Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions

Hosokawa, Kazuya; Ohnishi, Tomo̧ko; Miura, Naoki; Sameshima, Hisayo; Koide, Takao; Tanaka, Kenichi A.; Maruyama, Ikuro

doi:10.1016/j.thromres.2013.10.037

Cited by 24 publications

(23 citation statements)

References 49 publications

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“…T-TAS is an automated microchip-based flow chamber system developed for easy and quick assessment of platelet thrombus formation under physiological flow conditions, to approximate thrombus formation in vivo. [35][36][37][38][39][40][41] This system analyzes different thrombus formation processes using a simple procedure comprising two microchips with different thrombogenic surfaces: a platelet (PL) chip specific for measuring primary hemostatic ability and an atheroma (AR) chip for measuring fibrin-rich platelet thrombus formation (►Table 1). The PL chip is coated with type I collagen, and platelets adhere via von Willebrand factor (vWF) to the surface of the collagen and aggregate inside the microchip, leading to occlusion of the microchip capillaries.…”

Section: Measurement Of Thrombogenicity By T-tasmentioning

confidence: 99%

“…T-TAS can assess the influence of antithrombotic agents on platelet activation and coagulation reactions over a collagen or collagen/tissue thromboplastin-coated surface. [35][36][37][38][39][40][41] Here, we compare the scientific principle of T-TAS to other existing platelet function tests and review the use of T-TAS for measuring the antithrombotic effects of several antithrombotic agents in patients with various cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Measurement Of Thrombogenicity By T-tasmentioning

confidence: 99%

Section: Introductionmentioning

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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“…A number of studies have reported its potential utility in assessment of anti-platelet drugs e.g. aspirin, clopidogrel, PAR-1 and PAR-4 antagonists [6][7][8] and anti-thrombotic agents e.g. direct thrombin and factor Xa inhibitors [9].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Total Thrombus-Formation System (T-TAS): application to human and mouse blood analysis

et al. 2018

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The Total Thrombus-formation Analyser System (T-TAS) is a whole blood flow chamber system for the measurement of in vitro thrombus formation under variable shear stress conditions. Our current study sought to evaluate the potential utility of the T-TAS for the measurement of thrombus formation within human and mouse whole blood. T-TAS microchips (collagen, PL chip; collagen/tissue thromboplastin, AR chip) were used to analyse platelet or fibrin-rich thrombus formation respectively. Blood samples from humans (healthy and patients with mild bleeding disorders) and wild-type (WT), mice were tested. Light transmission lumiaggregometer (lumi-LTA) was performed in PRP using several concentrations of ADP, adrenaline, arachidonic acid, collagen, PAR-1 peptide and ristocetin. Thrombus growth (N=22)

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“…31 Similarly, based on a microchip-based flow chamber system, it was demonstrated that antithrombotic effects of another PAR1 inhibitor, SCH79797, was significantly enhanced in the presence of aspirin and a P2Y 12 receptor blocker. 32 …”

Section: Discussionmentioning

confidence: 99%

Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease

Gurbel

Bliden

Turner

et al. 2016

ATVB

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Objective Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report the first human use of a protease-activated receptor-1–based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications of percutaneous coronary interventions. Approach and Results PZ-128 was administered by 1 to 2 hours continuous intravenous infusion (0.01–2 mg/kg) to 31 subjects with coronary artery disease or multiple coronary artery disease risk factors. Safety, antiplatelet efficacy, and pharmacokinetics were assessed at baseline and 0.5, 1, 2, 6, 24 hours, and 7 to 10 days postdosing. The inhibitory effects of PZ-128 on platelet aggregation stimulated by the protease-activated receptor-1 agonist SFLLRN (8 μmol/L) at 30 minutes to 6 hours were dose dependent with 20% to 40% inhibition at 0.3 mg/kg, 40% to 60% at 0.5 mg/kg, and ≥80% to 100% at 1 to 2 mg/kg. The subgroup receiving aspirin in the 0.5 and 1-mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours and 95% to 100% inhibition by 6 hours. The inhibitory effects of 0.5 mg/kg PZ-128 were reversible with 50% recovery of aggregation to SFLLRN by 24 hours. There were no significant effects of PZ-128 on aggregation induced by AYPGKF, ADP, or collagen, indicating that the observed effects were specific to protease-activated receptor-1. The plasma half-life was 1.3 to 1.8 hours, and PZ-128 was nondetectable in urine. There were no effects on bleeding, coagulation, clinical chemistry, or ECG parameters. Conclusions PZ-128 is a promising antiplatelet agent that provides rapid, specific, dose dependent, and reversible inhibition of platelet protease-activated receptor-1 through a novel intracellular mechanism. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.

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Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions

Cited by 24 publications

References 49 publications

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

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

Evaluation of the Total Thrombus-Formation System (T-TAS): application to human and mouse blood analysis

Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease

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