produced a powerful antithrombotic effect after both topical and intravenous administrations (P =.02 and P =.005, respectively) without increasing the surgical bleeding. Heparin prevented thrombosis equally well as FFR-rFVIIa (P =.0007), but doubled the surgical bleeding compared with FFR-rFVIIa (P =.03) and controls (P =.008). In the topical study, the antithrombotic effect was achieved without altering parameters of plasma anticoagulation (prothrombin time and activated partial thromboplastin time) or producing detectable levels of FFR-rFVIIa in plasma.
  
  
  CONCLUSIONS
  In this model FFR-rFVIIa effectively inhibits thrombus formation without the expense of increased surgical bleeding, which indicates the potential of FFR-rFVIIa as an effective and safe strategy for prevention of thrombosis in reconstructive vascular surgery and various forms of percutaneous revascularization.
authors.affiliation: Department of Plastic and Reconstructive Surgery, University Hospital, Malmö, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Söderström
authors.forename: U
authors.initials: U
authors.lastname: Hedner
authors.forename: B
authors.initials: B
authors.lastname: Arnljots
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D016063:Blood Loss, Surgical; D002339:Carotid Arteries / Q000473:pathology / Q000601:surgery*; D015942:Factor VIIa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: D005343:Fibrinolytic Agents; C427263:phenylalanyl-phenylalanyl-arginyl-recombinant FVIIa; D006493:Heparin; D015942:Factor VIIa