Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood

In an in vitro study, anticoagulant and antiplatelet effects of the synthet ic, direct factor Xa inhibitor DX-9065a,(+)-2S-2-[4-[[(3S)-1-acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochlori de pentahydrate, which shows a high affinity and selectivity towards the en zyme, were investigated. Anticoagulant actions of DX-9065a were studied in human plasma using global clotting assays [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest(R)]. Th e effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on ago nist-induced platelet activation in whole blood was studied using flow cyto metric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest(R) was less affect ed and TT was not influenced. Furthermore, DX-9065a strongly inhibited the generation of thrombin without and after coagulation activation. The factor Xa inhibitor did not affect platelet activation mediated by either thrombi n receptor activating peptide, arachidonic acid or gamma-thrombin, but prev ented tissue factor- and factor Xa-induced activation of platelets in a con centration-dependent manner. Inactivation of factor Xa by a highly effectiv e and selective inhibitor, and the resulting inhibition of thrombin generat ion leads to strong anticoagulant and antiplatelet actions. The interferenc e with the coagulation system at the early level of factor Xa is expected t o be an effective approach for a successful anticoagulant/antithrombotic th erapy. (C) 1999 Lippincott Williams & Wilkins.