title: Partial versus complete factor VIII inhibition in a mouse model of venous thrombosis.
abstract: BACKGROUND
  Partial inhibition of Factor VIII (FVIII) may provide antithrombotic efficacy whilst avoiding excessive anticoagulation.
  
  
  METHODS
  We studied the anticoagulant effects of a partial (TB-402) and a complete (BO2C11) FVIII-inhibiting monoclonal antibody (MAb) on FVIII, aPTT, thrombin generation and fibrin deposition in a flow chamber model. The antithrombotic efficacy of TB-402 and BO2C11 was compared in a mouse model of venous thrombosis.
  
  
  RESULTS
  Both in vitro and ex vivo, the maximally achievable FVIII inhibition by TB-402 was about 25 to 30%. The degree of inhibition reached a plateau in vitro at 0.316 μg/mL and ex vivo after administering 0.1mg/kg and higher doses. BO2C11 strongly inhibited FVIII:C, up to 91% at 100 μg/mL in vitro, and by 88% ex vivo 1 hour after administering 1mg/kg to the mice. Whereas BO2C11 also markedly prolonged the aPTT and completely inhibited thrombin generation in vitro and ex vivo, the effect of TB-402 on the aPTT and on thrombin generation was limited. Similarly, in a dynamic flow chamber model, TB-402 and BO2C11 inhibited tissue factor-induced human fibrin deposition by 40% and 76%, respectively. In a mouse model of FeCl(3)-induced venous thrombosis, TB-402 (1mg/kg) inhibited thrombus formation to the same extent as BO2C11 (2mg/kg) and enoxaparin (5mg/kg), with a mean (±SD) occlusion time of 51 ± 13 minutes for TB-402, compared to 28 ± 6 minutes for the controls, 51 ± 13 minutes for BO2C11 and 55 ± 11 minutes for enoxaparin.
  
  
  CONCLUSIONS
  In this mouse model of venular thrombosis, partial FVIII inhibition yielded similar antithrombotic effects as nearly complete FVIII inhibition. These preclinical data are indicative of a therapeutic potential of partial FVIII inhibition in the management of venous thromboembolism.
authors.affiliation: Center for Molecular and Vascular Biology, KULeuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Emmerechts
authors.forename: T
authors.initials: T
authors.lastname: Vanassche
authors.forename: S
authors.initials: S
authors.lastname: Loyen
authors.forename: I
authors.initials: I
authors.lastname: Van Linthout
authors.forename: K
authors.initials: K
authors.lastname: Cludts
authors.forename: A
authors.initials: A
authors.lastname: Kauskot
authors.forename: C
authors.initials: C
authors.lastname: Long
authors.forename: M
authors.initials: M
authors.lastname: Jacquemin
authors.forename: M F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: P
authors.initials: P
authors.lastname: Verhamme
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology*; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D005343:Fibrinolytic Agents; D005169:Factor VIII