Partial versus complete factor VIII inhibition in a mouse model of venous thrombosis
| Autor: | C Long, Marc Jacquemin, Katrien Cludts, Jan Emmerechts, Serena Loyen, I Van Linthout, Marc Hoylaerts, Alexandre Kauskot, Thomas Vanassche, Peter Verhamme |
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| Rok vydání: | 2012 |
| Předmět: |
Venous Thrombosis
Factor VIII medicine.drug_class business.industry Anticoagulant Hematology Pharmacology medicine.disease Monoclonal antibody Thrombosis In vitro Disease Models Animal Mice Venous thrombosis Treatment Outcome Fibrinolytic Agents Anesthesia Antithrombotic medicine Animals Humans Thrombus business Ex vivo |
| Zdroj: | Thrombosis Research. 129:514-519 |
| ISSN: | 0049-3848 |
| DOI: | 10.1016/j.thromres.2011.06.027 |
| Popis: | 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 0.1 mg/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 1 mg/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 (1 mg/kg) inhibited thrombus formation to the same extent as BO2C11 (2 mg/kg) and enoxaparin (5 mg/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. |
| Databáze: | OpenAIRE |
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