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International audience; Background Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays.Objective To develop a pretest score for HIT.Design Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839).Setting Thirty-one tertiary hospitals in France, Switzerland, and Belgium.Patients Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts.Measurements Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results.Results Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); >= 40% decrease in platelet count over

Background: Unfractionated heparin (UFH) is used as an anticoagulant during the atrial fibrillation (AF) ablation procedure to prevent the occurrence of thromboembolic events. Guidelines recommend an activated clotting time (ACT) greater than 300 s (s) based on studies of patients treated with vitamin K antagonist (VKA) for their AF. However, direct oral anticoagulants (DOACs) have supplanted VKAs in AF and are now used as first-line therapy. It is recommended not to interrupt them during the procedure, which could interfere with the ACT measures. Objective: To assess the real-life relationship between ACT, DOAC concentrations, and UFH anti-Xa activity in patients treated by uninterrupted DOAC therapy. Methods: We conducted a single-center retrospective study. We analyzed consecutive patients with AF who underwent catheter ablation under DOAC therapy. Results: In total, 40 patients were included, including 15 (37.5%), 20 (50.0%), and 5 (12.5%) on rivaroxaban, apixaban, and dabigatran, respectively. Baseline ACT was significantly lower in the apixaban group. ACT was linearly correlated with the residual concentration of apixaban and dabigatran but not with rivaroxaban. After UFH injection, ACT was linearly correlated with the anti-Xa activity, regardless of DOAC. Patients in the apixaban group received a higher total dose of UFH during the procedure to achieve a target ACT > 300 s, which resulted in significantly higher anti-Xa activity during the procedure. Conclusion: Our results raise the question of optimal management of intra-procedural heparin therapy and highlight the limitations of the ACT test, particularly in patients on apixaban.

Background Since the onset of the COVID-19 pandemic, several cardiovascular manifestations have been described. Among them, venous thromboembolism (VTE) seems to be one of the most frequent, particularly in intensive care unit patients. We report two cases of COVID-19 patients developing acute pulmonary embolism (PE) after discharge from a first hospitalization for pneumonia of moderate severity. Case summary Two patients with positive RT-PCR test were initially hospitalized for non-severe COVID-19. Both received standard thromboprophylaxis during the index hospitalization and had no strong predisposing risk factors for VTE. Few days after discharge, they were both readmitted for worsening dyspnoea due to PE. One patient was positive for lupus anticoagulant. Discussion Worsening respiratory status in COVID-19 patients must encourage physicians to search for PE since SARS-CoV-2 infection may act as a precipitant risk factor for VTE. Patients may thus require more aggressive and longer thromboprophylaxis after COVID-19 related hospitalization.

International audience; PURPOSE:Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.METHODS:All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.RESULTS:150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p

Background and Objective: Host defence mechanisms to counter virus infection include the activation of the broncho-alveolar haemostasis. Fibrin degradation products secondary to extravascular fibrin breakdown could contribute to the marked increase in D-Dimers during COVID-19. We sought to examine the prognostic value on lung injury of D-Dimers in non-critically ill COVID-19 patients without thrombotic events. Methods: This study retrospectively analysed hospitalized COVID-19 patients classified according to a D-Dimers threshold following the COVID-19 associated haemostatic abnormalities (CAHA) classification at baseline and at peak (Stage 1: D-Dimers less than three-fold above normal, Stage 2: D-Dimers three- to six-fold above normal, Stage 3: D-Dimers six-fold above normal). The primary endpoint was the occurrence of critical lung injuries on chest computed tomography. The secondary outcome was the composite of in-hospital death or transfer to the intensive care unit (ICU). Results: Among the 123 patients included, critical lung injuries were evidenced in 8 (11.9%) patients in Stage 1, 6 (20%) in Stage 2 and 15 (57.7%) in Stage 3 (p = 0.001). D-Dimers staging at peak was an independent predictor of critical lung injuries regardless of the inflammatory burden assessed by CRP levels (OR 2.70, 95% CI (1.50&ndash, 4.86), p &lt, 0.001) and was significantly associated with increased in-hospital death or ICU transfer (14.9 % in Stage 1, 50.0% in Stage 2 and 57.7% in Stage 3 (p &lt, 0.001)). D-Dimers staging at peak was an independent predictor of in-hospital death or ICU transfer (OR 2.50, CI 95% (1.27&ndash, 4.93), p = 0.008). Conclusions: In the absence of overt thrombotic events, D-Dimers quantification is a relevant marker of critical lung injuries and dismal patient outcome.

Dual antiplatelet therapy (DAPT) has been proposed to explain the increased occurrence of bleeding events after transcatheter aortic valve replacement (TAVR) despite no relevant study exploring the extent of platelet inhibition. In the present study, we sought to assess whether P2YPatients were enrolled in a prospective registry at Nouvel Hôpital Civil, Strasbourg, France between February 2010 and May 2019. Vasodilator-stimulated phosphoprotein (VASP) flow cytometry test was assessed 24 h after the procedure. Responder to clopidogrel was defined by a platelet reactivity index ≤50%. The primary endpoint was 90-day major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, myocardial infarction, stroke, and heart failure hospitalization.Of the 828 patients with available VASP monitoring, 491 TAVR patients received preprocedural clopidogrel therapy. Responders were identified in 22% (n = 110) and low responders in 78% (n = 381) of patients. By multivariate Cox regression analysis, responders to clopidogrel (hazard ratio [HR]: 2.09; 95% confidence interval [CI]: 1.13 to 3.79: p = 0.02) and previous PCI (HR: 2.16; 95% CI: 1.02 to 4.68; p = 0.04) were identified as independent predictors of 90-day MACCE. The cumulative event-free survival rate at 90-day was significantly lower in the responder group (p = 0.008; log rank test).In conclusion, appropriate P2Y

Introduction: Cerebral venous thrombosis (CVT) is a rare disease with highly variable clinical presentation and outcome. Etiological assessment may be negative. The clinical and radiological presentation and evolution can be highly variable. The mechanisms involved in this variability remain unknown.Objective: The aim of this multicenter French study registered on ClinicalTrials.gov (NCT02013635) was therefore to prospectively recruit a cohort of patients with cerebral venous thrombosis (FPCCVT) in order to study thrombin generation and clot degradation, and to evaluate their influence on clinical radiological characteristics. The first part of the study was to compare our cohort with a reference cohort.Methods: This prospective, multicenter, French study was conducted from July 2011 to September 2016. Consecutive patients (aged >15 years) referred to the stroke units of 21 French centers and who had a diagnosis of symptomatic CVT were included. All patients gave their written informed consent. The diagnosis of CVT had to be confirmed by imaging. Clinical, radiological, biological, and etiological characteristics were recorded at baseline, at acute phase, at 3 months and at last follow-up visit. Thrombophilia screening and the choice of treatment were performed by the attending physician. All data were compared with data from the International Study on CVT published by Ferro et al.Results: Two hundred thirty-one patients were included: 117 (50.6%) had isolated intracranial hypertension, 96 (41.5%) had focal syndrome. During hospitalization, 229 (99.1%) patients received anticoagulant treatment. Median length of hospital stay was 10 days. Five patients died during hospitalization (2.2%). At 3 months, 216 patients (97.0%) had follow-up with neurological data based on an outpatient visit. The mean duration of antithrombotic treatment was 9 months, and the mean time to last follow-up was 10.5 months. At the end of follow-up, eight patients had died, and 26 patients were lost to follow-up. At least one risk factor was identified in 200 patients.Conclusions: We demonstrated that the FPCCVT cohort had radiological, biological, and etiological characteristics similar to the historical ISCVT cohort. Nevertheless, the initial clinical presentation was less severe in our study probably due to an improvement in diagnostic methods between the two studies.

Introduction Patients with atrial fibrillation (AF) are likely to have multiple co-morbidities and receive anticoagulants after TAVR, which lead to a poor prognosis including bleeding events. Closure time adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test used as a surrogate marker of high molecular weight (HMW) multimers defect of Von Willebrand factor (VWF). Our prior studies suggest that prolongation of CT-ADP (>180 seconds) after TAVR is a major determinant of early and late major/life-threatening bleeding complications (MLBCs). Purpose To evaluate the impact of post-procedural CT-ADP >180sec on bleeding events in AF patients. Methods We included 878 patients from our prospective TAVR registry between 2010 and 2019. Bleeding complications were assessed according to the VARC-2 (Valve Academic Research Consortium-2) criteria. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization within 1-year after TAVR. Ongoing primary haemostasis disorder was defined by post-procedure CT-ADP >180sec. Primary endpoint was the occurrence of MLBCs during the first year and the second endpoint was 1-year MACCE. Results Patients with AF had a higher incidence of all-cause mortality (15% vs. 8%, p=0.002), MACCE (29% vs. 20%, p=0.002), and MLBCs (20% vs. 12%, p=0.001) within 1-year compared to non-AF patients. When the cohort was split into 4 subgroups according to AF and CT-ADP >180sec, patients with AF and CT-ADP >180sec had the highest risk of MLBCs (log-rank test; p180sec had 4.6-fold higher risk of MLBCs within 1 year compared to non-AF patients with CT-ADP ≤180sec (hazard ratio: 4.60; 95% confidence interval: 2.18 - 9.68; p Conclusion Among TAVR patients, AF with post-procedural CT-ADP >180 sec was identified as a strong independent predictor of MLBCs at 1-year follow-up. Our study suggest that persistent primary haemostasis disorders contribute to a higher risk of bleeding events particularly in AF patients and may be considered for a tailored and risk-adjusted antithrombotic therapy after TAVR. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Matsushita received a grant from Edwards Lifesciences.

Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild to severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)–polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA assay (iv) occurring 5 to 30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccination. VITT’s incidence is 1 per 100.000 vaccinated people irrespective of age and up to 1 in 50.000 for people < 50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirus-vectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are sought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia., Graphical Abstract Graphical Abstract

Introduction. Acute pulmonary embolism (APE) is a frequent condition in patients with COVID-19 and is associated with worse outcomes. Previous studies suggested an immunothrombosis instead of a thrombus embolism, but the precise mechanisms remain unknown. Objective. To assess the determinants and prognosis of APE during COVID-19. Methods. We retrospectively included all consecutive patients with APE confirmed by computed tomography pulmonary angiography hospitalized at Strasbourg University Hospital from 1 March to 31 May 2019 and 1 March to 31 May 2020. A comprehensive set of clinical, biological, and imaging data during hospitalization was collected. The primary outcome was transfer to the intensive care unit (ICU). Results. APE was diagnosed in 140 patients: 59 (42.1%) with COVID-19, and 81 (57.9%) without COVID-19. A 812% reduction of non-COVID-19 related APE was registered during the 2020 period. COVID-19 patients showed a higher simplified pulmonary embolism severity index (sPESI) score (1.15 ± 0.76 vs. 0.83 ± 0.83, p = 0.019) and were more frequently transferred to the ICU (45.8% vs. 6.2%, p &lt, 0.001). No difference regarding the most proximal thrombus localization, Qanadli score (8.1 ± 6.9 vs. 9.0 ± 7.4, p = 0.45), the proportion of subsegmental (10.2% vs. 11.1%, p = 0.86), and segmental pulmonary embolism (35.6% vs. 24.7%, p = 0.16) was evidenced between COVID-19 and non-COVID-19 APE. In COVID-19 patients with subsegmental or segmental APE, thrombus was, in all cases (27/27 patients), localized in areas with COVID-19-related lung injuries. Marked inflammatory and prothrombotic biological markers were associated with COVID-19 APE. Conclusions. APE patients with COVID-19 have a particular clinico–radiological and biological profile and a dismal prognosis. Our results emphasize the preeminent role of inflammation and a prothrombotic state in these patients.

Among the distinctive features of coronavirus disease 2019 (COVID-19), numerous reports have stressed the importance of vascular damage associated with coagulopathy onset [1]. Histological analysis of pulmonary vessels in patients with COVID-19 revealed severe endothelial injury associated with intracellular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and disrupted endothelial cell membranes together with widespread thrombosis and occlusion of alveolar capillaries. Microparticles (MPs) shed by apoptotic/stimulated cells of various cellular lineages, including platelets, leukocytes, macrophages or endothelial cells, are reliable markers of vascular damage [2] released upon pro-inflammatory conditions and behave as active participants in the early steps of clot formation [3]. Circulating MPs promote procoagulant responses due to the exposure of tissue factor, the physiological activator of the coagulation cascade, and of negatively charged phospholipids, such as phosphatidylserine, required for the assembly of the tenase and prothrombinase coagulation complexes ultimately leading to thrombin generation, through which they can precisely be quantified [4]. MPs carry angiotensin-converting enzyme (ACE)1 and upregulate ACE1 expression in neighbouring endothelial cells [5]. By contrast, exosomes were recently reported to convey ACE2, the cell-entry receptor for SARS-CoV-2 [4], in the vasculature [6]. ACE2 converts angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7), which by virtue of its actions on the Mas receptor, limits the noxious effects of Ang II. Pioneering data have demonstrated that the renin–angiotensin system has a crucial role in severe acute injury and that ACE2 has a protective role in acute lung injury mediated by SARS-CoV [7]. According to this paradigm, the loss of ACE2 function following binding by SARS-CoV-2 may contribute to unopposed Ang II accumulation that further exacerbates tissue injury and promotes inflammation, MPs release and thrombosis. During SARS-CoV-2 infection, we hypothesised that various factors including inflammatory burden, Ang II, altered shear stress and hypoxic vasoconstriction, could enhance MPs shedding by various cell lineages including the alveolar vascular endothelium and contribute to clot formation., Procoagulant microparticles are associated with the extent of lung injuries in #COVID19 and pulmonary thrombosis https://bit.ly/3eX2LPc

Introduction Current recommendations support short-term dual antiplatelet therapy (DAPT) for patients undergoing transcatheter aortic valve replacement (TAVR) despite no relevant study exploring the extent of platelet inhibition by clopidogrel. Purpose To assess whether P2Y12 inhibition by clopidogrel as evaluated by vasodilator-stimulated phosphoprotein flow cytometry test (VASP-FCT) impacts 1-year clinical outcomes in patients undergoing TAVR. Methods Patients were included in a prospective registry between February 2010 and May 2019. VASP-FCT was assessed 24h after the procedure. Responder to clopidogrel was defined by a platelet reactivity index ≤50%. Results Of 640 patients who underwent TAVR with preprocedural clopidogrel therapy, we enrolled 491 patients for whom VASP data were available. Responders were identified in 22% (n=110) of patients and low responders were 78% (n=381) of patients. Low body mass index, active cancer, and clopidogrel on admission were found to be independent predictors of responder. Mean transaortic pressure gradient was lower in the responder group at 1-month post-TAVR (9.9±4.4 mmHg vs. 11.2±5.8 mmHg, p=0.03) but was similar at 1-year (11.5±6.2 mmHg vs. 11.9±7.4 mmHg, p=0.74). By multivariate Cox regression analysis, patients responding to clopidogrel (hazard ratio [HR]: 2.19; 95% confidence interval [CI]: 1.04 to 3.64; p=0.04), prior PCI (HR: 2.12; 95% CI: 1.07 to 4.37; p=0.03), and mean transaortic pressure gradient at baseline (HR: 0.07; 95% CI: 0.01 to 0.70; p=0.02) were identified as independent predictors of 1-year adverse clinical outcomes, including all-cause death, myocardial infarction, stroke, and heart failure hospitalization. Conclusions Appropriate P2Y12 inhibition by clopidogrel is a major determinant of adverse clinical events after TAVR. In sum, the present data challenges the need of DAPT as a standard therapy during TAVR. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction Paravalvular leakage (PVL) following transcatheter aortic valve replacement (TAVR) is associated with greater mortality. In clinical practice, determining PVL severity after TAVR remains challenging and often requires multiparametric assessment. Purpose This study sought to evaluate the respective value of various modalities of PVL assessments, including transthoracic echocardiography (TTE), cine-angiography, aortic regurgitation index (ARI), and closure time with adenosine diphosphate (CT-ADP), in the prediction of adverse clinical outcomes. Methods We included 1044 patients from our prospective TAVR registry between February 2010 and May 2019. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization within 1-year. Established cutoff values of ARI (180 sec) were used to assess the presence of PVL after TAVR. Results Moderate to severe PVL occurred in 14.2% and 5.2% of patients as measured by TTE and angiography. The rate of patients with ARI 180 sec were 36.5% and 24.9%, respectively. Among the four modalities, PVL evaluated by angiography predicted poorer clinical outcomes (Log rank test; p=0.001), whereas TTE, ARI 180 sec were not associated with 1-year MACCE. By multivariate Cox regression analysis, moderate to severe PVL by angiography was an independent predictor of 1-year MACCE (hazard ratio: 1.96; 95% confidence interval: 1.22–3.00; p=0.007). Conclusions Paravalvular leakage measured by angiography was evidenced as the most meaningful modality in the prediction of adverse clinical outcomes. Future multicenter studies are warranted to ensure these findings in the current TAVR era. Figure 1 Funding Acknowledgement Type of funding source: None

Background New-onset conduction abnormalities (CAs) following transcatheter aortic valve replacement (TAVR) are associated with hospital rehospitalization and long-term mortality, but available predictors are sparse. This study sought to determine clinical predictors of new-onset left bundle branch block (LBBB) and new permanent pacemaker (PPM) implantation in patients undergoing TAVR.Methods and Results:We enrolled 290 patients who received SAPIEN 3 (Edwards Lifesciences, Irvine, CA, USA; n=217) or Evolut R (Medtronic, Minneapolis, MN, USA; n=73) from a prospective registry at Nouvel Hopital Civil, Strasbourg, France between September 2014 and February 2018. Of 242 patients without pre-existing LBBB, 114 (47%) experienced new-onset LBBB and/or new PPM implantation. A difference between membranous septal length and implantation depth (∆MSID) was the only predictor of CAs for both types of valves. In the multivariate analysis, PR interval and ∆MSID remained as sole predictors of CAs. The risk for adverse clinical events, including all-cause death, myocardial infarction, stroke, and heart failure hospitalization, was higher for patients with CAs as compared with patients without CAs (hazard ratio: 2.10; 95% confidence interval: 1.26 to 3.57; P=0.004). Conclusions Computed tomography assessment of membranous septal anatomy and implantation depth predicted CAs after TAVR with new-generation valves. Future studies are required to identify whether adjustment of the implantation depth can reduce the risk of CAs and adverse clinical outcomes.

This is the first study to show a stepwise increase in venous thrombotic events according to COVID-19 coagulopathy (COVID-19-associated hemostatic abnormalities [CAHA]) staging and lung injuries assessed by chest computed tomography. Excess mortality and/or transfer to intensive care unit according to CAHA staging.

Background Stroke is a major cause of disability after transcatheter aortic valve replacement (TAVR) and stroke prediction models and data are crucially needed. Following TAVR, high molecular weight (HMW) multimers defect of von Willebrand factor (VWF) as assessed by closure time of adenosine diphosphate (CT-ADP) value > 180 seconds is an independent predictor of bleeding events. This study sought to identify predictors of ischemic neurological events in patients who underwent TAVR and the specific impact of HMW multimers defect of VWF. Methods Patients were prospectively enrolled between November 2012 and May 2018 at our institution. The CT-ADP, a point-of-care measure of hemostasis, was assessed the day before and 24 hours after the procedures. The rate of ischemic stroke and transient ischemic attack (TIA) was recorded up to 30 days after the procedures. Results Of 565 TAVR patients, ischemic stroke/TIA was observed in 21 (3.7%) patients within 30 days. Ischemic stroke/TIA was associated with major/life-threatening bleeding complications (MLBCs) (9 [43%] vs. 88 [16%], p = 0.002) and postprocedure CT-ADP > 180 seconds (10 [48%] vs. 116 [21%], p = 0.01). By multivariate analysis, MLBCs (odds ratio [OR]: 3.58; 95% confidence interval [CI]: 1.45–8.84; p = 0.006) and postprocedure CT-ADP > 180 seconds (OR: 3.38; 95% CI: 1.38–8.25; p = 0.008) were evidenced as independent predictors of ischemic stroke/TIA. Conclusion MLBCs and CT-ADP > 180 seconds were identified as predictors for ischemic stroke or TIA. The present study suggests that the defects of HMW multimers of the VWFs may contribute not only to bleeding events but also to thrombotic events.

The coagulopathy associated with Coronavirus disease 2019 (COVID-19) leads to a thrombotic burden. To date, solely interim thromboprophylaxis guidance have been established, gaps in evidence are remaining, especially for ambulatory COVID-19 patients. We report a case COVID-19 in a patient with Glanzmann thrombasthenia, a rare platelet disorder associated with a high bleeding tendency. Our experience emphasizes the difficulty to manage such a condition, given the balance between thrombotic and bleeding tendencies, and the unavailability of evidence-based guidelines. Moreover, we detail hereinafter how patient’s bleeding disorder made COVID-19 diagnosis very difficult, thus highlighting the limits in actual SARS-CoV-2 molecular assays.

International audience; The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare communities across the globe on an unprecedented scale. Patients have had diverse clinical outcomes, but those developing COVID-19-related coagulopathy have shown a disproportionately worse outcome. This narrative review summarizes current evidence regarding the epidemiology, clinical features, known and presumed pathophysiology-based models, and treatment guidance regarding COVID-19 coagulopathy.

Only a few studies on real-world clinical use of recombinant factor VIII -fusionned with Fc (rFVIIIFc, efmoroctocog alpha) have been performed to date, with data on the annual bleeding rate (ABR), the prophylaxis regimen, and FVIII consumption. The aim of our study was to report the real-world clinical application of rFVIIIFc with additional elements, both biological and clinical. A prospective monocentric study has been conducted in the Haemophilia treatment center (HTC) of the Strasbourg university hospital among the severe haemophilia A patients. Thirty male patients were enrolled in the study. After injection of rFVIIIFc, the average time spent above 5%, 2% and 1% of FVIII was respectively almost 3, 4 and 5 days. The average half-life was 15.8 hours. A strong linear correlation between incremental recovery of rFVIIIFc and weight and between rFVIIIFc half-life and basal VWF:Ag level was observed. FVIII activity measurement for rFVIIIFc showed similar results than those previously published. In the follow-up, residual FVIII activity was on average the one of a mild haemophilia patient, corroborated by the results of endogenous thrombin potential of the thrombin generation assay. In clinical practice, rFVIIIFc was well tolerated and patients were mostly satisfied or indifferent of the switch. A single failure was however noticed. No FVIII inhibitor has been detected. Decrease in FVIII consumption was observed, with reduced or unchanged ABR. The switch was an actual success for almost all of the 30 patients, corroborated by satisfactory clinical and biological results.

BACKGROUND: Periprocedural and late (>30 days) bleedings represent major complications after transcatheter aortic valve replacement and have been identified as potential areas for improved patient care. OBJECTIVES: The authors sought to evaluate the impact of ongoing primary hemostasis disorders on late major/life-threatening bleeding complications (MLBCs). METHODS: Bleedings were assessed according to the VARC-2 (Valve Academic Research Consortium-2) criteria. Closure time of adenosine diphosphate (CT-ADP), a surrogate marker of high molecular weight von Willebrand multimers proteolysis was assessed 24 h after the procedure. Ongoing primary hemostasis disorder was defined by a CT-ADP >180 s. RESULTS: Among 372 patients who survived at 30 days, MLBCs occurred in 42 patients (11.3%) at a median follow-up of 383 days (interquartile range: 188 to 574 days). MLBCs were mainly of gastrointestinal origin (42.8%) and were associated with increased overall mortality (hazard ratio [HR]: 5.66; 95% confidence interval [CI]: 3.10 to 10.31; p < 0.001) and cardiac mortality (HR: 11.62; 95% CI: 4.59 to 29.37; p < 0.001). A 2.5-fold elevation of MLBCs could be evidenced in patients with a CT-ADP > 180 s (27.4% vs. 11.5%; p < 0.001). Multivariate regression analysis identified paravalvular leak (PVL) (HR: 6.31; 95% CI: 3.43 to 11.60; p < 0.0001) and CT-ADP > 180 s (HR: 3.08; 95% CI: 1.62 to 5.81; p = 0.0005) as predictor of MLBCs. CONCLUSIONS: MLBCs after transcatheter aortic valve replacement are frequent and associated with an increased morbidity and mortality. PVL and CT-ADP >180 s were identified as strong predictors for MLBCs. These findings strongly suggest that persistent HMW defects contribute to enhanced bleeding risk in patients with residual PVL.

Anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW). This may be inaccurate in obese patients and lead to heparin overdose with a risk of bleeding.To validate the efficacy and safety of an adjusted calculation model of heparin dosing based on ideal body weight (IBW) rather than TBW in obese CPB patients, with an expected target mean plasma heparin concentration of 4.5 IU ml after onset of CPB in the experimental group.Randomised controlled study.University hospital.Sixty obese patients (BMI ≥ 30 kg m) scheduled for CPB were included from January to June 2016.Patients received a bolus dose of unfractionated heparin of either 300 IU kg of TBW or 340 IU kg of IBW before onset of CPB. Additional adjusted boluses were injected to maintain an activated clotting time (ACT) of at least 400 s.Plasma heparin concentration and ACT were measured at different time points. Total heparin doses and transfusion requirements were recorded.The target heparin concentration of 4.5 IU ml was reached in the IBW group at the onset of CPB and maintained at all time points during CPB. Heparin concentrations were significantly higher in the TBW group after the bolus (6.52 ± 0.97 vs. 4.54 ± 1.13 IU ml, P 0.001) and after cardioplegia (5.10 ± 1.03 vs. 4.31 ± 1.00 IU ml, P = 0.02). Total heparin doses were significantly higher in the TBW group. Mean ACT was significantly lower in the IBW group but remained over 400 s during CPB. The correlation between heparin and ACT was poor. Peri-operative bleeding and transfusion requirements were comparable. No thrombotic event occurred in the CPB circuit.The current IBW-adjusted regimen of heparin administration may be used efficiently in obese CPB patients, thereby avoiding overdose which cannot be accurately assessed by ACT monitoring alone.ClinicalTrials.gov identifier: NCT02675647.

Background Paravalvular aortic regurgitation (PVAR) remains a frequent postprocedural concern following transcatheter aortic valve replacement (TAVR). Persistence of flow turbulence results in the cleavage of high-molecular-weight von Willebrand multimers, primary haemostasis dysfunction and may favour bleedings. Recent data have emphasized the value of a point-of-care measure of von Willebrand factor–dependent platelet function (closure time [CT] adenosine diphosphate [ADP]) in the monitoring of immediate PVAR. This study examined whether CT-ADP could detect PVAR at 30 days and bleeding complications following TAVR. Methods CT-ADP was assessed at baseline and the day after the procedure. At 30 days, significant PVAR was defined as a circumferential extent of regurgitation more than 10% by transthoracic echocardiography. Events at follow-up were assessed according to the Valve Academic Research Consortium-2 consensus classification. Results Significant PVAR was diagnosed in 44 out of 219 patients (20.1%). Important reduction of CT-ADP could be found in patients without PVAR, contrasting with the lack of CT-ADP improvement in significant PVAR patients. By multivariate analysis, CT-ADP > 180 seconds (hazard ratio [HR]: 5.1, 95% confidence interval [CI]: 2.5–10.6; p 180 seconds was identified as an independent predictor of major/life-threatening bleeding (HR: 1.7, 95% CI [1.0–3.1]; p = 0.049). Major/life-threatening bleedings were at their highest levels in patients with postprocedural CT-ADP > 180 seconds (35.2 vs. 18.8%; p = 0.013). Conclusion Postprocedural CT-ADP > 180 seconds is an independent predictor of significant PVAR 30 days after TAVR and may independently contribute to major/life-threatening bleedings.

Background Dual antiplatelet therapy (DAPT) has been proposed to explain the increased occurrence of major bleeding events after transcatheter aortic valve replacement (TAVR) despite no relevant study exploring the extent of platelet inhibition by clopidogrel. Purpose To assess whether P2Y12 inhibition by clopidogrel as evaluated by vasodilator-stimulated phosphoprotein (VASP) flow cytometry test impacts clinical outcomes in patients undergoing TAVR. Methods Patients were enrolled in a prospective registry at Nouvel Hopital Civil, Strasbourg, France between February 2010 and May 2019. VASP flow cytometry test was assessed 24 h after the procedure. Responder to clopidogrel was defined by a platelet reactivity index ≤ 50%. The primary endpoint was 90-day major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, myocardial infarction, stroke, and heart failure hospitalization. The secondary endpoint was 1-year MACCE. Results Of the 828 patients with available VASP monitoring, we enrolled 491 TAVR patients with preprocedural clopidogrel therapy. Responders were identified in 22% (n = 110) and low responders in 78% (n = 381) of patients. By multivariate Cox regression analysis, patients responding to clopidogrel (hazard ratio [HR]: 2.16; 95% confidence interval [CI]: 1.16 to 3.91: P = 0.02) and previous PCI (HR: 2.24; 95% CI: 1.07 to 4.81; P = 0.03) were identified as independent predictors of 90-day MACCE. The cumulative event-free survival rate at 90-day and 1-year was significantly lower in the responder group ( Fig. 1 ). Conclusions Appropriate P2Y12 inhibition by clopidogrel is a major determinant of 90-day and 1-year post-TAVR adverse clinical events. In sum, the present data challenge DAPT as a standard therapy during TAVR.

BACKGROUND The heparin regimen providing anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW), but may be inaccurate in obese patients in whom TBW exceeds their ideal body weight. OBJECTIVES The objective is to compare the effects of heparin injection based on TBW on haemostatic parameters between obese and nonobese patients during cardiac surgery and to calculate the optimal heparin regimen. DESIGN Prospective comparative study. SETTING University hospital. PATIENTS Two groups of 50 patients (BMI≥ or

International audience; Background: The optimal scheme of thromboprophylaxis in bariatric surgery remains uncertain, because clinical practice is different between countries and randomized trials are lacking. Objectives: The primary objective of this randomized multicenter study was to determine the optimal regimen of enoxaparin providing an antifactor Xa peak activity between .3 and .5 IU/mL at equilibrium and to evaluate the course of procoagulant microparticles (MPs). Setting: University hospital. Methods: A total of 164 patients scheduled for gastric bypass were allocated to 3 groups (A, B, and C) of enoxaparin treatment (4000, 6000, or 2 x 4000 IU, respectively). Antifactor Xa activity was measured before and 4 hours after each injection from DO to D2. Doppler screening of the lower limbs was performed at D1, D9, and D30. Bleeding (BE) and thrombotic events (TE) were recorded during the first postoperative month. Total MPs were measured at DO, D9, and D30. MPs of leucocyte, platelet, and granulocyte origin were assessed in one third of the patients from each group. The 3 groups were compared by ANOVA. Results: A total of 135 patients were analyzed. The equilibrium of antifactor Xa peak levels was obtained 52 hours after the presurgery injection and 12.8%, 56.4%, and 27.3% of the patients reached the target in groups A, B, and C, respectively (P

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been the recommended antithrombotic treatment following transcatheter aortic valve replacement (TAVR) based on the empiric extrapolation from the experiences of percutaneous coronary intervention (PCI). However, several studies have

Background Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock. Methods In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin–eosin for inflammatory injury assessment. Results Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5+-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p

Background Paravalvular aortic regurgitation (PAVR) remains a frequent post-procedural concern following transcatheter aortic valve replacement (TAVR). Persistence of flow turbulence results in the cleavage of high molecular weight von Willebrand multimers, primary hemostasis dysfunction and may favour bleedings. Recent data have emphasized the value of a point-of-care measure of von Willebrand factor-dependent platelet function (closure-time (CT)-ADP) in the monitoring of immediate PA. This study examined whether CT-ADP could detect PAVR at 30 days and bleeding complications following TAVR. Methods CT-ADP was assessed at baseline and the day after the procedure. At 30 days, significant PAVR was defined as a circumferential extent of regurgitation greater than 10% by transthoracic echocardiography. Events at follow-up were assessed according to the VARC-2 classification. Results Significant PAVR was diagnosed in 44/219 patients. Important reduction of CT-ADP could be found in patients without PAVR, contrasting with the lack of CT-ADP improvement in significant PAVR patients. By univariate analysis, a self-expendable valve, valve size ≥ 31 mm and CT-ADP > 180 s were associated with PAVR. By multivariate analysis, CT-ADP > 180 s (HR 5.1 95% CI (2.5–10.6); P 180 s, but not PAVR, was proven to be an independent predictor of major/life-threatening bleeding (HR 1.813 (1.014–3.241); P = 0.045) [ Table 1 , Fig. 1 ]). Conclusion Post-procedural CT-ADP > 180 s is an independent predictor of significant PAVR 30 days after TAVR and may independently contribute to major/life-threatening bleedings. Other parameters such LVEF should be taken into account in the interpretation of prolonged CT-ADP time following valve implantation.

Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course. One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score. Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis. Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.

Background Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC-ox) induces specific morbidity with hemorrhagic complications (HC). The aim of this study was to identify preoperative, intraoperative and postoperative HC predictive factors after HIPEC-ox. Methods A prospective single center study that included all consecutive patients treated with curative-intent HIPEC-ox, whatever the origin of peritoneal disease, was conducted. All patients underwent systematic blood tests exploring primary hemostasis and endothelial activation before surgical incision (D0) and on postoperative days 2 (POD2) and 5 (POD5). Results Between May 2012 and August 2015, 47 patients were enrolled in the study. The overall HC rate was 38%. Major morbidity was significantly higher in patients with HC. Patients presenting HC were significantly more often affected with pseudomyxoma peritonei and had less preoperative chemotherapy. Multivariate analysis showed that a higher plasmatic level of Von Willebrand factor antigen at D0 (D0 VWF:Ag) was a protective predictive factor for HC (p = 0.049, HR: 0.97 CI 95% [0.94–1.00]). A D0 VWF:Ag level below 138% had a sensitivity of 87.5%, a specificity of 67% and an area under the curve of 80.3% (CI 95% [66.5–94], p Conclusions Through the identification of prognostic factors, this study highlighted a subgroup of patients with low risk of HC after HIPEC-ox. Based on these results, we propose a routine preoperative dosage of VWF that would help the surgeon to select the most suitable patients for HIPEC-ox.

IF 7.442; International audience; OBJECTIVES:Inadequate stratification of septic shock patients may result in inappropriate treatment allocation in randomized clinical trials, especially regarding anticoagulant. We previously reported that endothelial-derived microparticles are relevant biomarkers of sepsis-induced disseminated intravascular coagulation. In this validation cohort, we assess microparticles as surrogates of cell activation to improve early disseminated intravascular coagulation diagnosis and patient stratification.DESIGN:Prospective observational study in septic shock patients.SETTINGS:Four medical ICUs in university hospitals.PATIENTS AND METHODS:Two hundred sixty-five patients with septic shock from four ICUs were consecutively enrolled. Disseminated intravascular coagulation was diagnosed according to Japanese Association for Acute Medicine 2006 score. Endothelial- and leukocyte-derived circulating procoagulant microparticles were isolated and quantified by prothrombinase assay at admission, day 3, and day 7.INTERVENTION:None.MEASUREMENTS AND MAIN RESULTS:Two hundred fifty-nine patients were analyzed. Sixty-one had disseminated intravascular coagulation at admission, and 32 developed disseminated intravascular coagulation during the first 24 hours after admission. Multiple logistic regression model confirmed that endothelial cell-derived microparticles were associated with disseminated intravascular coagulation: CD105-microparticles (odds ratio, 2.13) and CD31-microparticles (odds ratio, 0.65) (p < 0.05). Furthermore, CD11a-microparticles to leukocyte ratio evidenced leukocyte activation (odds ratio, 1.59; p < 0.05). Prediction of disseminated intravascular coagulation was also analyzed after exclusion of patients with disseminated intravascular coagulation at admission. A new multiple logistic regression analysis demonstrated the association of CD105-microparticles (> 0.60 nM eq. PhtdSer; odds ratio, 1.67; p < 0.01), platelets count (≤ 127 g/L; odds ratio, 0.99; p < 0.01), and prothrombin time (≤ 58%; odds ratio, 0.98; p < 0.05) with disseminated intravascular coagulation. A combining score at admission is predictive of the absence of disseminated intravascular coagulation (area under the curve, 72.9%; specificity, 71.2%; sensitivity, 71.0%, with a negative predictive value of 93.1% and a positive predictive value of 31.0%).CONCLUSIONS:Procoagulant microparticles from endothelial cells and leukocytes reflect a vascular injury during sepsis-induced disseminated intravascular coagulation that precedes obvious activation of coagulation. A combination of prothrombin time, endothelium-derived CD105-microparticles, and platelet count at admission could predict the absence of disseminated intravascular coagulation and allow a better stratification in future randomized clinical trials.

Introduction The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk. Methods A total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics. Results The diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid. aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition. Conclusion Considering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.

BACKGROUND: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. OBJECTIVES: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. METHODS: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. RESULTS: A total of 24 obese females (39 +/- 10 years) with a mean body mass index of 35 +/- 4 kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels. CONCLUSION: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

Background: To assess the extent of endothelium, platelet, and leukocyte damage and coagulation activation induced by radiofrequency catheter ablation (RF) of atrial flutter. In the vasculature, procoagulant microparticles (MPs) are reliable markers of vascular damage. They provide an additional phospholipidic surface, enabling the assembly of the enzyme complexes of blood coagulation and consequent thrombin generation. Methods: MPs were measured in the venous blood of 33 patients with isthmus-dependent atrial flutter undergoing RF before (RF0), immediately after (RF1), and at day 1 (RF2) thereafter. Concentrations of PAI-1, vWF, and D-dimers were simultaneously determined. MPs procoagulant activities were determined using a functional prothrombinase assay. RF induces an early rise of platelet-derived MPs (platelet), vWF Ag, and D-dimers levels, which is concomitant with the decrease of PAI-1 concentrations. Conversely, no significant changes in endothelial-derived MPs could be evidenced. At RF2, sustained elevation of leukocytes-derived MPs, vWF, and D-dimers testified to an ongoing prothrombotic status. Conclusion: RF ablation of common flutter induces a prothrombotic state and the release of platelet and leukocyte-derived procoagulant microparticles. Whereas this activation of blood coagulation could be viewed as clinically marginal in right-sided procedures, its relevance in left-sided procedures should be established.