title: Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood.
abstract: In an in vitro study, anticoagulant and antiplatelet effects of the synthetic, direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride pentahydrate, which shows a high affinity and selectivity towards the enzyme, 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]. The effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on agonist-induced platelet activation in whole blood was studied using flow cytometric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest was less affected 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 thrombin receptor activating peptide, arachidonic acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation of platelets in a concentration-dependent manner. Inactivation of factor Xa by a highly effective and selective inhibitor, and the resulting inhibition of thrombin generation leads to strong anticoagulant and antiplatelet actions. The interference with the coagulation system at the early level of factor Xa is expected to be an effective approach for a successful anticoagulant/antithrombotic therapy.
authors.affiliation: Friedrich Schiller University Jena, Center for Vascular Biology and Medicine Erfurt, Germany. kaiser@zmkh.ef.uni-jena.de
authors.forename: B
authors.initials: B
authors.lastname: Kaiser
authors.forename: W
authors.initials: W
authors.lastname: Jeske
authors.forename: J M
authors.initials: JM
authors.lastname: Walenga
authors.forename: J
authors.initials: J
authors.lastname: Fareed
mesh_terms: D000925:Anticoagulants / Q000378:metabolism; D001792:Blood Platelets / Q000737:chemistry; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D009281:Naphthalenes / Q000378:metabolism*; D019007:P-Selectin / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D010314:Partial Thromboplastin Time; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000096:biosynthesis / Q000187:drug effects; D011422:Propionates / Q000378:metabolism*; D011517:Prothrombin Time; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013918:Thrombin Time
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; D015951:Factor Xa