title: Synthetic selective inhibitors of coagulation factor Xa strongly inhibit thrombin generation without affecting initial thrombin forming time necessary for platelet activation in hemostasis.
abstract: DX-9065a and JTV-803, synthetic selective inhibitors of activated factor X (FXa), have recently been demonstrated as strongly effective antithrombotic agents in animal thrombosis models, yet with a low risk of bleeding. The aim of the present study was to elucidate these characteristics. Using a chromogenic assay with purified coagulation factors, 73.9% of thrombin generation was suppressed by the addition of DX-9065a (0.20 microm) and 75.7% by JTV-803 (0.18 microm). Inhibition by argatroban (0.19 microm) was less (36.0%) and initial thrombin forming time (T50), the time required to generate 50% thrombin activity in vitro, which is considered important for platelet aggregation in hemostasis, was significantly prolonged by argatroban. In contrast, DX-9065a and JTV-803 had no apparent influence on T50, suggesting that initial thrombin was formed immediately, as in the control. We also investigated platelet aggregation in defibrinated plasma induced by tissue factor, to clarify whether initial thrombin contributes to hemostasis. Aggregation was not affected by the addition of either FXa inhibitor, whereas it was significantly reduced by argatroban. Our results suggest that initial thrombin, which is formed despite the presence of a FXa inhibitor, can activate platelets. We concluded that DX-9065a and JTV-803 are able to inhibit thrombin generation significantly without affecting the formation of initial thrombin for platelet activation, which may contribute to hemostasis through the preservation of normal bleeding time.
authors.affiliation: Departments of Internal Medicine, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan. iekom@hokuiryo-u.ac.jjp
authors.forename: M
authors.initials: M
authors.lastname: Ieko
authors.forename: T
authors.initials: T
authors.lastname: Tarumi
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: S
authors.initials: S
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Nakabayashi
authors.forename: T
authors.initials: T
authors.lastname: Koike
mesh_terms: D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001792:Blood Platelets; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D000925:Anticoagulants; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010875:Pipecolic Acids; D010880:Piperidines; D011422:Propionates; D011725:Pyridines; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D001120:Arginine; D013917:Thrombin; C031942:argatroban