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3. Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

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Astrid Marchal, Elizabeth T. Cirulli, Iva Neveux, Evangelos Bellos, Ryan S. Thwaites, Kelly M. Schiabor Barrett, Yu Zhang, Ivana Nemes-Bokun, Mariya Kalinova, Andrew Catchpole, Stuart G. Tangye, András N. Spaan, Justin B. Lack, Jade Ghosn, Charles Burdet, Guy Gorochov, Florence Tubach, Pierre Hausfater, Clifton L. Dalgard, Shen-Ying Zhang, Qian Zhang, Christopher Chiu, Jacques Fellay, Joseph J. Grzymski, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze, Alessandro Aiuti, Saleh Al-Muhsen, Fahd Al-Mulla, Ali Amara, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Lisa M. Arkin, Hagit Baris Feldman, Paul Bastard, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Anastasiia Bondarenko, Alessandro Borghesi, Ahmed A. Bousfiha, Petter Brodin, Yenan Bryceson, Manish J. Butte, Giorgio Casari, John Christodoulou, Roger Colobran, Antonio Condino-Neto, Stefan N. Constantinescu, Megan A. Cooper, Murkesh Desai, Beth A. Drolet, Xavier Duval, Jamila El Baghdadi, Philippine Eloy, Sara Espinosa-Padilla, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Eystein Husebye, Kohsuke Imai, Yuval Itan, Emmanuelle Jouanguy, Elżbieta Kaja, Timokratis Karamitros, Kai Kisand, Cheng-Lung Ku, Yu-Lung Lau, Yun Ling, Carrie L. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, France Mentré, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F.P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O'Farrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarström, Jean W. Pape, Rebeca Perez de Diego, Jordi Perez-Tur, David S. Perlin, Graziano Pesole, Anna M. Planas, Carolina Prando, Aurora Pujol, Anne Puel, Lluis Quintana-Murci, Sathishkumar Ramaswamy, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Anna Sediva, Mikko R.J. Seppänen, Mohammad Shahrooei, Anna Shcherbina, Ondrej Slaby, Andrew L. Snow, Pere Soler-Palacín, Vassili Soumelis, Ivan Tancevski, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian Thorball, Pierre Tiberghien, Sophie Trouillet-Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed J. Uddin, Diederik van de Beek, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Pawel Zawadzki, Serge Bureau, Yannick Vacher, Anne Gysembergh-Houal, Lauren Demerville, Abla Benleulmi-Chaachoua, Sebastien Abad, Radhiya Abassi, Abdelrafie Abdellaoui, Abdelkrim Abdelmalek, Hendy Abdoul, Helene Abergel, Fariza Abeud, Sophie Abgrall, Noemie Abisror, Marylise Adechian, Nordine Aderdour, Hakeem Farid Admane, Frederic Adnet, Sara Afritt, Helene Agostini, Claire Aguilar, Sophie Agut, Tommaso Francesco Aiello, Marc Ait Kaci, Hafid Ait Oufella, Gokula Ajeenthiravasan, Virginie Alauzy, Fanny Alby-Laurent, Lucie Allard, Marie-Alexandra Alyanakian, Blanca Amador Borrero, Sabrina Amam, Lucile Amrouche, Marc Andronikof, Dany Anglicheau, Nadia Anguel, Djillali Annane, Mohammed Aounzou, Caroline Aparicio, Gladys Aratus, Jean-Benoit Arlet, Jeremy Arzoine, Elisabeth Aslangul, Mona Assefi, Adeline Aubry, Laetitia Audiffred, Etienne Audureau, Christelle Nathalie Auger, Jean-Charles Auregan, Celine Awotar, Sonia Ayllon Milla, Delphine Azan, Laurene Azemar, Billal Azzouguen, Marwa Bachir Elrufaai, Aïda Badsi, Prissile Bakouboula, Coline Balcerowiak, Fanta Balde, Elodie Baldivia, Eliane-Flore Bangamingo, Amandine Baptiste, Fanny Baran-Marszak, Caroline Barau, Nathalie Barget, Flore Baronnet, Romain Barthelemy, Jean-Luc Baudel, Camille Baudry, Elodie Baudry, Laurent Beaugerie, Adel Belamri, Nicolas Belaube, Rhida Belilita, Pierre Bellassen, Rawan Belmokhtar, Isabel Beltran, Ruben Benainous, Mourad Benallaoua, Robert Benamouzig, Amélie Benbara, Jaouad Benhida, Anis Benkhelouf, Jihene Benlagha, Chahinez Benmostafa, Skander Benothmane, Miassa Bentifraouine, Laurence Berard, Quentin Bernier, Enora Berti, Astrid Bertier, Laure Berton, Simon Bessis, Alexandra Beurton, Celine Bianco, Clara Bianquis, Frank Bidar, Philippe Blanche, Clarisse Blayau, Alexandre Bleibtreu, Emmanuelle Blin, Coralie Bloch-Queyrat, Marie-Christophe Boissier, Diane Bollens, Marion Bolzoni, Rudy pierre Bompard, Nicolas Bonnet, Justine Bonnouvrier, Shirmonecrystal Botha, Wissam Boucenna, Fatiha Bouchama, Olivier Bouchaud, Hanane Bouchghoul, Taoueslylia Boudjebla, Noel Boudjema, Catherine Bouffard, Adrien Bougle, Meriem Bouguerra, Leila Bouras, Agnes Bourcier, Anne Bourgarit Durand, Anne Bourrier, Fabrice Bouscarat, Diane Bouvry, Nesrine Bouziri, Ons Bouzrara, Sarah Bribier, Delphine Brugier, Melanie Brunel, Eida Bui, Anne Buisson, Iryna Bukreyeva, Côme Bureau, Jacques Cadranel, Johann Cailhol, Ruxandra Calin, Clara Campos Vega, Pauline Canavaggio, Marta Cancella, Delphine Cantin, Albert Cao, Lionel Carbillon, Nicolas Carlier, Clementine Cassard, Guylaine Castor, Marion Cauchy, Olivier Cha, Benjamin Chaigne, Salima Challal, Karine Champion, Patrick Chariot, Julie Chas, Simon Chauveau, Anthony Chauvin, Clement Chauvin, Nathalie Chavarot, Kamélia Chebbout, Mustapha Cherai, Ilaria Cherubini, Amelie Chevalier, Thibault Chiarabini, Thierry Chinet, Richard Chocron, Pascaline Choinier, Juliette Chommeloux, Christophe Choquet, Laure Choupeaux, Benjamin Chousterman, Dragosmarius Ciocan, Ada Clarke, Gaëlle Clavere, Florian Clavier, Karine Clement, Sebastien Clerc, Yves Cohen, Fleur Cohen, Adrien Cohen, Audrey Coilly, Hester Colboc, Pauline Colin, Magalie Collet, Chloé Comarmond, Emeline Combacon, Alain Combes, Celine Comparon, Jean-Michel Constantin, Hugues Cordel, Anne-Gael Cordier, Adrien Costantini, Nathalie Costedoat Chalumeau, Camille Couffignal, Doriane Coupeau, Alain Creange, Yannie Cuvillier Lamarre, Charlène Da Silveira, Sandrine Dautheville Guibal El Kayani, Nathalie De Castro, Yann De Rycke, Lucie Del Pozo, Quentin Delannoy, Mathieu Delay, Robin Deleris, Juliette Delforge, Laëtitia Delphine, Noemie Demare, Sophie Demeret, Alexandre Demoule, Aurore Deniau, François Depret, Sophie Derolez, Ouda Derradji, Nawal Derridj, Vincent Descamps, Lydia Deschamps, Celine Desconclois, Cyrielle Desnos, Karine Desongins, Robin Dhote, Benjamin Diallo, Morgane Didier, Myriam Diemer, Stephane Diez, Juliette Djadi-Prat, Fatima-Zohra Djamouri Monnory, Siham Djebara, Naoual Djebra, Minette Djietcheu, Hadjer Djillali, Nouara Djouadi, Severine Donneger, Catarina Dos Santos, Nathalie Dournon, Martin Dres, Laura Droctove, Marie Drogrey, Margot Dropy, Elodie Drouet, Valérie Dubosq, Evelyne Dubreucq, Estelle Dubus, Boris Duchemann, Thibault Duchenoy, Emmanuel Dudoignon, Romain Dufau, Florence Dumas, Clara Duran, Emmanuelle Duron, Antoine Durrbach, Claudine Duvivier, Nathan Ebstein, Jihane El Khalifa, Alexandre Elabbadi, Caroline Elie, Gabriel Ernotte, Anne Esling, Martin Etienne, Xavier Eyer, Muriel Sarah Fartoukh, Takoua Fayali, Marion Fermaut, Arianna Fiorentino, Souha Fliss, Marie-Céline Fournier, Benjamin Fournier, Hélène Francois, Olivia Freynet, Yvann Frigout, Isaure Fromont, Axelle Fuentes, Thomas Furet, Joris Galand, Marc Garnier, Agnes Gaubert, Stéphane Gaudry, Samuel Gaugain, Damien Gauthier, Maxime Gautier, Sophie Georgin-Lavialle, Daniela Geromin, Mohamed Ghalayini, Bijan Ghaleh, Myriam Ghezal, Aude Gibelin, Linda Gimeno, Benoit Girard, Bénédicte Giroux Leprieur, Doryan Gomes, Elisabete Gomes-Pires, Anne Gouge, Amel Gouja, Helene Goulet, Sylvain Goupil, Jeanne Goupil De Bouille, Julien Gras, Segolene Greffe, Lamiae Grimaldi, Paul Guedeney, Bertrand Guidet, Matthias Guillo, Mariechristelle Gulczynski, Tassadit Hadjam, Didier Haguenauer, Soumeya Hammal, Nadjib Hammoudi, Olivier Hanon, Anarole Harrois, Coraline Hautem, Guillaume Hekimian, Nicholas Heming, Olivier Hermine, Sylvie Ho, Marie Houllier, Benjamin Huot, Tessa Huscenot, Wafa Ibn Saied, Ghilas Ikherbane, Meriem Imarazene, Patrick Ingiliz, Lina Iratni, Stephane Jaureguiberry, Jean-Francois Jean-Marc, Deleena Jeyarajasingham, Pauline Jouany, Veronique Jouis, Clement Jourdaine, Ouifiya Kafif, Rim Kallala, Sandrine Katsahian, Lilit Kelesyan, Vixra Keo, Flora Ketz, Warda Khamis, Enfel Khelili, Mehdi Khellaf, Christy Gaëlla Kotokpo Youkou, Ilias Kounis, Gaelle Kpalma, Jessica Krause, Vincent Labbe, Karine Lacombe, Jean-Marc Lacorte, Anne Gaelle Lafont, Emmanuel Lafont, Lynda Lagha, Lionel Lamhaut, Aymeric Lancelot, Cecilia Landman, Fanny Lanternier, Cecile Larcheveque, Caroline Lascoux Combe, Ludovic Lassel, Benjamin Laverdant, Christophe Lavergne, Jean-Rémi Lavillegrand, Pompilia Lazureanu, Loïc Le Guennec, Lamia Leberre, Claire Leblanc, Marion Leboyer, Francois Lecomte, Marine Lecorre, Romain Leenhardt, Marylou Lefebvre, Bénédicte Lefebvre, Paul Legendre, Anne Leger, Laurence Legros, Justyna Legrosse, Sébastien Lehuunghia, Julien Lemarec, Jeremie Leporrier-Ext, Manon Lesein, Hubert Lesur, Vincent Levy, Albert Levy, Edwige Lopes, Amanda Lopes, Vanessa Lopez, Julien Lopinto, Olivier Lortholary, Badr Louadah, Bénédicte Loze, Marie-Laure Lucas, Axelle Lucasamichi, Liem Binh Luong, Arouna Magazimama-Ext, David Maingret, Lakhdar Mameri, Philippe Manivet, Cylia Mansouri, Estelle Marcault, Jonathan Marey, Nathalie Marin, Clémence Marois, Olivier Martin, Lou Martineau, Cannelle Martinez-Lopez, Pierre Martyniuck, Pauline Mary De Farcy, Nessrine Marzouk, Rafik Masmoudi, Alexandre Mebazaa, Frédéric Mechai, Fabio Mecozzi, Chamseddine Mediouni, Bruno Megarbane, Mohamed Meghadecha, Élodie Mejean, Arsene Mekinian, Nour Mekki Abdelhadi, Rania Mekni, Thinhinan Sabrina Meliti, Breno Melo Lima, Paris Meng, Soraya Merbah, Fadhila Messani, Yasmine Messaoudi, Baboo-Irwinsingh Mewasing, Lydia Meziane, Carole Michelot-Burger, Françoise Mignot, Fadi Hillary Minka, Makoto Miyara, Pierre Moine, Jean-Michel Molina, Anaïs Montegnies-Boulet, Alexandra Monti, Claire Montlahuc, Anne-Lise Montout, Alexandre Moores, Caroline Morbieu, Helene Mortelette, Stéphane Mouly, Rosita Muzaffar, Cherifa Iness Nacerddine, Marine Nadal, Hajer Nadif, Kladoum Nassarmadji, Pierre Natella, Sandrine Ndingamondze, Stefan Neraal, Caroline Nguyen, Bao N'Guyen, Isabelle Nion Larmurier, Luc Nlomenyengue, Nicolas Noel, Hilario Nunes, Edris Omar, Zineb Ouazene, Elise Ouedraogo, Wassila Ouelaa, Anissa Oukhedouma, Yasmina Ould Amara, Herve Oya, Johanna Oziel, Thomas Padilla, Elena Paillaud, Solenne Paiva, Beatrice Parfait, Perrine Parize, Christophe Parizot, Antoine Parrot, Arthur Pavot, Laetitia Peaudecerf, Frédéric Pene, Marion Pepin, Julie Pernet, Claire Pernin, Mylène Petit, Olivier Peyrony, Marie-Pierre Pietri, Olivia Pietri, Marc Pineton De Chambrun, Michelle Pinson, Claire Pintado, Valentine Piquard, Christine Pires, Benjamin Planquette, Sandrine Poirier, Anne-Laure Pomel, Stéphanie Pons, Diane Ponscarme, Annegaelle Pourcelot, Valérie Pourcher, Anne Pouvaret, Florian Prever, Miresta Previlon, Margot Prevost, Marie-Julie Provoost, Cyril Quemeneur, Cédric Rafat, Agathe Rami, Brigitte Ranque, Maurice Raphael, Jean Herle Raphalen, Anna Rastoin, Mathieu Raux, Amani Rebai, Michael Reby, Alexis Regent, Asma Regrag, Matthieu Resche-Rigon, Quentin Ressaire, Christian Richard, Mariecaroline Richard, Maxence Robert, Benjamin Rohaut, Camille Rolland-Debord, Jacques Ropers, Anne-Marie Roque-Afonso, Charlotte Rosso, Mélanie Rousseaux, Nabila Rousseaux, Swasti Roux, Lorène Roux, Claire Rouzaud, Antoine Rozes, Emma Rubenstein, Jean-Marc Sabate, Sheila Sabet, Sophie-Caroline Sacleux, Nathalie Saidenberg Kermanach, Faouzi Saliba, Dominique Salmon, Laurent Savale, Guillaume Savary, Rebecca Sberro, Anne Scemla, Frederic Schlemmer, Mathieu Schwartz, Saïd Sedfi, Samia Sefir-Kribel, Philippe Seksik, Pierre Sellier, Agathe Selves, Nicole Sembach, Luca Semerano, Marie-Victoire Senat, Damien Sene, Alexandra Serris, Lucile Sese, Naima Sghiouar, Johanna Sigaux, Martin Siguier, Johanne Silvain, Noémie Simon, Tabassome Simon, Lina Innes Skandri, Miassa Slimani, Aurélie Snauwaert, Harry Sokol, Heithem Soliman, Nisrine Soltani, Benjamin Soyer, Gabriel Steg, Lydia Suarez, Tali-Anne Szwebel, Kossi Taffame, Yacine Tandjaoui-Lambiotte, Claire Tantet, Mariagrazia Tateo, Igor Theodose, Pierre clement Thiebaud, Caroline Thomas, Kelly Tiercelet, Julie Tisserand, Carole Tomczak, Krystel Torelino, Fatima Touam-Ext, Lilia Toumi, Gustave Toury, Mireille Toy-Miou, Olivia Tran Dinh Thanh Lien, Alexy Trandinh, Jean-Marc Treluyer, Baptiste Trinque, Jennifer Truchot, Sarah Tubiana, Simone Tunesi, Matthieu Turpin, Agathe Turpin, Tomas Urbina, Rafael Usubillaga Narvaez, Yurdagul Uzunhan, Prabakar Vaittinadaayar, Arnaud Valent, Maelle Valentian, Nadia Valin, Hélène Vallet, Marina Vaz, Miguel-Alejandro Vazquezibarra, Benoit Vedie, Laetitia Velly, Celine Verstuyft, Cedric Viallette, Eric Vicaut, Dorothee Vignes, Damien Vimpere, Myriam Virlouvet, Guillaume Voiriot, Lena Voisot, Emmanuel Weiss, Nicolas Weiss, Anaïs Winchenne, Youri Yordanov, Lara Zafrani, Mohamad Zaidan, Wissem Zaidi, Cathia Zak, Aida Zarhrate-Ghoul, Ouassila Zatout, Suzanne Zeino, Michel Zeitouni, Naïma Zemirli, Lorene Zerah, Ounsa Zia, Marianne Ziol, Oceane Zolario, Julien Zuber, Claire Andrejak, François Angoulvant, Delphine Bachelet, Marie Bartoli, Romain Basmaci, Sylvie Behillil, Marine Beluze, Dehbia Benkerrou, Krishna Bhavsar, Lila Bouadma, Sabelline Bouchez, Maude Bouscambert, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chirouze, Alexandra Coelho, Sandrine Couffin-Cadiergues, Eric d’Ortenzio, Marie-Pierre Debray, Laurene Deconinck, Dominique Deplanque, Diane Descamps, Mathilde Desvallée, Alpha Diallo, Alphonsine Diouf, Céline Dorival, François Dubos, Brigitte Elharrar, Vincent Enouf, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Eglantine Ferrand Devouge, Nathalie Gault, Alexandre Gaymard, Tristan Gigante, Morgane Gilg, Jérémie Guedj, Alexandre Hoctin, Isabelle Hoffmann, Ikram Houas, Jean-Sébastien Hulot, Salma Jaafoura, Florentia Kaguelidou, Sabrina Kali, Antoine Khalil, Coralie Khan, Cédric Laouénan, Samira Laribi, Minh Le, Quentin Le Hingrat, Soizic Le Mestre, Hervé Le Nagard, François-Xavier Lescure, Sophie Letrou, Yves Levy, Bruno Lina, Guillaume Lingas, Jean-Christophe Lucet, Denis Malvy, Marina Mambert, Amina Meziane, Hugo Mouquet, Jimmy Mullaert, Nadège Neant, Duc Nguyen, Marion Noret, Saad Nseir, Aurélie Papadopoulos, Christelle Paul, Nathan Peiffer-Smadja, Thomas Perpoint, Ventzislava Petrov-Sanchez, Gilles Peytavin, Huong Pham, Olivier Picone, Oriane Puéchal, Christian Rabaud, Manuel Rosa-Calatrava, Bénédicte Rossignol, Patrick Rossignol, Carine Roy, Marion Schneider, Richa Su, Coralie Tardivon, Marie-Capucine Tellier, François Téoulé, Olivier Terrier, Jean-François Timsit, Christelle Tual, Sylvie Van Der Werf, Noémie Vanel, Aurélie Veislinger, Benoit Visseaux, Aurélie Wiedemann, Yazdan Yazdanpanah, Loubna Alavoine, Charlotte Charpentier, Aline Dechanet, Jean-Luc Ecobichon, Wahiba Frezouls, Nadhira Houhou, Jonathan Lehacaut, Pauline Manchon, Mariama Nouroudine, Caroline Quintin, Michael Thy, Sylvie van der Werf, Valérie Vignali, Abir Chahine, Nawal Waucquier, Maria-Claire Migaud, Félix Djossou, Mayka Mergeay-Fabre, Aude Lucarelli, Magalie Demar, Léa Bruneau, Patrick Gérardin, Adrien Maillot, Christine Payet, Bruno Laviolle, Fabrice Laine, Christophe Paris, Mireille Desille-Dugast, Julie Fouchard, Thierry Pistone, Pauline Perreau, Valérie Gissot, Carole L.E. Goas, Samatha Montagne, Lucie Richard, Kévin Bouiller, Maxime Desmarets, Alexandre Meunier, Marilou Bourgeon, Benjamin Lefévre, Hélène Jeulin, Karine Legrand, Sandra Lomazzi, Bernard Tardy, Amandine Gagneux-Brunon, Frédérique Bertholon, Elisabeth Botelho-Nevers, Christelle Kouakam, Leturque Nicolas, Layidé Roufai, Karine Amat, Hélène Espérou, Samia Hendou, Giuseppe Foti, Giuseppe Citerio, Ernesto Contro, Alberto Pesci, Maria Grazia Valsecchi, Marina Cazzaniga, Giacomo Bellani, Jorge Abad, Giulia Accordino, Micol Angelini, Sergio Aguilera-Albesa, Aina Aguiló-Cucurull, Esra Akyüz Özkan, Ilad Alavi Darazam, Jonathan Antonio Roblero Albisures, Juan C. Aldave, Miquel Alfonso Ramos, Taj Ali Khan, Anna Aliberti, Seyed Alireza Nadji, Gulsum Alkan, Suzan A. AlKhater, Jerome Allardet-Servent, Luis M. Allende, Rebeca Alonso-Arias, Mohammed S. Alshahrani, Laia Alsina, Zahir Amoura, Arnau Antolí, Romain Arrestier, Mélodie Aubart, Teresa Auguet, Iryna Avramenko, Gökhan Aytekin, Axelle Azot, Seiamak Bahram, Fanny Bajolle, Fausto Baldanti, Aurélie Baldolli, Maite Ballester, Benoit Barrou, Federica Barzaghi, Sabrina Basso, Gulsum Iclal Bayhan, Liliana Bezrodnik, Agurtzane Bilbao, Geraldine Blanchard-Rohner, Ignacio Blanco, Adeline Blandinières, Daniel Blázquez-Gamero, Marketa Bloomfield, Mireia Bolivar-Prados, Raphael Borie, Elisabeth Botdhlo-Nevers, Aurore Bousquet, David Boutolleau, Claire Bouvattier, Oksana Boyarchuk, Juliette Bravais, M. Luisa Briones, Marie-Eve Brunner, Raffaele Bruno, Maria Rita P. Bueno, Huda Bukhari, Jacinta Bustamante, Juan José Cáceres Agra, Ruggero Capra, Raphael Carapito, Maria Carrabba, Carlos Casasnovas, Marion Caseris, Irene Cassaniti, Martin Castelle, Francesco Castelli, Martín Castillo de Vera, Mateus V. Castro, Emilie Catherinot, Jale Bengi Celik, Alessandro Ceschi, Martin Chalumeau, Bruno Charbit, Cécile Boulanger, Père Clavé, Bonaventura Clotet, Anna Codina, Cloé Comarmond, Patrizia Comoli, Angelo G. Corsico, Taner Coşkuner, Aleksandar Cvetkovski, Cyril Cyrus, David Dalmau, François Danion, David Ross Darley, Vincent Das, Nicolas Dauby, Stéphane Dauger, Paul De Munte, Loic de Pontual, Amin Dehban, Geoffroy Delplancq, Isabelle Desguerre, Antonio Di Sabatino, Jean-Luc Diehl, Stephanie Dobbelaere, Elena Domínguez-Garrido, Clément Dubost, Olov Ekwall, Şefika Elmas Bozdemir, Marwa H. Elnagdy, Melike Emiroglu, Akifumi Endo, Emine Hafize Erdeniz, Selma Erol Aytekin, Maria Pilar Etxart Lasa, Romain Euvrard, Giovanna Fabio, Laurence Faivre, Antonin Falck, Muriel Fartoukh, Morgane Faure, Miguel Fernandez Arquero, Ricard Ferrer, Jose Ferreres, Bruno Francois, Victoria Fumadó, Kitty S.C. Fung, Francesca Fusco, Alenka Gagro, Blanca Garcia Solis, Pierre Garçon, Pascale Gaussem, Zeynep Gayretli, Juana Gil-Herrera, Laurent Gilardin, Audrey Giraud Gatineau, Mònica Girona-Alarcón, Karen Alejandra Cifuentes Godínez, Jean-Christophe Goffard, Nacho Gonzales, Luis I. Gonzalez-Granado, Rafaela González-Montelongo, Antoine Guerder, Belgin Gülhan, Victor Daniel Gumucio, Leif Gunnar Hanitsch, Jan Gunst, Marta Gut, Jérôme Hadjadj, Selda Hancerli, Tetyana Hariyan, Nevin Hatipoglu, Deniz Heppekcan, Elisa Hernandez-Brito, Po-ki Ho, María Soledad Holanda-Peña, Juan P. Horcajada, Sami Hraiech, Linda Humbert, Ivan F.N. Hung, Alejandro D. Iglesias, Antonio Íñigo-Campos, Matthieu Jamme, María Jesús Arranz, Marie-Thérèse Jimeno, Iolanda Jordan, Saliha Kanık-Yüksek, Yalcin Kara, Aydın Karahan, Adem Karbuz, Kadriye Kart Yasar, Ozgur Kasapcopur, Kenichi Kashimada, Sevgi Keles, Yasemin Kendir Demirkol, Yasutoshi Kido, Can Kizil, Ahmet Osman Kılıç, Adam Klocperk, Antonia Koutsoukou, Zbigniew J. Król, Hatem Ksouri, Paul Kuentz, Arthur M.C. Kwan, Yat Wah M. Kwan, Janette S.Y. Kwok, Jean-Christophe Lagier, David S.Y. Lam, Vicky Lampropoulou, Fleur Le Bourgeois, Yee-Sin Leo, Rafael Leon Lopez, Daniel Leung, Michael Levin, Michael Levy, Romain Lévy, Zhi Li, Daniele Lilleri, Edson Jose Adrian Bolanos Lima, Agnes Linglart, Eduardo López-Collazo, José M. Lorenzo-Salazar, Céline Louapre, Catherine Lubetzki, Kwok-Cheung Lung, Charles-Edouard Luyt, David C. Lye, Cinthia Magnone, Enrico Marchioni, Carola Marioli, Majid Marjani, Laura Marques, Jesus Marquez Pereira, Andrea Martín-Nalda, David Martínez Pueyo, Javier Martinez-Picado, Iciar Marzana, Carmen Mata-Martínez, Alexis Mathian, Larissa R.B. Matos, Gail V. Matthews, Julien Mayaux, Raquel McLaughlin-Garcia, Philippe Meersseman, Jean-Louis Mège, Armand Mekontso-Dessap, Isabelle Melki, Federica Meloni, Jean-François Meritet, Paolo Merlani, Özge Metin Akcan, Mehdi Mezidi, Isabelle Migeotte, Maude Millereux, Matthieu Million, Tristan Mirault, Clotilde Mircher, Mehdi Mirsaeidi, Yoko Mizoguchi, Bhavi P. Modi, Francesco Mojoli, Elsa Moncomble, Abián Montesdeoca Melián, Antonio Morales Martinez, Francisco Morandeira, Pierre-Emmanuel Morange, Clémence Mordacq, Guillaume Morelle, Stéphane J. Mouly, Adrián Muñoz-Barrera, Cyril Nafati, Shintaro Nagashima, Yu Nakagama, Bénédicte Neven, João Farela Neves, Yuk-Yung Ng, Hubert Nielly, Yeray Novoa Medina, Esmeralda Nuñez Cuadros, Semsi Nur Karabela, J. Gonzalo Ocejo-Vinyals, Mehdi Oualha, Amani Ouedrani, Tayfun Özçelik, Aslinur Ozkaya-Parlakay, Michele Pagani, Maria Papadaki, Philippe Parola, Tiffany Pascreau, Stéphane Paul, Estela Paz-Artal, Sigifredo Pedraza, Nancy Carolina González Pellecer, Silvia Pellegrini, Rebeca Pérez de Diego, Xosé Luis Pérez-Fernández, Aurélien Philippe, Quentin Philippot, Adrien Picod, Marc Pineton de Chambrun, Antonio Piralla, Laura Planas-Serra, Dominique Ploin, Julien Poissy, Géraldine Poncelet, Garyphallia Poulakou, Marie S. Pouletty, Persia Pourshahnazari, Jia Li Qiu-Chen, Paul Quentric, Thomas Rambaud, Didier Raoult, Violette Raoult, Anne-Sophie Rebillat, Claire Redin, Léa Resmini, Pilar Ricart, Jean-Christophe Richard, Raúl Rigo-Bonnin, Nadia Rivet, Jacques G. Rivière, Gemma Rocamora-Blanch, Mathieu P. Rodero, Carlos Rodrigo, Luis Antonio Rodriguez, Carlos Rodriguez-Gallego, Agustí Rodriguez-Palmero, Carolina Soledad Romero, Anya Rothenbuhler, Damien Roux, Nikoletta Rovina, Flore Rozenberg, Yvon Ruch, Montse Ruiz, Maria Yolanda Ruiz del Prado, Juan Carlos Ruiz-Rodriguez, Joan Sabater-Riera, Kai Saks, Maria Salagianni, Oliver Sanchez, Adrián Sánchez-Montalvá, Silvia Sánchez-Ramón, Laire Schidlowski, Agatha Schluter, Julien Schmidt, Matthieu Schmidt, Catharina Schuetz, Cyril E. Schweitzer, Francesco Scolari, Luis Seijo, Analia Gisela Seminario, Piseth Seng, Sevtap Senoglu, Mikko Seppänen, Alex Serra Llovich, Virginie Siguret, Eleni Siouti, David M. Smadja, Nikaia Smith, Ali Sobh, Xavier Solanich, Jordi Solé-Violán, Catherine Soler, Betül Sözeri, Giulia Maria Stella, Yuriy Stepanovskiy, Annabelle Stoclin, Fabio Taccone, Jean-Luc Taupin, Simon J. Tavernier, Loreto Vidaur Tello, Benjamin Terrier, Guillaume Thiery, Karolina Thorn, Caroline Thumerelle, Imran Tipu, Martin Tolstrup, Gabriele Tomasoni, Julie Toubiana, Josep Trenado Alvarez, Vasiliki Triantafyllia, Jesús Troya, Owen T.Y. Tsang, Liina Tserel, Eugene Y.K. Tso, Alessandra Tucci, Şadiye Kübra Tüter Öz, Matilde Valeria Ursini, Takanori Utsumi, Pierre Vabres, Juan Valencia-Ramos, Ana Maria Van Den Rym, Isabelle Vandernoot, Valentina Velez-Santamaria, Silvia Patricia Zuniga Veliz, Mateus C. Vidigal, Sébastien Viel, Cédric Villain, Marie E. Vilaire-Meunier, Judit Villar-García, Audrey Vincent, Dimitri Van der Linden, Alla Volokha, Fanny Vuotto, Els Wauters, Alan K.L. Wu, Tak-Chiu Wu, Aysun Yahşi, Osman Yesilbas, Mehmet Yildiz, Barnaby E. Young, Ufuk Yükselmiş, Marco Zecca, Valentina Zuccaro, Jens Van Praet, Bart N. Lambrecht, Eva Van Braeckel, Cédric Bosteels, Levi Hoste, Eric Hoste, Fré Bauters, Jozefien De Clercq, Catherine Heijmans, Hans Slabbynck, Leslie Naesens, Benoit Florkin, Mary-Anne Young, Amanda Willis, Paloma Lapuente-Suanzes, Ana de Andrés-Martín, Matilda Berkell, Valerio Carelli, Alessia Fiorentino, Surbhi Malhotra, Alessandro Mattiaccio, Tommaso Pippucci, Marco Seri, Evelina Tacconelli, Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Harm Jan Bogaard, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, Sanne de Bruin, David T.P. Buis, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Mirjam Dijkstra, Dave A. Dongelmans, Romein W.G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H.T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan A.I. Pina-Fuentes, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Maurits C.F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A.P. Schrauwen, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, A.H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P.J. Vlaar, Miranda F. Tompkins, Camille Alba, Daniel N. Hupalo, John Rosenberger, Gauthaman Sukumar, Matthew D. Wilkerson, Xijun Zhang, Justin Lack, Andrew J. Oler, Kerry Dobbs, Ottavia M. Delmonte, Jeffrey J. Danielson, Andrea Biondi, Laura Rachele Bettini, Mariella D’Angiò, Ilaria Beretta, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Eugenia Quiros-Roldan, Camillo Rossi, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, and Gian Luigi Marseglia

Subjects
HLA, association, asymptomatic infection, COVID-19, population stratification, Genetics, QH426-470
Abstract

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Published
2024
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4. Bothrops venom-induced hemostasis disorders in the rat: Between Scylla and Charybdis.

Author

Sébastien Larréché, Lucie Chevillard, Georges Jourdi, Simon Mathé, Aurélie Servonnet, Bérangère S Joly, Virginie Siguret, Jean-Philippe Chippaux, and Bruno Mégarbane

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

Hemostasis impairment represents the most threatening consequence of Viperidae envenoming, notably with Bothrops genus. In the French departments of America, B. atrox envenomation in French Guiana may lead to bleeding while B. lanceolatus envenomation in Martinique to thrombosis. Bleeding related to B. atrox envenomation is attributed to vascular damage mediated by venom metalloproteinases and blood uncoagulable state resulting from thrombocytopenia and consumptive coagulopathy. Thrombosis related to B. lanceolatus envenomation are poorly understood. We aimed to compare the effects of B. atrox and B. lanceolatus venoms in the rat to identify the determinants of the hemorrhagic versus thrombotic complications. Viscoelastometry (ROTEM), platelet count, plasma fibrinogen, thrombin generation assay, fibrinography, endothelial (von Willebrand factor, ADAMTS13 activity, ICAM-1, and soluble E-selectin), and inflammatory biomarkers (IL-1β, IL-6, TNF-α, MCP-1, and PAI-1) were determined in blood samples obtained at H3, H6, and H24 after the subcutaneous venom versus saline injection. In comparison to the control, initial fibrinogen consumption was observed with the two venoms while thrombocytopenia and reduction in the clot amplitude only with B. atrox venom. Moreover, we showed an increase in thrombin generation at H3 with the two venoms, an increase in fibrin generation accompanied with hyperfibrinogenemia at H24 and an increase in inflammatory biomarkers with B. lanceolatus venom. No endothelial damage was found with the two venoms. To conclude, our data support two-sided hemostasis complications in Bothrops envenoming with an initial risk of hemorrhage related to platelet consumption and hypocoagulability followed by an increased risk of thrombosis promoted by the activated inflammatory response and rapid-onset fibrinogen restoration.

Published
2023
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5. Practical Nomogram Predicting Apixaban or Rivaroxaban Concentrations from Low-Molecular-Weight Heparin Anti-Xa Values: Special Interest in Acute Ischemic Stroke Patients

Author

Charlyne Brakta, Alain Stépanian, Peggy Reiner, Maxime Delrue, Mikaël Mazighi, Emmanuel Curis, and Virginie Siguret

Subjects
fibrinolysis, stroke, anticoagulant, doac, anti-xa, low-molecular-weight heparin, nomogram, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background and Purpose In patients with acute ischemic stroke (AIS) using a direct oral factor-Xa anticoagulant (DOAC) during the last 48 hours, a fixed plasma heparin-calibrated anti-Xa activity (0.5 IU/mL) was proposed as a threshold below which patients could be eligible for thrombolysis and/or thrombectomy. Besides, specific DOAC-calibrated anti-Xa thresholds up to 50 ng/mL have been proposed. However, specific DOAC assays are not widely available contrarily to low-molecularweight heparin (LMWH) anti-Xa activity. We developed and validated a nomogram for predicting apixaban and rivaroxaban concentrations based on LMWH anti-Xa assay. Methods Our prospective study included apixaban (n=325) and rivaroxaban (n=276) patients. On the same sample, we systematically measured specific DOAC concentration and LMWH anti-Xa activity, using STA®-Liquid-Anti-Xa (Stago) and specific DOAC- or LMWH-calibrators, respectively. The nomogram was built using quantifiable values for both assays on the derivation cohorts with a log-linear regression model. Model performances including sensitivity, specificity, and true positive rate for different thresholds were checked on the validation cohorts. Results The models built from the derivation cohorts predicted that values

Published
2023
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6. Bothrops atrox and Bothrops lanceolatus Venoms In Vitro Investigation: Composition, Procoagulant Effects, Co-Factor Dependency, and Correction Using Antivenoms

Author

Sébastien Larréché, Aurore Bousquet, Lucie Chevillard, Rabah Gahoual, Georges Jourdi, Anne-Laure Dupart, Christilla Bachelot-Loza, Pascale Gaussem, Virginie Siguret, Jean-Philippe Chippaux, and Bruno Mégarbane

Subjects
Bothrops, coagulation, venom composition, ROTEM, co-factor, antivenom, Medicine
Abstract

Bothrops venoms are rich in enzymes acting on platelets and coagulation. This action is dependent on two major co-factors, i.e., calcium and phospholipids, while antivenoms variably neutralize venom-related coagulopathy effects. Our aims were (i) to describe the composition of B. atrox and B. lanceolatus venoms; (ii) to study their activity on the whole blood using rotational thromboelastometry (ROTEM); (iii) to evaluate the contribution of calcium and phospholipids in their activity; and (iv) to compare the effectiveness of four antivenoms (Bothrofav™, Inoserp™ South America, Antivipmyn™ TRI, and PoliVal-ICP™) on the procoagulant activity of these two venoms. Venom composition was comparable. Both venoms exhibited hypercoagulant effects. B. lanceolatus venom was completely dependent on calcium but less dependent on phospholipids than B. atrox venom to induce in vitro coagulation. The four antivenoms neutralized the procoagulant activity of the two venoms; however, with quantitative differences. Bothrofav™ was more effective against both venoms than the three other antivenoms. The relatively similar venom-induced effects in vitro were unexpected considering the opposite clinical manifestations resulting from envenomation (i.e., systemic bleeding with B. atrox and thrombosis with B. lanceolatus). In vivo studies are warranted to better understand the pathophysiology of systemic bleeding and thrombosis associated with Bothrops bites.

Published
2023
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7. Thromboembolism and bleeding in systemic amyloidosis: a review

Author

Martin Nicol, Virginie Siguret, Giuseppe Vergaro, Alberto Aimo, Michele Emdin, Jean Guillaume Dillinger, Mathilde Baudet, Alain Cohen‐Solal, Camille Villesuzanne, Stephanie Harel, Bruno Royer, Bertrand Arnulf, and Damien Logeart

Subjects
Amyloidosis, Thromboembolism, Bleeding, Anticoagulative therapy, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract The assessment of both thromboembolic and haemorrhagic risks and their management in systemic amyloidosis have been poorly emphasized so far. This narrative review summarizes main evidence from literature with clinical perspective. The rate of thromboembolic events is as high as 5–10% amyloidosis patients, at least in patients with cardiac involvement, with deleterious impact on prognosis. The most known pro‐thrombotic factors are heart failure, atrial fibrillation, and atrial myopathy. Atrial fibrillation could occur in 20% to 75% of systemic amyloidosis patients. Cardiac thrombi are frequently observed in patients, particularly in immunoglobulin light chains (AL) amyloidosis, up to 30%, and it is advised to look for them systematically before cardioversion. In AL amyloidosis, nephrotic syndrome and the use of immunomodulatory drugs also favour thrombosis. On the other hand, the bleeding risk increases because of frequent amyloid digestive involvement as well as factor X deficiency, renal failure, and increased risk of dysautonomia‐related fall.

Published
2022
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8. Prognosis of hyperviscosity syndrome in newly diagnosed multiple myeloma in modern-era therapy: A real-life study

Author

Pierre-Edouard Debureaux, Stéphanie Harel, Nathalie Parquet, Virginie Lemiale, Virginie Siguret, Laurie Goubeau, Florence Morin, Bruno Royer, Wendy Cuccuini, Dikelele Elessa, Floriane Theves, Anne C. Brignier, Elie Azoulay, Bertrand Arnulf, and Alexis Talbot

Subjects
HVS, myeloma, prognosis, TPE, neurological, Immunologic diseases. Allergy, RC581-607
Abstract

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011-2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era.

Published
2022
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9. Pathophysiological Processes Underlying the High Prevalence of Deep Vein Thrombosis in Critically Ill COVID-19 Patients

Author

Sebastian Voicu, Chahinez Ketfi, Alain Stépanian, Benjamin G. Chousterman, Nassim Mohamedi, Virginie Siguret, Alexandre Mebazaa, Bruno Mégarbane, and Philippe Bonnin

Subjects
COVID-19, D-dimer, hemostasis disorder, deep vein thrombosis, venous stasis, Physiology, QP1-981
Abstract

Coronavirus disease 2019 (COVID-19) predisposes to deep vein thrombosis (DVT) and pulmonary embolism (PE) particularly in mechanically ventilated adults with severe pneumonia. The extremely high prevalence of DVT in the COVID-19 patients hospitalized in the intensive care unit (ICU) has been established between 25 and 84% based on studies including systematic duplex ultrasound of the lower limbs when prophylactic anticoagulation was systematically administrated. DVT prevalence has been shown to be markedly higher than in mechanically ventilated influenza patients (6–8%). Unusually high inflammatory and prothrombotic phenotype represents a striking feature of COVID-19 patients, as reflected by markedly elevated reactive protein C, fibrinogen, interleukin 6, von Willebrand factor, and factor VIII. Moreover, in critically ill patients, venous stasis has been associated with the prothrombotic phenotype attributed to COVID-19, which increases the risk of thrombosis. Venous stasis results among others from immobilization under muscular paralysis, mechanical ventilation with high positive end-expiratory pressure, and pulmonary microvascular network injuries or occlusions. Venous return to the heart is subsequently decreased with increase in central and peripheral venous pressures, marked proximal and distal veins dilation, and drops in venous blood flow velocities, leading to a spontaneous contrast “sludge pattern” in veins considered as prothrombotic. Together with endothelial lesions and hypercoagulability status, venous stasis completes the Virchow triad and considerably increases the prevalence of DVT and PE in critically ill COVID-19 patients, therefore raising questions regarding the optimal doses for thromboprophylaxis during ICU stay.

Published
2021
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10. Pain assessment and factors influencing pain during bone marrow aspiration: A prospective study.

Author

Nicolas Gendron, Sara Zia Chahabi, Géraldine Poenou, Nadia Rivet, Tiphaine Belleville-Rolland, Pierre Lemaire, Antoine Escuret, Michèle Ciaudo, Emmanuel Curis, Pascale Gaussem, Virginie Siguret, and Luc Darnige

Subjects
Medicine, Science
Abstract

Although bone marrow aspiration (BMA) is still considered a painful procedure, pain level remains poorly documented. We therefore conducted a prospective study intended to evaluate pain level in adult patients undergoing BMA at the sternal or iliac crest site to identify factors associated with pain. We enrolled a total of 448 patients who underwent 461 BMA and asked those patients to score their pain intensity after BMA using numerical pain rating scale (NPRS). The following factors: level of anxiety, quality of the information given to the patient, operator's experience, and bone texture were recorded using a standardized questionnaire. The median NPRS score was 3.5 (IQR [2.0; 5.0]) the sternal site (n = 405) was associated with an increased median NPRS score (3.5 [2.0; 5.0]) compared to the iliac crest (n = 56, 2.5 [1.0; 4.0]; p

Published
2019
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11. D-Dimer Level and Neutrophils Count as Predictive and Prognostic Factors of Pulmonary Embolism in Severe Non-ICU COVID-19 Patients

Author

Benjamin Thoreau, Joris Galland, Maxime Delrue, Marie Neuwirth, Alain Stepanian, Anthony Chauvin, Azeddine Dellal, Olivier Nallet, Melanie Roriz, Mathilde Devaux, Jonathan London, Gonzague Martin-Lecamp, Antoine Froissart, Nouara Arab, Bertrand Ferron, Marie-Helene Groff, Viviane Queyrel, Christine Lorut, Lucile Regard, Emilie Berthoux, Guillaume Bayer, Chloe Comarmond, Bertrand Lioger, Arsène Mekinian, Tali-Anne Szwebel, Thomas Sené, Blanca Amador-Borrero, Olivier Mangin, Pierre O. Sellier, Virginie Siguret, Stéphane Mouly, Jean-Philippe Kevorkian, Lariboisière COVID Group, Dominique Vodovar, and Damien Sene

Subjects
COVID-19, pulmonary embolism, D-dimer, neutrophil, anticoagulation, predictive factor, Microbiology, QR1-502
Abstract

The incidence of pulmonary embolism (PE) is high during severe Coronavirus Disease 2019 (COVID-19). We aimed to identify predictive and prognostic factors of PE in non-ICU hospitalized COVID-19 patients. In the retrospective multicenter observational CLOTVID cohort, we enrolled patients with confirmed RT-PCR COVID-19 who were hospitalized in a medicine ward and also underwent a CT pulmonary angiography for a PE suspicion. Baseline data, laboratory biomarkers, treatments, and outcomes were collected. Predictive and prognostics factors of PE were identified by using logistic multivariate and by Cox regression models, respectively. A total of 174 patients were enrolled, among whom 86 (median [IQR] age of 66 years [55–77]) had post-admission PE suspicion, with 30/86 (34.9%) PE being confirmed. PE occurrence was independently associated with the lack of long-term anticoagulation or thromboprophylaxis (OR [95%CI], 72.3 [3.6–4384.8]) D-dimers ≥ 2000 ng/mL (26.3 [4.1–537.8]) and neutrophils ≥ 7.0 G/L (5.8 [1.4–29.5]). The presence of these two biomarkers was associated with a higher risk of PE (p = 0.0002) and death or ICU transfer (HR [95%CI], 12.9 [2.5–67.8], p < 0.01). In hospitalized non-ICU severe COVID-19 patients with clinical PE suspicion, the lack of anticoagulation, D-dimers ≥ 2000 ng/mL, neutrophils ≥ 7.0 G/L, and these two biomarkers combined might be useful predictive markers of PE and prognosis, respectively.

Published
2021
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12. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia

Author

Patrizia Noris, Nicole Schlegel, Catherine Klersy, Paula G. Heller, Elisa Civaschi, Nuria Pujol-Moix, Fabrizio Fabris, Remi Favier, Paolo Gresele, Véronique Latger-Cannard, Adam Cuker, Paquita Nurden, Andreas Greinacher, Marco Cattaneo, Erica De Candia, Alessandro Pecci, Marie-Françoise Hurtaud-Roux, Ana C. Glembotsky, Eduardo Muñiz-Diaz, Maria Luigia Randi, Nathalie Trillot, Loredana Bury, Thomas Lecompte, Caterina Marconi, Anna Savoia, Carlo L. Balduini, Sophie Bayart, Anne Bauters, Schéhérazade Benabdallah-Guedira, Françoise Boehlen, Jeanne-Yvonne Borg, Roberta Bottega, James Bussel, Daniela De Rocco, Emmanuel de Maistre, Michela Faleschini, Emanuela Falcinelli, Silvia Ferrari, Alina Ferster, Tiziana Fierro, Dominique Fleury, Pierre Fontana, Chloé James, Francois Lanza, Véronique Le Cam Duchez, Giuseppe Loffredo, Pamela Magini, Dominique Martin-Coignard, Fanny Menard, Sandra Mercier, Annamaria Mezzasoma, Pietro Minuz, Ilaria Nichele, Lucia D. Notarangelo, Tommaso Pippucci, Gian Marco Podda, Catherine Pouymayou, Agnes Rigouzzo, Bruno Royer, Pierre Sie, Virginie Siguret, Catherine Trichet, Alessandra Tucci, Béatrice Saposnik, and Dino Veneri

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 109/L.

Published
2014
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13. A need for evidence-based clinical practice guidelines for the use of heparins in the elderly

Author

Isabelle Gouin-Thibault, Virginie Siguret, and Eric Pautas

Subjects
elderly, low molecular weight heparins, Geriatrics, RC952-954.6
Abstract

Isabelle Gouin-Thibault1,2, Virginie Siguret1,2, Eric Pautas2,31Assistance Publique Hôpitaux de Paris, Laboratoire d’Hématologie, Hôpital Charles Foix, Paris, France; 2Université Paris Descartes, INSERM U, Paris, France; 3Assistance Publique Hôpitaux de Paris, Unité de Gériatrie Aiguë, Hôpital Charles Foix, Paris, FranceAbstract: Low-molecular-weight heparins (LMWHs) have been widely studied in pivotal clinical trials or in several meta-analyses. However, the safety and optimal use of LMWHs in high-risk patients such as the very elderly remains uncertain since these patients are usually excluded from clinical trials. In terms of LMWHs in the elderly, the main concerns are renal failure and the risk of accumulation. A clinical approach consisting of a LMWH dose reduction in the elderly should be considered with great caution in terms of efficacy, since it has been tested neither in the treatment of VTE nor in VTE prophylaxis. If monitoring is considered in patients receiving therapeutic dose LMWHs, appropriate target ranges for peak anti-Xa activity levels should be used and so far, no anti-Xa activity-based guidelines have been issued. Moreover, no data support any laboratory monitoring in elderly patients treated with prophylactic dose LMWHs.Keywords: elderly patients, low-molecular-weight heparin, renal insufficiency, evidence-based medicine

Published
2010

14. 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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15. No VTE Recurrence After 1-Year Follow-Up of Hospitalized Patients With COVID-19 and a VTE Event

Author

Maxime Delrue, Alain Stépanian, Sebastian Voicu, Kladoum Nassarmadji, Damien Sène, Philippe Bonnin, Jean-Philippe Kevorkian, Pierre-Olivier Sellier, Jean-Michel Molina, Marie Neuwirth, Dominique Vodovar, Stéphane Mouly, Alexandre Mebazaa, Bruno Mégarbane, Virginie Siguret, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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, French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, INSERM UMRS-1144, Université Paris Cité, Réanimation Médicale et Toxicologique, Hôpital Lariboisière, and Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140)

Subjects
Pulmonary and Respiratory Medicine, [SDV]Life Sciences [q-bio], Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Abstract

International audience

Published
2022
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16. C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study

Author

Paul Billoir, Virginie Siguret, Elisabeth Masson Fron, Ludovic Drouet, Isabelle Crassard, Raphaël Marlu, Marianne Barbieux-Guillot, Pierre-Emmanuel Morange, Emmanuelle Robinet, Catherine Metzger, Valérie Wolff, Elisabeth André-Kerneis, Frédéric Klapczynski, Brigitte Martin-Bastenaire, Fernando Pico, Fanny Menard, Emmanuel Ellie, Geneviève Freyburger, François Rouanet, Hong-An Allano, Gaëlle Godenèche, Guillaume Mourey, Thierry Moulin, Micheline Berruyer, Laurent Derex, Catherine Trichet, Gwénaëlle Runavot, Agnès Le Querrec, Fausto Viader, Sophie Cluet-Dennetiere, Thomas Tarek Husein, Magali Donnard, Francisco Macian-Montoro, Catherine Ternisien, Benoît Guillon, Sophie Laplanche, Mathieu Zuber, Jean-Yves Peltier, Philippe Tassan, Bertrand Roussel, Sandrine Canaple, Emilie Scavazza, Nicolas Gaillard, Aude Triquenot Bagan, Véronique Le Cam Duchez, Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre Hospitalier de Meaux, Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier de la Côte Basque (CHCB), CHU Bordeaux [Bordeaux], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), and Université de Picardie Jules Verne (UPJV)

Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hematology
Abstract

International audience; IntroductionCerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis.MethodsThis prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation.ResultsTwo hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 μg/L [520-2075] vs 1220 μg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence.ConclusionTwo widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

Published
2023
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18. Is platelet function testing at the acute phase under P2Y12 inhibitors helpful in predicting bleeding in real-life patients with acute coronary syndrome? The AVALANCHE study

Author

Jean-Guillaume Dillinger, Caren Brumpt, Sara Hamadouche, Ludovic Drouet, Natacha Berge, Patrick Henry, Alain Stepanian, Virginie Siguret, and Claire Bal dit Sollier

Subjects
medicine.medical_specialty, Acute coronary syndrome, Prasugrel, Unstable angina, business.industry, Retrospective cohort study, General Medicine, medicine.disease, Clopidogrel, P2Y12, Internal medicine, medicine, Cardiology, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Ticagrelor, medicine.drug
Abstract

Summary Background In patients with acute coronary syndrome (ACS), current international guidelines recommend newer potent and predictable P2Y12 inhibitors as first-line treatment despite a greater bleeding risk compared with clopidogrel. Aim To determine if platelet function testing can predict bleeding in real-life patients with ACS treated with newer P2Y12 inhibitors. Methods In this retrospective study, all consecutive adults admitted to the Lariboisiere University Hospital for ACS, whatever the P2Y12 inhibitor prescribed, who had platelet function testing (vasodilator-stimulated phosphoprotein phosphorylation [VASP] index and aggregation tests) during the initial hospital stay were included. Follow-up was performed to record bleeding events according to the Bleeding Academic Research Consortium (BARC) classification. Results A total of 364 patients were included, treated with ticagrelor (n = 123), prasugrel (n = 105) or clopidogrel (n = 136); 42.3% after an ST-segment elevation myocardial infarction, 27.1% after a non-ST-segment elevation myocardial infarction and 30.6% with unstable angina. Mean age was 64 ± 11 years. Median VASP index was significantly lower with the newer P2Y12 inhibitors (14% under ticagrelor, 14% under prasugrel) than with clopidogrel (42%). Despite these differences in the degree of platelet inhibition, the occurrence of bleeding (BARC 2–5) during follow-up was 7.7% overall, and was similar for all P2Y12 inhibitors (ticagrelor 8.9%; prasugrel 6.6%; clopidogrel 7.4%). For each P2Y12 inhibitor, it was impossible to determine a VASP index threshold under which bleeding was significantly greater during follow-up. Similarly, ADP-induced aggregation was more profoundly inhibited by ticagrelor and prasugrel than by clopidogrel, but this did not allow a threshold to be set for increased haemorrhagic risk. Conclusions Despite the substantial occurrence of bleeding in patients with ACS during follow-up, neither the VASP index nor platelet aggregation test results measured at the acute phase were helpful in predicting bleeding risk. Whether platelet function testing could be helpful later in the course of treatment remains to be evaluated.

Published
2021
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19. Practical Nomogram Predicting Apixaban or Rivaroxaban Concentrations from Low-Molecular-Weight Heparin Anti-Xa Values: Special Interest in Acute Ischemic Stroke Patients

Author

Charlyne Brakta, Alain Stépanian, Peggy Reiner, Maxime Delrue, Mikaël Mazighi, Emmanuel Curis, and Virginie Siguret

Subjects
Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background and Purpose In patients with acute ischemic stroke (AIS) using a direct oral factor-Xa anticoagulant (DOAC) during the last 48 hours, a fixed plasma heparin-calibrated anti-Xa activity (0.5 IU/mL) was proposed as a threshold below which patients could be eligible for thrombolysis and/or thrombectomy. Besides, specific DOAC-calibrated anti-Xa thresholds up to 50 ng/mL have been proposed. However, specific DOAC assays are not widely available contrarily to low-molecularweight heparin (LMWH) anti-Xa activity. We developed and validated a nomogram for predicting apixaban and rivaroxaban concentrations based on LMWH anti-Xa assay.Methods Our prospective study included apixaban (n=325) and rivaroxaban (n=276) patients. On the same sample, we systematically measured specific DOAC concentration and LMWH anti-Xa activity, using STA®-Liquid-Anti-Xa (Stago) and specific DOAC- or LMWH-calibrators, respectively. The nomogram was built using quantifiable values for both assays on the derivation cohorts with a log-linear regression model. Model performances including sensitivity, specificity, and true positive rate for different thresholds were checked on the validation cohorts.Results The models built from the derivation cohorts predicted that values

Published
2022

20. 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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21. Case series of massive direct oral anticoagulant ingestion—Treatment and pharmacokinetics data

Author

Maxime Delrue, Lucie Chevillard, Alain Stépanian, Alessandra Dragoni, Laurence Camoin‐Jau, Sébastien Voicu, Isabelle Malissin, Nicolas Deye, Marc Gainnier, Virginie Siguret, Bruno Mégarbane, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], 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)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), 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, Hôpital de la Timone [CHU - APHM] (TIMONE), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), and Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal

Subjects
Pyridones, Clinical Biochemistry, Administration, Oral, Anticoagulants, Hemorrhage, General Medicine, Middle Aged, Biochemistry, Dabigatran, Cohort Studies, Eating, Rivaroxaban, Charcoal, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Atrial Fibrillation, Humans
Abstract

Direct oral anticoagulants (DOAC) are widely used due to favourable benefit/risk ratio. However, consequences of massive ingestion have been poorly investigated.We aimed to report outcome and pharmacokinetic parameters in patients who massively ingested DOACs.We conducted a 5-year cohort study including consecutive massive DOAC ingestion patients admitted to two critical care departments. Patients were managed in accordance with standards of care. We collected the main history, clinical, laboratory, management and outcome data. The time-course of plasma DOAC concentrations measured using specific assays was modelled.Twelve patients (3F/9M; age, 55 years [41-63], median [25th-75th percentiles]) were included. Ingestions involved rivaroxaban (n = 7), apixaban (n = 3) and dabigatran (n = 2), with presumed doses of 9.4-fold [5.0-22.0] the full daily dose. Six patients received activated charcoal but no antidote nor blood-derived product. No bleeding was observed. One patient died due to refractory cardiogenic shock related to bisoprolol co-intoxication. Highest observed peak plasma concentrations were 1720 ng/ml (rivaroxaban), 750 ng/ml (apixaban) and 644 ng/ml (dabigatran). Times to reach DOAC concentration below 50 ng/ml were ~20-45 h (rivaroxaban), ~125 h (apixaban) and ~30-50 h (dabigatran). Elimination half-lives were 2.5-25.5 h (rivaroxaban), 22.0 and 36.5 h (apixaban), and 5.8 and 15.5 h (dabigatran), with substantial interindividual variability and prolongation in case of cardiovascular failure related to co-intoxicants. Charcoal administration, even if delayed, may have contributed to limit toxicity, possibly by reducing absorption and/or enteroenteric recycling.No bleeding was observed in this series of massive DOAC ingestions despite elevated plasma concentrations. No patient required specific haemostatic agents. Charcoal administration should be considered to limit toxicity.

Published
2022
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22. White blood count, D‐dimers, and ferritin levels as predictive factors of pulmonary embolism suspected upon admission in noncritically ill COVID‐19 patients: The French multicenter CLOTVID retrospective study

Author

Galland, Joris, Thoreau, Benjamin, Delrue, Maxime, Neuwirth, Marie, Stepanian, Alain, Chauvin, Anthony, Dellal, Azeddine, Nallet, Olivier, Roriz, Melanie, Devaux, Mathilde, London, Jonathan, Martin‐Lecamp, Gonzague, Froissart, Antoine, Arab, Nouara, Ferron, Bertrand, Groff, Marie‐Helene, Queyrel, Viviane, Lorut, Christine, Regard, Lucile, Berthoux, Emilie, Bayer, Guillaume, Comarmond, Chloe, Lioger, Bertrand, Mekinian, Arsène, Szwebel, Tali‐Anne, Sené, Thomas, Amador‐Boreiro, Blanca, Mangin, Olivier, Sellier, Pierre‐Olivier, Mouly, Stephane, Kevorkian, Jean‐Philippe, Siguret, Virginie, Vodovar, Dominique, Sene, Damien, Mathieu, Albertini, Sara, Bouajila, Kimbimbi, Britany, Ruxandra, Burlacu, Léa, Cacoub, Karine, Champion, Véronique, Delcey, Jean‐Guillaume, Dillinger, Florine, Feron, Aline, Frazier, Funck‐Bretano, Thomas, Diane‐Cecile, Gauthier, Jean‐François, Gautier, Patrick, Henry, Tessa, Huscenot, Izabel, Sarah, Jaulerry, Mathilde, Moenes, Jouabli, Jean‐Baptiste, Julla, Marie, Laloi Michelin, Pierre, Leroy, Amanda, Lopes, Bruno, Megarbane, Maxime, Michon, Anne‐Lise, Munier, Yoram, Nahmani, Martin, Nicol, Eroan, Nicolas, Audrey, Poulat, Eric, Revue, Pascal, Richette, Jean‐Pierre, Riveline, Emma, Rubenstein, Adrien, Zanin, Clément, Aveneau, Paul, Bastard, Diane, Beauvais, Loredana, Boghez, Alix, Borderiou, Paul, Conway, Lavignia, Cosma, Vincent, Davy, Clément, Desjardin, Sandra, Devatine, Christel, Ducroz Gerardin, Charlotte, Dupe, Chloé, Gobert, Clotilde, Gros, Soumaya, Kadiri, Enmat, Khan, Sandrine, Ongnessek, Fatima, Rhmari, Isabelle, Sacco, Natalia, Saptefrat, Pauline, Schaupp, Justine, Serre, Georgios, Sideris, Sonia, Smati, Marine, Tournier, Pauline, Treca, Tony, Truong, Mathilde, Tuffier, Mattéo, Arcelli, Yvonnick, Boue, Alban, Copie, Nicolas, Deye, Jean‐Michel, Ekherian, Zaccaria, Errabih, Antoine, Gonde, Caroline, Grant, Emmanuelle, Guerin, Adèle, Magalhaes, Isabelle, Malissin, Edouard, Meurisse, Aymen, Mrad, Giulia, Naim, Philippe, Nguyen, Kiyoko, Nitenberg, Adrien, Pepin‐Lehalleur, Arthur, Perault, Lucile, Perrin, Maxime, Renaud, Laetitia, Sutterlin, Maxime, Delrue, Virginie, Siguret, and Alain, Stepanian

Subjects
medicine.medical_specialty, pulmonary embolism, Coronavirus disease 2019 (COVID-19), Ferritin levels, D‐dimer, Gastroenterology, SARS‐CoV‐2, Fibrin Fibrinogen Degradation Products, predictive factor, Leukocyte Count, 03 medical and health sciences, Patient Admission, 0302 clinical medicine, COVID‐19, Internal medicine, D-dimer, Humans, Medicine, white blood count, Retrospective Studies, biology, SARS-CoV-2, business.industry, ferritin, COVID-19, Retrospective cohort study, Original Articles, Hematology, General Medicine, Emergency department, medicine.disease, Pulmonary embolism, Ferritin, White blood count, 030220 oncology & carcinogenesis, Ferritins, biology.protein, Original Article, France, business, 030215 immunology
Abstract

Background A high prevalence of pulmonary embolism (PE) has been described during COVID‐19. Our aim was to identify predictive factors of PE in non‐ICU hospitalized COVID‐19 patients. Methods Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID‐19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. Results A total of 88 patients (median [IQR] age of 68 years [60‐78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D‐dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3‐74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3‐1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7‐553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D‐dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0‐397.9], P = .004). Conclusion The white blood count, the D‐dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non‐ICU COVID‐19 patients.

Published
2021
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24. Pathophysiology and abnormalities of hemostasis in intensive care patients with Covid-19

Author

Alain Stepanian, Bérangère S. Joly, Nicolas Béranger, Arezki Hadj-Ali, Virginie Siguret, Nathalie Itzhar-Baïkian, Maxime Delrue, Marie Neuwirth, and Agnès Veyradier

Subjects
Mechanical ventilation, medicine.medical_specialty, business.industry, viruses, medicine.medical_treatment, virus diseases, Hematology, Hypoxia (medical), medicine.disease_cause, Intensive care unit, Pathophysiology, law.invention, Microcirculation, law, Hemostasis, Intensive care, medicine, medicine.symptom, business, Intensive care medicine, Coronavirus
Abstract

Coronavirus disease 2019 (Covid-19), a severe acute respiratory syndrome caused by coronavirus 2 (Sars-CoV-2), has now spread to all continents. About 5-10 % of Covid-19 patients require intensive care unit admission and mechanical ventilation. Critically ill Covid-19 patients are prone to develop hypoxia, excessive inflammation and frequent thrombotic manifestations affecting both the macrocirculation and the microcirculation.

Published
2021
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25. 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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27. Plasma Serotonin is Elevated in Adult Patients with Sudden Sensorineural Hearing Loss

Author

Charlotte Hautefort, Ludovic Drouet, Romain Kania, Hélène Vitaux, Jean-Marie Launay, Nicolas Vodovar, Alain Stepanian, Jacques Callebert, Michael Eliezer, and Virginie Siguret

Subjects
Adult, Male, Serotonin, medicine.medical_specialty, Hyperhomocysteinemia, Homocysteine, Hearing Loss, Sensorineural, Serotonylation, 030204 cardiovascular system & hematology, Thrombophilia, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Von Willebrand factor, Internal medicine, medicine, Humans, 030223 otorhinolaryngology, Whole blood, biology, business.industry, Vasospasm, Hematology, Hearing Loss, Sudden, Middle Aged, medicine.disease, chemistry, Methylenetetrahydrofolate reductase, biology.protein, Female, business
Abstract

Background The roles of thrombophilia and cardiovascular risk factors in sudden sensorineural hearing loss (SSNHL) remain controversial. Cochlear microthrombosis and vasospasm have been hypothesized as possible pathogenic mechanisms of SSNHL. This article investigates the circulating serotonin and homocysteine levels besides thrombophilia screening in patients with idiopathic SSNHL. Methods A total of 133 SSNHL patients and age- and sex-matched controls were investigated (discovery cohort). Measurement included common inherited natural coagulation inhibitors, factor VIII, von Willebrand factor (VWF), antiphospholipid antibodies, homocysteine, and serotonin (whole blood, platelet, and plasma) levels, along with frequent relevant genetic variants. A validation cohort (128 SSNHL patients) was studied for homocysteine and serotonin levels. Results and Conclusion In the discovery cohort, 58.6% of patients exhibited thrombophilia, of which most had a low to moderate titers of antiphospholipid antibodies and high levels of factor VIII/VWF. Twenty-seven patients (20%) had mild-to-moderate hyperhomocysteinemia or were homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Regarding serotonin, SSNHL patients had elevated whole blood levels that remained within the normal range and normal platelet content. However, approximately 90% patients of both cohorts had elevated plasma serotonin. Elevated plasma serotoninemia was accompanied by serotonylation of platelet rhoA protein. This study shows that increased plasma serotonin appears as a biomarker of SSNHL (specificity: ∼96%, sensitivity: ∼90%) and could participate in the pathophysiology of SSNHL.

Published
2020
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28. [Relapse of acquired von Willebrand syndrome in a patient non-compliant with Crohn's disease]

Author

Myriam Hormi, Melchior Le Méné, Céline Comparon, Imededdine El Kout, Fanny Baran-Marszak, Nathalie Itzhar-Baikian, Virginie Siguret, Robin Dhote, Service d'hématologie biologique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Laboratoire de Virologie [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), 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), Service d'hématologie biologique, 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), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and SIGURET, Virginie

Subjects
Aged, 80 and over, acquired von Willebrand syndrome, [SDV]Life Sciences [q-bio], auto-antibodies, Hemorrhage, General Medicine, [SDV] Life Sciences [q-bio], Crohn's disease, von Willebrand Diseases, Crohn Disease, Recurrence, von Willebrand Factor, Humans, Female, Autoantibodies
Abstract

International audience; We report a case of acquired von Willebrand syndrome relapse in association with Crohn's disease, in a context of non-compliance in a 85-year-old woman suffering from epistaxis and melena. The acquired von Willebrand syndrome is a rare bleeding disorder. This case underlines the importance of maintaining the corticosteroid therapy in order to prevent the reappearance of autoantibodies and the recurrence of this syndrome.

Published
2022
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29. Anaesthetic and peri-operative management for thrombectomy procedures in stroke patients

Author

Hervé Quintard, Vincent Degos, Mikael Mazighi, Jérôme Berge, Pierre Boussemart, Russel Chabanne, Samy Figueiredo, Thomas Geeraerts, Yoann Launey, Ludovic Meuret, Jean-Marc Olivot, Julien Pottecher, Francesca Rapido, Sébastien Richard, Suzana Saleme, Virginie Siguret-Depasse, Olivier Naggara, Hugues De Courson, and Marc Garnier

Subjects
Anesthesiology and Pain Medicine, General Medicine, Critical Care and Intensive Care Medicine
Published
2023
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30. Potential usefulness of activated charcoal (DOAC remove®) for dRVVT testing in patients receiving Direct Oral AntiCoagulants

Author

Jessica Valaize, Pascale Gaussem, Emmanuel Curis, Julien Demagny, Alain Stepanian, Virginie Siguret, Fabienne Nedelec-Gac, Jérôme Duchemin, Maxime Delrue, Isabelle Gouin-Thibault, Luc Darnige, Xavier Delavenne, Georges Jourdi, Geoffrey Foulon-Pinto, Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Pontchaillou [Rennes], Hôpital Raymond Poincaré [AP-HP], Biostatistique, traitement et modélisation des données biologiques (BioSDTM - EA 7537), Université Paris Descartes - Paris 5 (UPD5), Biologie intégrative du tissu osseux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), AP-HP Hôpital Raymond Poincaré [Garches], Biostatistique, traitement et modélisation des données biologiques (BioSTM - EA 7537), Biologie Intégrative du Tissu Osseux (LBTO), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, and Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, medicine.medical_specialty, Dilute Russell's viper venom time, Administration, Oral, 030204 cardiovascular system & hematology, Thrombin time, Gastroenterology, Dabigatran, 03 medical and health sciences, 0302 clinical medicine, Rivaroxaban, Internal medicine, Antiphospholipid syndrome, medicine, Humans, Apixaban, In patient, Lupus anticoagulant, medicine.diagnostic_test, business.industry, Anticoagulants, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Activated charcoal, Charcoal, Lupus Coagulation Inhibitor, 030220 oncology & carcinogenesis, Female, Blood Coagulation Tests, business, medicine.drug
Abstract

International audience; Introduction Lupus Anticoagulant testing using dilute Russell Viper Venom Time (dRVVT) is challenging in patients receiving Direct Oral AntiCoagulants (DOAC) due to potential false positive results. In a multicenter study, we evaluated the in vitro removal of DOAC by activated charcoal (DOAC remove®), allowing reliable dRVVT testing. Materials and methods Patient samples were analyzed before and after treatment with DOAC remove® 49 apixaban, 48 rivaroxaban, 24 dabigatran and 30 none. DOAC plasma concentrations were measured using anti-Xa or diluted thrombin time assays. In a subset of 28 samples, DOAC concentrations were also measured using HPLC-MS/MS following treatment with DOAC remove®. DRVVT was performed using STA-Staclot dRVVT Screen®/Confirm® (Stago) or LAC-Screening®/Confirmation® (Siemens). Results Baseline median [min-max] concentrations were 94 [

Published
2019
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31. Thromboembolism and bleeding in systemic amyloidosis: a review

Author

Jean-Guillaume Dillinger, Virginie Siguret, Bruno Royer, Damien Logeart, Bertrand Arnulf, Mathilde Baudet, Michele Emdin, Giuseppe Vergaro, Martin Nicol, Stephanie Harel, Camille Villesuzanne, Alain Cohen-Solal, and Alberto Aimo

Subjects
medicine.medical_specialty, Amyloid, medicine.medical_treatment, Reviews, Review, Cardioversion, Internal medicine, Thromboembolism, medicine, AL amyloidosis, Diseases of the circulatory (Cardiovascular) system, Humans, Immunoglobulin Light-chain Amyloidosis, Amyloidosis, Anticoagulative therapy, Bleeding, Heart Failure, business.industry, Atrial fibrillation, medicine.disease, Thrombosis, Heart failure, RC666-701, Cardiology, Cardiology and Cardiovascular Medicine, business, Nephrotic syndrome
Abstract

The assessment of both thromboembolic and haemorrhagic risks and their management in systemic amyloidosis have been poorly emphasized so far. This narrative review summarizes main evidence from literature with clinical perspective. The rate of thromboembolic events is as high as 5–10% amyloidosis patients, at least in patients with cardiac involvement, with deleterious impact on prognosis. The most known pro‐thrombotic factors are heart failure, atrial fibrillation, and atrial myopathy. Atrial fibrillation could occur in 20% to 75% of systemic amyloidosis patients. Cardiac thrombi are frequently observed in patients, particularly in immunoglobulin light chains (AL) amyloidosis, up to 30%, and it is advised to look for them systematically before cardioversion. In AL amyloidosis, nephrotic syndrome and the use of immunomodulatory drugs also favour thrombosis. On the other hand, the bleeding risk increases because of frequent amyloid digestive involvement as well as factor X deficiency, renal failure, and increased risk of dysautonomia‐related fall.

Published
2021

32. Bleeding and Thrombosis: Insights into Pathophysiology of

Author

Sébastien, Larréché, Jean-Philippe, Chippaux, Lucie, Chevillard, Simon, Mathé, Dabor, Résière, Virginie, Siguret, and Bruno, Mégarbane

Subjects
Blood Platelets, Hemostasis, microthrombi, Antivenins, Hemorrhage, Thrombosis, thrombocytopenia, Review, Blood Coagulation Disorders, coagulopathy, Crotalid Venoms, Animals, Humans, hemorrhage, Blood Coagulation, snake venom
Abstract

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Published
2021

33. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients?

Author

Sebastian Voicu, Maxime Delrue, Marie Neuwirth, Virginie Siguret, Etienne Gayat, Bruno Mégarbane, Alain Stepanian, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), and Mégarbane, Bruno

Subjects
Anticardiolipin, 030204 cardiovascular system & hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, immune system diseases, Pandemic, Thrombosis, Medicine, Prospective Studies, Prospective cohort study, [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, Lupus anticoagulant, biology, Hematology, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Anti-β2-glycoprotein-I, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antibodies, Antiphospholipid, Antibody, Coronavirus Infections, Coronavirus disease 2019 (COVID-19), Critical Illness, Pneumonia, Viral, Article, Betacoronavirus, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Pandemics, Aged, SARS-CoV-2, business.industry, Critically ill, COVID-19, biology.organism_classification, medicine.disease, Immunology, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract

Highlights • The prevalence of aPL antibodies is poorly documented in ICU COVID-19 patients. • LA based on dRVVT system was positive in 85% of critically ill COVID-19 patients. • LA was not associated with thrombotic complications. • The prevalence of elevated anticardiolipin IgG/M/anti-beta2-GPI IgG was of 12%.

Published
2020
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34. Modified ROTEM for the detection of rivaroxaban and apixaban anticoagulant activity in whole blood

Author

Isabelle Gouin-Thibault, Virginie Siguret, Bernard Le Bonniec, Pascale Gaussem, Georges Jourdi, Charles Marc Samama, Sophie Gandrille, Alain Stepanian, Emmanuel Curis, Claire Pailleret, and Jean-Louis Golmard

Subjects
Adult, Male, Time Factors, Adolescent, Critical Care, Pyridones, Administration, Oral, Pharmacology, Fibrinogen, Sensitivity and Specificity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rivaroxaban, 030202 anesthesiology, medicine, Humans, Platelet, Blood Coagulation, Aged, Whole blood, Aged, 80 and over, business.industry, 030208 emergency & critical care medicine, Middle Aged, Thrombelastography, Thromboelastometry, Anesthesiology and Pain Medicine, Clotting time, Coagulation, Feasibility Studies, Pyrazoles, Female, Apixaban, business, Factor Xa Inhibitors, medicine.drug
Abstract

Background Rapid detection of the anticoagulant effect of oral factor Xa (FXa) inhibitors may be essential in several emergency clinical situations. Specific assays quantifying the drugs are performed in plasma and require a turnaround time that is too long to be useful in emergency situations. Rotational thromboelastometry (ROTEM) is a whole blood coagulation assay of blood viscoelasticity and could be of interest for FXa inhibitor detection in emergency. However, conventional ROTEM reagents only detect high amounts of inhibitors. Objective The aim of this study was first to assess the effect of whole blood components on the viscoelastic measurement of the effects of FXa inhibitors, and second to evaluate whether a modified ROTEM, triggered with a low amount of tissue factor and a saturating amount of phospholipid vesicles, can reliably detect low levels of FXa inhibitor activity in whole blood. Design Diagnostic test study. Settings A university research laboratory. From November 2014 to April 2016. Patients Sixty-six patients: 30 treated with rivaroxaban, 17 with apixaban and 19 without treatment. Intervention ROTEM was triggered with 2.5 pmol l of tissue factor and 10 μmol l of phospholipid vesicles. Main outcome measures Modified ROTEM parameters were measured in different experimental conditions: platelet-poor plasma (PPP), platelet-rich plasma, PPP supplemented with fibrinogen and reconstituted whole blood with various haematocrit levels adjusted between 30 and 60%. Modified ROTEM was further validated using whole blood from patients who were either treated or not treated with FXa inhibitors. Results Modified ROTEM allowed detection of as little as 25 ng ml FXa inhibitors in PPP, with at least a 1.4-fold increase of the clotting time (P ≤ 0.02). Neither changes of fibrinogen concentration nor variations of platelet count or haematocrit precluded FXa inhibitor detection. A lengthened modified ROTEM clotting time of more than 197 s allowed detection of FXa inhibitor concentrations above 30 ng ml in whole blood with 90% sensitivity and 85% specificity. Conclusion Modified ROTEM may be applicable in emergency situations for the detection of FXa inhibitors in whole blood.

Published
2019
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35. 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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36. Multifactorial hypercoagulable state associated with a thrombotic phenotype in phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG): Case report and brief review of the literature

Author

Geoffrey Foulon-Pinto, Nicolas Béranger, P. Charles, Alain Stepanian, Martine Alhenc-Gelas, Ludovic Drouet, Virginie Siguret, and Bertrand Lefrère

Subjects
biology, business.industry, Hematology, medicine.disease, Thrombin generation, Phenotype, Von Willebrand factor, Immunology, medicine, biology.protein, Pmm2 cdg, business, Congenital disorder of glycosylation, Phosphomannomutase
Published
2019
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37. Unexpected acute pulmonary embolism in an old COVID-19 patient with warfarin overdose: a case report

Author

Maxime Delrue, Virginie Siguret, Maxime Coutrot, and Bérangère S. Joly

Subjects
Pediatrics, medicine.medical_specialty, medicine.drug_class, Overdose, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Case report, medicine, AcademicSubjects/MED00200, 030212 general & internal medicine, business.industry, Pulmonary embolism, Anticoagulant, Warfarin, COVID-19, Atrial fibrillation, medicine.disease, Intensive care unit, Thrombosis, Respiratory failure, D-dimer, VKORC1, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background Severe acute respiratory syndrome coronavirus 2 disease is strongly associated with a high incidence of thrombotic events. Anticoagulation could be a cornerstone in successfully managing severe forms of coronavirus disease 2019 (COVID-19). However, optimal anticoagulant dosing in elderly patients is challenging because of high risk of both thrombosis and bleeding. Case summary We present here the case of an 89-year-old patient receiving warfarin for atrial fibrillation and valvular heart disease, admitted to the intensive care unit for respiratory failure due to COVID-19. The patient presented with a severe epistaxis associated with warfarin overdose [international normalized ratio (INR) > 10]. After a successful initial reversal using vitamin K per os, INR values greatly fluctuated up to 10, requiring repeated administrations of vitamin K. Despite starting low-molecular-weight heparin therapy at therapeutic dose as soon as INR value was below 2.0, the patient further developed an acute bilateral and proximal pulmonary embolism concomitantly with a sharp D-dimer increase. The combination of azithromycin intake, a known inhibitor of CYP2C9, with the presence of CYP2C9*2 and −1639G>A VKORC1, two variants associated with warfarin hypersensitivity, have likely contributed to explain the warfarin overdose and the difficulty to reverse warfarin effect in this patient. Discussion This case report illustrates the complexity of COVID-19 pathophysiology and its management for physicians, especially in patients receiving vitamin K antagonists (VKAs). Infection, concurrent medication use, and pharmacogenetic factors involved in VKA metabolism and pharmacodynamics may lead to a loss of control of anticoagulation. Pulmonary embolism should still be considered in COVID-19 patients even with effective or overdosed anticoagulant therapy.

Published
2021
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38. [Acquired hemophilia A: clinical and biological characteristics and therapeutic management of a series of eight patients hospitalized in Lariboisière and Saint-Louis hospitals]

Author

Nicolas Beranger, Alain Stepanian, Agnès Veyradier, Bérangère S. Joly, Nathalie Itzhar-Baïkian, Clara Noizat, and Virginie Siguret

Subjects
Autoimmune disease, Pediatrics, medicine.medical_specialty, Factor VIII, business.industry, Autoantibody, Hemorrhage, General Medicine, University hospital, medicine.disease, Hemophilia A, Hospitals, Cohort, medicine, Etiology, Acquired hemophilia, Humans, Observational study, business, Immunosuppressive Agents, Cohort study, Autoantibodies
Abstract

Acquired hemophilia A is a rare autoimmune disease, linked to the appearance of autoantibodies directed against circulating factor VIII, and characterized by a major hemorrhagic syndrome. Acquired hemophilia A is a life-threatening diagnostic and therapeutic medical emergency. We describe here the cohort of patients with acquired hemophilia A treated between 2015 and 2020 at Lariboisiere and Saint-Louis University Hospitals (Paris, France). We remind you here of the measures to be taken without delay in the face of any clinical and/or biological suspicion. Management is based on three main areas published in multicentre cohort studies, essentially observational: symptomatic treatment to control the hemorrhagic syndrome, immunosuppressive treatment to eradicate autoantibodies and manage their possible complications, and etiological treatment of the underlying pathology for secondary forms.

Published
2021

39. Is platelet function testing at the acute phase under P2Y

Author

Claire, Bal Dit Sollier, Natacha, Berge, Sara, Hamadouche, Caren, Brumpt, Alain, Stepanian, Patrick, Henry, Virginie, Siguret, Ludovic, Drouet, and Jean-Guillaume, Dillinger

Subjects
Adult, Percutaneous Coronary Intervention, Treatment Outcome, Purinergic P2Y Receptor Antagonists, Humans, Hemorrhage, Acute Coronary Syndrome, Middle Aged, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors, Aged, Retrospective Studies
Abstract

In patients with acute coronary syndrome (ACS), current international guidelines recommend newer potent and predictable P2YTo determine if platelet function testing can predict bleeding in real-life patients with ACS treated with newer P2YIn this retrospective study, all consecutive adults admitted to the Lariboisière University Hospital for ACS, whatever the P2YA total of 364 patients were included, treated with ticagrelor (n=123), prasugrel (n=105) or clopidogrel (n=136); 42.3% after an ST-segment elevation myocardial infarction, 27.1% after a non-ST-segment elevation myocardial infarction and 30.6% with unstable angina. Mean age was 64±11 years. Median VASP index was significantly lower with the newer P2YDespite the substantial occurrence of bleeding in patients with ACS during follow-up, neither the VASP index nor platelet aggregation test results measured at the acute phase were helpful in predicting bleeding risk. Whether platelet function testing could be helpful later in the course of treatment remains to be evaluated.

Published
2021

40. 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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41. Leucocytes, D-dimères et Ferritinémie comme Facteurs Prédictifs Indépendants d’Embolie Pulmonaire suspectée à l’admission chez les patients COVID-19 hospitalisés hors réanimation : étude rétrospective multicentrique française CLOTVID

Author

Olivier Mangin, B. Thoreau, J. Galland, Dominique Vodovar, Jonathan London, P. O. Sellier, Damien Sène, Anthony Chauvin, Maxime Delrue, Marie Neuwirth, Blanca Amador-Borrero, Jean-Philippe Kevorkian, Stéphane Mouly, Mathilde Devaux, Virginie Siguret, and Alain Stepanian

Subjects
Gynecology, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Gastroenterology, Internal Medicine, medicine, Co075, business
Abstract

Introduction Une prevalence elevee d’embolie pulmonaire (EP) a ete decrit au cours de la COVID-19, avec une morbi-mortalite significative. L’objectif etait d’identifier des facteurs predictifs d’EP chez des patients atteints de COVID-19 severes hospitalises hors reanimation. Patients et methodes Au cours d’une etude retrospective multicentrique nationale francaise, nous avons inclus entre le 6 et le 28 avril 2020, les patients atteints de COVID-19 confirmee par RT-PCR, hospitalises en service de Medecine Interne ou de Pneumologie, avec un angioscanner thoracique realise au Service d’Accueil des Urgences pour suspicion d’EP. Les donnees de base, les traitements et l’evolution ont ete recueillies lors de l’admission et au dernier suivi disponible. Des modeles de regression uni et multivaries ont ete utilises pour identifier les facteurs predictifs associes au diagnostic d’EP confirmee. Resultats Au total, 88 patients (âge median [interquartile range IQR] de 68 ans [60-78]) ont ete analyses. Sur la base de l’angioscanner thoracique, une EP a ete confirmee chez 47 (53,4 %) patients, et refutee chez 41 autres. Un taux de D-dimeres ≥ 3000 ng/mL (Odds ratio OR = 8,2 [intervalle de confiance a 95 %] 1,3-74,2, sensibilite (Se) 0,84, specificite (Sp) 0,78, p = 0,03), un taux de leucocytes ≥ 12 G/L (OR = 29,5 [2,3-1221,2], Se 0,47, Sp 0,92, p = 0,02) et une ferritinemie ≥ 480 μg/L (OR = 17,0 [1,7-553,3], Se 0,96, Sp 0,44, p = 0,03) etaient associes au diagnostic d’EP de maniere independante. L’association d’un taux de D-dimeres ≥ 3000 ng/mL et d’un taux de leucocytes ≥ 12 G/L etait tres associes au diagnostic d’EP (OR = 21,4 [4,0-397,9], p = 0,004). Conclusion Le taux de leucocytes, de D-dimeres et la ferritinemie sont des biomarqueurs simples et facilement disponibles a l’admission pour predire le diagnostic d’embolie pulmonaire chez des patients atteints de COVID-19 hospitalises hors reanimation. Ces biomarqueurs pourraient integrer la demarche diagnostique d’embolie pulmonaire et a l’initiation rapide d’une anticoagulation curative au cours de la COVID-19, et pourraient inversement reduire le nombre d’angioscanner thoracique non necessaire.

Published
2021
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42. 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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43. Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID-19

Author

Agnès Veyradier, Bérangère S. Joly, and Virginie Siguret

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Critical Illness, Pneumonia, Viral, Critical Care and Intensive Care Medicine, Betacoronavirus, Medicine, Humans, Intensive care medicine, Viral immunology, Pandemics, Hemostasis, Understanding the Disease, business.industry, Critically ill, SARS-CoV-2, Anticoagulants, COVID-19, Blood Coagulation Disorders, Pathophysiology, Critical illness, business, Coronavirus Infections, Cytokine Release Syndrome
Published
2020
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44. Deep venous thrombosis treated by rivaroxaban in a young patient with type Ia carbohydrate-deficient glycoprotein (CDG) syndrome

Author

Ludovic Drouet, Bertrand Lefrère, Arezki Hadj-Ali, Alain Stepanian, Martine Alhenc-Gelas, Nathalie Itzhar-Baïkian, Virginie Siguret, Agnès Veyradier, P. Charles, and Bérangère S. Joly

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, 030105 genetics & heredity, Gastroenterology, 03 medical and health sciences, Congenital Disorders of Glycosylation, Rare Diseases, Rivaroxaban, Protein C deficiency, Internal medicine, medicine, Humans, Vein, Factor XI, Venous Thrombosis, business.industry, Antithrombin, General Medicine, medicine.disease, Venous thrombosis, Treatment Outcome, medicine.anatomical_structure, Coagulation, Phosphotransferases (Phosphomutases), Female, business, medicine.drug, Rare disease
Abstract

Congenital disorders of glycosylation (CDG) are rare inborn diseases of glycan component of N-glycosylated proteins. We report here the case of a 28-year-old patient with CDG syndrome type Ia, who presented with a deep venous thrombosis in the left suro-popliteal vein with no known triggers or antecedents. The patient was treated with rivaroxaban for six months. Blood tests performed after discontinuing anticoagulant treatment showed multiple abnormalities affecting the proteins involved in haemostasis (both coagulation factors and inhibitors), i.e. a combined factor XI, antithrombin and protein C deficiency (35%, 41%, and 42% respectively) associated with a moderate increase of FVIII (179%) and VWFAg (163%) without inflammation. Patient results are here discussed with regard to the limited number of articles addressing haemostasis in this rare disease, as the occurrence of deep venous thrombosis remains uncommon in the literature.

Published
2018
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45. GFHT proposals on the practical use of argatroban — With specifics regarding vaccine-induced immune thrombotic thrombocytopaenia (VITT)

Author

Yannick Béjot, Anne Godier, B. Tardy, Isabelle Gouin-Thibault, Vincent Mémier, Guillaume Mourey, Virginie Siguret, Corinne Frere, Christine Mouton, Marie Toussaint-Hacquard, Philippe Nguyen, Bouhadjar Dahmani, Yves Gruel, Charlène Kuadjovi, Peggy Reiner, Céline Desconclois, Anne Bauters, Elodie Boissier, Alexandre Godon, Emmanuel de Maistre, Nadine Ajzenberg, Thomas Lecompte, Isabelle Crassard, Nathalie Hézard, Dominique Lasne, Georges Jourdi, Mathieu Laurichesse, Chloé James, Claire Flaujac, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), CHU Pessac, 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, 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), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpitaux Universitaires de Genève (HUG), 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), 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 ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], AP-HP - Hôpital Bichat - Claude Bernard [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, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Versailles, 78000 Le Chesnay, France, parent, Service d'Hématologie clinique [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), 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), 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), CHU Trousseau [Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Thrombocytopaenia, medicine.drug_class, [SDV]Life Sciences [q-bio], VITT, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Fibrinogen, Argatroban, 03 medical and health sciences, 0302 clinical medicine, Concomitant Therapy, medicine, Platelet, business.industry, Anticoagulant, COVID-19, Thrombosis, General Medicine, medicine.disease, 3. Good health, Anesthesiology and Pain Medicine, Clotting time, Direct thrombin inhibitor, 030220 oncology & carcinogenesis, Anesthesia, business, Vaccine, medicine.drug
Abstract

International audience; Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg × kg(-1) × min(-1), with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly advised to involve a health practitioner experienced in the management of difficult cases in haemostasis. The first laboratory assessment should be performed 4 h after the initiation of argatroban infusion, with further controls at 2-4-h intervals until steady state, and at least once daily thereafter. Importantly, full anticoagulation should be rapidly achieved in case of widespread thrombosis. Cerebral vein thrombosis (which is typical of VITT) should not call for an overly cautious anticoagulation scheme. Argatroban administration requires baseline laboratory assessment and should rely on an anti-IIa assay to derive argatroban plasma levels using a dedicated calibration, with a target range between 0.5 and 1.5 µg/mL. Target argatroban plasma levels can be refined based on meticulous appraisal of risk factors for bleeding and thrombosis, on frequent reassessments of clinical status with appropriate vascular imaging, and on the changes in daily platelet counts. Regarding the use of aPTT, baseline value and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient’s/mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged: one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg × kg(-1) × min(-1) up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.

Published
2021
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46. Prolongación del tiempo parcial de tromboplastina activada

Author

L Calmette, G Jourdi, M F Hurtaud, Virginie Siguret, E de Maistre, and Isabelle Gouin-Thibault

Subjects
03 medical and health sciences, 0302 clinical medicine, 030204 cardiovascular system & hematology, 030215 immunology
Abstract

El tiempo parcial de tromboplastina activada (TPTA) es una prueba de la coagulacion de primera linea, que permite explorar la cascada de la coagulacion (a excepcion de los factores VII y XIII) despues de la activacion de la fase de contacto en presencia de fosfolipidos y de iones de calcio. Se trata de una prueba cronometrica, estandarizada, fiable y automatizable. El resultado del TPTA se expresa en forma de una proporcion: el tiempo de la coagulacion del plasma «paciente» medido en segundos se relaciona con un tiempo de control que se determina en funcion del conjunto reactivo/aparato. El tiempo parcial de tromboplastina activada se utiliza en diversas indicaciones como el estudio de un sindrome hemorragico, en algunos casos con caracter preoperatorio, en el seguimiento de un tratamiento con heparina o para la busqueda de un anticoagulante circulante. Estan comercializados muchos reactivos, con diferentes sensibilidades. El proposito de este articulo consiste en revisar las recomendaciones en vigor sobre las condiciones preanaliticas, los intervalos de referencia, la sensibilidad de los reactivos en funcion de las indicaciones y el enfoque diagnostico ante una prolongacion del TPTA.

Published
2017
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47. Tiempo de Quick (tasa de protrombina), INR

Author

M F Hurtaud, E de Maistre, Isabelle Gouin-Thibault, Virginie Siguret, Georges Jourdi, and L Calmette

Subjects
03 medical and health sciences, 0302 clinical medicine, 060301 applied ethics, 06 humanities and the arts, 030204 cardiovascular system & hematology, 0603 philosophy, ethics and religion
Abstract

El tiempo de Quick es una prueba semiglobal de la coagulacion que permite estudiar ex vivo los factores de la via del factor tisular, tambien denominada via extrinseca de la coagulacion (factores VII, X, V, II y fibrinogeno). El resultado del tiempo de Quick se expresa en segundos o en proporcion en relacion con un control en los paises anglosajones. Puede convertirse en un porcentaje de actividad a partir de una recta de referencia (recta de Thivolle): es la tasa de protrombina. Esta prueba esta indicada en situaciones que requieren el estudio de la hemostasia: estudio de un sindrome hemorragico o de un sindrome por consumo, estudio de la funcion hepatica, evaluacion preoperatoria. Para el seguimiento de los pacientes tratados con antivitaminas K, el resultado se expresa con el indice normalizado internacional, con el fin de limitar las variaciones entre laboratorios, debido a la variabilidad de los resultados del tiempo de Quick segun el reactivo utilizado. Al igual que con todas las pruebas de hemostasia, el control de las diferentes etapas preanaliticas y analiticas garantiza un resultado fiable. Una disminucion aislada de la tasa de protrombina o asociada a la prolongacion del tiempo de tromboplastina parcial activada puede completarse mediante la determinacion de las concentraciones de fibrinogeno y de los factores de la coagulacion (II, V, VII y X), lo que permite refinar el diagnostico, al margen de cualquier tratamiento anticoagulante. El tiempo de Quick no es sensible a la presencia de heparina a concentraciones terapeuticas y posee baja sensibilidad al dabigatran, apixaban y edoxaban y una sensibilidad variable al rivaroxaban. En conclusion, la tasa de protrombina es una prueba clave en el estudio de la coagulacion asociada al tiempo parcial de tromboplastina activada.

Published
2017
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48. Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Author

Dabor Resiere, Sébastien Larréché, Lucie Chevillard, Jean-Philippe Chippaux, Virginie Siguret, Simon Mathé, Bruno Mégarbane, Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU de la Martinique [Fort de France], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Innovations thérapeutiques en hémostase (IThEM - U1140), and Chevillard, Lucie

Subjects
Pathology, medicine.medical_specialty, Thrombotic microangiopathy, QH301-705.5, Hydrostatic pressure, thrombocytopenia, Catalysis, Fibrin, coagulopathy, Inorganic Chemistry, Coagulopathy, Medicine, Platelet, Biology (General), Physical and Theoretical Chemistry, Envenomation, QD1-999, Molecular Biology, Spectroscopy, snake venom, microthrombi, biology, business.industry, Organic Chemistry, General Medicine, medicine.disease, Computer Science Applications, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Chemistry, Coagulation, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Hemostasis, biology.protein, hemorrhage, business
Abstract

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Published
2021
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49. 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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50. Tinzaparin Sodium Pharmacokinetics in Patients with Chronic Kidney Disease: Practical Implications

Author

Virginie Siguret, Hélène Helfer, and Isabelle Mahé

Subjects
medicine.medical_specialty, Urology, Renal function, Hemorrhage, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, Tinzaparin, Pharmacokinetics, Fibrinolytic Agents, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Renal Insufficiency, Chronic, business.industry, Cancer, General Medicine, Venous Thromboembolism, medicine.disease, Tinzaparin sodium, Renal Elimination, Current Opinion, Risk Adjustment, Cardiology and Cardiovascular Medicine, business, Kidney disease, medicine.drug
Abstract

Low-molecular-weight heparins (LMWHs) are the mainstay of the prophylaxis and treatment of venous thromboembolism (VTE). Due to their renal elimination, the risk of accumulation with the related bleeding risk may represent a limitation for the use of LMWHs in patients with chronic kidney disease (CKD) as the risk of major bleeding is increased in patients with creatinine clearance (CrCl)

Published
2019

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