The use of 1E12, a monoclonal anti-platelet factor 4 antibody, to improve the diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a complication of adenoviral-based vaccine against SARS-CoV-2 due to prothrombotic immunoglobulin (Ig) G antibodies to platelet factor 4 (PF4) and may be difficult to distinguish from heparin-induced thrombocytopenia (HIT) in patients treated with heparin. OBJECTIVES: We assessed the usefulness of competitive anti-PF4 enzyme immunoassays (EIAs) in this context. METHODS: The ability of F(ab')2 fragments of 1E12, 1C12, and 2E1, 3 monoclonal anti-PF4 antibodies, to inhibit the binding of human VITT or HIT antibodies to PF4 was evaluated using EIAs. Alanine-scanning mutagenesis was performed to define the amino acids involved in the interactions between the monoclonal antibodies and PF4. RESULTS: A strong inhibition of VITT IgG binding to PF4 was measured with 1E12 (median inhibition, 93%; n = 8), whereas it had no effect on the binding of HIT antibodies (median, 6%; n = 8). In contrast, 1C12 and 2E1 inhibited VITT (median, 74% and 76%, respectively) and HIT antibodies (median, 68% and 53%, respectively) binding to PF4. When a competitive anti-PF4 EIA was performed with 1E12 for 19 additional VITT samples, it strongly inhibited IgG binding to PF4, except for 1 patient, who had actually developed HIT according to the clinical history. Epitope mapping showed that 1E12 interacts with 5 key amino acids on PF4, of which 4 are also required for the binding of human VITT antibodies, thus explaining the competitive inhibition. CONCLUSION: A simple competitive anti-PF4 EIA with 1E12 could help confirm VITT diagnosis and distinguish it from HIT in patients when both diagnoses are possible.

Colon cancer surgery in von Willebrand disease type 3 setting triggering vascular abnormalities on bowel anastomosis.

Background: von Willebrand disease (VWD) is associated with vascular malformations in the gastrointestinal tract. This complication, more frequent in VWD types 2A and 3, may be due to abnormal angiogenesis, but the precise mechanism is still unclear. Angiogenesis and inflammation are closely linked and can potentiate each other. Key Clinical Question: Can colon inflammation in the setting of cancer surgery potentiate angiogenesis in the VWD setting? Clinical Approach: A woman with VWD type 3 underwent partial colectomy twice for an adenocarcinoma. After managing the first surgery with a plasma-derived von Willebrand factor (VWF) concentrate (Wilfactin; LFB), refractory gastrointestinal bleeding occurred from neovessels on bowel anastomosis. After a multidisciplinary discussion, a second surgery was undertaken with a recombinant VWF concentrate (Veyvondi; Takeda Pharmaceuticals). Pathologic neovessels were again observed on the new anastomosis. Conclusion: Colectomy was complicated twice by pathologic neovessels on bowel anastomosis in 2 distinct procedures managed either with plasma-derived VWF or with recombinant VWF.

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).

Communication from the Scientific Standardization Committees of the International Society on Thrombosis and Haemostasis on vascular endothelium-related biomarkers in disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is not a disease criterion but a pathomechanistic process that accompanies various underlying diseases. According to the International Society on Thrombosis and Haemostasis definition, endothelial injury is an essential component in addition to systemic coagulation activation. Despite this definition, current diagnostic criteria for DIC do not include biomarkers for vascular endothelial injury. Endothelial cells are critical for hemostatic regulation because they produce various antithrombotic substances and express anticoagulant factors at the same time as facilitating coagulation, inflammatory reactions, platelet aggregation, and fibrinolysis with acute injury. Endothelial cells also exhibit various receptors, adhesion molecules, and the critical role of glycocalyx that regulates cellular interactions in thromboinflammation. For clinicians, biomarkers suitable for assessing endothelial injury are not readily available. Although we still do not have ideal biomarkers, antithrombin activity and von Willebrand factor can be candidates for the endothelium-related markers because those reflect the severity and are available in most clinical settings. Further, the dysfunction of endothelial cell in DIC arising from various underlying diseases is likely highly variable. For example, the involvement of endothelial dysfunction is significant in sepsis-induced coagulopathy, while moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. Because of the complexity of disease status associated with DIC, further research searching clinically available endothelium-related biomarkers is expected to establish individualized diagnostic criteria and potential therapeutic approaches.

Modulation of inflammatory M1-macrophages phenotype by valvular interstitial cells.

BACKGROUND: Aortic valve stenosis involves inflammation, excess deposition of a collagen-rich extracellular matrix, and calcification. Recent studies have shown that M1 or inflammatory macrophages derived from infiltrating monocytes promote calcification of valvular interstitial cells, the most prevalent cell type of the aortic valve. We hypothesized that valvular interstitial cells could modulate inflammatory macrophages phenotype. METHODS: We first assessed macrophage phenotype in human aortic valve stenosis and control aortic valves from donors. Then, we examined profibrotic and inflammatory-related gene expression in valves and valvular interstitial cells. Finally, we investigated whether valvular interstitial cells can modify the phenotype of inflammatory macrophages. RESULTS: Circulating monocytes and plasma transforming growth factor beta-1 levels of patients with aortic valve stenosis were significantly higher compared with patients without aortic valve stenosis. Histologic analysis of thickened spongiosa of the aortic valve from patients with aortic valve stenosis showed a high macrophage infiltration but a low matrix metalloproteinase-9 expression compared with control aortic valves. On the other hand, valvular interstitial cell culture of aortic valve stenosis exhibited a profibrotic phenotype with a high expression of transforming growth factor beta-1 and transforming growth factor beta-1/transforming growth factor beta-3 ratio but a decreased expression of the peroxisome proliferator-activated receptor gamma nuclear receptor. Valvular interstitial cell-conditioned media of aortic valve stenosis led to a decrease in enzymatic activity of matrix metalloproteinase-9 and an increase in production of collagen in inflammatory macrophages compared with valvular interstitial cell-conditioned media from control aortic valve donors. CONCLUSIONS: These findings indicate that profibrotic valvular interstitial cells promote the imbalance of extracellular matrix remodeling by reducing matrix metalloproteinase-9 production on inflammatory macrophages that lead to excessive collagen deposition observed in aortic valve stenosis. Further investigation is needed to clarify the role of transforming growth factor beta-1/proliferator-activated receptor gamma nuclear receptor/matrix metalloproteinase-9 in aortic valve stenosis.

Successful and safe response to ibrutinib alone in treating relapsed Waldenström macrogobulinemia and related acquired von Willebrand syndrome: an option to consider.

Ibrutinib, a first-class Bruton tyrosine kinase inhibitor, is known to be associated with adverse bleeding events and has been recently approved for the treatment of relapse Waldenström macroglobulinemia (WM). Here, we report the exhaustive clinical and biological follow-up of 2 patients treated by ibrutinib alone in the context of relapsed WM with an acquired von Willebrand syndrome (AVWS) complication. In two cases, ibrutinib has been shown to be quickly efficient and safe for treating both AVWS and its underlying condition the WM, without bleeding complications. Interestingly, ibrutinib treatment brings a rapid and extended over time normalization of von Willebrand factor clearance. These observations show that ibrutinib is a valuable therapeutic option in relapsed WM patients associated with AVWS and highlighting the need for further cohort studies with long-term follow-up of patients to confirm the efficacy and safety of a treatment by ibrutinib for WM patients with AVWS complication.

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02972008.

Circulating Monocyte Subsets and Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR), as an alternative to open heart surgery, has revolutionized the treatment of severe aortic valve stenosis (AVS), the most common valvular disorder in the elderly. AVS is now considered a form of atherosclerosis and, like the latter, partly of inflammatory origin. Patients with high-grade AVS have a highly disturbed blood flow associated with high levels of shear stress. The immediate reopening of the valve during TAVR leads to a sudden restoration of a normal blood flow hemodynamic. Despite its good prognosis for patients, TAVR remains associated with bleeding or thrombotic postprocedural complications, involving mechanisms that are still poorly understood. Many studies report the close link between blood coagulation and inflammation, termed thromboinflammation, including monocytes as a major actor. The TAVR procedure represents a unique opportunity to study the influence of shear stress on human monocytes, key mediators of inflammation and hemostasis processes. The purpose of this study was to conduct a review of the literature to provide a comprehensive overview of the impact of TAVR on monocyte phenotype and subset repartition and the association of these parameters with the clinical outcomes of patients with severe AVS who underwent TAVR.

Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination.

As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA's Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S). Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.

von Willebrand disease: what does the future hold?

von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

OBJECTIVE: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism. CONCLUSIONS: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.

Prothrombin Time ratio can predict mortality in severe pediatric trauma: Study in a French trauma center level 1.

BACKGROUND: Injury results in more deaths in children than all other causes combined, but there is little data regarding the association of early coagulopathy on outcomes in pediatric patients with traumatic injuries. The aim of this study was to determine the optimal cut-off value for the Prothrombin Time ratio (PTr) and to show the diagnostic characteristics of the PTr to predict mortality. METHODS: We retrospectively included during 4 years all patients less than 16 years old referred to our trauma center for traumatic injury with ISS ≥9. RESULTS: A total of 272 children were included. Mean age was 9.4 ± 4.8 years and median ISS was 17 [interquartile range, 12 to 26]. Day 28 mortality was 6.7%. The optimal cut-off value in our population for predicting day 28 mortality was 1.24. Using this value, the sensitivity of PTr was 84%, specificity was 82%, positive likelihood ratio was 4.7, and negative likelihood ratio was 0.19. Early mortality (i.e., mortality at 24 h) was also well-predicted (1.0% versus 16.4%, p < .0001), as the need for massive transfuion. Similarly, patients with PTr ≥1.24 at admission presented with a higher rate of severe thoracic and abdominal trauma, higher ISS, higher likelihood of admission to an intensive care unit, longer hospitalization, and higher rate of significant procedure (e.g., surgery or embolization). CONCLUSIONS: Trauma-induced coagulopathy defined only by a PTr ≥1.24 could be used as a severity predictive marker and as a sensitive, specific, quick, and easy to use tool for admission triage of pediatric patients.

Paradoxical Increase of Stroke in Patients with Defect of High Molecular Weight Multimers of the von Willebrand Factors following Transcatheter Aortic Valve Replacement.

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.

Clinico-Biological Features and Clonal Hematopoiesis in Patients with Severe COVID-19.

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged <60 years, 60-70 years, 70-80 years, and >80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.

Texture parameters of R2* maps are correlated with iron concentration and red blood cells count in clot analogs: A 7-T micro-MRI study.

BACKGROUND AND PURPOSE: Previous studies have suggested that mechanical revascularization in acute ischemic stroke (AIS) patients could be affected by clot histology. In this 7-T micro-MRI study, we used R2* relaxometry of clot analogs to evaluate the relationship between texture parameters of R2* maps and clot constituents. MATERIALS AND METHODS: Twelve AIS clot analogs were experimentally generated to obtain a wide range of red blood cell concentrations. All clots underwent a MR acquisition using a 7-T micro-MR system. A 3D multi-echo gradient-echo sequence was performed and R2* maps were generated. First order and second order statistics of R2* histograms within the clots were calculated. Iron concentration in clots was measured using absorption spectrometry and red blood cell count (RBC) was obtained by histopathological analysis. RESULTS: RBC count was strongly correlated with iron concentration within clots (r=0.87, P<.001). Higher RBC count and iron concentration were significantly correlated with first order parameters including: (a) global positive shift of the R2* histogram with higher '10th percentile', 'median', 'mean' and '90th percentile'; (b) increase of the global magnitude of voxel values with higher 'total energy' and 'root mean squared'; (c) greater uniformity of the voxel values with higher 'uniformity' and lower 'entropy'. Second order statistical parameters confirmed that higher RBC count and iron concentration correlated with (a) greater concentration of high gray-level values in the image; (b) more "coarse" texture of R2* maps. CONCLUSIONS: Texture analysis of MRI-R2* maps can accurately estimate the red blood cell count and iron content of AIS clot analogs.

Position of the French Working Group on Perioperative Haemostasis (GIHP) on viscoelastic tests: What role for which indication in bleeding situations?

PURPOSE: Viscoelastic tests (VETs), thromboelastography (TEG®) and thromboelastometry (ROTEM®) are global tests of coagulation performed on whole blood. They evaluate the mechanical strength of a clot as it builds and develops after coagulation itself. The time required to obtain haemostasis results remains a major problem for clinicians dealing with bleeding, although some teams have developed a rapid laboratory response strategy. Indeed, the value of rapid point-of-care diagnostic devices such as VETs has increased over the years. However, VETs are not standardised and there are few recommendations from the learned societies regarding their use. In 2014, the recommendations of the International Society of Thrombosis and Haemostasis (ISTH) only concerned haemophilia. The French Working Group on Perioperative haemostasis (GIHP) therefore proposes to summarise knowledge on the clinical use of these techniques in the setting of emergency and perioperative medicine. METHODS: A review of the literature. PRINCIPAL FINDINGS: The role of the VETs seems established in the management of severe trauma and in cardiac surgery, both adult and paediatric. In other situations, their role remains to be defined: hepatic transplantation, postpartum haemorrhage, and non-cardiac surgery. They must be part of the global management of haemostasis based on algorithms defined in each centre and for each population of patients. Their position at the bedside or in the laboratory is a matter of discussion between clinicians and biologists. CONCLUSION: VETs must be included in algorithms. In consultation with the biology laboratory, these devices should be situated according to the way each centre functions.

Primary Hemostatic Disorders and Late Major Bleeding After Transcatheter Aortic Valve Replacement.

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.

Real-Time Monitoring of von Willebrand Factor in the Catheterization Laboratory: The Seatbelt of Mini-Invasive Transcatheter Aortic Valve Replacement?

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.