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For decades, numerous observations have shown an intimate relationship between von Willebrand factor (VWF) multimer profile and heart valve diseases (HVD). The current knowledge of the unique biophysical properties of VWF helps us to understand the longstanding observations concerning the bleeding complications in patients with severe HVD. Not only does the analysis of the VWF multimer profile provide an excellent evaluation of HVD severity, it is also a strong predictor of clinical events. Also of importance, VWF responds within minutes to any significant change in hemodynamic valve status, making it an accurate marker of the quality of surgical and transcatheter therapeutic interventions. The authors provide in this review a practical, comprehensive, and evidence-based framework of the concept of VWF as a biomarker in HVD, advocating for its implementation into the clinical decision-making process besides usual clinical and imaging evaluation. They also delineate critical knowledge gaps and research priorities to definitely validate this concept.

BACKGROUND Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown. OBJECTIVES To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding. PATIENTS/METHODS A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration. RESULTS GI bleeding source localization was significantly improved when including VCE exploration (P

International audience

Significant paravalvular regurgitation (PVR) remains a relatively frequent (4% to 9%) and deleterious complication of transcatheter aortic valve replacement (TAVR), even with the latest generation of bioprosthesis. Although mini-invasive TAVR without general anesthesia or transesophageal echocardiography (TEE) is progressively becoming the predominant approach, identification and grading of PVR in the catheterization laboratory remain an important and challenging clinical issue. The authors discuss how a recently reported blood biomarker reflecting the von Willebrand factor activity, that is, the closure time with adenosine diphosphate, can be successfully applied during the TAVR procedure to detect and monitor PVR in real time, with an excellent negative predictive value. This point-of-care testing performed directly in the catheterization laboratory may improve the diagnosis of PVR and rationalize the decision of whether or not to perform corrective measures. They further discuss how such a test could be a substitute for the multimodal approach combining TEE, hemodynamics, and cine-angiography, and help to secure the transition to the mini-invasive approach and facilitate the expanding indications of less invasive procedures to lower-risk patients without jeopardizing procedural and clinical outcomes.

International audience; Background: The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied.Objectives: The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS.Methods: We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS.Results: We demonstrated the proteolytic degradation of VWF multimers by high shear CF-MCS in a circulatory loop without pulsatility. We observed both in swine models and in a patient that the magnitude of the VWF degradation is modulated by the pulsatility level in the high shear-stress level condition, and that the restoration of pulsatility is a trigger for the endothelial release of VWF.Conclusions: We demonstrated that the VWF defect reflects the balance between degradation induced by the shear stress and the endothelial release of new VWF triggered by the pulsatility. This modulation of VWF levels could explain the relationship between pulsatility and bleeding observed in CF-MCS recipients. Preservation of pulsatility may be a new target to improve clinical outcomes of patients.

Calcific aortic valve disease (CAVD) affects 2–6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved. Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls. Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC. Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.

Importance The risk of postoperative pulmonary embolism has been reported to be highest during the first 5 weeks after surgery. However, how long the excess risk of postoperative pulmonary embolism persists remains unknown. Objective To assess the duration and magnitude of the late postoperative risk of pulmonary embolism among cancer-free middle-aged patients by the type of surgery. Design, Setting, and Participants Case-crossover analysis to compute the respective risks of pulmonary embolism after 6 types of surgery using data from a French national inpatient database, which covers a total of 203 million inpatient stays over an 8-year period between 2007 and 2014. Participants were cancer-free middle-aged adult patients (aged 45 to 64) with a diagnosis of a first pulmonary embolism. Exposures Hospital admission for surgery. Surgical procedures were classified into 6 types: (1) vascular surgery, (2) gynecological surgery, (3) gastrointestinal surgery, (4) hip or knee replacement, (5) fractures, and (6) other orthopedic operations. Main Outcomes and Measures Diagnosis of a first pulmonary embolism. Results A total of 60 703 patients were included (35 766 [58.9%] male; mean [SD] age, 56.6 [6.0] years). The risk of postoperative pulmonary embolism was elevated for at least 12 weeks after all types of surgery and was highest during the immediate postoperative period (1 to 6 weeks). The excess risk of postoperative pulmonary embolism ranged from odds ratio (OR), 5.24 (95% CI, 3.91-7.01) for vascular surgery to OR, 8.34 (95% CI, 6.07-11.45) for surgery for fractures. The risk remained elevated from 7 to 12 weeks, with the OR ranging from 2.26 (95% CI, 1.81-2.82) for gastrointestinal operations to 4.23 (95% CI, 3.01-5.92) for surgery for fractures. The risk was not clinically significant beyond 18 weeks postsurgery for all types of procedures. Conclusions and Relevance The risk of postoperative pulmonary embolism is elevated beyond 6 weeks postsurgery regardless of the type of procedure. The persistence of this excess risk suggests that further randomized clinical trials are required to evaluate whether the duration of postoperative prophylactic anticoagulation should be extended and to define the optimal duration of treatment with regard to both the thrombotic and bleeding risks.

For decades, numerous observations have shown an intimate relationship between von Willebrand factor (VWF) multimer profile and heart valve diseases (HVD). The current knowledge of the unique biophysical properties of VWF helps us to understand the longstanding observations concerning the bleeding complications in patients with severe HVD. Not only does the analysis of the VWF multimer profile provide an excellent evaluation of HVD severity, it is also a strong predictor of clinical events. Also of importance, VWF responds within minutes to any significant change in hemodynamic valve status, making it an accurate marker of the quality of surgical and transcatheter therapeutic interventions. The authors provide in this review a practical, comprehensive, and evidence-based framework of the concept of VWF as a biomarker in HVD, advocating for its implementation into the clinical decision-making process besides usual clinical and imaging evaluation. They also delineate critical knowledge gaps and research priorities to definitely validate this concept.

Significant paravalvular regurgitation (PVR) remains a relatively frequent (4% to 9%) and deleterious complication of transcatheter aortic valve replacement (TAVR), even with the latest generation of bioprosthesis. Although mini-invasive TAVR without general anesthesia or transesophageal echocardiography (TEE) is progressively becoming the predominant approach, identification and grading of PVR in the catheterization laboratory remain an important and challenging clinical issue. The authors discuss how a recently reported blood biomarker reflecting the von Willebrand factor activity, that is, the closure time with adenosine diphosphate, can be successfully applied during the TAVR procedure to detect and monitor PVR in real time, with an excellent negative predictive value. This point-of-care testing performed directly in the catheterization laboratory may improve the diagnosis of PVR and rationalize the decision of whether or not to perform corrective measures. They further discuss how such a test could be a substitute for the multimodal approach combining TEE, hemodynamics, and cine-angiography, and help to secure the transition to the mini-invasive approach and facilitate the expanding indications of less invasive procedures to lower-risk patients without jeopardizing procedural and clinical outcomes.

Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. Summary Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters.

Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR.We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation.After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year.The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.).

L’objectif est d’analyser les non-conformites (NC) des demandes de PSL depuis la mise en place en 2015 d’une prescription informatisee sur le logiciel eTrace Line (Mak System) couple a un logiciel de signature numerique RGS** (Bull) en comparaison aux donnees precedentes (2010, 2008). Au total, 260 demandes ont ete recueillies aleatoirement sur diverses tranches horaires, a l’aide d’une grille « type ». Les NC etaient listees selon leur type et leur gravite potentielle : NC « majeure » si retard de livraison d’une demande urgente et/ou risque transfusionnel pour le patient (erreur de patient, de protocole…). En 2017, 88 demandes avec ≥ 1 NC ont ete trouvees versus 131 en 2010 (p = 0,0002); 6 d’entre elles etaient « graves » versus 14 en 2010. Leur analyse a mis en evidence une reduction des erreurs de choix de produits et une amelioration de la mise a disposition du bilan immuno-hematologique (IH). A l’inverse, elle revele une inconstance dans l’utilisation de la signature numerique, des erreurs au niveau de la quantite de PSL souhaitee et des oublis de prelevements IH. La collaboration etroite avec les prescripteurs a permis d’instaurer un systeme de prescription informatisee ergonomique et securise entre le CHRU et l’EFS, dans le cadre d’un projet d’amelioration de l’organisation du systeme transfusionnel. La prescription informatisee a permis d’ameliorer la conformite des prescriptions grâce au parametrage : champs obligatoires a renseigner, protocoles automatiques declenches par des donnees IH, d’identite et de pathologie. Elle a permis de developper un transport des PSL dans les services par pneumatique, reduisant ainsi le delai d’acheminement en cas d’urgence vitale. Integree depuis fin 2017 dans le logiciel EFS, elle evite les erreurs de saisie. Cette etude revele cependant de nouveaux risques : un manque de signature numerique et de coordination medecins/IDE et surtout des erreurs d’identite patiente, pour lesquels des actions correctives sont en cours d’elaboration.

SummaryVon Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speeddependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWDpatients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWFproteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.Supplementary Material to this article is available online at www.thrombosis-online.com.

Objectif Analyser les avantages et inconvenients de 2 dispositifs de controle ultime au lit du malade : ABTest Card (Diagast) et carte Serafol (BioRad) dans l’hypothese d’un remplacement de la safety card AB (Diagast) utilisee avec satisfaction depuis plus de 15 ans dans notre centre. Methode Soixante-trois evaluations comparant ces 2 dispositifs ont ete effectuees par des soignants (55 IDE, 3 IADE et 5 medecins) au cours de reunions organisees dans differentes unites de soins a l’aide d’un questionnaire valide en CSTH. Une note de satisfaction de 1 (tres insatisfait) a 5 (tres satisfait) a ete attribuee a des criteres de presentation, realisation et lecture ainsi qu’une note de satisfaction en comparaison du dispositif actuel de 1 (tres inferieur) a 5 (tres superieur). Resultats La note de satisfaction globale obtenue etait similaire pour les 2 dispositifs (3,7 vs 3,6). Cependant l’hygiene et la facilite pour deposer le sang etaient mieux notees avec l’ABTest Card, tandis que les conditions de stockage et la rapidite de realisation/lecture l’etaient avec la carte Serafol. Avec ABTest Card, la note de satisfaction en comparaison du dispositif actuel etait de 3,3 (vs 2,6 avec Serafol) en raison de l’amelioration de l’hygiene du dispositif et de l’absence de risque de contamination entre les zones reactives. Les notes etaient dispersees, le changement de mode operatoire et de lecture de la reaction (chromogenique) apparaissant tres positif pour certains et perturbant pour d’autres. Les soignants semblent peu genes par le changement de sens de lecture de la carte Serafol, le mode de realisation et de lecture etant, par ailleurs, comparable au dispositif actuel. Par contre, la taille de la carte limite la place pour noter les informations necessaires et favorise une contamination entre les puits. Ce travail se poursuit par une enquete sur les difficultes rencontrees en cas de changement et les moyens d’y remedier afin d’assurer la securite transfusionnelle et limiter le risque d’erreur.