Inhibitory mechanisms of very low–dose rivaroxaban in non–ST-elevation myocardial infarction

Münzer, Patrick; Alnaggar, Nada; Geue, Sascha; Tegtmeyer, Roland; Rath, Dominik; Droppa, Michal; Seizer, Peter; Heitmeier, Stefan; Heemskerk, Johan W. M.; Jennings, Lisa K.; Storey, Robert F.; Angiolillo, Dominick J.; Rocca, Bianca; Spronk, Henri M. H.; Cate, Hugo Ten; Gawaz, Meinrad; Geisler, Tobias

doi:10.1182/bloodadvances.2017013573

Cited by 39 publications

(29 citation statements)

References 37 publications

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“…Using our multiparameter microfluidics assay 45 , we are the first to demonstrate that rivaroxaban treatment results in reduced in vitro thrombus growth and height using both mouse and human blood. These data extent work by others who demonstrated that rivaroxaban reduces in vitro thrombus formation in human blood [46][47][48] . Our data show a trend towards a reduced thrombus contraction in vitro with rivaroxaban.…”

Section: Discussionsupporting

confidence: 85%

Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery

Mastenbroek

Karel

Nagy

et al. 2020

Sci Rep

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While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.

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Section: Discussionsupporting

confidence: 85%

Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery

Mastenbroek

Karel

Nagy

et al. 2020

Sci Rep

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“…Borst et al showed that fibrin-rich platelet thrombus formation in AR chip was significantly inhibited by triple antiplatelet therapy with aspirin, clopidogrel, and very low-dose rivaroxaban in patients with non-ST-elevation myocardial infarction post-PCI. 67 Conventionally, the antiplatelet function of aspirin and clopidogrel (reactivity to agonist) and the anticoagulant ability of rivaroxaban have been measured separately. However, all of these drugs are used for the same purpose: to inhibit thrombosis.…”

Section: Comparison Of Methods For Various Platelet Function Assessmementioning

confidence: 99%

Total Thrombus-Formation Analysis System (T-TAS): Clinical Application of Quantitative Analysis of Thrombus Formation in Cardiovascular Disease

Kaikita

Hosokawa

Dahlen³

et al. 2019

Thromb Haemost

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Various antithrombotic agents are clinically used to inhibit the cascade of arterial or venous thrombosis in cardiovascular diseases. Dual antiplatelet therapy with aspirin and P2Y12 inhibitors is prescribed in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Direct oral anticoagulants (DOACs) are widely used for the prevention or treatment of thromboembolism in patients with atrial fibrillation (AF) and venous thromboembolism. However, there has been no definitive tool to simultaneously monitor the antithrombotic effects of these drugs. The Total Thrombus-Formation Analysis System (T-TAS), a microchip-based flow chamber system that mimics in vivo conditions for evaluating whole blood thrombogenicity, was developed for the quantitative analysis of thrombus formation in whole blood specimens. The utility of T-TAS has been evaluated in CAD patients treated with antiplatelet therapies. The T-TAS PL chip area under the flow pressure curve (AUC) accurately assesses primary hemostasis and is sensitive to the therapeutic effects of various antiplatelet therapies. In addition, low AUC results are a significant predictor of periprocedural bleeding events in CAD patients undergoing PCI. The T-TAS AR chip AUC result is useful for assessing the efficacy of DOACs and warfarin in AF patients undergoing catheter ablation, and it is also a potential independent predictor of periprocedural bleeding events and avoidance of thrombosis in patients having undergone total knee arthroplasty. In conclusion, T-TAS is a useful index for evaluating the total antithrombotic effects of combination antithrombotic agents in patients with various cardiovascular diseases.

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“…Even at the very low dose of 2.5 mg b.i.d., rivaroxaban reduced platelet-dependent thrombin generation and coagulation-dependent thrombus-formation in patients treated with aspirin plus P2Y 12 inhibitor, whereas pure platelet-dependent thrombus formation was not affected 14 . Indeed, FXa inhibition appears to have no significant effect on platelets 14 including in response to adenosine diphosphate, collagen, thrombin receptor-activating peptide, or arachidonic acid 15 . Apixaban may therefore favourably enhance endogenous fibrinolysis through reduction in platelet-dependent and non-platelet-dependent thrombin generation, which directly impact on the structure and stability of the thrombus and its resistance to fibrinolysis.…”

Section: Discussionmentioning

confidence: 87%

“…Blood spiked with rivaroxaban ex vivo showed reduced platelet aggregation induced by tissue factor and to a lesser extent induced by thrombin 12 , 13 . Even at the very low dose of 2.5 mg b.i.d., rivaroxaban reduced platelet-dependent thrombin generation and coagulation-dependent thrombus-formation in patients treated with aspirin plus P2Y 12 inhibitor, whereas pure platelet-dependent thrombus formation was not affected 14 . Indeed, FXa inhibition appears to have no significant effect on platelets 14 including in response to adenosine diphosphate, collagen, thrombin receptor-activating peptide, or arachidonic acid 15 .…”

Section: Discussionmentioning

confidence: 92%

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation

et al. 2019

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Aims Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). Methods and results In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591–2300) vs. 2758 (2014–3502) vs. 2135 (1752–2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0–61.0) vs. warfarin 61.0 (57.0–62.0) vs. aspirin 61.0 (59.0–61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779–2738) vs. on-treatment 1882 (1607–2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). Conclusion Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.

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Inhibitory mechanisms of very low–dose rivaroxaban in non–ST-elevation myocardial infarction

Cited by 39 publications

References 37 publications

Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery

Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery

Total Thrombus-Formation Analysis System (T-TAS): Clinical Application of Quantitative Analysis of Thrombus Formation in Cardiovascular Disease

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation

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