Partial versus complete factor VIII inhibition in a mouse model of venous thrombosis

Abstract

IntroductionPartial inhibition of Factor VIII (FVIII) may provide antithrombotic efficacy whilst avoiding excessive anticoagulation. Materials and MethodsWe 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. ResultsBoth 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 0.316μg/mL and ex vivo after administering 0.1mg/kg and higher doses. BO2C11 strongly inhibited FVIII:C, up to 91% at 100μg/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 FeCl3-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±13minutes for TB-402, compared to 28±6minutes for the controls, 51±13minutes for BO2C11 and 55±11minutes for enoxaparin. ConclusionsIn 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.