Effects of Direct Factor Xa Inhibitor, YM150, on Clot Formation and Clot Lysis In Vitro Compared with Other Anticoagulants.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3153-3153 ◽  
Author(s):  
Seiji Kaku ◽  
Ken-ichi Suzuki ◽  
Toshiyuki Funatsu ◽  
Minori Saitoh ◽  
Hiroyuki Koshio ◽  
...  
Keyword(s):  
Human Plasma ◽  
Statistical Significance ◽  
Factor Xa ◽  
Clot Formation ◽  
Thrombin Inhibitor ◽  
Clot Lysis ◽  
Factor Xa Inhibitor ◽  
Dependent Manner ◽  
Direct Factor ◽  
Clotting Time

Abstract The objective of this study was to evaluate the effects of direct factor Xa inhibitor, YM150 and its major in vivo metabolite, YM-222714, on clot formation and clot lysis compared with other anticoagulants, such as a direct thrombin inhibitor (melagatran), a pentasaccharide (fondaparinux), low molecular weight heparin (enoxaparin) and unfractionated heparin. To assess clot lysis, the tissue plasminogen activator (tPA)-induced clot lysis assay was used with human plasma triggered by low and high levels of tissue factor (TF). Under low TF conditions, clot formation was completely prevented by melagatran at 1 μmol/L, by fondaparinux at all concentrations examined (0.1 to 1 μg/mL), by enoxaparin at 0.3 and 1 IU/mL and by heparin at 0.1 and 0.3 U/mL. Even under high TF conditions, 0.3 U/mL heparin prevented any clot formation. Although melagatran, fondaparinux, enoxaparin, and heparin potently prevented plasma clot formation under low TF conditions, under high TF conditions they were less effective at prolonging the clotting time. Under both low and high TF conditions, YM150 and YM-222714 prolonged the clotting time in a concentration dependent manner at concentrations between 0.3 and 3 μmol/L. YM150 and YM-222714 significantly accelerated clot lysis under both low and high TF conditions, but their effects were most evident under high TF conditions. Lower concentrations of melagatran (0.1 and 0.3 μmol/L) enhanced clot lysis under low TF conditions, but under high TF conditions, enhancement of clot lysis required higher melagatran concentrations (0.3 μmol/L or more). Under high TF conditions, fondaparinux enhanced clot lysis only at the highest concentration tested (1 μg/mL). Enoxaparin and heparin enhanced clot lysis under low TF conditions at the lowest test concentrations (0.1 IU/mL and 0.03 U/mL, respectively). Both also enhanced clot lysis under high TF conditions, but their effect reached statistical significance only at higher concentrations (1 IU/mL and 0.1 U/mL, respectively). These results suggested that direct factor Xa inhibitors, YM150 and YM-222714, exert stable anticoagulant effects independently of TF concentration. Both inhibitors enhanced tPA-induced fibrinolysis in human plasma clotted via the extrinsic coagulation pathway. Useful characteristics of YM150 and YM-222714, such as a linear dose response and reliable anticoagulation independent of TF concentration, may lead to the creation of an anticoagulant that is easier to use in the clinical setting than existing products. Potentially beneficial antithrombotic effects, which can be promoted by accelerating endogenous fibrinolytic pathways, may further aid in the prevention or treatment of thrombosis.

Tranexamic Acid Failed to Reverse the Anticoagulant Effect and Bleeding by an Oral Direct Factor Xa Inhibitor Edoxaban

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 92-95 ◽  
Author(s):  
Yuko Honda ◽  
Taketoshi Furugohri ◽  
Yoshiyuki Morishima
Keyword(s):  
Tranexamic Acid ◽  
Bleeding Time ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Anticoagulant Effect ◽  
Clot Lysis ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Supratherapeutic Dose ◽  
Antifibrinolytic Agent

Background/Aims: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. Methods: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined. Results: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma. Conclusion: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats.

Comparison of YM150, an Oral, Direct Factor Xa Inhibitor, with Other Antithrombotic Agents in Rodent Venous and Arterial Thrombosis Models.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3155-3155 ◽  
Author(s):  
Minori Saitoh ◽  
Seiji Kaku ◽  
Toshiyuki Funatsu ◽  
Hiroyuki Koshio ◽  
Tsukasa Ishihara ◽  
...  
Keyword(s):  
Filter Paper ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Thrombin Inhibitor ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Antithrombotic Effect ◽  
Arterial Thrombus

Abstract YM150, an oral, direct factor Xa inhibitor, is currently being evaluated in Phase II studies as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery. In the present study, we compared the antithrombotic effect of YM150 with the effects of antithrombin-dependent indirect factor Xa inhibitors, enoxaparin and fondaparinux, and a direct thrombin inhibitor, ximelagatran, in ferric chloride (FeCl3)-induced venous and arterial thrombosis models in rats. We also evaluated the bleeding time in a rat tail transection model. Prior to any experimentation, male Sprague-Dawley rats, which had been fasting for at least 12 h, were anesthetized with urethane (1 g/kg, i.p.) or sodium pentobarbital (50 mg/kg, i.p.). YM150 and ximelagatran were administered intra-duodenally, and both enoxaparin and fondaparinux were given subcutaneously, 30 min prior to induction of thrombus or tail transection. All animals were kept warm with a heating pad during the experiments. Venous and arterial thromboses were produced, respectively, by the 5 min application of 8% FeCl3 soaked filter paper to the external surface of the inferior vena cava and 35% FeCl3 soaked filter paper to the abdominal aorta. The venous thrombosis model was supplemented by using a silk thread venous stenosis. To measure bleeding time, the tail was transected 5 mm from its tip. Blood was carefully blotted each 30 sec with a filter paper. Once a blood stain was observed, we defined bleeding as blood flow sustained over 30 sec. Bleeding time was defined as the sum of the bleeding periods during the 60 min observation in each animal. Administration of intra-duodenal YM150 significantly inhibited both venous and arterial thrombus formation at doses of 10 mg/kg or greater, and 3 mg/kg or greater, respectively. This indicated that YM150 promoted an antithrombotic effect at similar dose ranges for venous and arterial thromboses. In contrast, YM150 did not prolong the bleeding time at doses up to 30 mg/kg. Venous thrombus formation was inhibited by subcutaneous enoxaparin at doses of 100 IU/kg or greater and fondaparinux at doses of 0.03 mg/kg or greater. Arterial thrombus formation was inhibited by subcutaneous administration of 1000 IU/kg enoxaparin and 3 mg/kg fondaparinux. The results indicated that 10–100 times higher doses of these antithrombotics were needed to inhibit arterial thrombosis. Furthermore, enoxaparin at doses of 300 IU/kg or greater and fondaparinux at doses of 1 mg/kg or greater, significantly prolonged the bleeding time, suggesting that these two medications may be associated with increased risk of hemorrhage at concentrations used to prevent arterial thrombosis. At doses of 1 mg/kg or greater, intra-duodenal ximelagatran inhibited both venous and arterial thrombus formation. The dose-response curve for ximelagatran tended to be steeper than that for other anticoagulants tested. Antithrombotic doses of ximelagatran (1 mg/kg or greater), produced similar prolongations of bleeding time as those seen with administration of enoxaparin and fondaparinux. In conclusion, YM150, an oral direct factor Xa inhibitor, shows promise as an antithrombotic drug with potentially wider safety margins than current antithrombin-dependent factor Xa inhibitors and a thrombin inhibitor.

Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system

2011 ◽  
Vol 106 (12) ◽  
pp. 1076-1083 ◽  
Author(s):  
Nobutoshi Sugiyama ◽  
Yoshiyuki Morishima ◽  
Toshiro Shibano ◽  
Taketoshi Furugohri
Keyword(s):  
Human Plasma ◽  
Negative Feedback ◽  
Protein C ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Direct Factor

SummaryThere is increasing concern that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. Previously, we demonstrated that at certain doses a direct thrombin inhibitor, melag-atran, worsens the coagulation status induced by tissue factor (TF) in-jection in a rat model. We utilised an in vitro thrombin generation (TG) assay to determine if direct thrombin inhibitors could enhance TG in human plasma, and whether inhibition of the negative-feedback sys-tem [thrombin-thrombomodulin (TM)-protein C] contributed to the TG enhancement. TG in human plasma was assayed by means of the cali-brated automated thrombography. In this assay, direct factor Xa (FXa) inhibitors such as edoxaban and antithrombin (AT)-dependent anti-coagulants such as heparin did not increase, but simply suppressed TG. AT-independent thrombin inhibitors (melagatran, lepirudin, and active site blocked thrombin (IIai)) increased peak levels of TG (2.0, 1.6, and 2.2-fold, respectively) in the presence of 12 nM recombinant human soluble TM (rhsTM). Melagatran and lepirudin at higher concentrations began to suppress TG. In the absence of rhsTM, the enhancement of peak TG by melagatran decreased to 1.2-fold. Furthermore, in protein C-deficient plasma, AT-independent thrombin inhibitors failed to enhance TG. In addition, a human protein C neutralising antibody increased the peak height of TG in the presence of rhsTM. These results suggest that AT-independent thrombin inhibitors may activate throm-bogenesis by suppression of the thrombin-induced negative-feedback system through inhibition of protein C activation. In contrast, direct FXa inhibitors are more useful than AT-independent thrombin inhibitors in terms of lower possibility of activation of the coagulation pathway.

Anticoagulant Activity of β2-Glycoprotein I Is Potentiated by a Distinct Subgroup of Anticardiolipin Antibodies

1992 ◽  
Vol 68 (03) ◽  
pp. 297-300 ◽  
Author(s):  
Monica Galli ◽  
Paul Comfurius ◽  
Tiziano Barbui ◽  
Robert F A Zwaal ◽  
Edouard M Bevers
Keyword(s):  
Human Plasma ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Type A ◽  
Lipid Vesicles ◽  
Dependent Manner ◽  
Type B ◽  
Distinct Subgroup ◽  
Glycoprotein I ◽  
Thrombin Formation

SummaryPlasmas of 16 patients positive for both IgG anticardiolipin (aCL) antibodies and lupus anticoagulant (LA) antibodies were subjected to adsorption with liposomes containing cardiolipin. In 5 of these plasmas both the anticardiolipin and the anticoagulant activities were co-sedimented with the liposomes in a dose-dependent manner, whereas in the remaining cases only the anticardiolipin activity could be removed by the liposomes, leaving the anticoagulant activity (LA) in the supernatant plasma. aCL antibodies purified from the first 5 plasmas were defined as aCL-type A, while the term aCL-type B was used for antibodies in the other 11 plasmas, from which 2 were selected for this study.Prolongation of the dRVVT was produced by affinity-purified aCL-type A antibodies in plasma of human as well as animal (bovine, rat and goat) origin. aCL-type B antibodies were found to be devoid of anticoagulant activity, while the corresponding supernatants containing LA IgG produced prolongation of the dRVVT only in human plasma.These anticoagulant activities of aCL-type A and of LA IgG's were subsequently evaluated in human plasma depleted of β2-glycoprotein I (β2-GPI), a protein which was previously shown to be essential in the binding of aCL antibodies to anionic phospholipids. Prolongation of the dRVVT by aCL-type A antibodies was abolished using β2-GPI deficient plasma, but could be restored upon addition of β2-GPI. In contrast, LA IgG caused prolongation of the dRVVT irrespective of the presence or absence of β2-GPI.Since β2-GPI binds to negatively-charged phospholipids and impedes the conversion of prothrombin by the factor Xa/Va enzyme complex (Nimpf et al., Biochim Biophys Acta 1986; 884: 142–9), comparison was made of the effect of aCL-type A and aCL-type B antibodies on the rate of thrombin formation in the presence and absence of β2-GPI. This was measured in a system containing highly purified coagulation factors Xa, Va and prothrombin and lipid vesicles composed of 20 mole% phosphatidylserine and 80 mole% phosphatidylcholine. No inhibition on the rate of thrombin formation was observed with both types of aCL antibodies when either β2-GPI or the lipid vesicles were omitted. Addition of β2-GPI to the prothrombinase assay in the presence of lipid vesicles causes a time-dependent inhibition which was not affected by the presence of aCL-type B or non-specific IgG. In contrast, the presence of aCL-type A antibodies dramatically increased the anticoagulant effect of β2-GPI. These data indicate that the anticoagulant activity of aCL-type A antibodies in plasma is mediated by β2-GPI.

Pharmacokinetics, Biotransformation, and Mass Balance of Edoxaban, a Selective, Direct Factor Xa Inhibitor, in Humans

2012 ◽  
Vol 40 (12) ◽  
pp. 2250-2255 ◽  
Author(s):  
Mohinder S. Bathala ◽  
Hiroshi Masumoto ◽  
Toshihiro Oguma ◽  
Ling He ◽  
Chris Lowrie ◽  
...  
Keyword(s):  
Mass Balance ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor
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