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

Abstract

INTRODUCTION:

Partial inhibition of Factor VIII (FVIII) may provide antithrombotic efficacy whilst avoiding excessive anticoagulation.

MATERIALS AND 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: J Emmerechts, T Vanassche, S Loyen, I Van Linthout, K Cludts, A Kauskot, C Long, M Jacquemin, M F Hoylaerts, P Verhamme
• Journal: Thrombosis research (Thromb Res) Vol. 129 Issue 4 Pg. 514-9 (Apr 2012) ISSN: 1879-2472 [Electronic] United States
• PMID: 21777952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Fibrinolytic Agents
• Factor VIII

Topics

• Animals
• Disease Models, Animal
• Factor VIII (antagonists & inhibitors, immunology)
• Fibrinolytic Agents (administration & dosage)
• Humans
• Mice
• Treatment Outcome
• Venous Thrombosis (drug therapy, immunology)