key: cord-0799546-6ztq7cqc authors: Pineton de Chambrun, Marc; Frere, Corinne; Miyara, Makoto; Amoura, Zahir; Martin‐Toutain, Isabelle; Mathian, Alexis; Hekimian, Guillaume; Combes, Alain title: Response to Letter: “Reply to ‘High frequency of Antiphospholipid Antibodies in Critically‐ill COVID19 patients: a Link with Hypercoagulability?’” date: 2020-08-09 journal: J Intern Med DOI: 10.1111/joim.13166 sha: 630dfacd5bfa69b5ab755963e3ea385538e2ee3d doc_id: 799546 cord_uid: 6ztq7cqc We read with great interest the comment by Suarez‐Perez et al. on our article.[1] We share their concerns regarding the need for a cautious interpretation of antiphospholipid antibodies (aPLA) positivity in patients with coronary virus disease 2019 (COVID‐19). Herein, we would like to add further insights in the discussion. concerns regarding the need for a cautious interpretation of antiphospholipid antibodies (aPLA) positivity in patients with coronary virus disease 2019 . Herein, we would like to add further insights in the discussion. First, many studies from all around the world have reported heterogeneous frequencies of aPLA in various population of COVID-19 patients since our publication (Table 1) . It is uneasy yet to draw a clear conclusion on such contradictory findings. While several cohorts found comparable results [2] [3] [4] [5] [6] [7] [8] [9] , others reported very low percentage of positive patients [4, [10] [11] [12] [13] . A study linked the sickness of the COVID-19 to anti-cardiolipin (aCL) IgG frequency, suggesting that COVID-19 disease severity could explain the discrepancy between reports [5] . Second, although we agree Indeed, many viral infections have been previously shown to be associated with aPLA positivity, without further evidence of their pathogenic role, except in a few isolated cases [14] . Fourth, we acknowledge that the diagnosis of LA in COVID-19 is challenging since several factors, including pre-analytical, analytical and post-analytical factors, might be responsible for false-positive results. LA are detected by prolongation of phospholipid-dependent coagulation tests in vitro, in the absence of coagulation factor deficiency. The in vitro prolongation of coagulation tests is due to an interference with accumulation of coagulation factors on negatively charged phospholipids. Since C-reactive protein also interacts with phospholipids, a marked elevation in C-reactive protein, which is frequently observed in COVID-19 patients, might result in false positive aPLA results, further limiting interpretation of this testing in COVID-19 patients [15] . Fifth, other COVID-19-induced autoantibodies or autoimmune diseases have been reported [2, [16] [17] [18] . Of note, a recent study revealed a cumulative incidence of detectable anti PF4-heparin antibodies higher than expected (12% at 25 days) in 88 severe COVID-19 patients who received at least 5 days of unfractionated heparin [19] . Some reports disclosed cross-reactivity between SARS-CoV-2 and human proteins, suggesting that a molecular mimicry mechanism could explain these This article is protected by copyright. All rights reserved autoimmune manifestations [17, 20, 21] . Larger sample size studies are therefore urgently needed to determine the true frequencies of aPLA in COVID-19 patients, to evaluate their relation to disease severity and thrombotic events and to assess their persistence away from the acute infection. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved High frequency of antiphospholipid antibodies in critically ill COVID-19 patients: a link with hypercoagulability? Autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with COVID-19 Profile of natural anticoagulant, coagulant factor and antiphospholipid antibody in critically ill COVID-19 patients Brief Report: Anti-phospholipid antibodies in critically ill patients with Coronavirus Disease 2019 (COVID-19) Anti-cardiolipin IgG autoantibodies are an independent risk factor of COVID-19 severity Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients? High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Antiphospholipid antibodies in patients with COVID-19: a relevant observation? Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19 Accepted Article This article is protected by copyright. All rights reserved 10 High prevalence of antinuclear antibodies and lupus anticoagulant in patients hospitalized for SARS-CoV2 pneumonia Prothrombotic antiphospholipid antibodies in COVID-19 Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism Prevalence, specificity, and clinical association of antiphospholipid antibodies in COVID-19 patients: are the antibodies really guilty? medRxiv Antiphospholipid antibodies and infections Lupus Anticoagulant (LAC) testing in patients with inflammatory status: Does C-reactive protein interfere with LAC test results? Thrombosis Research The first case of acquired hemophilia A associated with SARS-CoV-2 infection Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19? Covid-19 associated autoimmune thrombotic thrombocytopenic purpura: Report of a case Heparin induced thrombocytopenia antibodies in COVID-19 Kanduc D. From Anti-SARS-CoV-2 Immune Responses to COVID-19 via Molecular Mimicry Accepted Article This article is protected by copyright. All rights reserved 21 Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases Coagulopathy and Antiphospholipid Antibodies in Patients with Lupus anticoagulant is frequent in patients with Covid-19