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During the Covid-19 pandemic, four patients were admitted to a healthcare centre. They were treated with vitamin K antagonists (AVK). We observed a substantial increase in their International Normalised Ratio (INR). The mean age of these patients was 90 (± 8 years). All had different usual long-term therapy treatments but had fixed doses of AVK to reach a stable INR. No changes to the background regimen were implemented. One patient presented a cough whereas the three others were asymptomatic. In the context of the pandemic, a reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 was carried out for each patient. The results of the RT-PCR rests were all positive and were associated with a substantially increased INR. Mr H. was admitted with an INR of 2.25 which increased to 5.93 the day after RT-PCR positivity. AVK treatment was stopped but the INR one day after was 7.89. Ms J. presented INR values between 1.96 and 4.58, 10 days later. a PCR test was conducted and AVK treatment was stopped, but the INR still increased to 5.85. The INR of Mr R. increased from 1.82 to 8.05, 24 hours after a positive PCR result. Ms F. presented a gradual increase in INR from 1.5 to 3.36, 72 hours after a positive PCR result and three days after discontinuation of AVK. This study suggest a link between the Covid-19 infection and an increased INR. It has been established that SARS-CoV-2 infection induces hypercoagulability in severe forms. Inversely, these four cases show a haemorrhagic risk as the INR increases. There could be a risk of overdose when patients are treated with AVK and are positive for Covid-19. This raises the question of discontinuing AVK and substituting it with another anticoagulant, or performing INR checks more frequently in the context of Covid-19. Moreover, an unexpected increase in INR should indicate the need to conduct a Covid-19 RT-PCR test in the context of this pandemic context.

During the Covid-19 pandemic, four patients were admitted in a healthcare center. They were treated by vitamin K antagonists (VKA). We observed a substantially increased of their International Normalized Ratio (INR) The mean age of patients was 90 (± 8). All had different usual long-term therapy treatments but had fixed doses of VKA to reach a stable INR. No change of background treatment were realized. One patient presented cough whereas the three others were asymptomatic. In the pandemic context, a reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 was realized for each patients. RT-PCR were all positives and were associated with a substantially increased INR. Mr H. was admitted with an INR of 2.25 and it increased to 5.93 the day after RT-PCR positivity. The VKA treatment was stopped but the INR one day after was 7.89. Mrs J. presented INR value from 1.96 to 4.58, 10 days later. PCR have been realized and VKA treatment was stopped: INR still increased up to 5.85. The INR of Mr R. increased from 1.82 to 8.05, 24 h after positive PCR results. Mrs F. presented a gradually increase of INR from 1.5 to 3.36, 72 h after PCR results three days after VKA discontinuation. Finally, this study suggest a link between the Covid-19 infection and an increased INR. It has been established that SARS-CoV-2 infection induces hypercoagulability in severe forms. Inversely, these four cases show a hemorrhagic risk with the elevation of the INR. It could have a risk of overdose when patients treated with VKA and positive to Covid-19. This raises the question of discontinuing VKA and substituting them with another anticoagulant, or performing INR controls more frequently in the context of Covid-19. Moreover, an unexpected increase of INR could lead to realize a Covid-19 RT-PCR in this pandemic context.

// Gabrielle Lui 1, 2 , Naim Bouazza 1, 2, 3 , Francoise Denoyelle 4 , Marion Moine 1 , Laurence Brugieres 5 , Pascal Chastagner 6 , Nadege Corradini 7 , Natacha Entz-Werle 8 , Cecile Verite 9 , Judith Landmanparker 10 , Helene Sudour-Bonnange 11 , Marlene Pasquet 12 , Arnauld Verschuur 13 , Cecile Faure-Conter 14 , Francois Doz 15, 16, * , Jean-Marc Treluyer 1, 2, 3, 17, * and On behalf of the SFCE (Societe Francaise des Cancers de l’Enfant et l’Adolescent) 1 University of Paris Descartes, EA 7323, Sorbonne Paris-Cite, France 2 CIC-1419 Inserm, Cochin-Necker, Paris, France 3 Clinical Research Unit of Paris Descartes Necker Cochin, AP-HP, Paris, France 4 Department of Pediatric Otolaryngology, Necker Children’s Hospital, Paris, France 5 Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France 6 Department of Pediatric Onco-Hematology, Children’s Hospital, Vandoeuvre Les Nancy, France 7 Pediatric Oncology Department, Mother-Children Hospital, Nantes, France 8 Pediatric Onco-Hematology Unit, CHU of Strasbourg, Strasbourg, France 9 Pediatric Hematology Department, Bordeaux University Hospital, Bordeaux, France 10 Sorbonne University, Department of Pediatric Hematology Oncology, APHP, Trousseau Hospital, Paris, France 11 Pediatric Oncology Unit, Children, Adolescents and Young Adults Unit, Oscar Lambret Center, Lille, France 12 Children’s Hospital, University Hospital of Toulouse, Toulouse, France 13 Pediatric Oncology Department, La Timone Children’s Hospital, Marseilles, France 14 Institute of Pediatric Hemato-Oncology, Lyon, France 15 Oncology Center SIREDO, Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Curie Institute, Paris, France 16 Paris Descartes University, Paris, France 17 Department of Clinical Pharmacology, Cochin Hospital AP-HP, Paris, France * These authors have contributed equally to this work Correspondence to: Gabrielle Lui, email: gabrielle.lui@aphp.fr Keywords: platinum; pharmacogenetics; ototoxicity; children; cancer Received: March 26, 2018 Accepted: June 25, 2018 Published: July 20, 2018 ABSTRACT Platinum is extensively used in the treatment of several childhood cancers. However, ototoxicity is one of the most notable adverse effects, especially in children. Several studies suggest that genetics may predict its occurrence. Here, polymorphisms associated with platinum-induced ototoxicity were selected from the literature and were investigated in a pediatric population treated with platinum-based agents. In this retrospective study, patients treated with cisplatin and/or carboplatin were screened. The patients with pre- and post-treatment audiogram (Brock criteria) available were included. We selected polymorphisms that have previously been associated with cisplatin ototoxicity with a minor allele frequency ≥30%. Deletion of GSTM1 and GSTT1 , rs1799735 ( GSTM3 ), rs1695 ( GSTP1 ), rs4880 ( SOD2 ), rs2228001 ( XPC ), rs1799793 ( XPD ) and rs4788863 ( SLC16A5 ) were investigated. Data of one hundred and six children matching the eligible criteria were analyzed. Thirty-three patients (31%) developed ototoxicity (with a Brock grade ≥2). The probability of hearing loss increased significantly in patients carrying the null genotype for GSTT1 (P = 0.03), A/A genotype at rs1695 (P = 0.01), and C/C genotype at rs1799793 (P = 0.008). We also showed an association of the cumulative doses of carboplatin with cisplatin ototoxicity (P