Miwa Ito

A novel quantitative assessment of whole blood thrombogenicity in patients treated with a non-vitamin K oral anticoagulant

Non-vitamin K oral anticoagulants(NOAC) negate complex patient management issues, such as frequent blood sampling, diet restriction, and drug interactions, that had to be dealt with during the warfarinonly era. However, there is no definite tool tomonitor the anticoagulant effects of NOACs, although some patients suffer from bleeding complications related to exceedingly high blood concentrations of NOACs. [1, 2] Routine tests, such as prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), can be problematic formonitoring the anticoagulant effects of all NOACs because each individual NOAC has a different characteristic chemical structure and different pharmacokinetic profile (e.g., plasma half-life and tissue penetration rate) [3]. Recently, the Total Thrombus-formation Analysis System (T-TASTM) [4,5], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation (Fig. 1A,B). In the present study, we sought to examine whether the T-TASTM was useful for the quantitative analysis of thrombogenicity in patients treated with the NOAC edoxaban (Fig. 1C, D). We recruited 20 consecutive patients (male: n = 8 [40%] and female: n=12 [60%], average age: 75.2±8.7 years)whowere scheduled

Total Thrombus‐Formation Analysis System (T‐TAS) Can Predict Periprocedural Bleeding Events in Patients Undergoing Catheter Ablation for Atrial Fibrillation

Background Non–vitamin K antagonist oral anticoagulants are used to prevent thromboembolism in patients with atrial fibrillation. The T‐TAS “Total Thrombus‐formation Analysis System” (Fujimori Kogyo Co Ltd) was developed for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, platelet chip [PL] ; collagen plus tissue factor, atheroma chip [AR]). We evaluated the utility of T‐TAS in predicting periprocedural bleeding in atrial fibrillation patients undergoing catheter ablation (CA). Methods and Results After exclusion of 20 from 148 consecutive patients undergoing CA, the remaining 128 patients were divided into 2 treatment groups: the warfarin group (n=30) and the non–vitamin K antagonist oral anticoagulants group (n=98). Blood samples obtained on the day of CA (anticoagulant‐free point) and at 3 and 30 days after CA were used in T‐TAS to compute the thrombus formation area under the curve (AUC; AUC for the first 10 minutes for PL tested at flow rate of 24 μL/min [PL 24‐AUC 10]; AUC for the first 30 minutes for AR tested at flow rate of 10 μL/min [AR 10‐AUC 30]). AR 10‐AUC 30 and PL 24‐AUC 10 levels were similar in the 2 groups on the day of CA. Levels of AR 10‐AUC 30, but not PL 24‐AUC 10, were significantly lower in the 2 groups at days 3 and 30 after CA. Multiple logistic regression analyses identified the AR 10‐AUC 30 level on the day of CA as a significant predictor of periprocedural bleeding events (odds ratio 5.7; 95% CI 1.54–21.1; P=0.009). Receiver operating characteristic analysis showed that the AR 10‐AUC 30 level on the day of CA significantly predicted periprocedural bleeding events (AUC 0.859, 95% CI 0.766–0.951; P<0.001). The cutoff AR 10‐AUC 30 level was 1648 for identification of periprocedural bleeding events. Conclusions These results suggested that the AR 10‐AUC 30 level determined by T‐TAS is a potentially useful marker for prediction of bleeding events in atrial fibrillation patients undergoing CA.

Prevalence and mechanism of rotor activation identified during atrial fibrillation by noncontact mapping: Lack of evidence for a role in the maintenance of atrial fibrillation

BACKGROUND It remains unclear whether atrial fibrillation (AF) is maintained by the rotor. OBJECTIVE We evaluated the role of the rotor and examined its mechanism. METHODS Among 75 patients with AF (60 paroxysmal, 15 persistent AF) who underwent 3-dimensional noncontact left atrial mapping during AF, we examined the prevalence and location of rotor activation and elucidated its mechanism. Catheter ablation was performed in a stepwise fashion (linear roof lesion and complex fractionated atrial electrogram ablation after pulmonary vein [PV) isolation) until AF termination. RESULTS Rotor activation was observed in 11 patients (14.7%; 10 paroxysmal and 1 persistent AF) (tachycardia cycle length 160.0 ± 19.8 ms). Rotors were observed transiently (duration 6128 ± 9094 ms) during AF at the roof (n = 5), septum (n = 3), and ostium of the left superior PV (n = 3). Five rotors circulated in clockwise and 6 in counterclockwise directions. The length of the block line at the center of the rotor was 15.2 ± 6.9 mm. The electrograms at the block line showed low-amplitude multiple deflections (n = 7) or double potentials (n = 4), and the amplitudes during rotor activation were significantly lower than those during sinus rhythm (0.27 ± 0.18 mV vs 1.22 ± 0.92 mV; P < .01). No conduction disturbances were found during sinus rhythm, suggesting that the central line of block was formed functionally. AF was terminated by PV isolation alone without additional lesions in patients with rotors. CONCLUSION Functionally formed rotor activation was observed during AF in a limited number of patients. These rotor activations may not be related to AF maintenance, but rather may reflect a transient organization of random propagation.

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

Background Periprocedural bleeding events are common after percutaneous coronary intervention. We evaluated the association of periprocedural bleeding events with thrombogenicity, which was measured quantitatively by the Total Thrombus‐formation Analysis System equipped with microchips and thrombogenic surfaces (collagen, platelet chip [PL]; collagen plus tissue factor, atheroma chip [AR]). Methods and Results Between August 2013 and March 2016, 313 consecutive patients with coronary artery disease undergoing elective percutaneous coronary intervention were enrolled. They were divided into those with or without periprocedural bleeding events. We determined the bleeding events as composites of major bleeding events defined by the International Society on Thrombosis and Hemostasis and minor bleeding events (eg, minor hematoma, arteriovenous shunt and pseudoaneurysm). Blood samples obtained at percutaneous coronary intervention were analyzed for thrombus formation area under the curve (PL24‐AUC10 for PL chip; AR10‐AUC30 for AR chip) by the Total Thrombus‐formation Analysis System and P2Y12 reaction unit by the VerifyNow system. Periprocedural bleeding events occurred in 37 patients. PL24‐AUC10 levels were significantly lower in patients with such events than those without (P=0.002). Multiple logistic regression analyses showed association between low PL24‐AUC10 levels and periprocedural bleeding events (odds ratio, 2.71 [1.22–5.99]; P=0.01) and association between PL24‐AUC10 and periprocedural bleeding events in 176 patients of the femoral approach group (odds ratio, 2.88 [1.11–7.49]; P=0.03). However, PL24‐AUC10 levels in 127 patients of the radial approach group were not significantly different in patients with or without periprocedural bleeding events. Conclusions PL24‐AUC10 measured by the Total Thrombus‐formation Analysis System is a potentially useful predictor of periprocedural bleeding events in coronary artery disease patients undergoing elective percutaneous coronary intervention.

Assessment of platelet-derived thrombogenicity with the total thrombus-formation analysis system in coronary artery disease patients receiving antiplatelet therapy.

Essentials Total thrombus‐formation analysis system (T‐TAS) quantitatively measures platelet thrombus formation. We examined the utility of T‐TAS in patients with coronary artery disease. T‐TAS can discriminate different types of the antiplatelet therapy in the same measuring method. Genetic background, cytochrome P‐450 2C19 genotypes, also influenced T‐TAS parameters.

Direct Oral Anticoagulants Form Thrombus Different From Warfarin in a Microchip Flow Chamber System

Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR10-AUC30 correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR10-AUC30 levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition.

Mid-systolic flow reversal in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy

An 80-year-old man with palpitations presented to our hospital. A 12-lead electrocardiogram showed atrial fibrillation, complete right bundle branch block (CRBBB), right axis deviation, and negative T waves in leads II, III, aVF, and V1–V4. A chest radiograph showed a cardiothoracic ratio of 58 %. A 2D transthoracic echocardiography showed LV hypertrophy (the interventricular septum was 14 mm thick and the LV posterior wall was 9 mm thick), mid-ventricular obstruction, and apical aneurysm. A pulsed Doppler echocardiogram showed systolic mid-ventricular obstruction and paradoxical jet flow typical for MVOCM [2]. Moreover, additional mid-systolic flow reversal was intermittently observed at the obstruction. This flow was observed between the systolic flow and paradoxical jet flow (Figs. 1, 2a). The patient underwent cardiac catheterization to enable visualization of the mechanism of this flow reversal and to examine whether the apical aneurysm was caused by myocardial infarction. Simultaneous LV pressure recordings showed that the basal pressure intermittently surpassed the apical pressure in mid-systole, which corroborated the echocardiographic data (Fig. 2b). Coronary arteriography yielded normal results. The patient was discharged with beta-blocker, calcium channel blocker, and anticoagulation.

Coronary blood flow volume change is negatively associated with platelet aggregability in patients with non-obstructive ischemic heart disease who have no anti-platelet agents

BACKGROUND Thrombus formation is one of the main pathogeneses of acute coronary syndrome with atherosclerotic rupture. Previous studies have reported that atherosclerosis increases platelet aggregability and that vascular endothelial dysfunction reflects early change of atherosclerosis. However, the relationship between coronary endothelial dysfunction and platelet reactivity remains unclear. Therefore, in this study, we investigated the relationship between them in non-obstructive ischemic heart disease (IHD) patients. METHODS Three hundred sixty-eight consecutive stable patients with suspected angina presenting non-obstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test and measured adenosine triphosphate-induced coronary flow reserve. Finally, 25 non-obstructive IHD patients who had no anti-platelet agents were assessed for the relationship between coronary blood flow volume (CBFV) change and platelet aggregability as P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay system. RESULTS CBFV change by intracoronary 20 μg/kg per minute acetylcholine provocation showed a significant negative correlation with platelet aggregability as PRU (r = 0.44, P = 0.03). Conversely, there was no significant correlation between PRU and endothelial function as coronary flow reserve. Furthermore, multivariable linear regression analysis indicated that an incremental CBFV change was independently associated with PRU (β = 0.63, P < 0.001) in non-obstructive IHD patients. CONCLUSIONS In patients with non-obstructive IHD, CBFV change was significantly associated with platelet aggregability, indicating that coronary endothelial dysfunction might mediate higher platelet aggregability.

A case of pulmonary thromboembolism due to coagulation factor V Leiden in Japan ~ usefulness of next generation sequencing~

BackgroundBecause the venous thromboembolisms (VTEs) due to the coagulation factor V R506Q (FV Leiden) mutation is often seen in Caucasians, the VTE onset in Japan has not been reported.Case presentationA 34-year-old man from north Africa experiencing sudden dyspnea went to a hospital for advice.The patient had pain in his right leg and a high plasma D-dimer level. A contrast-enhanced computed tomography scan revealed a contrast deficit in the bilateral pulmonary artery and in the right lower extremity. The patient was diagnosed with VTE, and anticoagulation therapy was initiated. Our targeted gene panel sequencing revealed that the occurrence of VTE was attributed to a presence of the FV Leiden mutation.ConclusionsThis is the first report demonstrating VTE caused by the FV Leiden mutation in Japan.

Edoxaban Enhances Thromboprophylaxis by Physiotherapy After Total Knee Arthroplasty ― The Randomized Controlled ESCORT-TKA Trial ―

BACKGROUND The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA.Methods and Results:The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR10-AUC30) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR10-AUC30was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045). CONCLUSIONS The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors.