Total Thrombus‐formation Analysis System Predicts Periprocedural Bleeding Events in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention

Oimatsu, Yu; Kaikita, Koichi; Ishii, Masanobu; Mitsuse, Tatsuro; Ito, Miwa; Arima, Yuichiro; Sueta, Daisuke; Takahashi, Aya; Iwashita, Satomi; Yamamoto, Eiichiro; Kojima, Sunao; Hokimoto, Seiji; Tsujita, Kenichi

doi:10.1161/jaha.116.005263

Cited by 25 publications

(21 citation statements)

References 29 publications

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“…Interestingly, the extent of inhibition of thrombus formation parameters with VLD rivaroxaban in addition to DAPT in this study was in the range of predicting low bleeding risk using T-TAS, as reported recently. 37 In conclusion, the present study demonstrates consistent effects by addition of rivaroxaban at an ex vivo dose equivalent to the VLD (2.5 mg) oral regimen to standard DAPT with both clopidogrel and ticagrelor on markers of TG and shear-dependent thrombus formation in real-world non-ST-elevation patients with ACS. There were no additional effects of VLD rivaroxaban in combination with DAPT on platelet aggregation induced by major platelet agonists (via protease-activated receptor 1, P2Y 12 , and GPVI) and on collagen-dependent thrombus formation under high arterial shear rates, using the PL-chip.…”

Section: Discussionsupporting

confidence: 64%

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

et al. 2018

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Very low-dose (VLD) factor Xa (FXa) inhibition, in combination with acetylsalicylic acid (ASA) and clopidogrel, is associated with improved outcomes in patients with acute coronary syndrome (ACS) with a tolerable bleeding risk profile. To date, there are no data documenting platelet inhibition and the anticoagulatory effects of VLD FXa inhibition on top of guideline-adherent dual-antiplatelet therapy (DAPT) in patients with ACS. Patients with non-ST-elevation myocardial infarction (NSTEMI) receiving oral DAPT (ASA + clopidogrel, n = 20; or ASA + ticagrelor, n = 20) were prospectively enrolled in a nonrandomized study. Coagulation- and platelet-dependent thrombin generation (TG), measured by means of the calibrated automated thrombogram, were significantly decreased after in vitro and in vivo addition of rivaroxaban. As shown by a total thrombus-formation analysis approach, rivaroxaban treatment led to a significantly decreased coagulation-dependent (AR-chip) thrombus formation in patients treated with ASA plus P2Y inhibitor (clopidogrel/ticagrelor), whereas the pure platelet-dependent (PL-chip) thrombus formation was not affected at all. Adjunctive rivaroxaban therapy was not associated with significant differences in platelet aggregation assessed by light-transmission aggregometry (LTA). Nevertheless, according to fluorescence-activated cell sorter analysis, VLD rivaroxaban treatment resulted in a significantly reduced expression of platelet HMGB-1, whereas P-selectin exposure was not affected. Furthermore, an enhanced effect of rivaroxaban on total thrombus formation and TG was observed in particular in clopidogrel nonresponder patients defined as adenosine 5'-diphosphate-induced LTA ≥40%. VLD rivaroxaban reduces thrombus formation and platelet-dependent TG in patients with ACS receiving DAPT, which can be of potential ischemic benefit. This trial was registered at www.clinicaltrials.gov as #NCT01417884.

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Section: Discussionsupporting

confidence: 64%

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

et al. 2018

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“…Oimatsu et al reported that PL-AUC levels were significantly lower in patients with than in those without such events, and that there was a significant association between low PL-AUC levels and periprocedural bleeding events as defined by the International Society on Thrombosis and Haemostasis. 66 Yamazaki et al performed analysis of CVD patient samples on aspirin alone, clopidogrel alone, and DAPT with PL chip and VerifyNow system. The AUC for PL chip was lower for those in the DAPT group than those in the aspirin or clopidogrel alone group.…”

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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“…21 T-TAS has also been shown to have utility in periprocedural analysis of bleeding events for patients undergoing percutaneous coronary intervention. 22 However, no prior assessments of T-TAS have been made in predicting thrombotic complications. One limitation with T-TAS and the AR chip is utilization of tissue factor (tF) and collagen as an activator of clotting.…”

Section: Discussionmentioning

confidence: 99%

“…Although few correlations to TEG were found, T-TAS has been proven to predict nonoperative procedural bleeding events. 22,31 However, the utility of microfluidics to risk stratify patients for postoperative thrombotic complications remain largely unexplored. Other pathologic occlusion events in disease states such as sickle cell disease, 32 tumors, 33 and cardiovascular disease 34 have been tested in in vitro models, but have not been used clinically to risk stratify patients.…”

Section: Discussionmentioning

confidence: 99%

Microfluidics contrasted to thrombelastography: perplexities in defining hypercoagulability

Lawson

Moore

et al. 2018

Journal of Surgical Research

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Background: Elevated clot strength (maximum amplitude [MA]) measured by thrombelastography (TEG) is associated with thrombotic complications. However, it remains unclear how MA translates to thrombotic risks, as this measurement is independent of time, blood flow, and clot degradation. We hypothesize that under flow conditions, increased clot strength correlates to time-dependent measurements of coagulation and resistance to fibrinolysis. Materials and methods: Surgical patients at high risk of thrombotic complications were analyzed with TEG and total thrombus-formation analysis system (T-TAS). TEG hypercoagulability was defined as an r <10.2 min, angle >59, MA >66 or LY30 <0.2% (based off of healthy control data, n = 141). The T-TAS AR and PL chips were used to measure clotting at arterial shear rates. T-TAS measurements include occlusion start time, occlusion time (OT), occlusion speed (OSp), and total clot generation (area under the curve). These measurements were correlated to TEG indices (R time, angle, MA, and LY30). Both T-TAS and TEG assays were challenged with tissue plasminogen activator (t-PA) to assess clot resistance to fibrinolysis. Results: Thirty subjects were analyzed, including five controls. TEG-defined hypercoagulability by MA was detectedin52% of the inflammatory bowel disease/cancer patients; 0%was detected in the controls. There were no TEG measurements that significantly correlated with T-TAS AR and PL chip. However, in the presence of t-PA, T-TAS AR determined OSp to have an inverse relationship with TEG angle (−0.477, P = 0.012) and LY30 (−0.449, P = 0.019), and a positive correlation with R time (0.441 P = 0.021). In hypercoagulability determined by TEG MA, T-TAS PL had a significantly reduced OT (4:07 versus 6:27 min, P = 0.043). In hypercoagulability defined by TEG LY30, T-TAS PL had discordant findings, with a significantly prolonged OT (6:36 versus 4:30 min, P = 0.044) and a slower OSp (10.5 versus 19.0 kPa/min, P = 0.030). Conclusions: Microfluidic coagulation assessment with T-TAS has an overall poor correlation with most TEG measurements in a predominantly hypercoagulable patient population, except in the presence of t-PA. The one anticipated finding was an elevated MA having a shorter time to platelet-mediated microfluidic occlusion, supporting the role of platelets and hypercoagulability. However, hypercoagulability defined by LY30 had opposing results in which a low LY30 was associated with a longer PL time to occlusion and slower OSp. These discordant findings warrant ongoing investigation into the relationship between clot strength and fibrinolysis under different flow conditions.

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Total Thrombus‐formation Analysis System Predicts Periprocedural Bleeding Events in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention

Cited by 25 publications

References 29 publications

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

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

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

Microfluidics contrasted to thrombelastography: perplexities in defining hypercoagulability

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