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International audience; Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is associated with the highest incidence of venous thromboembolism (VTE) of any cancer type. However, little is known about risk factors for VTE or its outcomes in patients with PDAC.Methods: We collected data from a prospective, observational study performed at multiple centers in France from May 2014 through November 2018 (the Base Clinico-Biologique de l'Adénocarcinome Pancréatique [BACAP] study) linked to a database of patients with a new diagnosis of PDAC of any stage. Data were collected from 731 patients at baseline and during clinical follow-up or in the event of symptoms. The primary endpoint was the onset of VTE during follow-up. The secondary endpoints were progression-free survival (PFS) and overall survival (OS) times.Results: During a median follow-up of 19.3 months, 152 patients (20.79%) developed a VTE. The median time from PDAC diagnosis to the onset of VTE was 4.49 months. Cumulative incidence values of VTE were 8.07% (95% confidence interval [CI], 6.31-10.29) at 3 months and 19.21% (95% CI, 16.27-22.62) at 12 months. In multivariate analysis, PDAC primary tumor location (isthmus vs head: hazard ratio [HR], 2.06; 95% CI, 1.09-3.91; P = .027) and stage (locally advanced vs resectable or borderline: HR, 1.66; 95% CI, 1.10-2.51, P = .016; metastatic vs resectable or borderline: HR, 2.50; 95% CI, 1.64-3.79; P < .001) were independent risk factors for the onset of VTE. Patients who developed VTE during follow-up had shorter times of PFS (HR, 1.74; 95% CI, 1.19-2.54; P = .004) and OS (HR, 2.02; 95% CI, 1.57-2.60; P < .001).Conclusion: In an analysis of data from the BACAP study, we found that frequent and early onsets of VTE after diagnoses of PDAC are associated with significant decreases in times of PFS and OS. Studies are needed to determine whether primary prophylaxis of VTE in patients with PDAC will improve morbidity and mortality related to VTE. (ClinicalTrials.gov, Number: clinicaltrials.gov as number NCT02818829).

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This article has been withdrawn at the request of the publisher. The article was submitted for inclusion in the Supplement of full papers from the 8th International Symposium on Women's Health Issues in Thrombosis and Haemostasis (WHITH), to be published in 2019, but on acceptance it was mistakenly treated as if it were a regular article in the Journal. The article will feature in the Supplement. The Publisher apologizes to the authors of this article and to readers for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal .

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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.

International audience; Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients and leads to a significant increase in health care costs. Cancer patients often suffer from multiple co-morbidities and have both a greater risk of VTE recurrence and bleeding compared to non-cancer patients. Anticoagulation is therefore challenging. For many years, long-term therapy with Low-Molecular-Weight Heparin (LMWH) was the standard of care for the management of cancer-associated VTE. Direct oral anticoagulants (DOAC), which offer the convenience of an oral administration and have a rapid onset of action, have recently been proposed as a new option in this setting. Head-to-head comparisons between DOAC and LMWHs for the treatment of established VTE are now available, and data on the efficacy and safety of these drugs for primary prophylaxis of VTE in ambulatory cancer patients receiving systemic anticancer therapy are emerging. This narrative review aims to summarize the main recent advances in the prevention and treatment of cancer-associated VTE, including recent data on the use of individualized factors to stratify the risk of VTE in each individual patient, quality-of-life in patients treated with LMWH, and the place that DOACs will likely take in the cancer-associated VTE management landscape.

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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.

We report herein the successful perioperative management of a 57-year-old man with a type I Glanzmann thrombasthenia undergoing coronary artery bypass graft surgery and right carotid endarterectomy. The patient suffered from several lesions in the three major coronary arteries and in the right carotid necessitating surgery. Prophylactic human leukocyte antigen (HLA)-matched platelets transfusions were continuous administrated before, and through the immediate perioperative period. Posttransfusion platelet recovery was monitored using flow cytometry to determine the percentage of circulating platelet expressing CD61 (β3). No bleeding complications occurred during and following the procedure. The patient did not develop HLA antibodies or αIIbβ3 antibodies. Thrombophilia screening revealed a heterozygous G20210A prothrombin gene mutation. The patient also suffered from an atrial fibrillation, necessitating anticoagulation therapy. During the hospital stay, a treatment with vitamin K antagonists for stroke prevention was initiated. The patient was discharged 8 days following surgery, and no further complications occurred during the 6 months follow-up.

International audience; Background: Light transmission aggregometry (LTA) is considered as the gold standard for testing platelet function in the setting of both platelet disorders suspicion and response to antiplatelet therapy evaluation. LTA requires however specialized equipment, substantial blood sample volumes, is technically challenging and time-consuming.Aim: To evaluate an automated platelet aggregation method performed on a routine coagulation analyzer Sysmex CS-2000i. Methods: 46 patients presenting a bleeding syndrome and 62 patients with acute coronary syndrome receiving dual antiplatelet therapy were studied in total. Platelet aggregations were performed on CS-2000i equipped with a dedicated software and on APACT-4004 (Elitech, France) as the reference instrument. Aggregation was measured by monitoring the changes in light absorbance occurring in response to ADP 2.5, 5 and 10µM, collagen 3.3 µg/mL, epinephrin 10µM, ristocetin 1.25 mg/mL and arachidonic acid 0.5 mg/mL in platelet rich plasma (PRP). PRP were tested simultaneously on both CS-2000i and APACT-4004 devices. Platelet stirred speed were 800 rpm for both instruments.Results: Significant correlations were observed between CS-2000i and LTA after all stimulations (p< 0.001). Patients presenting a bleeding syndrome had similar aggregation profiles with both methods. A single patient presented a severe platelet disorder (Glanzmann Thrombasthenia) and its PRP showed defective aggregation in response to all agonists except ristocetin with both instruments. Finally, the inter-agreement rates for CS-2000i and APACT-4004 to detect low responders to thienopyridines or aspirine were strong (weighted kappa> 0.70).Conclusion: Platelet aggregation on the routine coagulation analyzer CS-2000i is an easily accessible, handy, reliable, standardized, and rapid tool to assess platelet function which allows to skirt most of the LTA limitations.

Introduction L’infarctus renal est une pathologie rare qui doit etre evoque devant tout syndrome douloureux lombaire. Les causes les plus frequentes sont les pathologies emboligenes, la fibrodysplasie de l’artere renale ou un traumatisme. Observation Un homme de 46 ans, sans antecedent, hormis un tabagisme de 23 paquets-annee sevre depuis 6 ans, presente une lombalgie droite irradiant en hemi-ceinture, vingt-quatre heures apres une seance d’osteopathie avec compression abdominale majeure. Les douleurs etaient permanentes, associees a des nausees et des vomissements. L’examen physique etait normal. L’echographie abdomino-pelvienne etait normale ; le scanner abdomino-pelvien avec injection de produit de contraste retrouvait une thrombose de l’artere renale droite avec defaut de rehaussement du pole inferieur du rein droit evoquant un infarctus renal. Biologiquement, on ne notait pas de syndrome inflammatoire, le ionogramme sanguin et la fonction renale etaient normaux. Le taux de LDH etait augmente a 1863 UI/l. Absence de proteinurie et d’hematurie microscopique. Un traitement par heparine en IVSE a ete debute, relaye secondairement par voie sous-cutanee avant l’instauration d’un traitement par antivitamine K per os. Le bilan etiologique a elimine une cause emboligene : ECG, Holter-ECG, echographie cardiaque transthoracique, angioscanner de la crosse aortique normaux. La numeration formule sanguine etait normale. Absence d’anticorps antiphospholipides et de cryoglobuline. Le scanner ne retrouvait pas d’anomalie en faveur d’une dysplasie. Le patient a ete revu en consultation a un et 3 mois. Le scanner de controle montrait une repermeabilisation de l’artere renale. Le traitement par antivitamine K a ete stoppe au bout de six mois. Discussion La thrombose de l’artere renale touche habituellement la partie proximale ou le tiers moyen du tronc principal, tandis qu’un embole touchera preferentiellement les branches peripheriques de l’artere renale. Dans notre cas, aucun facteur a l’origine de l’infarctus renal n’a ete identifie, hormis la compression majeure et soutenue de la paroi abdominale durant la seance d’osteopathie. Les mecanismes traumatiques sont bien decrits dans la litterature. Devant la normalite du bilan etiologique, l’origine post-traumatique a ete retenue. Conclusion L’infarctus renal est une pathologie rare dont l’origine traumatique est connue. Le recours a des therapeutiques alternatives doit se faire de maniere encadree et douce.

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.

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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.

International audience; Previous epidemiologic studies investigating central venous catheter (CVC)-related venous thromboembolism (CRT) were conducted in heterogenous cancer populations and data in breast cancer (BC) remain limited. To investigate the Doppler ultrasound (DUS)-CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS-CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS-CRT patients, a nested case–control study analyzed the role of thrombophilia. Among 524 patients, the DUS-CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS-CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS-CRT. Age >50 years (OR, 1.80; 95% CI, 1.01–3.22), BMI >30 kg/m² (OR, 2.64; 95% CI, 1.46–4.76) and comorbidities (OR, 2.05; 95% CI, 1.18–3.56) were associated with DUS-CRT. No biomarkers was found to predict DUS-CRT. In multivariate analysis, BMI >30 kg/m² (OR, 2.66; 95%CI, 1.46–4.84) and lobular carcinoma histology (OR, 2.56; 95%CI, 1.32–4.96) remained the only significant DUS-CRT risk factors. Thrombophilia did not account for DUS-CRT. Only clinical parameters identified high risk DUS-CRT patients who may be considered for thromboprophylaxis.

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.

Venous thromboembolism (VTE) is a common complication in patients with cancer and is associated with poor prognosis. Low-molecular-weight heparins (LMWHs) are the standard of care for the treatment of cancer-associated thrombosis. Primary VTE prophylaxis with LMWH is recommended after cancer surgery and in hospitalized patients with reduced mobility. However, owing to wide variations in VTE and bleeding risk, based on disease stage, anti-cancer treatments, and individual patient characteristics, routine primary prophylaxis is not recommended in ambulatory cancer patients undergoing chemotherapy. Efforts are under way to validate risk assessment models that will help identify those patients in whom the benefits of primary prophylaxis will outweigh the risks. In recent months, long-awaited dedicated clinical trials assessing the direct oral anticoagulants (DOACs) in patients with cancer have reported promising results. In comparison with the LMWHs, the DOACs were reported to be non-inferior to prevent VTE recurrence. However, there was an increased risk of bleeding, particularly in gastrointestinal cancers. Safe and optimal treatment with the DOACs in the patient with cancer will require vigilant patient selection based on patient characteristics, co-morbidities, and the potential for drug–drug interactions.

Le congres de l’ASCO est un congres de cancerologie pure ou la part reservee a la thrombose veineuse, que ce soit la thrombose veineuse profonde des membres inferieurs (TVP) ou l’embolie pulmonaire (EP), est habituellement faible. Les publications sur les thromboses sur catheter veineux central, qui representent quand meme 3 % des patients uniquement pour les evenements symptomatiques, sont encore plus rares. Cette edition 2015 qui, comme les annees precedentes, s’est deroulee [...]

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

SummarySymptomatic venous thromboembolism (VTE) occurs 4-7 times more frequently in cancer patients as compared to non-cancer patients. A significant number of risk factors, which can be subcategorised as patient-, cancer- or treatment-related, have been shown to influence the risk of VTE during malignancy and further incorporated in risk-assessment models. Safe and efficient thromboprophylaxis regimens allow substantial decreased in VTE rates, since VTE is most often a largely preventable disease, but thromboprophylaxis remains underused in cancer compared to non-cancer patients. If thromboprophylaxis is warranted in cancer patients undergoing surgery or hospitalised for acute medical illness or with a lower mobility in the absence of contraindications to anticoagulants, its benefit remains controversial in outpatients and may be limited to locally advanced or metastatic pancreatic or lung cancer treated with chemotherapy. The International Initiative on Thrombosis and Cancer-CME free mobile app (ios and android), based on the International Clinical Practice Guidelines (CPG), facilitates their implementation and dissemination of knowledge worldwide so as to improve VTE treatment and prophylaxis in cancer patients.

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

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

L’association entre thrombose et cancer est a ce jour clairement etablie. Le risque de la maladie thromboembolique veineuse (MTEV) chez le patient atteint de cancer varie selon differents facteurs lies au patient, a la tumeur elle-meme et au traitement. Ainsi, le lien etroit entre la MTEV et le type de cancer est complexe et du a des interconnexions entre la progression tumorale, le processus inflammatoire et l’hemostase. Plusieurs biomarqueurs ont ete identifies dans la detection de thromboses chez les patients atteints de cancer. Cette revue se propose de faire une synthese des biomarqueurs conventionnels, utilises en routine et inclus dans des scores de risques, et de discuter des biomarqueurs emergents.

For a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1–ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis.

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.

Introduction Les recommandations internationales pour le traitement curatif de la maladie thromboembolique veineuse (MTEV) constituee chez les malades atteints de cancer reposent sur l’utilisation prolongee des heparines de bas poids moleculaire (HBPM). Les anticoagulants oraux directs (AOD) n’ont pas ete compares aux HBPM dans ce contexte clinique et en l’absence de donnees probantes, ils ne doivent pas etre utilises en premiere intention. Cependant, des etudes observationnelles recentes montrent que ceux-ci sont de plus en plus souvent prescrits. Malades Nous rapportons 3 cas de patients traites par AOD pour MTEV constituee dans un contexte de neoplasie et discutons le mauvais usage et la iatrogenie potentielle de ces medicaments. Le premier cas est celui d’une patiente de 57 ans ayant presente une embolie pulmonaire traitee par dabigatran dans un contexte d’adenocarcinome infiltrant du sein droit traite par chimiotherapie et hormonotherapie. Le second cas est celui d’un patient de 73 ans traite par rivaroxaban pour une thrombose veineuse proximale diagnostiquee dans un contexte de cancer colorectal traite par hemicolectomie droite et chimiotherapie adjuvante. Le troisieme cas est celui d’un patient de 75 ans traite par apixaban au long cours pour MTEV recidivante dans un contexte d’adenocarcinome de la prostate traite par radiotherapie et hormonotherapie. Discussion Bien que les resultats des analyses en sous-groupes des etudes prospectives randomisees ayant valide l’utilisation des AOD dans le traitement de la MTEV suggerent que, chez les patients atteints de cancer, les AOD reduisent le risque de recidive de MTEV sans augmenter le risque d’hemorragie, en « vie reelle », le risque de iatrogenie lie a l’utilisation de ces medicaments s’avere eleve chez les patients avec multiples comorbidites, dont le cancer, comme en temoignent les resultats des premieres etudes observationnelles publiees sur le sujet. De surcroit, la prise en charge des complications hemorragiques sous AOD, en l’absence d’antidote, est toujours complexe. Conclusion Ces 3 cas cliniques illustrent les dangers potentiels lies au mesusage des AOD chez les patients atteints de cancer. Une plus large diffusion des recommandations de bonne pratique clinique et une collaboration etroite entre oncologues et medecins vasculaires permettront d’eviter les erreurs de prescriptions chez des patients exposes, du fait de leur maladie neoplasique, a un risque accru de iatrogenie.

We read with great interest the paper by Navi et al. [(1)][1] in a recent issue of the Journal . In their work, the authors highlight that patients with incident cancer face a substantially increased short-term risk of myocardial infarction and ischemic stroke, depending on cancer type and stage

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.

AIMS We assessed prospectively the association between occurrence of post-discharge non-CABG-related TIMI major and minor bleeding and post-treatment platelet reactivity in patients with non-ST elevation acute coronary syndrome (NSTE ACS). METHODS AND RESULTS Five hundred and ninety-seven consecutive patients admitted with NSTE ACS were prospectively included. Between hospital discharge and one month follow-up, we observed 16 (2.7%) non-CABG-related TIMI haemorrhagic complications including five (0.84%) major and 11 (1.8%) minor bleeds. Patients with bleeding had significantly lower post-treatment values of ADP-induced aggregation (43+/-14% versus. 56+/-19%, p=0.002) and platelet reactivity index VASP (43+/-14% versus 54+/-23%; p=0.04) and a trend for lower values of arachidonic acid-induced aggregation (2.4+/-5.4 versus 13+/-21; p=0.27). After stratification by quartiles based on post-treatment ADP-induced platelet aggregation, we identified patients in the first quartile as hyper-responders with very low post-treatment platelet reactivity, below

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.

Hereditary factor XI (FXI) deficiency is an autosomal bleeding disorder of variable severity but without a clear relationship between bleeding and FXI levels or mutation location or both. In the present study, the molecular basis of FXI deficiency in 16 patients from 12 families originating from the Marseilles area in the south of France was studied. FXI defect was evidenced by routine laboratory tests showing prolonged activated partial thromboplastin times and decreased factor XI activities. The promotor region, exons 1-15, and the exon-intron boundaries of the FXI gene were sequenced. Four novel mutations were found; three were missense mutations (Cys212Ser, Gly350Arg and Thr381Leu resulting from heterozygote mutation in exon 7, 10 and 11, respectively), and one was a one base deletion in exon 4 that induces a frameshift creating a stop codon four residues later (Thr57Ile fsX4). Eight previously reported mutations were also found. Contrarily to the Jewish, Basques or Briton populations, no recurrent mutation was identified. This cohort also illustrates that bleeding events occur not exclusively and not systematically in severe FXI deficiency but also in patients characterized by a mild FXI deficiency.

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.