Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models

Furugohri, Taketoshi; Shiozaki, Yoko; Muramatsu, Shigeki; Honda, Yuko; Matsumoto, Chizuru; Isobe, Keisuke; Sugiyama, Nobutoshi

doi:10.1016/j.ejphar.2005.03.009

Cited by 37 publications

(25 citation statements)

References 32 publications

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“…All three DTIs produced a paradoxical increase in peak and slope of thrombin generation at low therapeutic concentrations with hirudin giving the strongest pattern. This paradoxical effect of DTIs on thrombin generation at low therapeutic concentrations in vitro and possibly in vivo has been noted before, and potential mechanisms involve suppression of negative feedback inhibition of thrombin generation by activated protein C [15,27] and presence of a2-macroglobulin [28]. In the mid-to-high concentration range, whereas hirudin and dabigatran concentrationdependently inhibited peak and slope, bivalirudin had little to no effect.…”

Section: Discussionmentioning

confidence: 89%

Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro

Wang

et al. 2013

Blood Coagulation &Amp; Fibrinolysis

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Section: Discussionmentioning

confidence: 89%

Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro

Wang

et al. 2013

Blood Coagulation &Amp; Fibrinolysis

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“…24,28 TGA has further been correlated with thrombus formation in multiple animal thrombosis models. 27,29,44 Thus, the procoagulant alterations identified in these ex vivo assays are expected to correspond to increased thrombotic tendency in vivo. This is illustrated by the increased thrombus burden seen in this study using the in vivo IVC ligation model.…”

Section: Discussionmentioning

confidence: 99%

Disease Severity Correlates with Thrombotic Capacity in Experimental Nephrotic Syndrome

Kerlin

Waller

Sharma

et al. 2015

Journal of the American Society of Nephrology

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Thrombotic disease, a major life-threatening complication of nephrotic syndrome, has been associated with proteinuria and hypoalbuminemia severity. However, it is not fully understood how disease severity correlates with severity of the acquired hypercoagulopathy of nephrotic syndrome. Without this knowledge, the utility of proteinuria and/or hypoalbuminemia as biomarkers of thrombotic risk remains limited. Here, we show that two well established ex vivo hypercoagulopathy assays, thrombin generation and rotational thromboelastometry, are highly correlated with proteinuria and hypoalbuminemia in the puromycin aminonucleoside and adriamycin rat models of nephrotic syndrome. Notably, in the puromycin aminonucleoside model, hyperfibrinogenemia and antithrombin deficiency were also correlated with proteinuria severity, consistent with reports in human nephrotic syndrome. Importantly, although coagulation was not spontaneously activated in vivo with increasing proteinuria, vascular injury induced a more robust thrombotic response in nephrotic animals. In conclusion, hypercoagulopathy is highly correlated with nephrotic disease severity, but overt thrombosis may require an initiating insult, such as vascular injury. Our results suggest that proteinuria and/or hypoalbuminemia could be developed as clinically meaningful surrogate biomarkers of hypercoagulopathy to identify patients with nephrotic syndrome at highest risk for thrombotic disease and potentially target them for anticoagulant pharmacoprophylaxis.

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“…18 Interestingly, direct thrombin inhibitors, such as melagatran and dabigatran, also showed a concentration-dependent inhibition of thrombin generation over the whole range in the absence of thrombomodulin or in protein C-deficient plasma but increased thrombin generation at low concentrations in the presence of thrombomodulin. 18,19 This suggests that low concentrations of a direct thrombin inhibitor may partly suppress the negative feedback by activated protein C. However, whether this effect will influence clinical efficacy or safety remains to be investigated. …”

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confidence: 99%

Rivaroxaban: A New Oral Factor Xa Inhibitor

Perzborn

Roehrig

Straub

et al. 2010

ATVB

238

153

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Abstract-Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has Ͼ10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC 50 ], Ͼ20 mol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K i ], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k on ], 1.7ϫ10 7 mol/L Ϫ1 s Ϫ1 ) and reversibly (kinetic dissociation rate constant [k off ], 5ϫ10 Ϫ3 s Ϫ1 ). By inhibiting prothrombinase complex-bound (IC 50 , 2.1 nmol/L) and clot-associated factor Xa (IC 50 , 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5-to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile. (Arterioscler Thromb Vasc Biol. 2010;30:376-381.) Key Words: anticoagulants Ⅲ blood coagulation Ⅲ factor Xa Ⅲ rivaroxaban Ⅲ venous thromboembolism F actor Xa is a coagulation factor that acts at the convergence point of the intrinsic and extrinsic pathways in the blood coagulation system. 1 It catalyzes the cleavage of prothrombin and, therefore, is critical for thrombin generation (Figure 1). 1,2 Indirect factor Xa inhibitors, such as fondaparinux and biotinylated idraparinux, exert their thrombotic effect by binding to antithrombin; therefore, their efficacy depends on the circulating level of antithrombin. They are parenteral agents and cannot be administered orally. 3 Rivaroxaban is the first direct factor Xa inhibitor to be licensed (in the European Union 4 and several other countries) for the prevention of venous thromboembolism (VTE) in adult patients after elective hip or knee arthroplasty. Studies of rivaroxaban in the treatment of VTE, prevention of cardiovascular events in patients with acute coronary syndrome, prevention of stroke in those with atrial fibrillation, and prevention of VTE in hospitalized medically ill patients are ongoing (Supplementary Table I, available at http:// atvb.ahajournals.org). Other direct factor Xa inhibitors are also in advanced development; apixaban and edoxaban (DU-176b) are undergoing phase III study, whereas betrixaban and YM150 have passed clinical phase II testing. This review discusses the properties of rivaroxaban and findings from clinical trials. See accompanying article on page 369 Pharmacological PropertiesCompound C...

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Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models

Cited by 37 publications

References 32 publications

Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro

Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro

Disease Severity Correlates with Thrombotic Capacity in Experimental Nephrotic Syndrome

Rivaroxaban: A New Oral Factor Xa Inhibitor

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