Publications by authors named "Sophie Susen"

110 Publications

Anticoagulation in COVID-19: not strong for too long?

Anaesth Crit Care Pain Med 2021 Mar 30:100857. Epub 2021 Mar 30.

Department of Anaesthesiology and Critical Care, Grenoble Alpes University Hospital, Grenoble, France.

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http://dx.doi.org/10.1016/j.accpm.2021.100857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008784PMC
March 2021

Von Willebrand disease: What does the future hold?

Blood 2021 Mar 4. Epub 2021 Mar 4.

INSERM, Le Kremlin-Bicetre, France.

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 to reach 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 adeno-associated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase FVIII levels in VWD-type 3 or 2N patients will be 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) will be 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.
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http://dx.doi.org/10.1182/blood.2020008501DOI Listing
March 2021

Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

Arterioscler Thromb Vasc Biol 2021 Feb 25:ATVBAHA120315595. Epub 2021 Feb 25.

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, France (A. Dupont, A.R., S. Staessens, M.M., M.R., D.C., E.J., F.L., B.S., F.V., S. Susen).

Objective: Whether endotheliopathy only mirrors coronavirus disease 2019 (COVID-19) severity or plays an intrinsic role in microvascular thrombosis and organ failure remains unanswered. We assessed whether markers of endothelial damage and immune dysregulation were associated with organ failure, thrombus formation, and death. Approach and Results: Markers of endothelial damage (VWF:Ag [von Willebrand factor antigen], PAI-1 [plasminogen activator inhibitor-1], syndecan-1, TFPI [tissue factor pathway inhibitor], and soluble thrombomodulin), complement activation (C5a and C5b-9), cytokines (IL [interleukin]-6, TNF [tumor necrosis factor]-α, and IL-2R), and neutrophil extracellular traps (cell-free DNA, nucleosomes, and myeloperoxidase-DNA) were measured at intensive care unit admission in 82 patients with COVID-19. We also analyzed the histological composition of thrombi collected in critically ill living patients successfully weaned from extracorporeal membrane oxygenation. Beside respiratory failure, VWF:Ag, PAI-1, TFPI, and syndecan-1 were independently associated with liver injury and multiorgan failure development, underlining the direct role of endotheliopathy in organ failure. Nucleosomes were also associated with liver injury, multiorgan failure, and death which occurred in 38%, 60%, and 27% of patients, respectively. Moreover, dysregulated immune response including cytokines, complement, and neutrophil extracellular traps was associated with markers of endothelial damage, respiratory failure, and liver injury. COVID-19 thrombi retrieved from extracorporeal membrane oxygenation circuitry contained accumulation of neutrophils, VWF, and significantly higher amount of neutrophil extracellular traps when compared with non-COVID-19 thrombi.

Conclusions: We provide new associative data supporting that endotheliopathy and dysregulated immune responses are involved in respiratory and liver failure through microvascular damage in patients with severe COVID-19.
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http://dx.doi.org/10.1161/ATVBAHA.120.315595DOI Listing
February 2021

Von Willebrand disease type 2B with a novel mutation in the VWF gene.

Ann Saudi Med 2021 Jan-Feb;41(1):59-61. Epub 2021 Feb 4.

From the Department of hematology, CHU Saint-Etienne, Sant Etienne, Rhone-Alpes, France.

We report a 38-year-old woman who presented with a subdural hematoma after minor facial trauma in a stressful situation. The laboratory data showed a subnormal platelet count (166×10/L), VWF:RCo activity was 45% and VWF:Ag was 53% with a VWF:RCo/VWF Ag ratio of 0.79. Hemostasis results and gene analysis revealed von Willebrand disease (VWD) type 2B with normal multimers and a novel mutation c.4136 G>T (R1379L), which appears to be a novel mutation of VWD type 2B that is mainly diagnosed with hypersensitivity to ristocetin and an hyperfixation of platelet Willebrand to a recombinant Gp1b. SIMILAR CASES PUBLISHED: None.
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http://dx.doi.org/10.5144/0256-4947.2021.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868623PMC
February 2021

Clinical phenotype, fibrinogen supplementation and health-related quality of life in patients with afibrinogenemia.

Blood 2021 Jan 27. Epub 2021 Jan 27.

University Hospital of Geneva, Geneva, Switzerland.

Due to its low prevalence, epidemiologic data on afibrinogenemia are limited and none are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n=72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n=37) received more than one injection per week and 16.6% (n=34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa and a previous thrombotic event were statistically correlated with a worse HRQoL. In conclusion, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined.
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http://dx.doi.org/10.1182/blood.2020009472DOI Listing
January 2021

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With Coronavirus Disease 2019 Pneumonia.

Chest 2021 Jan 16. Epub 2021 Jan 16.

Department of Anesthesiology and Critical Care, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris University, Paris, France.

Background: Because of the high risk of thrombotic complications (TCs) during severe acute respiratory syndrome coronavirus 2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent.

Research Question: What is the incidence of TC in critically ill patients with coronavirus disease 2019 (COVID-19) and what is the relationship between the dose of anticoagulant therapy and the incidence of TC?

Study Design And Methods: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight.

Results: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99]) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75).

Interpretation: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill COVID-19 patients without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results.

Trial Registry: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832130PMC
January 2021

Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature.

Front Immunol 2020 18;11:558811. Epub 2020 Dec 18.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, France.

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4 lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4 plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4 plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10 [5.7 10-1.79 10]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10 [2.0 10-6.0 10]), a polyclonal setting in which all IgG4 plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10 at diagnosis and 1.0 10 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4 plasma cell proliferation.
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http://dx.doi.org/10.3389/fimmu.2020.558811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793697PMC
December 2020

Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Clin Transl Immunology 2020 23;9(12):e1217. Epub 2020 Dec 23.

Institut d'Immunologie CHU de Lille Lille France.

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot).

Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T-CoV-Spot assay, we assessed T-cell and antibody responses in mild, moderate and severe SARS-CoV-2 patients and in control samples collected before the outbreak.

Results: Specific T cells were assessed in 60 consecutive patients (mild,  = 26; moderate,  = 10; and severe patients,  = 24) during their follow-up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in  = 60 (100%),  = 56 (93.3%),  = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T-CoV-Spot assay showed a specificity of 96.7% (95% CI, 88.5-99.6%) and a specificity of 90.3% (75.2-98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti-S1 and anti-RBD serum antibodies.

Conclusion: IFNγ T-CoV-Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long-lived memory T-cell response after vaccination. Our study demonstrates that SARS-CoV-2 patients developing a severe disease achieve a higher adaptive immune response.
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http://dx.doi.org/10.1002/cti2.1217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757425PMC
December 2020

Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis.

Radiology 2021 02 15;298(2):E70-E80. Epub 2020 Dec 15.

From the Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (Y.J.S.); Medical Research Collaborating Center (H.H.) and Department of Radiology (S.H.Y.), Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; Department of Radiology, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (M.O.); Department of Radiology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris Centre, Paris, France (F.B., M.P.R.); Department of Diagnostic Radiology, Papa Giovanni XXIII, Bergamo, Italy (C.V.); Department of Radiology, Military Hospital Begin, Saint Mande, France (A.G.); Resuscitation Center, Centre Hospitalier Universitaire de Lille, Université de Lille, Institut National de la Santé et de la Recherche Médicale U1285, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8576-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France (J.P.); Department of Hematology and Transfusion, Pôle de Biologie Pathologie Génétique, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Université de Lille, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1011-European Genomic Institute for Diabetes, Lille, France (S.S.); Institute of Cardiometabolism and Nutrition, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale Unité de Recherche sur les Maladies Cardiovasculaires, le Métabolisme et la Nutrition 1166, Paris, France; Intensive Medicine-Resuscitation Department, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France (G.H.); Department of Internal Medicine, Centre Hospitalier Universitaire de Nantes, Nantes, France (M.A.); Angiology Unit, Hôpital Fribourgeois-Hôpital Cantonal, Fribourg, Switzerland (D.P.); Multipurpose Resuscitation Service, Centre Hospitalier Victor Dupouy, Argenteuil, France (D.C.); Department of Intensive Care Medicine, Centre Hospitalier du Valais Romand de l'Hôpital du Valais (site de Sion), Sion, Switzerland (J.D., B.S.); and Department of Radiology, King's College Hospital National Health Service Foundation Trust, London, England (C.F., G.G., H.R.).

Background The association of pulmonary embolism (PE) with deep vein thrombosis (DVT) in patients with coronavirus disease 2019 (COVID-19) remains unclear, and the diagnostic accuracy of D-dimer tests for PE is unknown. Purpose To conduct meta-analysis of the study-level incidence of PE and DVT and to evaluate the diagnostic accuracy of D-dimer tests for PE from multicenter individual patient data. Materials and Methods A systematic literature search identified studies evaluating the incidence of PE or DVT in patients with COVID-19 from January 1, 2020, to June 15, 2020. These outcomes were pooled using a random-effects model and were further evaluated using metaregression analysis. The diagnostic accuracy of D-dimer tests for PE was estimated on the basis of individual patient data using the summary receiver operating characteristic curve. Results Twenty-seven studies with 3342 patients with COVID-19 were included in the analysis. The pooled incidence rates of PE and DVT were 16.5% (95% CI: 11.6, 22.9; = 0.93) and 14.8% (95% CI: 8.5, 24.5; = 0.94), respectively. PE was more frequently found in patients who were admitted to the intensive care unit (ICU) (24.7% [95% CI: 18.6, 32.1] vs 10.5% [95% CI: 5.1, 20.2] in those not admitted to the ICU) and in studies with universal screening using CT pulmonary angiography. DVT was present in 42.4% of patients with PE. D-dimer tests had an area under the receiver operating characteristic curve of 0.737 for PE, and D-dimer levels of 500 and 1000 μg/L showed high sensitivity (96% and 91%, respectively) but low specificity (10% and 24%, respectively). Conclusion Pulmonary embolism (PE) and deep vein thrombosis (DVT) occurred in 16.5% and 14.8% of patients with coronavirus disease 2019 (COVID-19), respectively, and more than half of patients with PE lacked DVT. The cutoffs of D-dimer levels used to exclude PE in preexisting guidelines seem applicable to patients with COVID-19. © RSNA, 2020 See also the editorial by Woodard in this issue.
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http://dx.doi.org/10.1148/radiol.2020203557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745997PMC
February 2021

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

Arterioscler Thromb Vasc Biol 2021 01 5;41(1):415-429. Epub 2020 Nov 5.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, France (N.G., A.B., E.R., S.I., S.L., A. Cras, N.N., J.R., P.G., D.M.S.).

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 (VIC) mesenchymal-like phenotype was confirmed by CD90/CD73/CD44 expression and multipotent-like differentiation ability. When VIC were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VIC 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 VIC-conditioned media and confirmed at the mRNA level in VIC compared with control VIC. Conditioned media from VIC 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 VIC 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 VIC 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.
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http://dx.doi.org/10.1161/ATVBAHA.120.314287DOI Listing
January 2021

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

Am J Emerg Med 2020 10 4;38(10):2041-2044. Epub 2020 Jul 4.

CHU de Lille, Pôle d'anesthésie-réanimation, Lille F-59000, France; CHU Lille, Pôle de l'Urgence, Lille F-59000, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajem.2020.06.075DOI Listing
October 2020

Gastrointestinal bleeding from angiodysplasia in von Willebrand disease: Improved diagnosis and outcome prediction using videocapsule on top of conventional endoscopy.

J Thromb Haemost 2021 Feb 29;19(2):380-386. Epub 2020 Nov 29.

Department of Hematology and Transfusion, CHU Lille, Institut d'Hématologie Transfusion, Lille, France.

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 < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01).

Conclusion: VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse.
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http://dx.doi.org/10.1111/jth.15155DOI Listing
February 2021

The challenge of genetically unresolved haemophilia A patients: Interest of the combination of whole F8 gene sequencing and functional assays.

Haemophilia 2020 Nov 23;26(6):1056-1063. Epub 2020 Oct 23.

Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.

Background: The causative variant remains unidentified in 2%-5% of haemophilia A (HA) patients despite an exhaustive sequencing of the full F8 coding sequence, splice consensus sequences, 5'/3' untranslated regions and copy number variant (CNV) analysis. Next-generation sequencing (NGS) has provided significant improvements for a complete F8 analysis.

Aim: The aim of this study was to identify and characterize pathogenic non-coding variants in F8 of 15 French and Canadian HA patients genetically unresolved, through the use of NGS, mRNA sequencing and functional confirmation of aberrant splicing.

Methods: We sequenced the entire F8 gene using an NGS capture method. We analysed F8 mRNA in order to detect aberrant transcripts. The pathogenic effect of candidate intronic variants was further confirmed using a minigene assay.

Results: After bioinformatic analysis, 11 deep intronic variants were identified in 13 patients (8 new variants and 3 previously reported). Three variants were confirmed to be likely pathogenic with the presence of an aberrant transcript during mRNA analysis and minigene assay. We also found a small intronic deletion in 6 patients, recently described as causing mild HA.

Conclusion: With this comprehensive work combining NGS and functional assays, we report new deep intronic variants that cause HA through splicing alteration mechanism. Functional analyses are critical to confirm the pathogenic effect of these variants and will be invaluable in the future to study the large number of variants of uncertain significance that may affect splicing that will be found in the human genome.
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http://dx.doi.org/10.1111/hae.14179DOI Listing
November 2020

Coagulation markers are independent predictors of increased oxygen requirements and thrombosis in COVID-19: Response from Original Authors Susen, et al.

J Thromb Haemost 2020 12;18(12):3385-3386

Inserm, UMR_1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1111/jth.15101DOI Listing
December 2020

Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.

J Thromb Haemost 2020 11 18;18(11):2942-2953. Epub 2020 Sep 18.

Department of Hematology and Transfusion, Pôle de Biologie Pathologie Génétique, Institut Pasteur de Lille, UMR1011-EGID, Univ. Lille, Inserm, CHU Lille, Lille, France.

Background: Hypercoagulability seems to contribute to SARS-CoV-2 pneumonia pathogenesis. However, age and metabolic syndrome are potential confounders when assessing the value of coagulation biomarkers' prediction of COVID-19 outcomes. We assessed whether coagulation biomarkers, including factor VIII (FVIII) and von Willebrand factor (VWF) levels, measured at time of admission, were predictive of COVID-19 adverse outcomes irrespective of age and major comorbidities associated with metabolic syndrome.

Methods: Blood was sampled at admission in 243 adult COVID-19 patients for analysis of coagulation biomarkers including FVIII and VWF on platelet-poor plasma. The association between baseline C-reactive protein (CRP), activated partial thromboplastin time ratio, prothrombin time ratio, D-dimers, fibrinogen, FVIII, VWF antigen (VWF:Ag), and FVIII/VWF:Ag ratio levels and adverse outcomes (increased oxygen requirements, thrombosis, and death at day 30) was assessed by regression analysis after adjustment on age, sex, body mass index (BMI), diabetes, and hypertension.

Results: In univariable regression analysis increased CRP (subdistribution hazard ratio [SHR], 1.68; 95% confidence interval [CI], 1.26-2.23), increased fibrinogen (SHR, 1.32; 95% CI, 1.04-1.68), and decreased FVIII/VWF:Ag ratio (SHR, 0.70; 95% CI, 0.52-0.96) levels at admission were significantly associated with the risk of increased oxygen requirement during follow-up. Leucocytes (SHR, 1.36; 95% CI, 1.04-1.76), platelets (SHR,1.71; 95% CI, 1.11-2.62), D-dimers (SHR, 2.48; 95% CI, 1.66-3.78), and FVIII (SHR, 1.78; 95% CI, 1.17-2.68) were associated with early onset of thrombosis after admission. After adjustment for age, sex, BMI, hypertension, and diabetes, these associations were not modified.

Conclusion: Coagulation biomarkers are early and independent predictors of increased oxygen requirement in COVID-19 patients.
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http://dx.doi.org/10.1111/jth.15067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461161PMC
November 2020

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

Thromb Haemost 2020 Sep 29;120(9):1330-1338. Epub 2020 Jul 29.

Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Université de Strasbourg, Strasbourg, France.

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%],  = 0.002) and postprocedure CT-ADP > 180 seconds (10 [48%] vs. 116 [21%],  = 0.01). By multivariate analysis, MLBCs (odds ratio [OR]: 3.58; 95% confidence interval [CI]: 1.45-8.84;  = 0.006) and postprocedure CT-ADP > 180 seconds (OR: 3.38; 95% CI: 1.38-8.25;  = 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.
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http://dx.doi.org/10.1055/s-0040-1713424DOI Listing
September 2020

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

Cancers (Basel) 2020 Jul 21;12(7). Epub 2020 Jul 21.

UMR 9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Institut de Recherche contre le Cancer de Lille, University Lille, CNRS, Inserm, CHU Lille, F-59000 Lille, France.

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.
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http://dx.doi.org/10.3390/cancers12071992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409316PMC
July 2020

Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin.

Arterioscler Thromb Vasc Biol 2020 09 23;40(9):2127-2142. Epub 2020 Jul 23.

From the Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France (M.U.A., N.R., M.L.B., E.J.-B., F.L., C.G., P.H.M.).

Objective: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kβ, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator).

Conclusions: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.
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http://dx.doi.org/10.1161/ATVBAHA.120.314301DOI Listing
September 2020

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

Crit Care 2020 06 19;24(1):364. Epub 2020 Jun 19.

Department of Hematology-Hemostasis, Tours University Hospital, CHRU Tours, Tours, France.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 μg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.
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http://dx.doi.org/10.1186/s13054-020-03000-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303590PMC
June 2020

Management of von Willebrand disease with a factor VIII-poor von Willebrand factor concentrate: Results from a prospective observational post-marketing study.

J Thromb Haemost 2020 08 25;18(8):1922-1933. Epub 2020 Jun 25.

Hemophilia Treatment Centre, University Hospital of Caen, Caen, France.

Background: A triple-secured plasma-derived von Willebrand factor (pdVWF) almost devoid of factor VIII (FVIII):WILFACTIN , was approved in France in 2003, and then in other countries for the treatment of patients with von Willebrand disease (VWD).

Objective: To investigate long-term safety and efficacy of the product in real-life over the first 5 post-approval years.

Patients/methods: This prospective, observational, national post-marketing study (PMS) enrolled patients of all ages and VWD types. Patients were observed for up to 3 years and treated for one or more occasions. Efficacy was assessed for each major event. Breakthrough bleeding rate 3 days post-infusion and annualized bleeding rate (ABR) were also evaluated for long-term prophylaxis.

Results: Overall, 155 of 174 patients enrolled from 31 centers were eligible for efficacy assessment. Most patients (76.8%) were severely affected (VWF:RCo ≤ 15 IU/dL). They were treated for 743 bleeds and 140 surgeries including childbirth. Efficacy outcomes were excellent/good for 98.2% of 56 major surgeries and 94.0% of 67 major bleeds. Approximately 75% of 49 major mucosal bleeds were effectively managed without FVIII co-administration. In 32 patients receiving prophylaxis, breakthrough bleeding occurred in 1.5% of infusions and median ABR was 1.0 for 20 patients treated ≥ 12 months. Excellent tolerability was confirmed with no safety concerns. No thrombotic events were observed.

Conclusions: Results from this PMS increase the clinical experience of a FVIII-poor pdVWF in patients of all ages and VWD types including those with thrombotic risk factors and emphasize that giving FVIII is not always mandatory to effectively treat patients with severe VWD.
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http://dx.doi.org/10.1111/jth.14928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496521PMC
August 2020

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence.

Circulation 2020 07 24;142(2):184-186. Epub 2020 Apr 24.

Université de Lille, Inserm, CHU Lille, Department of Hematology and Transfusion, Pôle de Biologie Pathologie Génétique, Institut Pasteur de Lille, UMR1011-EGID, France (F.L., E.J., A.R., S.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047430DOI Listing
July 2020

Diagnosis and management of heparin-induced thrombocytopenia.

Anaesth Crit Care Pain Med 2020 04 13;39(2):291-310. Epub 2020 Apr 13.

Service d'anesthésie-réanimation, hôpital européen Georges-Pompidou, INSERM UMRS-1140, université Paris Descartes, 25, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.accpm.2020.03.012DOI Listing
April 2020

Analysis of the association of MPO and MMP-9 with stroke severity and outcome: Cohort study.

Neurology 2020 07 28;95(1):e97-e108. Epub 2020 Feb 28.

From the Departments of Neurology (I.M., A.-M.M., C.C., D.L.) and Medical Pharmacology (S.G., R.B.), Degenerative and Vascular Cognitive Disorders, University Hospital CHU Lille, Inserm U1171, University of Lille, France; Department of Human Neurosciences (I.M.), "Sapienza" University of Rome, Italy; and European Genomic Institute for Diabetes (M.T., A.D., S.S., A.T., E.V., B.S.), University Hospital CHU Lille, Inserm U1011, Institut Pasteur of Lille, University of Lille, France.

Objective: In acute cerebral ischemia, circulating neutrophil count and neutrophil-to-lymphocyte ratio (NLR) are positively associated with stroke severity and worse outcomes. Mediators of this effect are unknown. We aimed to investigate (1) the relationship between plasma matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) concentrations with stroke severity and outcome and (2) MMP-9 and MPO release after ex vivo stimulation of neutrophils by recombinant tissue plasminogen activator (rtPA).

Methods: We analyzed data collected in 255 patients with supratentorial cerebral infarcts recruited within 48 hours of symptoms onset irrespective of rtPA treatment. The endpoints were excellent outcome (modified Rankin Scale score 0-1), symptomatic intracerebral hemorrhage (European Cooperative Acute Stroke Study-II definition), and death at 3 months. The role of rtPA treatment on peripheral neutrophil degranulation was investigated in 18 patients within 4.5 hours and after 72 hours.

Results: Neutrophil counts, NLR, and MPO plasma concentrations, but not MMP-9, were positively correlated with stroke severity. Higher neutrophil counts and NLR were independently associated with worse outcomes and higher mortality rates at month 3. Higher MPO plasma concentrations, but not MMP-9, were associated with worse outcome. Neutrophil-derived MMP-9, after ex vivo rtPA stimulation, but not MPO, were higher after 72 hours in patients treated by IV rtPA but not associated with hemorrhagic transformation.

Conclusions: Neutrophil counts, NLR, and MPO plasma concentrations are associated with worse outcome in patients with acute cerebral ischemia, in contrast to MMP-9. Further investigations are needed to deepen our knowledge on MPO's role in the deleterious effect of neutrophils because it could represent a potential therapeutic target.
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http://dx.doi.org/10.1212/WNL.0000000000009179DOI Listing
July 2020

PATCH trial: explanatory analyses.

Blood 2020 04;135(16):1406-1409

Department of Neurology, Amsterdam University Medical Centres, location Academic Medical Centre, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1182/blood.2019003298DOI Listing
April 2020

Activated Clotting Time Monitoring during Atrial Fibrillation Catheter Ablation: Does the Anticoagulant Matter?

J Clin Med 2020 Jan 27;9(2). Epub 2020 Jan 27.

Université de Paris, Innovations Thérapeutiques en Hémostase, INSERM 1140, 4 avenue de l'observatoire, F-75006 Paris, France.

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs) with intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 s, as for vitamin K antagonist (VKA). We determined whether ACT monitoring might be transposed from VKA to DOAC-treated patients. Blood was taken from 124 patients receiving uninterrupted dabigatran, rivaroxaban, apixaban, or VKA or being untreated. DOAC concentration or INR (VKA) were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU . At baseline, anticoagulants prolonged ACT differently, ACT was longer with dabigatran and shorter with apixaban despite similar concentrations. ACT strongly correlated with INR and dabigatran concentration, but not with apixaban or rivaroxaban concentrations. Moreover, UFH effects on ACT prolongation depended on the anticoagulant: dose-response curves in samples with VKA and dabigatran were parallel whereas ACT prolongation in response to UFH was significantly smaller with rivaroxaban and especially apixaban. Therefore, UFH to achieve ACT at 300 s might be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa-inhibitors, especially apixaban. Targeting 300 s might expose to UFH overdosing and bleeding, questioning the current anticoagulation strategy.
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http://dx.doi.org/10.3390/jcm9020350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074080PMC
January 2020