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1. Assessment of DOAC in GEriatrics (Adage Study): Rivaroxaban/Apixaban Concentrations and Thrombin Generation Profiles in NVAF Very Elderly Patients

Author

Geoffrey Foulon-Pinto, Carmelo Lafuente-Lafuente, Georges Jourdi, Julien Le Guen, Fatoumata Tall, Etienne Puymirat, Maxime Delrue, Léa Rivière, Flora Ketz, Isabelle Gouin-Thibault, François Mullier, Pascale Gaussem, Eric Pautas, Thomas Lecompte, Emmanuel Curis, Virginie Siguret, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Laboratoire de biologie clinique, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Catholique de Louvain = Catholic University of Louvain (UCL), Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'angiologie et hémostase, Hôpitaux Universitaires de Genève (HUG), Geneva Planet Group, Université de Genève = University of Geneva (UNIGE), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), and Hôpital Lariboisière-Fernand-Widal [APHP]

Subjects
[SDV]Life Sciences [q-bio], Hematology
Abstract

Background Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. Aims To investigate: (1) DOAC concentration–time profiles; (2) thrombin generation (TG); and (3) clinical outcomes 6 months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. Methods Adage-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged ≥80 years, receiving DOAC for at least 4 days. Each patient had one to five blood samples at different time points over 20 days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). Results We included 215 patients (women 71.1%, mean age: 87 ± 4 years), 104 rivaroxaban and 111 apixaban, and 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (coefficient of variation) whatever the regimen, at C max [49–46%] and C min [75–61%] in 15 mg rivaroxaban and 2.5 mg apixaban patients, respectively. The dose regimen was associated with C max and C min plasma concentrations in apixaban (p = 0.0058 and p = 0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak height (STG-ThromboScreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thromboembolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. Conclusion Our study provides original data in very elderly patients receiving DOAC in a real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.

Published
2022
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2. Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial

Author

Zuily, Stéphane, Lefèvre, Benjamin, Sanchez, Olivier, Empis de Vendin, Ombeline, de Ciancio, Guillaume, Arlet, Jean-Benoît, Khider, Lina, Terriat, Béatrice, Greigert, Hélène, Robert, Céline, Louis, Guillaume, Trinh-Duc, Albert, Rispal, Patrick, Accassat, Sandrine, Thiery, Guillaume, Montani, David, Azarian, Réza, Meneveau, Nicolas, Soudet, Simon, Le Mao, Raphaël, Maurier, François, Le Moing, Vincent, Quéré, Isabelle, Yelnik, Cécile, Lefebvre, Nicolas, Martinot, Martin, Delrue, Maxime, Benhamou, Ygal, Parent, Florence, Roy, Pierre-Marie, Presles, Emilie, Goehringer, François, Mismetti, Patrick, Bertoletti, Laurent, Rossignol, Patrick, Couturaud, Francis, Wahl, Denis, Thilly, Nathalie, Laporte, Silvy, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), F-Crin Innovte [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHR de Metz-Thionville, Centre Hospitalier Agen-Nérac, Hôpital Bicêtre, Université Paris-Saclay, Centre Hospitalier de Versailles André Mignot (CHV), Department of Cardiology, University Hospital Jean Minjoz, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), UNEOS, Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lapeyronie [Montpellier] (CHU), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lille, CHU Lille, Centre National de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpitaux Civils de Colmar, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA), CHU d'Angers [Département Urgences], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université Jean Monnet - Saint-Étienne (UJM), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Service de Chirurgie Vasculaire [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre Hospitalier Princesse Grace, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole., and COVI-DOSE investigators: Stéphane Zuily, Francis Couturaud, François Goehringer, Silvy Laporte, Patrick Mismetti, Emilie Presles, Patrick Rossignol, Nathalie Thilly, Denis Wahl, Thomas Lecompte, Emmanuel Oger, Marie-Antoinette Sevestre, Florence Parent, Ygal Benhamou, Pierre-Marie Roy, Tristan Gigante, Morgane Gilg, Pierre-Luc Maclot, Bénédicte Rossignol, Jonathan Udot, Hélène Bouteille, Andréa Buchmuller, Céline Peurière, El Mehdi Siaghy, Valérie Bouaziz, Charlotte Daguin, Benjamin Grosjean, Véronique Saunier, Laurence Verger, Madlyne Jacquot, Nadine Petitpain, Martin Charly, Laurent Tordella, Emilie Presles, Guillaume Baronnet, Elisabeth Baux, Athanase Benetos, Jean-Baptiste Blanvillain, Marie Conrad, Guilhem Courte, Aurélie Cravoisy-Popovic, Virginie Dufrost, Sébastien Gibot, Philippe Guerci, Laure Joly, Antoine Kimmoun, Matthieu Koszutski, Alexandrine Larue, Bruno Levy, Marie-Reine Losser, Mathieu Mattei, Lionel Nace, Emmanuel Novy, Pierre Perez, Jean-Pierre Pertek, Camille Rigaux, Alexis Sauvage, Evelyne Schvoerer, Carine Thivilier, Lev Volkov, Piotr Zieminski, Manil Benlounes, Charles Cheng, Jean-Baptiste de Fréminville, Grégoire Détriché, Emmanuel Flammarion, Guillaume Goudot, Amer Hamdan, Raphaël Hindré, Corina Manoli, Emmanuel Messas, Adrien Michon, Tristan Mirault, Jean Pastré, Marie-Aude Penet, Benjamin Planquette, Geoffroy Volle, Rémy Hamdan, Aline Laubriet-Jazayeri, Vincent Petit, Lionel Piroth, Jean Pierre Quenot, Mélissa Saccu, Damien Barraud, Zoé Cavalli, Rostane Gaci, Mathilde Andreu, Laurent Bertoletti, Andréa Buchmuller, Elodie De Magalhaes, Sophie Bulifon, Athénaïs Boucly, Nathan Ebstein, Marc Humbert, Xavier Jaïs, Mitja Jevnikar, Laurent Savale, Andrei Horia Seferian, Charlotte Colin, Timothée Ganem, Mehdi Roumila, Romain Chopard, Matthieu Besutti, Basile Mouhat, Claire Andrejak, Stéphane Dupas, Gaëlle Le Roy, Santhi Samy-Modeliar, Anne Coste, Alexandre Fauche, David Goetghebeur, Christophe Gut-Gobert, Clément Hoffmann, Baptiste Hourmant, Cécile L'hévéder, Emmanuelle Lemoigne, Olivier Nepveu, Raphaël Paret, Gaël Picart, Saïd Azerkan, Chadia Boudaa, Julien Campagne, Peter Eszto, Benoît Godbert, Jean-François Guichard, Marion Heschung, Antoine Legoff, Jacques Mariot, Pascale Martin, Magalie Mercy, Julie Perrin, Stéphane Raymond, Nathalie Vernier, Pierre Fesler, Pierrick Henneton, Cédric Mercuzot, Nathalie Pansu, Lucas Perez, Loïc Andre, Edgar Bakhache, Marie-Charlotte Chopin, Marie Gilbert, Marc Lambert, Mohammad Ryadh Pokeerbux, François Danion, Yves Hansmann, Estelle Rougier, Yvon Ruch, Dominique Stéphan, Axel Ursenbach, Isabelle Connerade, Simon Gravier, Damien Kayser, Jean-Marc Michel, Mahsa Mohseni, Waël Younes, Ruxandra Burlacu, Amanda Lopes, Stéphane Mouly, Kladoum Nassarmadji, Damien Sène, Virginie Siguret, Alain Stepanian, Cédric Annweiler, Antoine Brangier, Vincent Dubee, Samir Henni, Jeanne Hersant, Jocelyne Loison, Léa Kern, Jean-Baptiste Laine, Claire Neveux-Brecheteau, Lucia Perez, Ruben Benainous, Bénédicte Giroux-Leprieur, Marilucy Lopez-Sublet, Saïda Khaled-Jousselin, Yohann Bernard, Amélie Amiot, Jessica Breistroff, Emilie Detry, Kadidiatou Diallo, Agnès Didier, Nathalie Dumont, Julie Egensperger, Aurélie Emmerich, Nelly François, Fanny Gallo, Valérie George, Quentin Gérome, Aurélie Gutehrle, Laure Lehman, Séverine Petit, Vanessa Piard, Maximilien Saint-Gilles, Olivier Terenzi, Amélie Marquette, Hélène Mortelette, Mathilde Audry, Amélie Cransac, Marine Maillard, Anaïs Boyer, Floriana Gallo, Arielle Urbing, Imane Zahaf, Alexandra Byczko, Amina Chaalal, Georgette Berlier, Corinne Bernabe, Souad Bezzeghoud, Caroline Chaudier, Carole Chauvet, Marina Davier, Carine Labruyere, Estelle Perrin, Michaël Pierre, Claire-Annissa Chekirine, Florence Voivret, Ramdane Meftali, Ouaffa Sabri, Anaïs Beulaygue, Julie Gall, Laure Girard, Soumia Haddaoui, Scheherazade Rami, Auriane Couderc, Aude Le Breton, Marie-Line Perruche, Cindy Claudon, Ludivine Roussel, Aude Barnier, Tiphaine Blanchard, Bénédicte Le Gall, Mélanie Pelouin, Anne-Sophie Veillon, Quam Aquereburu, Charlène Delaygue, Zahoua Ait Idir, Jérémy Drugeon, Déborah Dubrulle, Rabah Tezkratt, Anne-Sophie Frantz, Julie Drouaine, Jacqueline Dubois, Magali Eyriey, Elina Haerrel, Mélinda Beaudenon, Mialy Guenet, Thibaud Lecerf, Stéphanie Marechal-Girault, Sami Rehaiem, Romain Simon, Florence Dangeul-Potier, Morgane Goulvent, Souha Fliss, Fadhila Messani, Béatrice Mizejewski, Brigitte Mugnier, Valérie Opderbeck, Brigitte Risse

Subjects
Anticoagulation, Heparin, [SDV]Life Sciences [q-bio], COVID-19, Venous thromboembolism
Abstract

International audience; Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.

Published
2023
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3. Induced forms of α2-macroglobulin neutralize heparin and direct oral anticoagulant effects

Author

Sophie Gandrille, Xavier Declèves, Johan Abdoul, Georges Jourdi, Claire Pailleret, Isabelle Gouin-Thibault, Elisa Frezza, Charles Marc Samama, Virginie Siguret, Samuela Pasquali, Pascale Gaussem, N. Neveux, Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fonds de dotation CSL Behring pour la recherche, CSL Behring, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Lariboisière-Fernand-Widal [APHP], Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de biologie de la nutrition (LBN), Université Paris Cité (UPCité), and Hôpital Cochin [AP-HP]

Subjects
medicine.drug_class, [SDV]Life Sciences [q-bio], 02 engineering and technology, Pharmacology, Fondaparinux, Biochemistry, Dabigatran, 03 medical and health sciences, Rivaroxaban, Structural Biology, medicine, Apixaban, Molecular Biology, 030304 developmental biology, Whole blood, 0303 health sciences, Heparin, Chemistry, Anticoagulant, General Medicine, 021001 nanoscience & nanotechnology, Antidote, Apixaban, Dabigatran, Fondaparinux, Heparin, Rivaroxaban, 3. Good health, Thromboelastometry, Antidote, 0210 nano-technology, medicine.drug
Abstract

International audience; Alpha2-macroglobulin (α2M) is a physiological macromolecule that facilitates the clearance of many proteinases, cytokines and growth factors in human. Here, we explored the effect of induced forms of α2M on anticoagulant drugs. Gla-domainless factor Xa (GDFXa) and methylamine (MA)-induced α2M were prepared and characterized by electrophoresis, immunonephelometry, chromogenic, clot waveform and rotational thromboelastometry assays. Samples from healthy volunteers and anticoagulated patients were included. In vivo neutralization of anticoagulants was evaluated in C57Bl/6JRj mouse bleeding-model. Anticoagulant binding sites on induced α2M were depicted by computer-aided energy minimization modeling. GDFXa-induced α2M neutralized dabigatran and heparins in plasma and whole blood. In mice, a single IV dose of GDFXa-induced α2M following anticoagulant administration significantly reduced blood loss and bleeding time. Being far easier to prepare, we investigated the efficacy of MA-induced α2M. It neutralized rivaroxaban, apixaban, dabigatran and heparins in spiked samples in a concentration-dependent manner and in samples from treated patients. Molecular docking analysis evidenced the ability of MA-induced α2M to bind non-covalently these compounds via some deeply buried binding sites. Induced forms of α2M have the potential to neutralize direct oral anticoagulants and heparins, and might be developed as a universal antidote in case of major bleeding or urgent surgery. © 2021 Elsevier B.V.

Published
2021
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4. Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence

Author

Luisa Alessandra Atehortua Martinez, Emmanuel Curis, Nawel Mekdad, Claire Larrieu, Cindie Courtin, Laurent Jourdren, Corinne Blugeon, Jean-Louis Laplanche, Bruno Megarbane, Cynthia Marie-Claire, Nadia Benturquia, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire de biomathématiques, EA 7537 [Paris] (BioSTM), Université Paris Cité - UFR Pharmacie [Santé] (UPCité UFR Pharmacie), Université Paris Cité (UPCité)-Université Paris Cité (UPCité), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de l'Ecole Normale Supérieure (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenomiqueENS (Genomique ENS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Marie-Claire, Cynthia

Subjects
Pharmacology, Male, immediate early genes, variability, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Individuality, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, conditioned place preference, Nucleus Accumbens, Extinction, Psychological, Rats, Rats, Sprague-Dawley, Psychiatry and Mental health, transcriptomics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cocaine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, RNA, Pharmacology (medical), Transcriptome
Abstract

Background: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. Aims: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Methods: A cocaine-CPP paradigm in male Sprague–Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference. Results: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes ( Fos, Egr2, Nr4a1, and Zbtb37) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP. Conclusion: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine’s rewarding effects.

Published
2022
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5. Diagnosis and follow‐up of thrombotic thrombocytopenic purpura with an automated chemiluminescent ADAMTS13 activity immunoassay

Author

Nicolas Beranger, Alain Stepanian, Adeline Delton, Agnès Veyradier, Sandrine Benghezal, Paul Coppo, Bérangère S. Joly, Sophie Capdenat, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
chemiluminescent assay, medicine.medical_specialty, Thrombotic microangiopathy, diagnosis, Thrombotic thrombocytopenic purpura, 030204 cardiovascular system & hematology, Gastroenterology, Adamts13 activity, law.invention, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, law, hemic and lymphatic diseases, Internal medicine, medicine, thrombotic thrombocytopenic purpura, Chemiluminescence, ADAMTS13 protein, biology, medicine.diagnostic_test, lcsh:RC633-647.5, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, lcsh:Diseases of the blood and blood-forming organs, Hematology, medicine.disease, ADAMTS13, 3. Good health, Technical performance, biological monitoring, Original Articles ‐ Hemostasis, Immunoassay, biology.protein, Original Article, business, 030215 immunology
Abstract

International audience; Background: Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening thrombotic microangiopathy (TMA) caused by a severe functional deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats‐13), the specific von Willebrand factor (VWF) cleaving protease. ADAMTS13 activity is essential to diagnose TTP but remains challenging to assess, as reference ADAMTS13 activity assays are manual and time consuming. Current techniques also lack robustness in low detectable ADAMTS13 activity range, which could prove problematic for therapy‐driven monitoring.Objectives: The HemosIL AcuStar ADAMTS13 activity assay is a fast, automated chemiluminescent assay, the performance of which remains to be evaluated prospectively on very large cohorts of patients with TMA and in real‐life conditions.Patients and Methods: Our study was conducted over two successive sequences: a retrospective evaluation followed by a “real‐life” prospective evaluation. Overall, we evaluated the HemosIL AcuStar ADAMTS13 activity assay on 539 citrated plasma samples. We extensively studied linearity, limit of detection, contamination, intra‐assay and interassay precisions with a specific focus on levels < 25 IU/dL. Diagnostic performances for the detection of < 10 IU/dL ADAMTS13 activity and overall method comparison were conducted with the fluorescence resonance energy transfer (FRETS)‐VWF73 assay as the reference method.Results: Technical performance proved excellent. Robustness in low detectable ADAMTS13 activity range was good, potentially qualifying this assay for therapy‐driven monitoring. Comparison with the FRETS‐VWF73 assay was satisfactory (r2 = .83, P < .0001) as were the diagnostic performances for acute‐phase TTP (specificity, 99.7%; positive predictive value, 99.2%).Conclusion: The HemosIL AcuStar ADAMTS13 activity assay is a fast, reliable, automated technique well adapted as a first‐line ADAMTS13 activity assay for TTP diagnosis and follow‐up.

Published
2021
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6. Contrast between Prevalence of HIT Antibodies and Confirmed HIT in Hospitalized COVID-19 Patients: A Prospective Study with Clinical Implications

Author

Damien Sène, Benjamin G. Chousterman, Bruno Mégarbane, Maxime Delrue, Marie Neuwirth, Thomas Lecompte, Caren Brumpt, Alain Stepanian, Virginie Siguret, Ruxandra Burlacu, Nassim Mohamedi, Sebastian Voicu, Mégarbane, Bruno, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Hôpital Lariboisière-Fernand-Widal [APHP], Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpitaux Universitaires de Genève (HUG), and Université de Genève = University of Geneva (UNIGE)

Subjects
[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 2019-20 coronavirus outbreak, medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, Hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Internal medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Medicine, Antibody, business, Prospective cohort study
Abstract

International audience

Published
2020
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7. Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals

Author

Rajagopal Krishnamoorthy, Yusuke Nakamura, Alice Giontella, Elisa Danese, Munir Pirmohamed, Hoi Y. Tong, Angela Tagetti, Marie-Anne Loriot, Pietro Minuz, Anke H. Maitland-van der Zee, Sheng-Lan Tan, Jim K Burmester, Richard B. Kim, Jamila Alessandra Perini, Ming Ta Michael Lee, Nita A. Limdi, Min Huang, Mohamed H. Shahin, Guilherme Suarez-Kurtz, Vanessa Roldán, Carlos Isaza, Hersh Sagreiya, Hye Sun Gwak, Vijay Kumar Kutala, Han-Jing Cen, Russ B. Altman, Antonio J. Carcas, Kunihiko Itoh, Vaiva Lesauskaite, Richard L. Berg, Cristina Mazzaccara, Kyung Eun Lee, Mariana R. Botton, Jieying Eunice Zhang, Anthonius de Boer, Yumao Zhang, Inna Y. Gong, Marianne K. Kringen, Paola Borgiani, Taimour Y. Langaee, Monica Taljaard, Vacis Tatarunas, Panos Deloukas, Chrisly Dillon, Alberto M. Borobia, Michael D. Caldwell, Katarzyna Drozda, Larisa H. Cavallari, Julie A. Johnson, Stephane Bourgeois, Lucia Sacchetti, Saurabh Singh Rathore, Stuart A. Scott, Martina Montagnana, Li-Zi Zhao, Charles A. Rivers, Mahmut Ozer, Taisei Mushiroda, Cristina Lucía Dávila-Fajardo, Andras Paldi, Marisa Cañadas-Garre, Rocío González-Conejero, Talitha I. Verhoef, Sherief Khalifa, Ivet Suriapranata, Carlo Federico Zambon, Balraj Mittal, Sara Raimondi, Ece Genc, Virginie Siguret, Andrea H. Ramirez, Cinzia Ciccacci, Keita Hirai, Enrique Jiménez-Varo, Hong-Hao Zhou, Anil Pathare, Steven A. Lubitz, Josh C. Denny, Aditi Shendre, Leonardo Beltrán, Kari Bente Foss Haug, Cristiano Fava, Vittorio Pengo, Department of Biochemistry, Università degli Studi di Pavia = University of Pavia (UNIPV), Department of Morphological and Biomedical Sciences, Università degli studi di Verona = University of Verona (UNIVR), Laboratoire de Mécanique et d'Acoustique [Marseille] (LMA ), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Queen Mary University of London (QMUL), Merck and Co., Merck & Co. Inc, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paediatric Pulmonology, Pulmonology, APH - Personalized Medicine, Danese, Elisa, Raimondi, Sara, Montagnana, Martina, Tagetti, Angela, Langaee, Taimour, Borgiani, Paola, Ciccacci, Cinzia, Carcas, Antonio J, Borobia, Alberto M, Tong, Hoi Y, Dávila-Fajardo, Cristina, Rodrigues Botton, Mariana, Bourgeois, Stephane, Deloukas, Pano, Caldwell, Michael D, Burmester, Jim K, Berg, Richard L, Cavallari, Larisa H, Drozda, Katarzyna, Huang, Min, Zhao, Li-Zi, Cen, Han-Jing, Gonzalez-Conejero, Rocio, Roldan, Vanessa, Nakamura, Yusuke, Mushiroda, Taisei, Gong, Inna Y, Kim, Richard B, Hirai, Keita, Itoh, Kunihiko, Isaza, Carlo, Beltrán, Leonardo, Jiménez-Varo, Enrique, Cañadas-Garre, Marisa, Giontella, Alice, Kringen, Marianne K, Haug, Kari Bente Fo, Gwak, Hye Sun, Lee, Kyung Eun, Minuz, Pietro, Lee, Ming Ta Michael, Lubitz, Steven A, Scott, Stuart, Mazzaccara, Cristina, Sacchetti, Lucia, Genç, Ece, Özer, Mahmut, Pathare, Anil, Krishnamoorthy, Rajagopal, Paldi, Andra, Siguret, Virginie, Loriot, Marie-Anne, Kutala, Vijay Kumar, Suarez-Kurtz, Guilherme, Perini, Jamila, Denny, Josh C, Ramirez, Andrea H, Mittal, Balraj, Rathore, Saurabh Singh, Sagreiya, Hersh, Altman, Ru, Shahin, Mohamed Hossam A, Khalifa, Sherief I, Limdi, Nita A, Rivers, Charle, Shendre, Aditi, Dillon, Chrisly, Suriapranata, Ivet M, Zhou, Hong-Hao, Tan, Sheng-Lan, Tatarunas, Vaci, Lesauskaite, Vaiva, Zhang, Yumao, Maitland-van der Zee, Anke H, Verhoef, Talitha I, de Boer, Anthoniu, Taljaard, Monica, Zambon, Carlo Federico, Pengo, Vittorio, Zhang, Jieying Eunice, Pirmohamed, Munir, Johnson, Julie A, and Fava, Cristiano

Subjects
CYP2C9, CYP4F2, VKORC1, coumarin drugs, meta-analysis, pharmacogenetics, predictive models, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030226 pharmacology & pharmacy, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Coumarins, Internal medicine, Vitamin K Epoxide Reductases, Taverne, medicine, Humans, Pharmacology (medical), heterocyclic compounds, Dosing, Cytochrome P450 Family 4, Aged, Cytochrome P-450 CYP2C9, Pharmacology, Aged, 80 and over, Acenocoumarol, Dose-Response Relationship, Drug, business.industry, Middle Aged, Confidence interval, Settore MED/03 - Genetica Medica, 030220 oncology & carcinogenesis, Meta-analysis, Female, business, Pharmacogenetics, medicine.drug
Abstract

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

Published
2019
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8. Prevention of venous thromboembolism and haemostasis monitoring in patients with COVID-19: Updated proposals (April 2021)

Author

Alexandre Godon, Charles Ambroise Tacquard, Alexandre Mansour, Delphine Garrigue, Philippe Nguyen, Dominique Lasne, Sophie Testa, Jerrold H. Levy, Pierre Albaladejo, Yves Gruel, Sophie Susen, Anne Godier, P. Albaladejo, N. Blais, F. Bonhomme, A. Borel-Derlon, A. Cohen, J.-P. Collet, E. de Maistre, P. Fontana, D. Garrigue Huet, A. Godier, Y. Gruel, A. Godon, B. Ickx, S. Laporte, D. Lasne, J. Llau, G. Le Gal, T. Lecompte, S. Lessire, J.H. Levy, D. Longrois, S. Madi-Jebara, A. Mansour, M. Mazighi, P. Mismetti, P.E. Morange, S. Motte, F. Mullier, N. Nathan, P. Nguyen, G. Pernod, N. Rosencher, S. Roullet, P.M. Roy, S. Schlumberger, P. Sié, A. Steib, S. Susen, C.A. Tacquard, S. Testa, A. Vincentelli, P. Zufferey, E Boissier, B Dumont, C James, V. Siguret, BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205] (Brain Tech Lab ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Service d'Anesthésie-Réanimation [Strasbourg], Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Istituti Ospitalieri di Cremona, Duke University [Durham], CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Lille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire (CHU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Hôpitaux Universitaires de Genève (HUG), Université de Genève = University of Geneva (UNIGE), CHU UCL Namur, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], FHU NeuroVasc [Site Sainte-Anne, Paris] (GHU-PPN), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Biologie Intégrative du Tissu Osseux (LBTO), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), F-Crin Innovte [CHU Saint-Etienne], Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Roche, and Sanofi

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, [SDV]Life Sciences [q-bio], COVID-19, Retrospective cohort study, General Medicine, Perioperative, Critical Care and Intensive Care Medicine, medicine.disease, Thrombosis, Article, Anticoagulation, Thrombotic risk, Anesthesiology and Pain Medicine, Intensive care, Bleeding risk, Epidemiology, Medicine, In patient, business, Intensive care medicine, Thromboprophylaxis, Venous thromboembolism
Abstract

In April 2020, in response to the high thrombotic risk associated with COVID-19, the GIHP and GFHT published proposals for the prevention of venous thromboembolism (VTE) and haemostasis monitoring in patients with COVID-19 [1]. In February 2021, six authors from the proposals (CT, AM, AlG, AnG, SS, YG, PA) decided to update them. This update was justified by several points: - The epidemiology of thrombotic complications has been described. - Different anticoagulation regimens have been reported, and retrospective studies have suggested that higher-than-standard prophylactic anticoagulation may be beneficial. - Initially underestimated, bleeding complications have emerged as a limitation of increased-dose anticoagulation and occur later than thrombotic events. - The first results of large-scale randomised controlled studies on increased doses of anticoagulation have been published. - Immunomodulatory therapies (corticosteroids, interleukin-6 receptor antagonists) are now widely used, but their effect on the thrombotic risk is unknown. - Despite improved survival, thrombotic complications remain a concern [2].

Published
2021
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9. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP

Author

Jean-François Augusto, Naïke Bigé, Lionel Galicier, Alain Wynckel, Nihal Martis, Michael Bubenheim, Ygal Benhamou, Antoine Dossier, Claire Presne, Elie Azoulay, Virginie Rieu, Agnès Veyradier, Sandrine Malot, François Provôt, Christelle Barbet, Miguel Hie, Amélie Seguin, Sten de Witte, Pascale Poullin, M. Ulrich, Paul Coppo, Thierry Krummel, François Lhote, Yahsou Delmas, Pierre Perez, Anne Charvet Rumpler, Ruben Benainous, Olivier Moranne, Salvy-Córdoba, Nathalie, Centre de référence des microangiopathies thrombotiques [CHU Saint-Antoine] (Cnr-mat), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Service d'Anesthésie réanimation [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Néphrologie [Hôpital Albert Calmette], Hôpital Albert Calmette [Lille], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de médecine interne [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Brabois, CHU, Partenaires INRAE, Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Delafontaine, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre hospitalier [Valenciennes, Nord], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Libourne, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Normandie Université (NU)-Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Compassionate Use Trials, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Combined Modality Therapy, MESH: Von Willebrand Factor, medicine.medical_treatment, Plenary Paper, Salvage therapy, 030204 cardiovascular system & hematology, Severity of Illness Index, Biochemistry, MESH: Historically Controlled Study, 0302 clinical medicine, Adrenal Cortex Hormones, Prospective Studies, Thiamine, Prospective cohort study, MESH: Treatment Outcome, MESH: Middle Aged, Plasma Exchange, MESH: Compassionate Use Trials, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Immunosuppression, Hematology, Middle Aged, MESH: Plasma Exchange, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Combined Modality Therapy, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Treatment Outcome, MESH: Thromboembolism, 030220 oncology & carcinogenesis, Disease Progression, Drug Therapy, Combination, Female, MESH: Disease Progression, Rituximab, MESH: Rituximab, MESH: Hemorrhage, medicine.drug, Adult, medicine.medical_specialty, MESH: Purpura, Thrombotic Thrombocytopenic, Immunology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Hemorrhage, MESH: Single-Domain Antibodies, MESH: Adrenal Cortex Hormones, 03 medical and health sciences, Thromboembolism, MESH: Severity of Illness Index, Internal medicine, von Willebrand Factor, medicine, Humans, MESH: Platelet Count, MESH: ADAMTS13 Protein, Adverse effect, Immunosuppression Therapy, MESH: Humans, Purpura, Thrombotic Thrombocytopenic, Platelet Count, business.industry, Historically Controlled Study, MESH: Adult, Cell Biology, Single-Domain Antibodies, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Drug Therapy, Combination, Regimen, Caplacizumab, business, MESH: Female
Abstract

The anti–von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Published
2021
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10. Immunogenic hotspots in the spacer domain of ADAMTS13 in immune‐mediated thrombotic thrombocytopenic purpura

Author

Heidi Rossmann, Paul Coppo, Bérangère S. Joly, Elien Roose, Andres Männik, Agnès Veyradier, Tanja Falter, Jan Voorberg, Edwige Tellier, Leydi Carolina Velásquez Pereira, Gilles Kaplanski, Bernhard Lämmle, Hendrik B. Feys, Marienn Réti, Simon F. De Meyer, Nuno A. G. Graça, Kadri Kangro, Charis von Auer, Karen Vanhoorelbeke, György Sinkovits, Zoltán Prohászka, Université Catholique de Louvain = Catholic University of Louvain (UCL), University of Amsterdam [Amsterdam] (UvA), Hungarian Academy of Sciences (MTA), Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Johannes Gutenberg - Universität Mainz (JGU), Research Group on Combinatorial Algorithms and Algorithmic Graph Theory (Ghent University), Universiteit Gent = Ghent University [Belgium] (UGENT), Vrije Universiteit Amsterdam [Amsterdam] (VU), Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Icosagen Cell Factory, European Project: 675746,H2020,H2020-MSCA-ITN-2015,PROFILE(2015), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Universiteit Gent = Ghent University (UGENT), Icosagen [Tartumaa, Estonia], Experimental Vascular Medicine, Landsteiner Laboratory, ACS - Microcirculation, and AII - Inflammatory diseases

Subjects
autoantibodies, ADAMTS13 Protein, 030204 cardiovascular system & hematology, Epitope, 03 medical and health sciences, Epitopes, 0302 clinical medicine, Von Willebrand factor, immunophenotyping, hemic and lymphatic diseases, Humans, thrombotic thrombocytopenic purpura, chemistry.chemical_classification, biology, Purpura, Thrombotic Thrombocytopenic, Autoantibody, Hematology, Molecular biology, ADAMTS13, 3. Good health, Amino acid, epitope mapping, Epitope mapping, chemistry, Polyclonal antibodies, Immunoglobulin G, biology.protein, DNA, Intergenic, Antibody, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by anti-ADAMTS13 autoantibodies inducing a severe deficiency of ADAMTS13. Epitope mapping studies on samples obtained during acute iTTP episodes have shown that the iTTP immune response is polyclonal, with almost all patients having autoantibodies targeting the spacer domain of ADAMTS13.Objectives To identify the immunogenic hotspots in the spacer domain of ADAMTS13.Patients/methods A library of 11 full-length ADAMTS13 spacer hybrids was created in which amino acid regions of the spacer domain of ADAMTS13 were exchanged by the corresponding region of the spacer domain of ADAMTS1. Next, the full-length ADAMTS13 spacer hybrids were used in enzyme-linked immunosorbent assay to epitope map anti-spacer autoantibodies in 138 samples from acute and remission iTTP patients.Results Sixteen different anti-spacer autoantibody profiles were identified with a similar distribution in acute and remission patients. There was no association between the anti-spacer autoantibody profiles and disease severity. Almost all iTTP samples contained anti-spacer autoantibodies against the following three regions: amino acid residues 588-592, 602-610, and 657-666 (hybrids E, G, and M). Between 31% and 57% of the samples had anti-spacer autoantibodies against amino acid regions 572-579, 629-638, 667-676 (hybrids C, J, and N). In contrast, none of the samples had anti-spacer autoantibodies against amino acid regions 556-563, 564-571, 649-656, and 677-685 (hybrids A, B, L, and O).Conclusion We identified three hotspot regions (amino acid regions 588-592, 602-610, and 657-666) in the spacer domain of ADAMTS13 that are targeted by anti-spacer autoantibodies found in a large cohort of iTTP patients.

Published
2021
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11. Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP

Author

Andres Männik, Gilles Kaplanski, Kadri Kangro, Elien Roose, Alexandre Curie, Bérangère S. Joly, Claudia Tersteeg, Edwige Tellier, Agnès Veyradier, Paul Coppo, Simon F. De Meyer, Laure De Waele, Karen Vanhoorelbeke, Laboratory for Thrombosis Research, Interdisciplinary Research Center, Catholic University of Leuven, Service de Néphrologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Icosagen Cell Factory, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des microangiopathies thrombotiques [CHU Saint-Antoine] (Cnr-mat), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Icosagen [Tartumaa, Estonia], and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Purpura, Thrombotic Thrombocytopenic, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, 030204 cardiovascular system & hematology, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Affinity chromatography, hemic and lymphatic diseases, medicine, Humans, MESH: Autoantibodies, Cysteine, MESH: ADAMTS13 Protein, Autoantibodies, 030304 developmental biology, MESH: Immunoglobulin G, Purpura, Thrombocytopenic, Idiopathic, 0303 health sciences, MESH: Humans, Purpura, Thrombotic Thrombocytopenic, biology, Chemistry, fungi, MESH: Purpura, Thrombocytopenic, Idiopathic, Autoantibody, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, MESH: Cysteine, medicine.disease, Stimulus Report, Molecular biology, ADAMTS13, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Healthy individuals, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, Antibody
Abstract

Key Points An open ADAMTS13 conformation is a novel biomarker for iTTP and is induced by anti-ADAMTS13 autoantibodies.The autoantibodies against the CS region play an important role in the appearance of an open ADAMTS13 conformation., Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.

Published
2021
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12. Study of thrombin generation with St Genesia to evaluate xaban pharmacodynamics: Analytical performances over 18 months

Author

Thomas Lecompte, Virginie Siguret, Isabelle Gouin-Thibault, Guillaume Paris, Johan Abdoul, Julien Perrin, Georges Jourdi, Emmanuel Curis, Geoffrey Foulon-Pinto, Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d’Hématologie Biologique [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hématologie clinique, Hôpital Cochin, Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Paris, France., Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Clinique [Rennes], CHU Pontchaillou [Rennes], Laboratoire de biomathématiques, EA 7537 [Paris] (BioSTM), Université de Paris - UFR Pharmacie [Santé] (UP UFR Pharmacie), Université de Paris (UP)-Université de Paris (UP), Service de biostatistiques et information médicale [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Hôpitaux Universitaires de Genève (HUG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité - UFR Pharmacie [Santé] (UPCité UFR Pharmacie), Université Paris Cité (UPCité)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Biostatistique, traitement et modélisation des données biologiques = Biostatistic, Biological Data treatment and Modelisation (BioSTM - URP_7537), and Université Paris Cité (UPCité)

Subjects
anticoagulants, Pyridones, [SDV]Life Sciences [q-bio], Clinical Biochemistry, quality controls, 030204 cardiovascular system & hematology, Thrombomodulin, Thrombin generation, 03 medical and health sciences, 0302 clinical medicine, Rivaroxaban, medicine, Humans, In patient, coagulation, Blood Coagulation, Reproducibility, Chromatography, Chemistry, Biochemistry (medical), Thrombin, Reproducibility of Results, Hematology, General Medicine, Repeatability, xaban, Pharmacodynamics, thrombin generation, Pyrazoles, Apixaban, Blood Coagulation Tests, 030215 immunology, medicine.drug, Factor Xa Inhibitors
Abstract

International audience; INTRODUCTION: ST Genesia is a new automated system enabling quantitative standardized evaluation of thrombin generation (TG), for example, in patients receiving anti-Xa direct inhibitors (xabans). Data on its analytical performances are scarce. METHODS: Over an 18-month period, repeatability, reproducibility, and accuracy were assessed using STG-ThromboScreen (without or with thrombomodulin) or STG-DrugScreen reagents (corresponding to intermediate/high tissue-factor concentration, respectively), and controls. Furthermore, reproducibility was assessed using commercialized lyophilized and frozen normal pooled plasmas. Rivaroxaban and apixaban impacts on TG parameters were assessed using spiking experiments. Finally, a comparison with the Calibrated Automated Thrombogram method (CAT) (PPP reagent) was performed using plasma from healthy volunteers enrolled in the DRIVING-studyNCT 01627665) before and after rivaroxaban intake. RESULTS: For all dedicated quality control (QC) levels, inter-series coefficients of variations (CV) were

Published
2020
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13. HLA-DRB1*11 is a strong risk factor for acquired thrombotic thrombocytopenic purpura in children

Author

Alain Stepanian, Agnès Veyradier, Paul Coppo, Michael Darmon, Hervé Chambost, Jérôme Harambat, Bérangère S. Joly, Fanny Fouyssac, Vincent Guigonis, Pascale Loiseau, Thierry Leblanc, Service d’Hématologie Biologique [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), AP-HP - Hôpital Antoine Béclère [Clamart], Programme Hospitalier Recherche Clinique AOM 05012CSL-Behring AP-HP-2017-47-26, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and Lucas, Nelly

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Human leukocyte antigen, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, Risk Factors, medicine, HLA-DQ beta-Chains, Humans, Risk factor, Child, Letters to the Editor, HLA-DRB1, ComputingMilieux_MISCELLANEOUS, Acquired Thrombotic Thrombocytopenic Purpura, Purpura, Thrombotic Thrombocytopenic, biology, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, ADAMTS13, 3. Good health, Immunology, biology.protein, business, HLA-DRB1 Chains, 030215 immunology
Abstract

International audience

Published
2020
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14. Refractory Auto-Immune Thrombotic Thrombocytopenic Pupura Successfully Treated With Caplacizumab

Author

Chloé Mellaza, Nicolas Henry, Pierre-Marie Fayolle, Satar Mortaza, Jean-François Subra, Agnès Veyradier, Paul Coppo, Jean-François Augusto, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Adaptation et diversité en milieu marin (AD2M), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d’Hématologie Biologique [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
medicine.medical_specialty, Thrombotic microangiopathy, Encephalopathy, Thrombotic thrombocytopenic purpura, 030204 cardiovascular system & hematology, caplacizumab, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, law, Internal medicine, hemic and lymphatic diseases, Mechanical hemolytic anemia, medicine, case report, 030212 general & internal medicine, refractor, platelet, lcsh:R5-920, biology, business.industry, thrombotic thrombocitopenic purpura, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, Intensive care unit, 3. Good health, biology.protein, Medicine, Rituximab, Caplacizumab, lcsh:Medicine (General), business, medicine.drug
Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by mechanical hemolytic anemia, profound thrombocytopenia, and neurological manifestations. Acquired auto-immune TTP, the most prevalent cause of TTP, is induced by the presence of inhibitory anti-ADAMTS13 auto-antibodies. Modern treatment of acquired TTP relies on plasma exchange, rituximab, and steroids. Caplacizumab (Cablivi®), a humanized single-variable domain immunoglobulin that targets the A1 domain of the ultra-large von Willebrand factor, inhibits the interaction between ultra-large vWFand platelets. In two clinical trials, caplacizumab, in addition to conventional treatment, shortened the delay to platelet count normalization in comparison to conventional treatment plus placebo, without increasing significantly hemorrhagic complications. Moreover, caplacizumab was associated with reduced occurrence of a secondary endpoint associating death, TTP recurrence, and major thromboembolic events. Here, we report the off-label use of caplacizumab in a 68-year-old patient with confirmed acquired TTP, severe thrombocytopenia, and generalized tonic–clonic seizures requiring mechanical ventilation and admission in the intensive care unit. Conventional treatment was rapidly started. Despite the intensification of plasma exchange treatment with twice-daily sessions, steroid continuation, and a second rituximab infusion on day 6, thrombotic microangiopathy worsened with thrombocytopenia at 21 g/L on day 8 from admission. We also considered using caplacizumab, which we could obtain and start on day 12 from admission, as it was available under a temporary authorization use in France. As soon as 12 h after caplacizumab initiation, we observed a significant increase of platelet count and improvement of other hemolytic parameters. We observed resolution of encephalopathy and complete recovery of motor paralysis, allowing us to stop mechanical ventilation on day 14. Caplacizumab was maintained for 128 days until day 139 from initial admission. The patient is going well 10 months after initial admission, without any neurological sequelae, and TTP did not relapse. To the best of our knowledge, this is the first reported use of caplacizumab in such a condition. This case report suggests that caplacizumab use may help to reduce the rate of refractory TTP episodes.

Published
2020
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15. von Willebrand factor/ADAMTS13 axis and venous thromboembolism in moderate-to-severe COVID-19 patients

Author

Sebastian Voicu, Nicolas Beranger, Philippe Bonnin, Maxime Delrue, Damien Sène, Virginie Siguret, Alain Stepanian, Marie Neuwirth, Benjamin G. Chousterman, Bruno Mégarbane, Bérangère S. Joly, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, and Mégarbane, Bruno

Subjects
Moderate to severe, Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ADAMTS13 Protein, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Von Willebrand factor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, von Willebrand Factor, medicine, Humans, Prospective Studies, Aged, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, business.industry, SARS-CoV-2, COVID-19, Hematology, Venous Thromboembolism, Middle Aged, medicine.disease, ADAMTS13, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Venous thrombosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, biology.protein, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, business, Venous thromboembolism
Abstract

International audience

Published
2020
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16. High prevalence of deep vein thrombosis in mechanically ventilated COVID-19 patients

Author

Alain Stepanian, Isabelle Malissin, Alexandre Mebazaa, Sebastian Voicu, Arthur Le Gall, Benjamin G. Chousterman, Bruno Mégarbane, Philippe Bonnin, Nicolas Deye, Virgine Siguret, Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Mathematical and Mechanical Modeling with Data Interaction in Simulations for Medicine (M3DISIM), Laboratoire de mécanique des solides (LMS), École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service d’Hématologie Biologique [CHU Lariboisière], Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), viruses, Deep vein, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Pneumonia, Viral, 030204 cardiovascular system & hematology, Article, deep vein thrombosis, 03 medical and health sciences, 0302 clinical medicine, vascular ultrasound, Internal medicine, medicine, Prevalence, Humans, 030212 general & internal medicine, Prospective Studies, Respiratory system, skin and connective tissue diseases, Prospective cohort study, hemostasis disorder, Pandemics, Coagulation Disorder, ARDS, acute respiratory distress syndrome, Venous Thrombosis, business.industry, DVT, deep vein thrombosis, fungi, virus diseases, COVID-19, medicine.disease, Thrombosis, ICU, intensive care unit, Respiration, Artificial, respiratory tract diseases, Pneumonia, medicine.anatomical_structure, COVID-19, Coronavirus disease, SARS-CoV-2, severe acute respiratory syndrome coronavirus, D-dimer, Cardiology, Female, business, Cardiology and Cardiovascular Medicine, Coronavirus Infections
Abstract

Patients with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumonia with SARS-CoV-2 present with coagulation disorders and marked susceptibility to thrombosis ([1][1],[2][2]). However, the exact prevalence of deep vein thrombosis (DVT) has been poorly investigated, although the risk

Published
2020
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17. Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura

Author

Ygal Benhamou, Andreas Greinacher, Rob Fijnheer, Gilles Kaplanski, Aline Vandenbulcke, Agnès Veyradier, An Sofie Schelpe, György Sinkovits, Bernhard Lämmle, Charlotte Dekimpe, Marienn Réti, Jan Voorberg, Tanja Falter, Elien Roose, Karen Vanhoorelbeke, Flora Peyvandi, Charis von Auer, Ilaria Mancini, Maelle Le Besnerais, Hans Deckmyn, Inge Pareyn, Heidi Rossmann, Edwige Tellier, Hendrik B. Feys, Bérangère S. Joly, Paul Coppo, Zoltán Prohászka, Simon F. De Meyer, Lucas, Nelly, Innovative training network: Immunoprofile-directed stratification of patients with the autoimmune disorder thrombotic thrombocytopenic purpura - PROFILE - - H20202015-10-01 - 2019-09-30 - 675746 - VALID, Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hungarian Academy of Sciences (MTA), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Ghent University Hospital, Central European University [Budapest, Hongrie] (CEU), University of Amsterdam [Amsterdam] (UvA), Greifswald University Hospital, University Medical Center [Utrecht], Department of Physics [Budapest], Budapest University of Technology and Economics [Budapest] (BME), CEREST-TC [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), KU Leuven OT/14/071Projet National de Recherche Clinique 2007 (Marseille, France) 2007/23Agency for Innovation and Entrepreneurship (Flanders, Belgium) 141136, European Project: 675746,H2020,H2020-MSCA-ITN-2015,PROFILE(2015), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Johannes Gutenberg - Universität Mainz (JGU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Experimental Vascular Medicine, Landsteiner Laboratory, AII - Inflammatory diseases, and ACS - Microcirculation

Subjects
Male, 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Protein Conformation, Immunology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Biochemistry, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Autoantibodies, Subclinical infection, Purpura, Thrombocytopenic, Idiopathic, Hematology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, Autoantibody, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Middle Aged, medicine.disease, ADAMTS13, 3. Good health, 030104 developmental biology, biology.protein, Female, Rituximab, business, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies, 030215 immunology, medicine.drug
Abstract

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was 50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management. ispartof: BLOOD vol:136 issue:3 pages:353-361 ispartof: location:United States status: published

Published
2020
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18. Are Screening Tests Reliable to Rule Out Direct Oral Anticoagulant Plasma Levels at Various Thresholds (30, 50, or 100 ng/mL) in Emergency Situations?

Author

Alain Stepanian, Bérangère S. Joly, Arnaud Jabet, Jean-Louis Golmard, Isabelle Gouin-Thibault, Claire Flaujac, Virginie Siguret, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière-Fernand-Widal [APHP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier de Versailles André Mignot (CHV), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Biologique [CHU Lariboisière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP]

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Screening test, Pyridones, [SDV]Life Sciences [q-bio], Thrombin Time, MEDLINE, Administration, Oral, 030204 cardiovascular system & hematology, Thrombin time, Critical Care and Intensive Care Medicine, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Text mining, Rivaroxaban, Reference Values, medicine, Humans, 030212 general & internal medicine, Emergency Treatment, medicine.diagnostic_test, business.industry, Anticoagulants, Plasma levels, Emergency situations, Dabigatran, Emergency medicine, Oral anticoagulant, Pyrazoles, Partial Thromboplastin Time, Cardiology and Cardiovascular Medicine, business, Partial thromboplastin time
Abstract

International audience

Published
2018
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19. Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

Author

Audrey Carlo, Isabelle Gouin-Thibault, Patrick Mismetti, Xavier Delavenne, Pascale Gaussem, Thomas Lecompte, Marie-Anne Loriot, Joe-Elie Salem, Emmanuel Curis, Christian Funck-Brentano, Anne Blanchard, Virginie Siguret, Johan Abdoul, Michel Azizi, Université Paris-Est Marne-la-Vallée (UPEM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Diagnostica Stago, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Paris Est, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Groupe de recherche sur la thrombose, pharmacologie des antithrombotiques et situations à risque (GRT), Université Jean Monnet - Saint-Étienne (UJM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'investigation clinique Paris Est (CIC Paris-Est), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Jonchère, Laurent, Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Adult, Male, medicine.drug_mechanism_of_action, Adolescent, Genotype, [SDV]Life Sciences [q-bio], Population, Factor Xa Inhibitor, 030204 cardiovascular system & hematology, Pharmacology, Thrombomodulin, Models, Biological, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pharmacokinetics, Rivaroxaban, medicine, Humans, education, Blood Coagulation, ComputingMilieux_MISCELLANEOUS, pharmacodynamic model, education.field_of_study, Biological Variation, Individual, Cross-Over Studies, Chemistry, Thrombin, thrombomodulin, Hematology, Active protein, Middle Aged, Healthy Volunteers, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Enzyme Activation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, thrombin generation, Pharmacodynamics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Monitoring, Blood sampling, medicine.drug, ATP Binding Cassette Transporter 1, Factor Xa Inhibitors, Protein C
Abstract

Background Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented. Objectives (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability. Methods Sixty healthy male volunteers (DRIVING-NCT01627665) received a single 40-mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST-Genesia system (Stago), using two tissue-factor (TF) concentrations, in the absence (-), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration. Results Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (-TM) (C50 ) were of 284 and 33.2 ng/mL, respectively: +TM, C50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C50 population coefficients of variation were of 12.2% (-TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model. Conclusions This low-rivaroxaban to moderate-rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.

Published
2019
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20. Modified ROTEM for the detection of rivaroxaban and apixaban anticoagulant activity in whole blood

Author

Pailleret, Claire, Jourdi, Georges, Siguret, Virginie, Gouin-Thibault, Isabelle, Gandrille, Sophie, Stepanian, Alain, Curis, Emmanuel, Golmard, Jean-Louis, Gaussem, Pascale, Le Bonniec, Bernard, Samama, Charles, Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Biostatistique, traitement et modélisation des données biologiques (BioSTM - EA 7537), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biostatistiques [Paris], and Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

International audience

Published
2019
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21. Vitamin K antagonists and emergencies

Author

Karim Tazarourte, Yves Zerbib, Virginie Siguret, Claire Pailleret, Frédéric Lapostolle, Anne-Céline Martin, Bernard Vigué, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital d'instruction des Armées Percy, Service de Santé des Armées, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Collège universitaire de médecine générale, UFR Lyon, Sciences et Société, Historicité, Éducation et Pratiques (EA S2HEP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Urgences Médicales, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon

Subjects
Vitamin, Male, medicine.medical_specialty, Vitamin K, medicine.drug_class, [SDV]Life Sciences [q-bio], Hemorrhage, 030204 cardiovascular system & hematology, Asymptomatic, Risk Assessment, Sensitivity and Specificity, Drug Administration Schedule, 03 medical and health sciences, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, International Normalized Ratio, Intensive care medicine, Dose-Response Relationship, Drug, business.industry, valvular heart disease, Anticoagulant, Anticoagulants, Thrombosis, medicine.disease, Prothrombin complex concentrate, Primary Prevention, chemistry, Emergency Medicine, Female, Neurosurgery, Patient Safety, medicine.symptom, Emergencies, Risk assessment, business, Emergency Service, Hospital, medicine.drug
Abstract

The recent emergence of 'non-VKA' oral anticoagulants may have led to some forgetting that vitamin K antagonists (VKA) are by far the most widely prescribed oral anticoagulants worldwide. Consequently, we decided to summarize the information available on them. This paper presents the problems facing emergency physicians confronted with patients on VKAs in 10 points, from pharmacological data to emergency management. Vitamin K antagonists remain preferable in many situations including in the elderly, in patients with extreme body weights, severe chronic kidney or liver disease or valvular heart disease, and in patients taking VKAs with well-controlled international normalized ratios (INRs). Given the way VKAs work, a stable anticoagulant state can only be achieved at the earliest 5 days after starting therapy. The induction phase of VKA treatment is associated with the highest risk of bleeding; validated algorithms based on INR values have to be followed. VKA asymptomatic overdoses and 'non-severe' hemorrhage are managed by omitting a dose or stopping treatment plus administering vitamin K depending on the INR. Major bleeding is managed using a VKA reversal strategy. A prothrombin complex concentrate infusion plus vitamin K is preferred to rapidly achieve an INR of up to 1.5 and maintain a normal coagulation profile. The INR must be measured 30 min after the infusion. Before an invasive procedure, if an INR of less than 1.5 (

Published
2018
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22. Open ADAMTS13 Conformation in Immune-Mediated Thrombotic Thrombocytopenic Purpura Is Induced By Anti-ADAMTS13 Autoantibodies and Corresponds with an Ongoing ADAMTS13 Pathology

Author

Elien Roose, György Sinkovits, Rob Fijnheer, Paul Coppo, Andreas Greinacher, Agnès Veyradier, Gilles Kaplanski, Maelle Le Besnerais, Zoltán Prohászka, Jan Voorberg, Hans Deckmyn, Edwige Tellier, Nele Vandeputte, Inge Pareyn, Karen Vanhoorelbeke, Ilaria Mancini, Flora Peyvandi, Ygal Benhamou, Simon F. De Meyer, Aline Vandenbulcke, An-Sofie Schelpe, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), The Wellcome Trust Sanger Institute [Cambridge], Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratory for Thrombosis Research, Interdisciplinary Research Center, Catholic University of Leuven, Clinical Chemistry and Hematology, University Medical Center [Utrecht], Faculty of Medicine, 3rd Department of Internal Medicine, Semmelweis University [Budapest], Università degli Studi di Milano = University of Milan (UNIMI), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Catholique de Louvain = Catholic University of Louvain (UCL), Aix Marseille Université (AMU), Semmelweis Univ, Dept Internal Med 33, Budapest, Hungary, Partenaires INRAE, Semmelweis Univ, Res Grp Immunol & Hematol, Budapest, Hungary, Angelo Bianchi Bonomi Centre for Haemophilia and Thrombosis, Sanquin Research, University of Amsterdam [Amsterdam] (UvA), Universität Greifswald - University of Greifswald, Semmelweis University, Luigi Villa Foundation, Univ Paris 06 (PSL), Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris (AP-HP), American Society of Hematology (ASH). USA., Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), University of Milan, Centre recherche en CardioVasculaire et Nutrition (C2VN), Service de Médecine Interne [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, CHU Saint-Antoine [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière

Subjects
medicine.medical_specialty, business.operation, [SDV]Life Sciences [q-bio], Immunology, Octapharma, Biochemistry, Adamts13 activity, Molecular conformation, 03 medical and health sciences, 0302 clinical medicine, Remission phase, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Plasma samples, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, 3. Good health, Family medicine, Adamts13 gene, Disease remission, business, 030215 immunology
Abstract

Background. Deficient ADAMTS13 activity (TS13:act 50%. However, also iTTP patients in remission with a persistent ( Aim. Determine ADAMTS13 conformation in plasma of iTTP patients during acute TTP and remission when TS13:act is 50% and investigate if anti-ADAMTS13 autoAbs induce conformational changes in ADAMTS13. Methods. TS13:act was determined in 120 iTTP plasma samples from 4 different centers (Marseille, Milan, Budapest, Utrecht). Samples were categorized according to the presence of clinical symptoms (acute versusremission) and their TS13:act in remission (>50%, 10-50%, Results. Of the 120 iTTP plasma samples, 46 were obtained during the acute (clinical signs present) and 74 during the remission phase (clinical signs absent). Further subdividing remission samples showed that TS13:act was >50% in 41, 10-50% in 14 and 50%, confirming our previous results. Interestingly, ADAMTS13 was open in 93% and 89% of remission samples with TS13:act 10-50% and Conclusion. We show that ADAMTS13 is not only in the open conformation in iTTP patient plasma during the acute phase but also in remission when TS13:act is Disclosures Peyvandi: Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria. Coppo:Ablynx: Consultancy. Veyradier:LFB: Other: Investigator. Vanhoorelbeke:Shire: Consultancy; Ablynx: Consultancy.

Published
2018
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23. Predictive features of chronic kidney disease in atypical haemolytic uremic syndrome

Author

Matthieu Jamme, Quentin Raimbourg, Dominique Chauveau, Amélie Seguin, Claire Presne, Pierre Perez, Pierre Gobert, Alain Wynckel, François Provôt, Yahsou Delmas, Christiane Mousson, Aude Servais, Laurence Vrigneaud, Agnès Veyradier, Eric Rondeau, Paul Coppo, French Thrombotic Microangiopathies Reference Centre, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Service de Néphrologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de Néphrologie - Immunologie Clinique [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-PRES Université de Toulouse, Service de réanimation médicale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Néphrologie [Amiens], CHU Amiens-Picardie-hôpital Sud, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Henri Duffaut (Avignon), Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Néphrologie [Hôpital Albert Calmette], Hôpital Albert Calmette [Lille], Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie [Valenciennes], Centre Hospitalier de Valenciennes, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse]-PRES Université de Toulouse, Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Male, Multivariate analysis, Physiology, Complement System, lcsh:Medicine, 030204 cardiovascular system & hematology, urologic and male genital diseases, Biochemistry, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Animal Cells, Immune Physiology, Chronic Kidney Disease, Medicine and Health Sciences, Renal Transplantation, Renal Failure, 030212 general & internal medicine, lcsh:Science, Atypical Hemolytic Uremic Syndrome, Multidisciplinary, Immune System Proteins, Area under the curve, Eculizumab, Middle Aged, Prognosis, 3. Good health, Body Fluids, Blood, Nephrology, Creatinine, Cohort, Female, Anatomy, Cellular Types, medicine.drug, Research Article, Adult, Platelets, medicine.medical_specialty, Immunology, Renal function, Surgical and Invasive Medical Procedures, Urinary System Procedures, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, Intensive care medicine, Transplantation, Blood Cells, business.industry, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, Renal System, Organ Transplantation, medicine.disease, chemistry, Immune System, lcsh:Q, Complication, business, Biomarkers, Kidney disease
Abstract

French Thrombotic Microangiopathies Reference Centre; International audience; Chronic kidney disease (CKD) is a frequent and serious complication of atypical haemolytic uremic syndrome (aHUS). We aimed to develop a simple accurate model to predict the risk of renal dysfunction in aHUS based on clinical and biological features available at hospital admission. Renal function at 1-year follow-up, based on an estimated glomerular filtration rate < 60mL/min/1.73m 2 as assessed by the Modification of Diet in Renal Disease equation, was used as an indicator of significant CKD. Prospectively collected data from a cohort of 156 aHUS patients who did not receive eculizumab were used to identify predictors of CKD. Covariates associated with renal impairment were identified by multivariate analysis. The model performance was assessed and a scoring system for clinical practice was constructed from the regression coefficient. Multivariate analyses identified three predictors of CKD: a high serum creatinine level, a high mean arterial pressure and a mildly decreased platelet count. The prognostic model had a good discriminative ability (area under the curve = .84). The scoring system ranged from 0 to 5, with corresponding risks of CKD ranging from 18% to 100%. This model accurately predicts development of 1-year CKD in patients with aHUS using clinical and biological features available on admission. After further validation , this model may assist in clinical decision making.

Published
2017
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24. Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors

Author

Suella Martino, Mathieu Jamme, Christophe Deligny, Marc Busson, Pascale Loiseau, Elie Azoulay, Lionel Galicier, Frédéric Pène, François Provôt, Antoine Dossier, Samir Saheb, Agnès Veyradier, Paul Coppo, French Reference Center for Thrombotic Microangiopathies, Centre de Référence des microangiopathies thrombotiques ( CNR-MAT ), service d'hématologie-CHU Saint-Antoine [APHP], Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service de Médecine interne [CHU de Fort-de France], CHU de Fort de France, Laboratoire Jean Dausset d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de réanimation médicale, Université Paris Diderot - Paris 7 ( UPD7 ), Service d'immunologie clinique, Université Paris Descartes - Paris 5 ( UPD5 ), Service de Néphrologie [Hôpital Albert Calmette], Hôpital Albert Calmette [Lille], Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Pierre et Marie Curie - Paris 6 (UPMC), HAL-UPMC, Gestionnaire, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Pitié-Salpêtrière [AP-HP]

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Epidemiology, Physiology, Ethnic group, lcsh:Medicine, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, 0302 clinical medicine, Gene Frequency, Risk Factors, Animal Cells, Medicine and Health Sciences, Medicine, HLA-DQ beta-Chains, Ethnicities, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Registries, lcsh:Science, education.field_of_study, Multidisciplinary, Mortality rate, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Thrombotic Thrombocytopenic Purpura, Middle Aged, Prognosis, 3. Good health, Body Fluids, Purpura, Treatment Outcome, Blood, Female, medicine.symptom, Anatomy, Cellular Types, Research Article, Adult, Platelets, medicine.medical_specialty, Death Rates, Population, Thrombotic thrombocytopenic purpura, Black People, Genetic Predisposition, White People, Ethnic Epidemiology, 03 medical and health sciences, Population Metrics, Diagnostic Medicine, Internal medicine, Genetic predisposition, Genetics, Humans, Allele, education, Allele frequency, Alleles, Demography, Blood Cells, Purpura, Thrombotic Thrombocytopenic, Population Biology, business.industry, lcsh:R, Biology and Life Sciences, Human Genetics, Cell Biology, medicine.disease, Thrombocytopenia, Surgery, Black or African American, People and Places, Genetics of Disease, lcsh:Q, Population Groupings, business, 030215 immunology, HLA-DRB1 Chains, Africans
Abstract

French Reference Center for Thrombotic Microangiopathies; International audience; Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.

Published
2016
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25. Thrombotic microangiopathy associated with anti-neutrophil cytoplasmic antibody-associated vasculitis: a French nationwide retrospective case-control study and literature review.

Author

Dellal A, Bige N, Hilliquin P, Boffa JJ, Rondeau E, Hatron PY, Deligny C, Bally S, Maury E, Veyradier A, Buob D, Fain O, Coppo P, and Mekinian A

Subjects
Adolescent, Adult, Aged, Case-Control Studies, Female, France epidemiology, Humans, Male, Middle Aged, Registries, Retrospective Studies, Thrombotic Microangiopathies immunology, Young Adult, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Thrombotic Microangiopathies epidemiology
Published
2019
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