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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3235-3240
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Antithrombotic effects of controlled inhibition of factor VIII
with a partially inhibitory human monoclonal antibody in a murine vena
cava thrombosis model
Inderjit Singh,
Alberto Smith,
Beatrijs Vanzieleghem,
Désiré Collen,
Kevin Burnand,
Jean-Marie Saint-Remy, and
Marc Jacquemin
From the Center for Molecular and Vascular Biology,
University of Leuven, Belgium; and Academic Department of Surgery, St
Thomas' Hospital, London, United Kingdom.
The human monoclonal antibody mAb-LE2E9 partially inactivates human
factor VIII (FVIII), leaving approximately 10% residual activity. The
antithrombotic efficacy of the antibody was evaluated in mouse models
of inferior vena cava thrombosis. Thrombi were induced in wild-type
mice given either the antibody or saline. No thrombi occurred in any of
8 mice treated with mAb-LE2E9, whereas 6 of 8 control mice developed
thrombi (P = .007). Treatment with mAb-LE2E9 did not
result in a severe bleeding phenotype: a tail-cutting experiment that
resulted in death of C57BL/6 FVIII-deficient (FVIII /)
mice did not cause hemorrhagic death in mice treated with mAb-LE2E9. To
evaluate the antithrombotic effect of mAb-LE2E9 in presence of human
FVIII, thrombus formation was induced in FVIII/ mice
reconstituted intravenously with recombinant human FVIII (rhFVIII) or
rhFVIII preincubated with mAb-LE2E9. Only 1 of 9 mice produced a
thrombus in the rhFVIII/antibody complex-treated group, compared with
7 of 9 in the control group (P = .015).
FVIII/ mice were also reconstituted with rhFVIII and
then injected with either mAb-LE2E9 or saline. One of 14 mice in the
group treated with the antibody developed a thrombus, compared with 10 of 14 in the control group (P = .001). The thrombi
occurring in antibody-treated animals were smaller than in controls
(P < .01). All animals survived, and there were no
bleeding complications. Thus, the mAb-LE2E9 antibody inhibits
thrombosis without causing an overt bleeding tendency.
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