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Vol. 283, Issue 1, 16-22, 1997
Sanofi Recherche, Toulouse, France
Factor Xa, as with thrombin, binds to the clot and contributes to the
propensity of thrombi to activate the coagulation system. The aim of
this work was to compare the extent of prothrombinase inhibition
produced by two factor Xa inhibitors: the antithrombin III-dependent
synthetic pentasaccharide (SR 90107/Org 31540) and DX-9065A, a direct
factor Xa inhibitor. When incubated together with prothrombin, factor
Xa, phospholipids, antithrombin III and calcium, clots formed from
human plasma exhibited a prothrombinase activity as measured through
fragment 1-2 (F1+2) generation. Ten washes of the clot
were required to achieve complete removal of unbound factor Xa. The
absence of F1+2 generation brought about by washed clots in
buffer when factor V was omitted, or in the presence of annexin V,
indicated that they contained bound factor Xa and phospholipids but no
factor V/Va. In all tested experimental conditions, clot-bound-factor
Xa-induced F1+2 generation was inhibited by SR 90107/AT and
DX-9065A with IC50 in the same range of concentrations (0.5 µM). In contrast, the inhibition of prothrombinase formed with factor
Xa, factor Va phospholipids and calcium in buffer was observed at
significantly lower concentrations of DX-9065A than of SR 90107/AT
(respective IC50 concentrations: 0.1 and 70 µM).
In vivo, fibrin accretion onto a preformed thrombus as
well as venous thrombosis induced in the jugular vein of rabbits was
inhibited by SR 90107 and DX-9065A in the same range of concentrations
therefore showing that inhibition of clot-bound factor Xa is a
predominant factor for the antithrombotic activity of both direct and
indirect inhibitors for factor Xa.
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