Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in von Willebrand disease murine models.

The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant von Willebrand factor (VWF) concentrates have started to emerge. Here, we report an original approach using synthetic platelet (SP) nanoparticles for the treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF, and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SPs to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from mice with VWD-2B and deficient VWF (VWF-KO, ie, type 3 VWD). In vivo, using a tail-clip assay, SP treatment reduced blood loss by 35% in mice with VWD-2B and 68% in mice with VWF-KO. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen-binding peptide, although not sufficient by itself, was crucial for SP efficacy in VWD-2B; whereas all 3 peptides appeared necessary for mice with VWF-KO. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of mice with VWF-KO led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability.

A nanobody against the VWF A3 domain detects ADAMTS13-induced proteolysis in congenital and acquired VWD.

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A-group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high-molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.

Restrictive versus Decision Support Guided Fluid Therapy During Major Hepatic Resection Surgery: A Randomized Controlled Trial.

BACKGROUND: Fluid therapy during major hepatic resection aims at minimizing fluids during the dissection phase to reduce central venous pressure (CVP), retrograde liver blood flow, and venous bleeding. This strategy, however, may lead to hyperlactatemia. The Acumen™ Assisted Fluid Management system uses novel decision support software whose algorithm helps clinicians optimize fluid therapy. We tested the hypothesis that using this decision support system could decrease arterial lactate at the end of major hepatic resection when compared to a more restrictive fluid strategy. METHODS: This two-arm, prospective, randomized controlled, assessor-and patient-blinded superiority study included consecutive patients undergoing major liver surgery equipped with an arterial catheter linked to an uncalibrated stroke volume monitor. In the decision support group, fluid therapy was guided throughout the entire procedure using the assisted fluid management software. In the restrictive fluid group, clinicians were recommended to restrict fluid infusion to 1-2 ml.kg-1.h-1 until the completion of hepatectomy. They then administered fluids based on advanced hemodynamic variables. Noradrenaline was titrated in all patients to maintain a mean arterial pressure >65mmHg. The primary outcome was arterial lactate level upon completion of surgery (i.e., skin closure). RESULTS: Ninety patients were enrolled over a 7-month period. The primary outcome was lower in the decision support group than in the restrictive group (median[Q1-Q3] 2.5[1.9-3.7]mmol.L-1 vs 4.6[3.1-5.4]mmol.L-1, median difference -2.1, 95%CI(-2.7,-1.2), p<0.001). Among secondary exploratory outcomes, there was no difference in blood loss (median[Q1-Q3] 450[300-600]ml vs 500[300-800]ml, p=0.727) although CVP was higher in the decision support group (mean (SD) of 7.7(2.0)mmHg vs 6.6(1.1)mmHg, p<0.002). CONCLUSION: Patients managed using a clinical decision support system to guide fluid administration during major hepatic resection had a lower arterial lactate concentration at the end of surgery when compared to a more restrictive fluid strategy. Future trials are necessary to make conclusive recommendations that will change clinical practice.

Day-case robotic-assisted partial nephrectomy: feasibility and preliminary results of a prospective evaluation (UroCCR-25 AMBU-REIN study).

PURPOSE: Robotic partial nephrectomy (RPN) is a minimally-invasive technique used to treat renal tumors. A clinical pathway and prospective research protocol (AMBU-REIN) were specifically set up to establish and assess the routine use of day-case RPN. METHODS: The AMBU-REIN study was conducted in the framework of the French research network on kidney cancer UroCCR (NCT03293563). We present our initial experience of patients treated using day-case RPN and released from our hospital on the same day, focusing on patient selection, safety and patient satisfaction using the EVAN-G validated questionnaire. RESULTS: Between September 2016 and September 2019, 429 RPN were performed and 82 patients were consecutively selected for day-case RPN. Patients were managed using transperitoneal RPN with off-clamp tumorectomy for 66/82 cases. Mean tumor size was 2.7 ± 1.2 cm. There were no immediate severe postoperative complications; 7/82 patients were kept under observation overnight and discharged the following day. The follow-up at day 30 indicated postoperative complications, readmissions, and mortality rates of 1.2, 1.2, and 0%, respectively. Next-day patient satisfaction questionnaires indicated that patients were generally highly satisfied, with a mean ± standard deviation global score of 83.6 ± 10.3%. "Attention" was rated the highest overall (mean 94.8 ± 10.5%), while "pain management" scored the lowest (61.2 ± 20.5%). CONCLUSIONS: This prospective case series is the first to demonstrate the safety and feasibility of day-case RPN. For selected patients and through a dedicated, nurse-led clinical pathway, it provided a high level of patient satisfaction. Expected benefits on healthcare cost savings warrant further investigation.

Intraoperative measurement of the respiratory exchange ratio predicts postoperative complications after liver transplantation.

BACKGROUND: During surgery, any mismatch between oxygen delivery (DO2) and consumption (VO2) can promote the development of postoperative complications. The respiratory exchange ratio (RER), defined as the ratio of carbon dioxide (CO2) production (VCO2) to VO2, may be a useful noninvasive tool for detecting inadequate DO2. The primary objective of this study was to test the hypothesis that RER measured during liver transplantation may predict postoperative morbidity. Secondary objectives were to assess the ability of other variables used to assess the DO2/VO2 relationship, including arterial lactate, mixed venous oxygen saturation, and veno-arterial difference in the partial pressure of carbon dioxide (VAPCO2gap), to predict postoperative complications. METHODS: This retrospective study included consecutive adult patients who underwent liver transplantation for end stage liver disease from June 27th, 2020, to September 5th, 2021. Patients with acute liver failure were excluded. All patients were routinely equipped with a pulmonary artery catheter. The primary analysis was a receiver operating characteristic (ROC) curve constructed to investigate the discriminative ability of the mean RER measured during surgery to predict postoperative complications. RER was calculated at five standardized time points during the surgery, at the same time as measurement of blood lactate levels and arterial and mixed venous blood gases, which were compared as a secondary analysis. RESULTS: Of the 115 patients included, 57 developed at least one postoperative complication. The mean RER (median [25-75] percentiles) during surgery was significantly higher in patients with complications than in those without (1.04[0.96-1.12] vs 0.88[0.84-0.94]; p < 0.001). The area under the ROC curve was 0.87 (95%CI: 0.80-0.93; p < 0.001) with a RER value (Youden index) of 0.92 giving a sensitivity of 91% and a specificity of 74% for predicting the occurrence of postoperative complications. The RER outperformed all other measured variables assessing the DO2/VO2 relationship (arterial lactate, SvO2, and VAPCO2gap) in predicting postoperative complications. CONCLUSION: During liver transplantation, the RER can reliably predict postoperative complications. Implementing this measure intraoperatively may provide a warning for physicians of impending complications and justify more aggressive optimization of oxygen delivery. Further studies are required to determine whether correcting the RER is feasible and could reduce the incidence of complications.

Effects of capnometry monitoring during recovery in the post-anaesthesia care unit: a randomized controlled trial in adults (CAPNOSSPI).

PURPOSE: Continuous capnography should be used on patients admitted to post-anaesthesia care units (PACUs) with endotracheal tubes, but this monitoring is not always performed. Optimized ventilation in the PACU could be part of the global standards of practice to maintain the benefits of perioperative ventilation. The main objective was to study the rate of patients with alveolar hypoventilation before tracheal extubation or Laryngeal Mask Airway (LMA) removal upon the measurement of continuous capnography. METHODS: In this prospective, parallel-group, randomized controlled study, we enrolled adult patients admitted to the PACU after general anaesthesia with an endotracheal tube or LMA in place. Patients were randomly assigned to two groups: in the Capno + group, nurses managed the patients with access to the capnometer and end-tidal carbon dioxide pressure (PETCO2) measurements; in the Capno- group, nurses monitored the patients without seeing PETCO2 measurements. The primary outcome was the percentage of patients with PETCO2 measurements above 45 mm Hg during the minute before extubation. Secondary endpoints included the delay in recovering spontaneous breathing, rate of hypoxemia, delay before extubation, and length of stay in the PACU. RESULTS: Forty-eight patients were randomized into the two groups. The percentage of patients with PETCO2 > 45 mm Hg the minute before extubation was significantly decreased in the Capno + group (83.3% versus 54,1% in the Capno- and Capno + groups respectively, p = 0.029). There were no significant differences concerning secondary endpoints. CONCLUSIONS: The use of PETCO2 monitoring improves patient safety by decreasing the incidence of CO2 retention during recovery from general anaesthesia. This study suggests that this monitoring should be integrated in the PACU. The risk of hypoxemia can also be prevented through the early recognition of apnoea. CLINICAL TRIAL REGISTRY: clinicaltrial.gov. identifier: NCT03370081.

Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), and its effect on the outcomes of liver transplantation (LT) for PSC is unclear. We retrospectively collected data from adults who underwent LT for PSC from 1989 to January 2018 in 4 French LT centers. We compared the rates of patient and graft survivals and of complications after LT. Among 87 patients, 52 (60%) had preexisting IBD. Excluding those who died within the first 3 months, the 10-year patient survival and graft survival rates were 92.6% (95% confidence interval [CI], 84.3%-100%) and 77.1% (53.8%-85.3%), respectively, in the PSC with IBD (PSC-IBD) group and 97.1% (91.4%-100%; P = 0.44) and 83.2% (69.6%-96.9%; P = 0.43) in the isolated PSC group, respectively. Exposure to azathioprine after LT was significantly associated with mortality (odds ratio [OR], 15.55; 1.31-184.0; P = 0.03), whereas exposure to mycophenolate mofetil was associated with improved survival (OR, 0.17; 95% CI, 0.04-0.82; P = 0.03), possibly an era effect. The rate of recurrent PSC was 21% in the PSC-IBD group and 11% in the isolated PSC group (P = 0.24). Severe infections occurred in 125 per 1000 person-years in both groups. Exposure to mycophenolate mofetil was associated with a lower risk of infection (OR, 0.26; 95% CI, 0.08-0.85; P = 0.03). The presence of IBD was associated with cytomegalovirus (CMV) infection (OR, 3.24; 95% CI, 1.05-9.98; P = 0.04). IBD prior to LT for PSC may not affect patient or transplant survival but may increase the risk of CMV infection.

Peri-operative management of pheochromocytoma with intravenous urapidil to prevent hemodynamic instability: A 17-year experience.

BACKGROUND AND AIMS: Surgery for pheochromocytoma (PCC) can cause excessive catecholamine release with severe hypertension. Alpha blockade is the mainstay of preoperative management. The aim of this study was to evaluate the efficacy and tolerance of intra-venous (IV) urapidil, a competitive short acting α1 receptor antagonist, in the prevention of peri-operative hemodynamic instability of patients with PCC. MATERIAL AND METHODS: This retrospective observational study included 75 patients (79 PCC) for PCC removal surgery from 2001 to 2017 at the Bordeaux University Hospital. They received, 3 days before surgery, continuous intravenous infusion of urapidil with stepwise increase to the maximum tolerated dose. Urapidil was maintained during the procedure and stopped after clamping the adrenal vein. Plasma catecholamine concentrations were measured during surgery. Hypertensive peaks (SAP >160 mmHg) and tachycardia >100 beats/min were treated with boluses of nicardipine 2 mg and esmolol 0.5 mg/kg. RESULTS: We recorded 20/79 (25%) cases with systolic arterial pressure (SAP) >180 mmHg. Only 11/79 (14%) had hypotension with SAP <80 mmHg. Peaks of catecholamine secretions were observed preferentially during peritoneal insufflation and tumor dissection (P < 0.05). A correlation was found between tumor size (mm) and the highest norepinephrine levels [r = 0.288, P = 0.015], and between hypertensive peaks (mmHg) and the highest norepinephrine levels [r = 0.45, P = 0.017]. No mortality was reported. The median [range] postoperative hospital stay was 4 [2-9] days. CONCLUSION: IV urapidil limits hypertensive and hypotensive peaks during PCC surgery, and corresponds to surgical imperatives allowing a short hospital stay, due to its "on-off" effect.

Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra® ): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP).

INTRODUCTION: Emicizumab (Hemlibra® ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. AIM: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. METHODS: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. RESULTS: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. CONCLUSION: The lack of data means that it is only possible to issue proposals rather than recommendations.

Fibrinolysis in trauma patients: wide variability demonstrated by the Lysis Timer.

Hyperfibrinolysis contributes to the pathophysiology of trauma-induced coagulopathy. At present, systematic administration of tranexamic acid (TXA) is recommended in all patients in the early phase of trauma. However, there is some debate regarding whether TXA is beneficial in all trauma patients. A rapid and accurate tool to diagnose hyperfibrinolysis may be useful for tailoring TXA treatment. We conducted a proof-of-concept study of consecutive adult trauma patients. A first blood sample was obtained at the time of pre-hospital care (T1). Patients received 1 g of TXA after T1. A second sample was obtained on arrival at the emergency unit (T2). We examined coagulation, fibrin and fibrinogen formation and degradation. Fibrinolysis was assessed by determining tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1) activity and global fibrinolysis capacity assay using a device developed by Hyphen BioMed: the Lysis Timer (GFC/LT). The study population consisted of 20 patients (42 ± 21 years, index of severity score 32 ± 21). Both coagulation and fibrinolysis were altered at T1. GFC/LT values exhibited hyperfibrinolysis only in five patients. Principal component analysis carried out at T1 showed two main axes of alteration. The major axis was related to coagulation, altered in all patients, while the second axis was related to fibrinolysis. GFC/LT was mainly influenced by PAI-1 activity while fibrin monomers were related to the severity of trauma. At T2, GFC/LT exhibited the marked effect of TXA on clot lysis time. In conclusion, GFC/LT demonstrated huge variation in the fibrinolytic response to trauma.

Impact of Systemic Vascular Resistance on the Accuracy of the Pulsioflex Device.

BACKGROUND: The accuracy of currently available devices using pulse contour analysis without external calibration for cardiac index (CI) estimation is negatively impacted by hyperdynamic states, low systemic vascular resistance (SVR), and abrupt changes in SVR. The aim of this study was to evaluate the accuracy of a new device, the Pulsioflex (Pulsion Medical System), in patients undergoing liver transplantation. METHODS: Thirty consecutive patients scheduled for liver transplantation were included. CI was monitored using pulmonary arterial catheter (CI-PAC) and Pulsioflex (CI-Pulsio). Simultaneous CI measurements were made intraoperatively at 9 different stages of the procedure. RESULTS: Two hundred seventy pairs of measurements were analyzed. The median CI-Pulsio values (3.3; interquartile range, 2.8-3.8 L·min·m) were significantly different from the median CI-PAC (4.1; interquartile range, 3.1-5.0 L·min·m; P < .0001). Bland and Altman analysis showed a mean bias of 0.8 L·min·m and 95% limit of agreement from -2.5 to 4.1 L·min·m. Percentage error was 65% (95% confidence interval, 60%-71%). Considering the variations in CI between 2 stages, the comparison between changes in CI-PAC and changes in CI-Pulsio showed a mean bias of 0.1 L·min·m and 95% limit of agreement of -2.1 to 2.2 L·min·m. When excluding changes in CI <0.5 L·min·m (154 paired analyzed), the concordance rate was 62% (95% confidence interval, 54%-70%). The bias between CI-PAC and CI-Pulsio was negatively correlated with SVR (r = -0.67, P < .0001). The bias between changes in CI-PAC and changes in CI-Pulsio was also negatively correlated with changes in SVR (r = -0.52, P < .0001). CONCLUSIONS: In patients undergoing liver transplantation, Pulsioflex does not accurately estimate CI. Its accuracy is highly impacted by SVR, and it is not able to track changes in CI when large variations in SVR occur.

Automated, continuous and non-invasive assessment of pulse pressure variations using CNAP® system.

Non-invasive respiratory variations in arterial pulse pressure using infrared-plethysmography (PPVCNAP) are able to predict fluid responsiveness in mechanically ventilated patients. However, they cannot be continuously monitored. The present study evaluated a new algorithm allowing continuous measurements of PPVCNAP (PPVCNAPauto) (CNSystem, Graz, Austria). Thirty-five patients undergoing vascular surgery were studied after induction of general anaesthesia. Stroke volume was measured using the VigileoTM/FloTracTM. Invasive pulse pressure variations were manually calculated using an arterial line (PPVART) and PPVCNAPauto was continuously displayed. PPVART and PPVCNAPauto were simultaneously recorded before and after volume expansion (500 ml hydroxyethylstarch). Subjects were defined as responders if stroke volume increased by ≥15 %. Twenty-one patients were responders. Before volume expansion, PPVART and PPVCNAPauto exhibited a bias of 0.1 % and limits of agreement from -7.9 % to 7.9 %. After volume expansion, PPVART and PPVCNAPauto exhibited a bias of -0.4 % and limits of agreement from -5.3 % to 4.5 %. A 14 % baseline PPVART threshold discriminated responders with a sensitivity of 86 % (95 % CI 64-97 %) and a specificity of 100 % (95 % CI 77-100 %). Area under the receiver operating characteristic (ROC) curve for PPVART was 0.93 (95 % CI 0.79-0.99). A 15 % baseline PPVCNAPauto threshold discriminated responders with a sensitivity of 76% (95 % CI 53-92 %) and a specificity of 93 % (95 % CI 66-99 %). Area under the ROC curves for PPVCNAPauto was 0.91 (95 % CI 0.76-0.98), which was not different from that for PPVART. When compared with PPVART, PPVCNAPauto performs satisfactorily in assessing fluid responsiveness in hemodynamically stable surgical patients.

Management of bleeding and transfusion during liver transplantation before and after the introduction of a rotational thromboelastometry-based algorithm.

Orthotopic liver transplantation (OLT) remains a potentially hemorrhagic procedure. Rotational thromboelastometry (ROTEM) is a point-of-care device used to monitor coagulation during OLT. Whether it allows blood loss and transfusions to be reduced during OLT remains controversial. Excellent correlations and predictive values have been found between ROTEM parameters and fibrinogen. We hypothesized that the use of a ROTEM-based transfusion algorithm during OLT would lead to more fibrinogen transfusion and decreased bleeding and blood transfusion. Sixty adult patients were consecutively included in a prospective, without-versus-with study: 30 in the group without ROTEM results and 30 in the group with the ROTEM-based algorithm. A small and nonsignificant increase in median fibrinogen transfusions was found for the with group (6.0 g versus 4.5 g, P = 0.50). It was not associated with a decrease in blood transfusions or in the number of patients exposed to blood products.

Noninvasive assessment of macrovesicular liver steatosis in cadaveric donors based on computed tomography liver-to-spleen attenuation ratio.

Fatty liver disease, including liver steatosis, is a major health problem worldwide. In liver transplantation, macrovesicular steatosis in donor livers is a major cause of graft failure and remains difficult to assess. On one hand, several imaging modalities can be used for the assessment of liver fat, but liver biopsy, which is still considered the gold standard, may be difficult to perform in this context. On the other hand, computed tomography (CT) is commonly used by teams managing cadaveric donors to assess donors and to minimize the risk of complications in recipients. The purpose of our study was to validate the use of CT as a semiquantitative method for assessing macrovesicular steatosis in cadaveric donors with liver biopsy as a reference standard. A total of 109 consecutive cadaveric donors were included between October 2009 and May 2011. Brain death was diagnosed according to French legislation. Liver biopsy and then CT were performed on the same day to determine the degree of macrovesicular steatosis. All liver biopsies and CT scans were analyzed in a double-blinded fashion by a senior pathologist and a senior radiologist, respectively. For CT, we used the liver-to-spleen (L/S) attenuation ratio, which is a validated method for determining 30% or greater steatosis in living liver donors. Fourteen of 109 biopsies exhibited macrovesicular steatosis > 30% upon histologic analysis. A receiver operating characteristic curve was generated for the L/S ratio to identify its ability to predict significant steatosis, which was defined as >30%. A cutoff value of 0.9 for the CT L/S ratio provided a sensitivity of 79% and a specificity of 97% to detect significant steatosis.

Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.

BACKGROUND: The aim of this study was to compare outcomes of early (<15 days) versus delayed carotid endarterectomy (CEA) in symptomatic patients. METHODS: All CEA procedures performed for symptomatic carotid stenosis between January 2006 and May 2010 were retrospectively reviewed. Postoperative mortality (within 30 days), stroke, and myocardial infarction (MI) rates were analyzed in the early and delayed CEA groups. RESULTS: During the study period, 149 patients were included. Carotid revascularization was performed within 15 days after symptom onset in 62 (41.6%) patients and longer than 15 days after symptom onset in 87 (58.4%) patients. The mean time lapse between onset of neurological symptoms and surgery was 9.3 days (range 1-15) in the early surgery group and 47.9 days (range 16-157) in the delayed surgery group. Thirty-day combined stroke and death rates were, respectively, 1.7% and 3.5% in the early and the delayed surgery groups. Thirty-day combined stroke, death, and MI rates were, respectively, 1.7% and 5.9% in the early and the delayed surgery groups. CONCLUSION: During the study period, the reduction of the symptom-to-knife time in application to the carotid revascularization guidelines did not impact our outcomes suggesting that early CEA achieves 30-day mortality and morbidity rates at least equivalent to those of delayed CEA.

Sonorheometry Device Thresholds in Liver Transplantation: An Observational Retrospective Study.

BACKGROUND: Liver transplantation (LT) remains a potentially haemorrhagic procedure whose perioperative bleeding and transfusion could be better monitored using point-of-care devices. Quantra® is a device based on sonorheometry to assess whole blood clot formation. Our aims were to describe Quantra® parameters during LT and to study their correlations with standard laboratory parameters, and to determine Quantra® cut-off values for thrombocytopenia, hypofibrinogenemia and coagulation factors' deficit. METHODS: In 34 patients undergoing LT, blood samples were collected before surgical incision, 15 min after the beginning of the anhepatic phase, and 15 min after arterial revascularization of the graft. RESULTS: Clotting time (CT) was well correlated with prothrombin (PT) ratio and activated partial thromboplastin time (aPTT) ratio. Platelet contribution to clot stiffness (PCS) was correlated with platelets (ρ = 0.82, p < 0.001) and fibrinogen contribution clot stiffness (FCS) with fibrinogen (Fg) (ρ = 0.74, p < 0.001). CT predicted a PT ratio < 30% with an area under the curve (AUC) of 0.93 (95% CI 0.87-0.98; p < 0.001). PCS predicted a platelet count < 50 G/L with an AUC of 0.87 (95% CI 0.76-0.98, p < 0.001). FCS predicted a Fg < 1.0, 1.2 or 1.5 g/L, with an AUC of 0.86 (95% CI 0.77-094, p < 0.001), 0.82 (95% CI 0.74-0.91, p < 0.001) and 0.88 (95% CI 0.82-0.95, p < 0.001), respectively. CONCLUSION: Quantra® provides a rapid assessment of haemostasis during LT.

Are Viscoelastometric Assays of Old Generation Ready for Disposal? Comment on Volod et al. Viscoelastic Hemostatic Assays: A Primer on Legacy and New Generation Devices. J. Clin. Med. 2022, 11, 860.

With the advent of new viscoelastometric hemostatic assay (VHA) devices, with ready-to-use cartridge reagents allowing for their use by people without special laboratory skills, the appreciation of the actual clinical value of VHAs in settings such as severe trauma, post-partum hemorrhage, cardiac surgery and liver transplantation still needs to be fully validated. While two of the newest versions remain based on a 'cup and pin' system (ROTEM® sigma, ClotPro®), two other new devices (TEG® 6s, Quantra®) rely on very different technologies: clotting blood is no longer in contact with the probe and challenged by oscillation of one of the components but explored with ultrasound exposure. A systematic literature search (including Sonoclot®) retrieved 20 observational studies (19 prospective). Most studies pointed to imperfect agreements, highlighting the non-interchangeability of devices. Only a few studies, often with a limited number of patients enrolled, used a clinical outcome. No study compared VHA results with conventional laboratory assays obtained through a rapid tests panel. Clinical evidence of the utility of the new VHAs largely remains to be proven through randomized clinical trials, with clinically relevant outcomes, and compared to rapid panel hemostasis testing. The availability of new, improved VHA devices provides an impetus and an opportunity to do so.

Angiopoietin-2 binds to multiple interactive sites within von Willebrand factor.

Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2). Objectives: At present, the molecular basis of the VWF-Ang-2 interaction is poorly understood. Here, we used immunosorbent-binding assays and specific recombinant VWF fragments to analyze VWF-Ang-2 interactions. Results: We found that VWF bound to immobilized Ang-2 most efficiently (half-maximal binding at 0.5 ± 0.1 µg/mL) under conditions of high CaCl2 (10 mM) and slightly acidic pH (6.4-7.0). Interestingly, several isolated recombinant VWF domains (A1/Fc, A2/Fc, D4/Fc, and D'D3-HPC4) displayed dose-dependent binding to immobilized Ang-2. Binding appeared specific, as antibodies against D'D3, A1, and A2 significantly reduced the binding of these domains to Ang-2. Complexes between VWF and Ang-2 in plasma could be detected by immunoprecipitation- and immunosorbent assays. Unexpectedly, control experiments also revealed complexes between VWF and angiopoietin-1 (Ang-1), a protein structurally homologous to Ang-2. Furthermore, direct binding studies showed dose-dependent binding of VWF to immobilized Ang-1 (half-maximal binding at 1.8 ± 1.0 µg/mL). Interestingly, rather than competing for Ang-1 binding, Ang-2 enhanced the binding of VWF to Ang-1 about 3-fold. Competition experiments further revealed that binding to VWF does not prevent Ang-1 and Ang-2 from binding to Tie-2. Conclusion: Our data show that both Ang-1 and Ang-2 bind to VWF, seemingly using different interactive sites. Ang-2 modulates the binding of VWF to Ang-1, the (patho)-physiological consequences of which remain to be investigated.

Evaluation of stroke volume variations obtained with the pressure recording analytic method.

OBJECTIVE: To investigate whether stroke volume variations obtained with the pressure recording analytic method can predict fluid responsiveness in mechanically ventilated patients with circulatory failure. DESIGN: Prospective study. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Thirty-five mechanically ventilated patients with circulatory failure for whom the decision to give fluid was taken by the physician were included. Exclusion criteria were: Arrhythmia, tidal volume <8 mL/kg, left ventricular ejection fraction<50%, right ventricular dysfunction, and heart rate/respiratory rate ratio <3.6. INTERVENTIONS: Fluid challenge with 500 mL of saline over 15 mins. MEASUREMENTS AND MAIN RESULTS: Stroke volume variations and cardiac output obtained with a pressure recording analytic method, pulse pressure variations, and cardiac output estimated by echocardiography were recorded before and after volume expansion. Patients were defined as responders if stroke volume obtained using echocardiography increased by ≥15% after volume expansion. Nineteen patients responded to the fluid challenge. Median [interquartile range, 25% to 75%] stroke volume variation values at baseline were not different in responders and nonresponders (10% [8-16] vs. 14% [12-16]), whereas pulse pressure variations were significantly higher in responders (17% [13-19] vs. 7% [5-10]; p < .0001). A 12.6% stroke volume variations threshold discriminated between responders and nonresponders with a sensitivity of 63% (95% confidence interval 38% to 84%) and a specificity of 69% (95% confidence interval 41% to 89%). A 10% pulse pressure variation threshold discriminated between responders and nonresponders with a sensitivity of 89% (95% confidence interval 67% to 99%) and a specificity of 88% (95% confidence interval 62% to 98%). The area under the receiver operating characteristic curves was different between pulse pressure variations (0.95; 95% confidence interval 0.82-0.99) and stroke volume variations (0.60; 95% confidence interval 0.43-0.76); p < .0001). Volume expansion-induced changes in cardiac output measured using echocardiography or pressure recording analytic method were not correlated (r = 0.14; p > .05) and the concordance rate of the direction of change in cardiac output was 60%. CONCLUSION: Stroke volume variations obtained with a pressure recording analytic method cannot predict fluid responsiveness in intensive care unit patients under mechanical ventilation. Cardiac output measured by this device is not able to track changes in cardiac output induced by volume expansion.