title: Differential effects of TAK-442, a novel orally active direct factor Xa inhibitor, and ximelagatran, a thrombin inhibitor, on factor V-mediated feedback on coagulation cascade and bleeding.
abstract: Thrombin amplifies the blood coagulation via factor V (FV)-mediated positive feedback loop. We hypothesised that factor Xa (FXa) inhibitors would interfere more gradually with this feedback activation loop than thrombin inhibitors, thereby achieving a better balance between haemostasis and prevention of thrombosis. In this study, we compared the effects of TAK-442, a novel FXa inhibitor, versus ximelagatran, a thrombin inhibitor, on FV-mediated positive feedback, venous thrombosis and bleeding. In normal plasma, TAK-442 delayed the onset of tissue factor-induced thrombin generation and prolonged prothrombin time (PT) with more gradual concentration-response curve than melagatran, the active form of ximelagatran. The effect of melagatran on the onset of thrombin generation decreased in an FVa-concentration-dependent manner in FV-deficient plasma supplemented with FVa. Furthermore, in FV-deficient plasma, the PT-prolonging potency of melagatran was markedly increased with a change in its concentration-response curve from steep to gradual. In the rat venous thrombosis model, TAK-442 (10 mg/kg, p.o.) prevented thrombus formation by 55% with 1.2 times prolongation of PT; a similar effect was observed in ximelagatran-treated (3 mg/kg, p.o.) rats. TAK-442 at 100 mg/kg prolonged PT by only 2.1 times with no change in bleeding time (BT), whereas ximelagatran at 10 mg/kg prolonged PT by 3.9 times and significantly increased BT. These results suggest that the differential effects of the two agents on FV-mediated amplification of thrombin generation may underlie the observation of a wider therapeutic window for TAK-442 than for ximelagatran.
authors.affiliation: Pharmacology Research Laboratories, Takeda Pharmaceutical Company Ltd., Osaka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Konishi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiroe
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000633:toxicity; D000991:Antithrombins / Q000008:administration & dosage* / Q000633:toxicity; D001384:Azetidines / Q000008:administration & dosage* / Q000633:toxicity; D001596:Benzylamines / Q000008:administration & dosage* / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D025461:Feedback, Physiological; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D010743:Phospholipids / Q000097:blood; D011517:Prothrombin Time; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013450:Sulfones / Q000008:administration & dosage* / Q000633:toxicity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D020246:Venous Thrombosis / Q000097:blood / Q000517:prevention & control*
chemical_list: C553657:1-(1-(3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoyl)piperidin-4-yl)tetrahydropyrimidin-2(1H)-one; D000925:Anticoagulants; D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D010743:Phospholipids; D011744:Pyrimidinones; D013450:Sulfones; C426686:ximelagatran; D005165:Factor V; D013925:Thromboplastin; D013917:Thrombin; D015951:Factor Xa