title: Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects.
abstract: BACKGROUND
  In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study.
  
  
  RESULTS
  Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2.
  
  
  CONCLUSIONS
  During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.
authors.affiliation: Department of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam, Netherlands.
authors.forename: P W
authors.initials: PW
authors.lastname: Friederich
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: K A
authors.initials: KA
authors.lastname: Bauer
authors.forename: G P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: W E
authors.initials: WE
authors.lastname: Rote
authors.forename: D
authors.initials: D
authors.lastname: Breederveld
authors.forename: T
authors.initials: T
authors.lastname: Keller
authors.forename: M
authors.initials: M
authors.lastname: Spataro
authors.forename: S
authors.initials: S
authors.lastname: Barzegar
authors.forename: H R
authors.initials: HR
authors.lastname: Büller
mesh_terms: D000328:Adult; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005164:Factor IX / Q000187:drug effects / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology*; D005170:Factor X / Q000187:drug effects / Q000378:metabolism; D015801:Helminth Proteins / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D015801:Helminth Proteins; D011994:Recombinant Proteins; C400226:anti-coagulant protein C2, Ancylostoma caninum; D005164:Factor IX; D005170:Factor X; D015942:Factor VIIa; D013917:Thrombin