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INTRODUCTION We aimed to evaluate the performance of the fully automated multiparameter CN-6000 hemostasis analyzer. METHODS Performance evaluation of the CN-6000 analyzer was conducted for 10 tests including prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen level, anti-Xa activity, and antithrombin activity using a unique portfolio of liquid ready-to-use reagents. Precision, sample and reagent carryovers, throughput, and sample turnaround time (STAT) function were prospectively assessed. Results from 343 samples (normal subjects, critically ill patients, patients receiving anticoagulants, subjects with high or low fibrinogen levels, and patients with decreased levels of factor II, V, VII, and X) were compared to those obtained on the STA-R Max 2® analyzer using dedicated reagents. RESULTS Total precision (coefficient of variation) was below 7% for all parameters in both normal and pathological ranges. For all analyzed parameters, results obtained on the CN-6000 were strongly correlated with those obtained on the STA-R Max 2®analyzer. Agreement between both instruments was excellent for all assays. The CN-6000 demonstrated a 30% higher throughput compared to the STA-R Max 2® (258 vs 185 tests per hour for a panel of tests including PT, aPTT, fibrinogen, factor V, anti-Xa, and D-Dimer). STAT turnaround time for critical care samples testing was

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35–56) years, with a median body mass index of 30 (27–35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8–16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin–antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p

International audience; Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used in Coronavirus disease-19 (COVID-19) patients with the most severe forms of acute respiratory distress syndrome (ARDS). Its use is associated with a significant hemostatic challenge, especially in COVID- 19 patients who have been demonstrated to otherwise present a COVID-19-associated coagulopathy. The systematic use of unfractionated heparin therapy to prevent circuit thrombosis is warranted during ECMO support. The clinical presentation and management of heparin-induced thrombocytopenia, which is a rare but life-threatening complication of heparin therapy, has not been described in those patients yet. We report herein two cases of laboratory-confirmed HIT in COVID-19 patients with severe ARDS admitted to our intensive care unit for VV-ECMO support and the successful use of argatroban as an alternative therapy. We also provide a brief literature review of best evidence for managing such patients. The diagnosis and management of HIT is particularly challenging in COVID-19 patients receiving ECMO support. An increased awareness is warranted in those patients who already present a procoagulant state leading to higher rates of thrombotic events which can confuse the issues. Argatroban seems to be an appropriate and safe therapeutic option in COVID-19 patients with HIT while on VV-ECMO.

Coronavirus disease 2019 (COVID‐19) is associated with both severe systemic inflammation and a prothrombotic state, as reflected by significant increases in fibrinogen and D‐dimers levels that have been associated with poor prognosis and high rates of severe pulmonary embolism. A recent report suggested a role for antiphospholipid antibodies (aPLA) in the thrombotic manifestations associated with severe COVID‐19. As we also recently noticed unexplained lengthening of activated partial thromboplastin time (aPTT) in some critically ill COVID‐19 patients, we explored our patients for aPLA positivity.

Background A strong association between on-thienopyridine platelet reactivity (PR) and the risk of both thrombotic and bleeding events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) has been demonstrated. However, no study has analyzed the relationship between on-ticagrelor PR and clinical outcome in this clinical setting. Objectives We aimed to investigate the relationship between on-ticagrelor PR, assessed by the vasodilator-stimulated phosphoprotein (VASP) index, and clinical outcome in patients with ACS undergoing PCI. Methods We performed a prospective, multicenter, observational study of patients undergoing PCI for ACS. PR was measured using the VASP index following ticagrelor loading dose. The primary study endpoint was the rate of Bleeding Academic Research Consortium (BARC) type ≥2 at 1 year. The key secondary endpoint was the rate of major adverse cardiovascular events (MACE) defined as the composite of cardiovascular death, myocardial infarction, stroke, and urgent revascularization. Results We included 570 ACS patients, among whom 33.9% had ST-elevation myocardial infarction. BARC type ≥2 bleeding occurred in 10.9% and MACE in 13.8%. PR was not associated with BARC ≥2 or with MACE (p = 0.12 and p = 0.56, respectively). No relationship between PR and outcomes was observed, neither when PR was analyzed quantitatively nor when it was analyzed qualitatively (low on-treatment PR [LTPR] vs. no LTPR). Conclusion On-ticagrelor PR measured by the VASP was not associated with bleeding or thrombotic events in ACS patients undergoing PCI. PR measured by the VASP should not be used as a surrogate endpoint in studies on ticagrelor.

The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. We suggest that free radical scavengers could be beneficial for the most vulnerable patients. In this Comment article, Becker and colleagues consider how the excessive release of reactive oxygen species by neutrophils may perpetuate red blood cell dysfunction, thrombosis and tissue damage in severe cases of COVID-19.

Background: Percutaneous left atrial appendage closure (LAAC) exposes to the risk of device thrombosis in patients with atrial fibrillation who frequently have a contraindication to full anticoagulation. Thereby, dual antiplatelet therapy (DAPT) is usually preferred. No randomized study has evaluated nonvitamin K antagonist oral anticoagulant after LAAC, and we decided to evaluate the efficacy and safety of reduced doses of rivaroxaban after LAAC. Methods: ADRIFT (Assessment of Dual Antiplatelet Therapy Versus Rivaroxaban in Atrial Fibrillation Patients Treated With Left Atrial Appendage Closure) is a multicenter, phase IIb study, which randomized 105 patients after successful LAAC to either rivaroxaban 10 mg (R 10 , n=37), rivaroxaban 15 mg (R 15 , n=35), or DAPT with aspirin 75 mg and clopidogrel 75 mg (n=33). The primary end point was thrombin generation (prothrombin fragments 1+2) measured 2 to 4 hours after drug intake, 10 days after treatment initiation. Thrombin-antithrombin complex, D-dimers, rivaroxaban concentrations were also measured at 10 days and 3 months. Clinical end points were evaluated at 3-month follow-up. Results: The primary end point was reduced with R 10 (179 pmol/L [interquartile range (IQR), 129–273], P 15 (163 pmol/L [IQR, 112–231], P 10 and R 15 while rivaroxaban concentrations increased significantly from 184 ng/mL (IQR, 127–290) with R 10 to 274 ng/mL (IQR, 192–377) with R 15 , P Conclusions: Thrombin generation measured after LAAC was lower in patients treated by reduced rivaroxaban doses than DAPT, supporting an alternative to the antithrombotic regimens currently used after LAAC and deserves further evaluation in larger studies. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03273322.

International audience; Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg × kg(-1) × min(-1), with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly advised to involve a health practitioner experienced in the management of difficult cases in haemostasis. The first laboratory assessment should be performed 4 h after the initiation of argatroban infusion, with further controls at 2-4-h intervals until steady state, and at least once daily thereafter. Importantly, full anticoagulation should be rapidly achieved in case of widespread thrombosis. Cerebral vein thrombosis (which is typical of VITT) should not call for an overly cautious anticoagulation scheme. Argatroban administration requires baseline laboratory assessment and should rely on an anti-IIa assay to derive argatroban plasma levels using a dedicated calibration, with a target range between 0.5 and 1.5 µg/mL. Target argatroban plasma levels can be refined based on meticulous appraisal of risk factors for bleeding and thrombosis, on frequent reassessments of clinical status with appropriate vascular imaging, and on the changes in daily platelet counts. Regarding the use of aPTT, baseline value and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient’s/mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged: one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg × kg(-1) × min(-1) up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.

International audience; Over the past two decades, aspirin has emerged as a promising chemoprotective agent to prevent colorectal cancer (CRC). In 2016, the mounting evidence supporting its chemoprotective effect, from both basic science and clinical research, led the US Preventive Services Task Force to recommend regular use of low-dose aspirin in some subgroups of patients for whom the benefits are deemed to outweigh the risks. In contrast, data on the chemoprotective effect of aspirin against other cancers are less clear and remain controversial. Most data come from secondary analyses of cardiovascular prevention trials, with only a limited number reporting cancer outcomes as a prespecified endpoint, and overall unclear findings. Moreover, the potential chemoprotective effect of aspirin against other cancers has been recently questioned with the publication of 3 long-awaited trials of aspirin in the primary prevention of cardiovascular diseases reporting no benefit of aspirin on overall cancer incidence and cancer-related mortality. Data on the chemoprotective effects of other antiplatelet agents remain scarce and inconclusive, and further research to examine their benefit are warranted. In this narrative review, we summarize current clinical evidence and continuing controversies on the potential chemoprotective properties of antiplatelet agents against cancer.

International audience; BackgroundTicagrelor induces more potent platelet reactivity (PR) inhibition with reduced interindividual variability compared with clopidogrel. Although on-clopidogrel PR was shown to correlate with ischemia and bleeding events, data regarding PR from ticagrelor and the outcomes are lacking.MethodsThis study aimed to determine the association between PR after a ticagrelor loading dose (LD), assessed by the vasodilator-stimulated phosphoprotein index (VASP), and thrombotic and bleeding events in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention. The authors performed a prospective, multicenter observational study on patients treated with percutaneous coronary intervention for ACS. The VASP index was used to assess PR after ticagrelor LD. The primary endpoint was the link between major adverse cardiac events (MACE) and PR.ResultsAmong the included 530 patients with ACS, 185 (34.5%) were admitted for ST-segment elevation myocardial infarction. This study observed high potency and limited interindividual variability after the ticagrelor LD (VASP 19.1 ± 16.6%). At 1 month, 21 MACE (3.8%) and 29 Academic Research Consortium ≥2 bleeding events (5.5%) were recorded. Neither MACE nor bleeding were associated with PR (p = 0.34 and p = 0.78, respectively). However, there was a strong association between PR and the occurrence of definite acute stent thrombosis (p = 0.03). PR was the only factor associated with acute definite stent thrombosis.ConclusionIn patients receiving a ticagrelor LD while undergoing percutaneous coronary intervention for ACS, PR using the VASP does not predict MACE or bleeding at 1 month, but it is significantly associated with the occurrence of definite acute ST.

International audience; BACKGROUND:Ticagrelor induces more potent platelet reactivity (PR) inhibition with reduced interindividual variability compared to clopidogrel. Although on-clopidogrel PR was shown to correlate with ischemia and bleeding events, no study has investigated the relationship between on-ticagrelor PR and outcome.OBJECTIVES:We aimed to evaluate the relationship between on-ticagrelor PR, assessed by the vasodilator-stimulated phosphoprotein index (VASP), and thrombotic and bleeding events in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention (PCI).METHODS:We performed a prospective, multicenter observational study on patients treated with PCI for ACS. The VASP index was used to assess PR after ticagrelor loading dose (LD). The primary endpoint was the link between major adverse cardiovascular events (MACE) and PR.RESULTS:Among the 530 patients with ACS included, 183 (34.5%) were admitted for ST elevation myocardial infarction. We observed high potency and limited interindividual variability after the ticagrelor LD (VASP 19.1% ± 16.6%). At 1 month, 21 (3.8%) MACE and 29 (5.5%) bleedings ≥ 2 according to the Bleedings Academic Research Consortium (BARC) scale were recorded. Neither MACE nor bleeding was associated with PR (P = .34 and P = .78, respectively). However, there was a strong association between PR and the occurrence of definite acute stent thrombosis (P = .03). Platelet reactivity was the only factor associated with acute definite stent thrombosis.CONCLUSION:In patients receiving a ticagrelor LD while undergoing PCI for ACS, PR using the VASP did not predict MACE or bleeding, but it was significantly associated with the occurrence of definite acute stent thrombosis.

International audience

International audience; Bivalirudin is associated with an increased risk of acute stent thrombosis (AST) compared to unfractionated heparin (UFH) in acute coronary syndrome patients (ACS) during short-duration percutaneous coronary intervention (PCI). The mechanisms involved are unknown. We aimed to investigate the antithrombotic efficacy of bivalirudin compared to UFH during PCI. In a monocenter study, we prospectively enrolled 30 patients undergoing PCI for a non– ST elevation ACS. They were randomly assigned to a single intravenous (IV) bolus of UFH (70 IU/kg) or an IV bolus of bivalirudin 0.75 mg/kg followed by a 1.75 mg/kg/h infusion during PCI. All patients received a loading dose (LD) of 180 mg of ticagrelor at the time of PCI. The VASP index and activated partial thromboplastin time (aPTT) were used to assess the course of platelet reactivity (PR) and antithrombotic activity. The two groups were similar regarding baseline, angiographic, and interventional characteristics. There was no difference between the two groups in the course of PR following ticagrelor LD. An optimal PR inhibition was obtained 4 h after the LD of ticagrelor. The level of antithrombotic activity was significantly lower in the bivalirudin group compared to the UFH group (p < 0.001) during PCI but similar at 2 and 4 h post-PCI. We observed that, in ACS undergoing PCI, the antithrombotic efficacy of an IV bolus of bivalirudin is significantly lower than that of a 70-IU/kg UFH bolus. This could contribute to the excess in thrombotic acute events observed during short-duration PCI.

Background Ticagrelor induces more potent platelet reactivity (PR) inhibition with reduced interindividual variability compared to clopidogrel. Although on-clopidogrel PR was shown to correlate with ischemia and bleeding events, data regarding PR from ticagrelor and the outcomes are lacking. Purpose We aimed to determine the association between PR after a ticagrelor loading dose (LD), assessed by the vasodilator-stimulated phosphoprotein index (VASP), and thrombotic and bleeding events in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention (PCI). Methods We performed a prospective, multicenter observational study on patients treated with PCI for ACS. The VASP index was used to assess PR after ticagrelor LD. The primary endpoint was the link between major adverse cardiovascular events (MACE) and PR. Results Among the included 530 patients with ACS, 185 (34.5%) were admitted for ST elevation myocardial infarction. We observed high potency and limited interindividual variability after the ticagrelor LD (VASP 19.1 ± 16.6%). At 1 month, 21 (3.8%) MACE and 29 (5.5%) bleedings Academic Research Consortium ≥ 2 events were recorded. Neither MACE nor bleeding were associated with PR (P = 0.34and p = 0.78 respectively). However, there was a strong association between PR and the occurrence of definite acute stent thrombosis (P = 0.03). PR was the only factor associated with acute definite stent thrombosis. Conclusion In patients receiving a ticagrelor LD while undergoing PCI for ACS, PR using the VASP does not predict MACE or bleeding, but it is significantly associated with the occurrence of definite acute ST.

Background The clinical benefit of anti-platelet agents in patients with chronic kidney disease (CKD) is uncertain. In addition, the risk–benefit ratio of potent oral P2Y12-adenosine diphosphate (ADP) receptor antagonists (PPAs), namely, prasugrel and ticagrelor, compared with clopidogrel in CKD patients suffering from acute coronary syndrome (ACS) remains unknown. Objective We performed a meta-analysis of all studies comparing the clinical outcomes of PPA and clopidogrel therapy in CKD patients suffering from ACS. Methods We searched PubMed, the Cochrane library, Google Scholar, Clinical trial.org and the abstracts of international cardiology congresses from April 2000 to October 2017. Clinical studies comparing PPA with clopidogrel in ACS patients with CKD were selected. Our literature research identified five studies which were included in the meta-analysis. The primary endpoint was a composite of major adverse cardiovascular events (MACEs) at the latest follow-up available. Secondary endpoint included bleedings. Results We included data from three sub-group analysis of randomized clinical trials and two prospective observational studies (n = 31,234). Overall, PPAs were associated with lower rates of major cardiovascular events, with a pooled hazard ratio (pHR) of 0.88 (95% confidence interval [CI]: 0.79–0.99; p = 0.03), without increased bleedings (pHR = 1.10) (95% CI: 0.95–1.27; p = 0.18). In a sensitivity analysis restricted to studies enrolling invasively managed patients, the benefit of PPA on MACE was maintained (pHR = 0.85) (95% CI: 0.77–0.93; p Conclusion Compared with clopidogrel, PPAs were associated with a reduced rate of MACE without increased bleedings in CKD patients with ACS. Among invasively managed patients, this benefit from PPA included a reduction in mortality.

Background Platelet function is associated with adverse events in patients with cardiovascular disease (CVD). Methods and Results We examined associations of baseline platelet function with incident CVD events in the community‐based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991–1995) and Omni cohort (1994–1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 μg/mL), ADP (0.05–15 μmol/L), and epinephrine (0.01–15 μmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow‐up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 μmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13–2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02–1.33] [P=0.029] for highest quartile of ADP response at 1.0 μmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke. Conclusions Intrinsic hyperreactivity to low‐dose ADP in our community‐based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20‐year follow‐up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor‐refractive populations.

SummaryPretreatment with a loading dose (LD) of clopidogrel or ticagrelor before percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is supported by the guidelines, but debated following a recent meta-analysis on clopidogrel pretreatment and the ACCOAST trial. In this trial prasugrel pretreatment failed to reduce ischaemic events. The timing of optimal platelet reactivity (PR) inhibition of ticagrelor and prasugrel in non ST-elevation ACS (NSTE ACS) is yet undetermined. In the present study, we aimed to investigate the delay required to reach optimal PR inhibition in NSTE ACS following a LD of ticagrelor or prasugrel. Consecutive patients undergoing PCI for NSTE ACS were randomised in this monocentre study. The Vasodilatorphosphoprotein index (VASP) was used to measure PR before the LD and then at 30 minutes, 1, 2, 4 and 24 hours (h) post-LD. Optimal PR inhibition was defined as a VASP< 50 %. We randomised 24 patients to ticagrelor or prasugrel LD. One hour after the LD, 29 % of patients had a VASP > 50 % (ticagrelor and prasugrel: 25 vs 33 %; p=0.7). Optimal PR inhibition was obtained 2 h after the LD in both groups (12/12 with ticagrelor and 11/12 with prasugrel). At that time, the mean VASP index was 19 ± 16 % (95 %CI: 12–25). Maximal PR inhibition was reached after 4 h: 11 ± 10 % (95 %CI: 6–15). In NSTE ACS undergoing PCI a LD of ticagrelor or prasugrel given during the procedure provides optimal P2Y12-ADP receptor blockade in 2 h and maximal inhibition within 4 h.

Background Venous thromboembolism (VTE) is a leading cause of death in obese patients undergoing bariatric surgery (BS), but there is neither consensus nor high-level guidelines yet on VTE prophylaxis in this specific population. Objective We aimed to evaluate patterns of BS perioperative thromboprophylaxis practices. Setting French obesity specialized care centers (CSO), which are tertiary care referral hospitals for the most severe cases of obesity Methods A detailed questionnaire survey (11 opened, 15 closed questions) investigating their prophylactic schemes of anticoagulation (molecule, dose, weight-adjustment, duration, associated measures, follow-up) was sent to the 37 CSO. Results Completion rate was 92%. Over 90% of respondents indicated using low molecular weight heparin. Enoxaparin was the most commonly used molecule (89%), twice daily (71%), started mostly 6 hours after BS (74%), whereas fondaparinux (9%), dalteparin (6%), and tinzaparin (6%) were less often prescribed. Dosing varied significantly according to centers from 4000 to 12,000 IU/d, with the most commonly used dose being 8000 IU once daily, 83%, as well as treatment duration (1 week, 9%; 3 weeks, 47%). Half CSO adjusted low molecular weight heparin dose to weight. Biological monitoring was performed in 88%. Only 1 center followed systematically anti-Xa activity. Associated measures such as elastic stoking or intermittent pneumatic compression were used in 32% and 26%, respectively, and both were used in 39%. Conclusion This study finds significant discrepancies in thromboprophylaxis practices in obese patients undergoing BS, particularly with respect to treatment duration and dose adjustment, highlighting the urgent need for improved implementation of existing clinical practice guidelines in this VTE high-risk population.

We read with interest the article by Achilles et al. [1] in a recent issue of the Journal of Thrombosis and Haemostasis, in which the authors raised a concern regarding the safety of the oral direct thrombin inhibitor (ODTI) dabigatran. The authors aimed to investigate a potential mechanism involved in the increased risk of myocardial infarction (MI) observed in several trials of patients treated with dabigatran when compared head-to-head with patients treated with indirectly acting therapeutic anticoagulants. In this brief report, platelet reactivity and thrombin receptor expression were measured in 13 patients before and after planned initiation of dabigatran medication. This article is protected by copyright. All rights reserved.

SummaryOptimal P2Y12 receptor blockade is critical to prevent ischaemic recurrence in patients undergoing percutaneous coronary intervention (PCI). We aimed to compare the level of platelet reactivity (PR) inhibition achieved by prasugrel and ticagrelor loading dose (LD) in diabetic acute coronary syndrome (ACS) patients undergoing PCI. We performed a single-center prospective open-label randomised trial. Patients with diabetes mellitus undergoing PCI for an ACS were randomised to receive prasugrel 60 mg or ticagrelor 180 mg. The primary endpoint of the study was the level of platelet reactivity (PR) assessed between 6 and 18 hours post-LD using the VASP index. We randomised 100 diabetic patients undergoing PCI for an ACS. No difference was observed in baseline characteristics between the two groups. In particular, the rate of patient receiving insulin therapy was identical (25 vs 28.6%; p =0.7). Ticagrelor achieved a significantly lower PR compared to prasugrel loading dose (17.3 ± 14.2 vs 27.7 ± 23.3%; p=0.009). In addition the rate of high on-treatment platelet reactivity, defined by a VASP ≥50%, tend to be lower in the ticagrelor group although the difference did not reach statistical significance (6 vs 16%; p=0.2). The rate of low on treatment PR was identical (60 vs 54%; p=0.8). The present study demonstrates that ticagrelor LD is superior to prasugrel LD to reduce PR in ACS patients with diabetes mellitus. Whether the higher potency of ticagrelor could translate into a clinical benefit should be investigated.

Dual antiplatelet therapy is critical to inhibit platelet reactivity in order to prevent ischemic recurrences in stented patients. However, studies have observed a variable blockade of the P2Y12 adenosine diphosphate receptor between patients following clopidogrel intake. This interindividual variability in the biological response is not uncommon with clopidogrel (about 50%) and even prasugrel (20%). High on-treatment platelet reactivity (HTPR) is correlated with thrombotic events following percutaneous coronary intervention. Several studies suggested that tailoring of antiplatelet therapy based on platelet reactivity (PR) monitoring could safely reduce the rate of major adverse cardiovascular events in HTPR patients. In addition, low on-treatment PR was recently associated with bleeding events both in patients treated with prasugrel and clopidogrel. Of importance, bleedings are associated with a poor prognosis in stented patients. Overall, the potential of PR monitoring to individualize antiplatelet therapy might benefit stented patients by reducing both ischemic and bleeding risks. However, such strategies remain to be evaluated in adequately designed large-scale randomized clinical trials.

International audience; Clinical trials have demonstrated an excess of acute stent thrombosis (AST) in acute coronary syndromes patients (ACS) undergoing percutaneous coronary intervention (PCI) with bivalirudin compared to heparin. We aimed to investigate the potential mechanisms responsible for thrombus formation under bivalirudin.; We compared heparin and bivalirudin during PCI for ACS in a prospective monocentre randomized study. Twenty patients were included after coronary angiography and received a loading dose (LD) of 180mg of ticagrelor at the time of PCI. They were randomly assigned to heparin (70UI/kg) intra-venous (IV) bolus or bivalirudin IV bolus of 0.75mg/kg followed by an infusion of 1.75mg/kg/h until the end of the PCI. The VASP index and thrombin generation test were used to assess the course of platelet reactivity (PR) and thrombin generation.; Thrombin generation and PR were identical in both groups at baseline. There was no difference in the course of PR following the LD over time. An optimal PR inhibition was reached 4h after the LD of ticagrelor. Heparin and bivalirudin infusion effectively inhibited thrombin generation during PCI. However, 4h after the end of bivalirudin infusion, thrombin generation had returned to its baseline value whereas in the heparin group it remained significantly inhibited compared to baseline and to the bivalirudin group 4h after the end of the infusion (p

International audience; Essentials Patients with α-1-antitrypsin (α1-AT) Pittsburgh exhibit a mild bleeding tendency. A new case of α1-AT Pittsburgh with suspected high antifibrinolytic potential was studied. We showed that α1-AT Pittsburgh inhibits tissue plasminogen activator and plasmin. The antifibrinolytic potential of the variant contributes to explaining the mild bleeding phenotype.; α1 -Antitrypsin (α1 -AT) Pittsburgh has a Met358 to Arg substitution at the reactive Met-Ser site of α1 -AT, which enables the protein to act as a potent thrombin inhibitor. Four patients with α1 -AT Pittsburgh have been described to date. An additional young girl was recently diagnosed with α1 -AT Pittsburgh in our center after presenting with a large hematoma in the forearm. Interestingly, all of these patients showed a potent thrombin inhibitor in the plasma and a mild bleeding phenotype. This observation suggests that the in vivo consequences of the mutation may contribute to the maintenance of normal hemostatic balance. We assessed inhibition of the fibrinolytic system by the variant protein by evaluating the fibrinolysis inhibitory potential of the patient's plasma, purified wild-type α1 -AT and purified Pittsburgh α1 -AT with an electrophoretic zymography system, western blotting, and clot fibrinolysis. Our results indicate that the patient's plasma and purified α1 -AT Pittsburgh have strong potential to inhibit tissue-type plasminogen activator and plasmin.

International audience; P2Y12-ADP receptor blockade during percutaneous coronary intervention (PCI) is critical to prevent thrombotic events. In patients under chronic P2Y12 blockers, the use of additional loading dose (LD) before an elective PCI is debated. We aimed to investigate the rate of high on-treatment platelet reactivity (HTPR) in patients undergoing elective PCI during chronic clopidogrel or ticagrelor therapy.We performed a sub-group analysis of a randomized trial comparing ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients undergoing PCI. Multi-vessel disease patients requiring a staged PCI one month after the ACS were included. The VASP (vasodilatatory phosphoprotein) index, which is a specific and reproducible platelet assay to measure P2Y12-ADP receptor activity, was used to assess the biological efficacy of the maintenance dose (MD) of ticagrelor and clopidogrel before PCI. Forty-one patients in each group of randomization required a staged PCI. They were similar regarding the baseline demographic, clinical and angiographic characteristics. The mean VASP index in the ticagrelor group was 20.7±8.8% compared to 51.8±17% in the clopidogrel group (p

Prasugrel and ticagrelor are potent P2Y12-ADP receptor antagonists which are superior to clopidogrel in acute coronary syndromes. To date no clinical trial directly compared these two drugs. Platelet reactivity correlates with ischemic and bleeding events in patients undergoing percutaneous coronary intervention. Recent pharmacological studies have observed a delayed onset of action of these two drugs in ST-segment elevation myocardial infarction (STEMI). We provide the first adequately powered pharmacological study comparing PR following ticagrelor and prasugrel loading dose (LD) in STEMI patients when the maximal biological effect is reached. In the present study, ticagrelor was associated with a lower rate of high on-treatment PR compared to prasugrel.

SummaryObjectivesWe investigated the agreement between different platelet tests to identify clopidogrel non response.BackgroundBiological definition of clopidogrel non response remains controversial. Different platelet tests have been linked with recurrent ischemic events and proposed for daily practice.MethodsWe prospectively investigated the agreement of platelet tests to isolate clopidogrel non response in patients receiving high 150mg clopidogrel maintenance dose after coronary stenting. Clopidogrel response was assessed with ADP-induced aggregation (ADP-Ag) (non response if >70%), Platelet reactivity index VASP (PRI VASP) (non response if >50%) and Verify Now Point-of-care assay (VN) (non response if PRU>240 AU).ResultsSeventy consecutive patients were included. The rates of non-responders were respectively: 13% (n=9) with the ADP-Ag, 39% (n=27) with the PRI VASP and 33% (n=23) with the VN. We observed significant correlation between different platelet tests assessing clopidogrel response: r=0.55 (p

Objectives This study sought to compare the effect of 2 proton pump inhibitors (PPIs) on platelet response to clopidogrel after coronary stenting for non–ST-segment elevation acute coronary syndrome (NSTE ACS). Background Use of omeprazole has been reported to significantly decrease the clopidogrel antiplatelet effect because of cytochrome P450 interaction. Because all PPIs are metabolized by CYP2C19, but to a varying degree, we hypothesized that the reported negative omeprazole–clopidogrel drug interaction may not be caused by a class effect. Methods A total of 104 patients undergoing coronary stenting for NSTE ACS were prospectively included and randomized to omeprazole or pantoprazole 20 mg. They received at discharge 75-mg aspirin and 150-mg clopidogrel. Platelet reactivity index (PRI) vasoactive stimulated phosphoprotein (VASP) was used to assess clopidogrel response and adenosine diphosphate (ADP)–induced aggregation for platelet reactivity (ADP-Ag). Results After 1 month, patients receiving pantoprazole had a significantly better platelet response to clopidogrel as assessed with the PRI VASP: 36 ± 20% versus 48 ± 17% (p = 0.007). We identified more clopidogrel nonresponders in the omeprazole group than in the pantoprazole group: 44% versus 23% (p = 0.04), odds ratio: 2.6 (95% confidence interval: 1.2 to 6.2). Conversely, we did not observe any significant difference in platelet reactivity with ADP-Ag between the omeprazole and pantoprazole groups: 52 ± 15% and 50 ± 18%, respectively (p = 0.29). Conclusions The present findings suggest the preferential use of pantoprazole compared with omeprazole in patients receiving clopidogrel to avoid any potential negative interaction with CYP2C19.

Background Increased doses of antiplatelet therapy have been proposed to overcome the variability of response. However, the chronic dose of aspirin after DES remains controversial. Methods and results We assessed in a prospective and randomized study the benefit of higher dose of aspirin, in association with clopidogrel, on aspirin response and non COX-specific platelet testing in patients receiving Drug Eluting Stent (DES) for stable angina pectoris. 50 consecutive patients receiving DES for stable angina pectoris were prospectively included. They received loading dose of 250 mg aspirin and 600 mg clopidogrel and antiplatelet response was assessed with Arachidonic Acid-induced aggregation (AA-Ag) and ADP-induced aggregation (ADP-Ag) for aspirin and clopidogrel response respectively. Patients were randomized to either 75 or 160 mg of aspirin with 150 mg clopidogrel and platelet testing were repeated one month after hospital discharge. The two groups (aspirin “75 mg” or “160 mg”) had no difference for aspirin response: AA-Ag (5.2 ± 1.7% vs 6 ± 2%, p = 0.75) and non COX-specific pathway testing: ADP-Ag (47 ± 3% vs 49 ± 4%, p = 0.61). Conclusion The present study did not show any benefit of higher dose of aspirin neither on aspirin responsiveness, nor on inhibition of non COX-specific pathway. These data does not support use of higher dose than 75 mg of aspirin in association with clopidogrel in patients receiving DES, especially while higher doses have been associated with increased bleeding risk.

Objectives We investigated the hypothesis that biological aspirin "resistance" may often be related to noncompliance in patients undergoing coronary stenting. Background Premature discontinuation of antiplatelet therapy has been identified as a major risk factor for stent thrombosis and prior aspirin withdrawal has been associated with poor prognosis after acute coronary syndrome. Methods We prospectively investigated the occurrence of aspirin noncompliance in 136 consecutive patients undergoing coronary stenting receiving aspirin 75 mg daily. We analyzed posttreatment maximal intensity of arachidonic acid–induced platelet aggregation (AA-Ag) during hospitalization after controlled intake of aspirin and 1 month after hospital discharge. After 1 month, all "nonresponders" received controlled aspirin 75 mg and assessment of response was repeated. Aspirin nonresponse was defined by AA-Ag >30%. Results During inhospital period, the range of AA-Ag varied from 0% to 34% with a mean value of 7.5% ± 10%, and 4 patients (3%) were classified as nonresponders. One month after discharge, AA-Ag of the population was significantly higher than during the hospital phase (15.3 ± 23 vs 7.5 ± 10%, P = .0004), and 19 patients (14%) were identified as nonresponders. After controlled administration of aspirin, all but one of these nonresponders became responders and were identified as patients with noncompliance rather than biological resistance. Conclusion Aspirin resistance is rare in compliant patients using methods that directly indicate the degree of platelet cyclooxygenase inhibition. More than 10% of patients receiving aspirin for coronary stenting are noncompliant for aspirin therapy during the first month after stenting. These results suggest a need for improved education of these patients.

Objectives The aim of this study was to assess, in clopidogrel nonresponders undergoing elective percutaneous coronary intervention (PCI), the benefit of adjusted antiplatelet therapy with glycoprotein (GP) IIb/IIIa antagonist administration during PCI for 1-month clinical outcome. Background Numerous biological studies have reported interindividual variability in platelet response to clopidogrel with clinical relevance, and high post-treatment platelet reactivity (adenosine diphosphate-induced aggregation g70%) has been proposed to define nonresponse to clopidogrel. These nonresponders might benefit from tailored antiplatelet therapy. Methods One hundred forty-nine clopidogrel nonresponders referred for elective PCI were prospectively included and randomized to “conventional group” (n = 75) or “active group” with GP IIb/IIIa antagonist (n = 74). All patients received 250-mg aspirin and 600-mg clopidogrel before PCI and platelet testing. Results The rate of cardiovascular events at 1 month was significantly lower in the “active group” than in the “conventional group”: 19% (n = 14) versus 40% (n = 30), p = 0.006, odds ratio: 2.8; 95% confidence interval: 1.4 to 6.0. No patient in either group had post-procedural Thrombolysis In Myocardial Infarction major bleeding or required transfusions. Conclusions The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel nonresponders without increased bleeding risk.

SummaryVariability in platelet response to antiplatelet therapy and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. It was the aim of the present study to assess whether the response to aspirin and clopidogrel may be influenced by the 807 C/T polymorphism of the glycoprotein Ia (GpIa) gene in patients with non-ST elevation acute coronary syndrome (NSTE ACS). Six hundred one NSTE ACS patients were included in our study and were divided into three groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples were drawn. Post-treatment platelet reactivity was assessed by post treatment ADP 10 µM-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression. Non-response to dual antiplatelet therapy was defined by high post-treatment platelet reactivity (HPPR= ADP-Ag>70%). Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameters profiles was observed within patients having the same genotype, for ADP-Ag (p=0.33), PRIVASP (p=0.72) and P-selectin expression (p=0.37). The genotype frequencies of the 807 C/T polymorphism of the GpIa gene were similar in responders and non-responders defined by persistent HPPR (p=0.104). In conclusion, our study did not show any influence of 807 C/T polymorphism of GpIa gene on post-treatment platelet reactivity assessed by ADP-Ag, PRI VASP or P-selectin expression in 601 NSTE ACS patients.

SummaryClopidogrel responsiveness has been proposed to be involved in recurrent ischemic events after stenting for non-ST elevation acute coronary syndromes (NSTE ACS). However, its biological definition is not consensual. We assess the value ofADP-induced platelet aggregation (ADP-Ag) and platelet reactivity indexVASP (PRI VASP) in predicting recurrent ischemic events in patients with NSTE ACS undergoing percutaneous coronary intervention (PCI). We studied 195 consecutive NSTE ACS patients undergoing PCI after a 600 mg loading dose of clopidogrel. ADPAg and PRI VASP were analysed. The primary end-point was recurrent ischemic events within 30 days of PCI. It occurred in 14 patients (7%). Construction of ROC curves to examine the value of predictive models showed that sensitivity and specificity for primary endpoint were 79% and 76%, respectively, for a maximal intensity of ADP-Ag ≥70%, 93% and 50% for PRIVASP> 53%. The positive and negative predictive values were 21% and 98%, respectively, for ADP-Ag ≥70%, 12% and 99% for PRIVASP> 53%. In patients with NSTE ACS undergoing PCI, ADP-Ag and PRI VASP identify low responders to clopidogrel with an increased risk of recurrent ischemic events with respective cut-off values of 70% and 53%.

SummaryHigh post-treatment platelet reactivity (HPPR= adenosine diphosphate [ADP] 10 µM-induced platelet aggregation > 70%) identifies low responders to dual antiplatelet therapy with increased risk of recurrent cardiovascular (CV) events after stenting for non-ST elevation acute coronary syndromes (NSTEACS). This study was designed to compare the incidence of periprocedural myocardial infarction (MI) after stenting for NSTEACS patients between non-responders to dual antiplatelet therapy defined by HPPR and normo-responders. One hundred ninety NSTE-ACS consecutive patients undergoing coronary stenting were included in this prospective study. They received 250 mg aspirin and a 600 mg loading dose of clopidogrel at least 12 hours (h) before percutaneous coronary intervention (PCI). A single post-treatment blood sample was obtained before PCI to analyze maximal intensity of ADP-induced platelet aggregation, and troponin levels were analyzed before PCI, and 12 and 24 h after PCI. Troponin I was considered elevated if > 0.4 ng/ ml. HPPR was present in 22% of patients (n=42). Periprocedural MI occurred significantly more frequently in patients with HPPR than in the normo-responders (43% vs. 24%, p=0.014). After being correlated with recurrent ischemic events after stenting for NSTE-ACS, the HPPR seems to be also a marker of increased risk of periprocedural MI for NSTE-ACS patients.

Guidelines recommend a ticagrelor loading dose (LD) before PCI or a prasugrel LD at the time of percutaneous coronary intervention (PCI) in intermediate and high-risk non–ST-elevation acute coronary syndrome (NSTE-ACS). However, achieving an optimal PR inhibition at the time of PCI is critical to prevent adverse events and depends on the timing of LD intake in relation to PCI. We aimed to compare the rate of myonecrosis related to PCI in patients with NSTE-ACS receiving ticagrelor pretreatment versus prasugrel at the time of intervention. We prospectively randomized 213 patients with NSTE-ACS to a 180 mg of ticagrelor LD given as soon as possible after admission and before PCI or to a 60 mg LD of prasugrel given at the time of PCI. The primary end point was the rate of periprocedural myonecrosis as defined by an increase of >5 times the ninety-ninth percentiles in troponin-negative patients or a 20% increase in troponin-positive patients. The 2 groups were similar regarding baseline characteristics including clinical setting (p = 0.2). Procedural characteristics were also identical including the number of treated vessels and stenting procedures. Patients in the prasugrel group more often required emergent PCI (p = 0.001). Patients in the ticagrelor group had less periprocedural myonecrosis compared with those in the prasugrel group (19.8% vs 38.3%; p = 0.03). The rate of major adverse cardiovascular events and Bleeding Academic Research Consortium ≥2 at 1-month follow-up was low and similar between the 2 groups. In conclusion, a ticagrelor LD as soon as possible before PCI is superior to prasugrel at the time of PCI to prevent periprocedural myonecrosis in NSTE-ACS.

ObjectivesWe analyzed the benefit of a 600-mg clopidogrel loading dose on platelet reactivity and clinical outcomes after stenting for non–ST-segment elevation acute coronary syndrome (NSTE ACS).BackgroundHigh post-treatment platelet reactivity (HPPR = adenosine diphosphate 10 μmol·l−1[ADP]–induced platelet aggregation >70%) is a marker for low responders to dual antiplatelet therapy with increased risk of recurrent cardiovascular (CV) events after stenting for NSTE ACS.MethodsA total of 292 consecutive NSTE ACS patients undergoing coronary stenting were included and randomly received a 300-mg (n = 146) or 600-mg (n = 146) loading dose of clopidogrel at least 12 h before percutaneous coronary intervention. A single post-treatment blood sample was obtained before percutaneous coronary intervention to analyze maximal intensity of ADP-induced platelet aggregation and platelet surface expression of P-selectin. One-month follow-up CV events were recorded.ResultsThe ADP-induced platelet aggregation and expression of P-selectin were significantly lower in patients receiving 600 mg than in those receiving 300 mg (mean ± SD: 50 ± 19% vs. 61± 16%, p < 0.0001 and 0.38 ± 0.24 arbitrary units vs. 0.60 ± 0.40 arbitrary units; p < 0.0001 respectively). Persistence of HPPR was less common in patients receiving 600 mg than in those receiving 300 mg (15 vs. 25%, p = 0.03). During the 1-month follow-up, 18 CV events (12%) occurred in the 300-mg group versus 7 (5%) in the 600-mg group (p = 0.02); this difference was not affected by adjustment for conventional CV risk factors (p = 0.035).ConclusionsIn NSTE ACS patients undergoing coronary stenting, a 600-mg loading dose of clopidogrel shows its benefit on platelet reactivity and clinical prognosis.

Summary. Background and objectives: Low response toantiplatelet therapy may be a risk factor for the developmentof ischemic complications in patients with non-ST segmentelevation acute coronary syndrome (NSTE ACS) undergoingcoronary stenting. Methods: We prospectively studied theplatelet response to both clopidogrel and aspirin in 106 NSTEACS consecutive patients undergoing percutaneous coronaryintervention(PCI) with stenting. A single post-treatment bloodsample was obtained just before PCI and analyzed by plateletaggregometry using both ADP and arachidonic acid (AA) asagonists to explore the responses to clopidogrel and aspirin,respectively. Patients were divided into quartiles according tothe ADP or AA induced maximal intensity of plateletaggregation. Patients of the highest quartile (quartile 4) weredefined as the low-responders. Results: Twelve recurrentcardiovascular (CV) events occurred during the 1-monthfollow-up. Clinical outcome was significantly associated withplateletresponsetoclopidogrel[Quartile4vs.1,2,3:OR(95%CI) 22.4 (4.6–109)]. Low platelet response to aspirin wassignificantly correlated with clopidogrel low response ( P ¼0.003) but contributed less to CV events [OR (95%CI): 5.76(1.54–35.61)]. Conclusions: A post-treatment ADP-inducedplatelet aggregation performed just before PCI identifies lowresponderstodualantiplatelettherapywithanincreasedriskofrecurrent CV events.Keywords: acute coronary syndrome, aspirin, clopidogrel, non-responders, recurrent cardiovascular event, stenting.IntroductionIn combination with aspirin, clopidogrel is now the treatmentof choice to prevent stent thrombosis in patients undergoingpercutaneous coronary intervention (PCI) [1] and to reducemajor adverse cardiovascular (CV) events in patients withnon-ST segment elevation acute coronary syndrome (NSTEACS) [2,3].Nevertheless, numerous studies have reported inter-individ-ual variability in platelet response to clopidogrel [4–10] andaspirin [11], and identified patientswho didnotachieveplateletinhibition as low-responders or resistants.The concept of clopidogrel resistance has increasinglyemerged in the literature but its clinical relevance, as a riskfactor for thrombotic events, has been explored in only twosmall studies [12,13]. In these studies, response to clopidogrelwas defined as the difference between baseline and post-treatment maximal intensity of platelet aggregation [4–10].Several issues can be raised regarding this approach: first it didnot take into account the absolute level of pre and post-treatment platelet activity and second it is not suitable for dailyclinical practice as the majority of ACS patients are urgently-treated and many others are already on chronic clopidogrel oraspirin therapy at the admission to the hospital. In addition,recent studies support that post-platelet reactivity is a betterestimate of thrombotic risk rather than clopidogrel responsive-ness [5,14]Accordingly, we analyzed the inter-individual variabilityin platelet response to clopidogrel and aspirin based on a

Background The clinical benefit of ticagrelor compared to clopidogrel in ACS patients suggested off-target property. Such pleiotropic effect could be mediated by circulating endothelial progenitor cells (EPC) which are critical for vascular healing. We aimed to investigate the impact of ticagrelor on EPC in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Methods We prospectively randomized 106 ACS patients to ticagrelor or clopidogrel. Sub-populations of CD34+ circulating progenitor cells (PC) were analyzed by flow cytometry allowing one to determine the levels of CD34+ PC, CD34+CD45+ Hematopoietic PC, CD34+133+ immature PC and CD34+KDR+ EPC on admission and at 1month. Changes in PC level were calculated as the difference between 1month and baseline value. Results The 2 groups were similar regarding baseline characteristics including PC numbers on admission. The 2 groups had similar change in overall CD34+ PC and hematopoietic CD34+45+ PC level (p=0.2). On the contrary, when considering CD34+133+ PC and CD34+KDR+ EPC, we observed that patients treated by ticagrelor had a significantly higher increase in levels of these PC subtypes compared to those treated by clopidogrel (0.23 (−0.33; 0.79) vs 0.00 (−0.5; 0.34); p=0.04 and 0.01 (−0.04; 0.05) vs −0.01 (−0.06; 0.03); p=0.02). Changes in the level of CD34+CD133+ PC correlated with platelet activity measured by the VASP index (r=−0.30; p=0.008). By contrast the increase in the level of CD34+KDR+ EPC in the ticagrelor group was independent of platelet activity. Conclusions Ticagrelor increases the number of EPC in ACS patients suggesting a benefit on endothelial regeneration that may participate in the pleiotropic property of the drug.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Platelet activity is critical in coronary artery disease patients to prevent acute thrombotic complications [(1)][1]. Indeed, an extensive literature has clearly demonstrated that the level of platelet reactivity (PR) inhibition correlated with the clinical outcome including cardiovascular death

The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥50%.One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17±14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6-22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p=0.9).In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index16%.

Prasugrel is a new-generation thienopyridine that exhibits a more potent, less variable, and faster platelet blockade of the purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) -adenosine diphosphate (ADP) receptor compared with clopidogrel, as demonstrated by the results of early phase studies

SummaryPlatelet response to clopidogrel shows inter-individual variability that is partially explained by genetic polymorphisms. This variability affects clinical outcome when clopidogrel is administered in patients with acute coronary syndrome (ACS). Catecholamines, released during ACS, contribute to platelet aggregation through platelet α2A- (α2A-AR) and β2-adrenergic receptor (β2-AR) stimulation. It was the objective of this study to assess the potential influence of α2A-AR and β2-AR gene polymorphisms on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel in ACS. We screened 641 ACS patients for 6.3/6.7 kb α2A-AR polymorphism, and for Arg16Gly and Gln27Glu β2-AR polymorphism. After 600 mg clopidogrel, we assessed ADP 10 μmol-induced platelet aggregation (ADP-Ag) and vasoactive stimulated phosphoprotein (VASP). All single nucleotide polymorphisms were in Hardy-Weinberg equilibrium. A slight though negligible association was found between 6.3 kb allele of α2A-AR with platelet reactivity ADPAg induced (beta: –2.91 [-5.68;-0.14], p=0.04). A borderline not significant reduction in PRI VASP was observed in 6.3 kb α2A-AR carriers (beta: –3.81 [-0.09;7.72], p=0.06). No significant effect on platelet parameters was observed for the other tested polymorphisms. Common α2A- and β2-adrenergic receptor polymorphisms do not show any major impact on residual platelet reactivity in non-ST-elevation ACS when a dual antiplatelet therapy with 250 mg aspirin and 600 mg clopidogrel is administered.

A low response to clopidogrel has been associated with an increased risk of stent thrombosis. However, the definition of a nonresponse to clopidogrel remains controversial, and different tests have been used to assess the clopidogrel response. The present study was designed to assess the predictive value of adenosine diphosphate (ADP)-induced platelet aggregation (ADP-Ag) and the Platelet Reactivity Index of vasodilator-stimulated phosphoprotein for the occurrence of stent thrombosis in patients admitted for non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention. A total of 598 consecutive patients with non-ST-elevation acute coronary syndrome undergoing coronary stenting were prospectively included. They received 600 mg of clopidogrelor=12 hours before percutaneous coronary intervention. Acute or subacute definite or probable stent thrombosis occurred in 11 patients (1.8%). These patients had significantly greater ADP-Ag compared to patients free of stent thrombosis (68 +/- 14% vs 56 +/- 19%, p = 0.002) but only a trend toward a greater Platelet Reactivity Index of vasodilator-stimulated phosphoprotein (62 +/- 14% vs 53 +/- 23%, p = 0.19). The construction of receiver operating characteristic curves to examine the most predictive value of ADP-Ag for stent thrombosis gave a threshold of ADP-Ag of67% to identify low responders. These patients were at a greater risk of stent thrombosis than the clopidogrel responders (4.3% vs 0.8%, odds ratio 5.8, 95% confidence interval 1.9 to 24.6, p = 0.003). In conclusion, in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ADP-Ag is a good parameter to identify clopidogrel nonresponders who are at increased risk of stent thrombosis, with a cutoff value of ADP-Ag of67%.

Objectives We have prospectively investigated the association between aspirin and clopidogrel responses and the clinical predictors of non response. Methods 635 Non ST Elevation Acute Coronary Syndrome (NSTE ACS) patients were included and received loading doses of 250 mg aspirin and 600 mg clopidogrel. We analyzed post-treatment maximal intensity of arachidonic acid and ADP-induced platelet aggregation (AA-Ag and ADP-Ag) and Platelet Reactivity Index of VAsodilator-Stimulated Phosphoprotein (PRI VASP). Aspirin and clopidogrel non responses were defined respectively by AA-Ag > 30% and ADP-Ag > 70%. Results Aspirin non responders patients had significantly higher ADP-Ag and PRI VASP than aspirin responders: 63.7 ± 15.9% vs 55 ± 19% (p = 0.0001) and 73.6 ± 13.3% vs 53 ±23% (p = 0.0001) respectively and the rate of clopidogrel non responders was higher among aspirin non responders than aspirin responders: 36.7% vs 22.7% (p = 0.003). In addition, clopidogrel non responders had significantly higher AA-Ag and rate of aspirin non responders than clopidogrel responders: 21.6 ± 24% vs 10.3 ± 19% (p = 0.0001) and 22.8% vs 12.9% (p = 0.003) respectively. Age and Body Mass Index (BMI) were significantly associated with non response to Clopidogrel (p = 0.035 and 0.02 respectively) and diabetes mellitus by trend (p = 0.07). Conclusion We observed a relationship between aspirin and clopidogrel non responses and an association between age, BMI and diabetes mellitus and clopidogrel response.