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,...

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Published in:	Thrombosis research Vol. 129; no. 4; pp. 514 - 519
Main Authors:	Emmerechts, J, Vanassche, T, Loyen, S, Van Linthout, I, Cludts, K, Kauskot, A, Long, C, Jacquemin, M, Hoylaerts, M.F, Verhamme, P
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-04-2012 Elsevier
Subjects:	Animals Biological and medical sciences Blood and lymphatic vessels Blood. Blood coagulation. Reticuloendothelial system Cardiology. Vascular system Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Factor VIII - antagonists & inhibitors Factor VIII - immunology Fibrinolytic Agents - administration & dosage Hematology, Oncology and Palliative Medicine Humans Medical sciences Mice Pharmacology. Drug treatments Treatment Outcome Venous Thrombosis - drug therapy Venous Thrombosis - immunology Vascular disease Vertebrata Mammalia Mouse Animal Rodentia Factor VIII Cardiovascular disease Venous thrombosis Comparative study Venous disease
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Summary:	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 0.1 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 FeCl3 -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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0049-3848 1879-2472
DOI:	10.1016/j.thromres.2011.06.027