Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

The procoagulant activity of a thrombus is essentially due to clot-associated factor IIa and factor Xa activities.The aim of this review is to underline that specific antithrombin and anti-Xa drugs, such as r-hirudin and DX 9065a, respectively, are complementary, and could be used in combination in clinical trials in patients with acute arterial thrombosis such as coronary syndromes. After standardization of the in-vitro techniques for clot-bound thrombin and clot-associated factor Xa, we have studied the anticoagulant effect of unfractionated heparin and a low-molecular heparin in an in-vitro model. We have confirmed the inability of heparins to inhibit clot-bound thrombin and clot-associated factor Xa. We have compared r-hirudin, a direct thrombin inhibitor, with DX9065a, a direct factor Xa inhibitor. We have observed that r-hirudin inhibited clot-bound thrombin but not clot-bound factor Xa. After r-hirudin treatment interruption, a hypercoagulation rebound has been reported and it could be in relation with the persistence of factor Xa activity in the clot. We have demonstrated that DX9065a inhibits clot-bound factor Xa but does not inhibit clot-bound factor IIa. The complementary effect of DX9065a and r-hirudin is demonstrated in this experimental model. It is likely that several other combinations of drugs may also exhibit an increase of the antithrombotic activity which could be of interest in clinical implication for the treatment of several groups of patients at high risk of arterial thrombosis.