key: cord-0709824-zhl6klau
authors: Vollmer, Olivier; Tacquard, Charles; Dieudonné, Yannick; Nespola, Benoit; Sattler, Laurent; Grunebaum, Lélia; Gies, Vincent; Radosavljevic, Mirjana; Kaeuffer, Charlotte; Hansmann, Yves; Weber, Jean-Christophe; Martin, Thierry; Arnaud, Laurent; Morel, Olivier; Guffroy, Aurélien; Collange, Olivier; Mertes, Paul Michel; Korganow, Anne-Sophie; Delabranche, Xavier; Poindron, Vincent
title: Follow-up of COVID-19 patients: LA is transient but other aPLs are persistent
date: 2021-04-16
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2021.102822
sha: 416bb6a79dee09815d5f5e3cd1ee0384876d5f38
doc_id: 709824
cord_uid: zhl6klau

nan

In the context of the COVID-19 pandemic, frequent thrombosis were reported, with up to 43% of clinically relevant thrombotic events in critically patients [1] . Several abnormalities in coagulation parameters, endothelial cells activation and multiple cytokines production have been described resulting in a procoagulant state [2] . A prolonged activated partial-thromboplastin time (aPTT) was identified in a significant number of patients, associated with the presence of a Lupus Anticoagulant (LA) [3] [4] [5] .

Besides, studies showed an increased prevalence of other antiphospholipid antibodies (aPLs) with different targets and/or isotypes in infected patients [6, 7] . aPLs appeared associated with thrombosis and severity of COVID-19 [6, 8, 9] and were demonstrated as pathogenic in a murine model with induced vascular injury [7] . Recent findings raise the question of whether LA and other aPLs persist over time and thereby whether COVID-19 with thrombosis and aPLs could be considered as an unusual, induced antiphospholipid syndrome (APS). Several concerns arise from the current literature on COVID-19. LA positivity could be difficult to interpret as many patients did not have LA detection with aPTT and diluted Russell's Viper Venom Time (dRVVT) at admission in the hospital. Moreover, the inflammatory context, coagulation disorders or anticoagulant therapy could influence LA detection [3, 10] . Siguret et al. showed LA as labile when measured a few days after first identification [11] but there is to date no systematic follow-up of the patients who presented COVID-19 infection and LA and/or aPLs. In the present study we aimed to describe the prevalence and persistence over time of criteria aPLs in a cohort of hospitalized COVID-19 patients who were tested positive for LA and assess their association with thrombosis.

Included patients were at least 18 years of age, had RT-PCR confirmed SARS-CoV-2 severe to critical infection according to WHO guidelines [12] and were positive for LA, between March 03 rd and April 11 th 2020. Study was approved by the Institutional Board of Strasbourg University Hospital (CE-2020-85). Data were collected from routine care. LA activity of patient plasma was assessed by the dRVVT (STA®-Staclot dRVV Screen and confirm reagent, Stago), and LA sensitive aPPT (STA®-PPT LA reagent, Stago) according to ISTH guidelines [13] . IgM and IgG anticardiolipin antibodies (aCLs) J o u r n a l P r e -p r o o f were evaluated through a fluorescence enzyme immunoassay (FEIA) designed as a sandwich assay on a Phadia 250 (Thermofisher, Phadia Uppsala Sweden). Anti-β2GPI antibodies were assessed using a sandwich ELISA (Inova Diagnostic, San Diego, CA, USA). Non-criteria aPLs titers were determined by ELISA. Screening for antinuclear antibodies (ANAs) was performed on HEp-2 cells (Zeus Scientific, USA). Fisher's exact test was used for categorial variables and Mann Whitney or unpaired t-test were used for quantitative variables according to variable distribution. Multivariate analysis including variable with P value < 0.10 on univariate analysis was performed using multiple logistic regression.

Statistical analysis was performed with JMP software version 7.10 (SAS institute, USA).

We identified 79 patients with COVID-19 and LA ( Figure 1 ). Patients characteristics were concordant with previously published data [14, 15] . Patients had severe to critical COVID-19 with hospitalization for a median duration of 23 days and 66 (83.5%) required mechanical ventilation (Table 1) . Computed tomography (CT) quantification of pneumonia was performed for 69 patients with at least 25% involvement in the majority of cases (85.5%). All patients received standard of care as needed. Among the 79 LA positive patients, 50.6% displayed one thrombosis with 7.59% having at least one recurrence. Regarding the vascular distribution of thrombosis, 75% had venous thrombosis, 25% had arterial thrombosis and 25% had a catheter or ECMO oxygenator or Renal Replacement Therapy circuit clotting. Importantly, 82.5% of patients with thrombosis received a prophylaxis either with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) before the first thrombotic event.

The median highest CRP was 286 mg/l [16.7-492] (Table 1 ). Groups were similar for age, sex and BMI, cardiovascular risk factors and previous history of thrombotic events. There was no difference regarding COVID severity and anticoagulant therapies. We found a strong association between thrombosis and positivity of aCLs IgM (11/27 [41%] patients with thrombosis vs 2/29 [7%] patients without thrombosis, p = 0.004, OR=9.28 IC95 2.0 to 44.4).

Forty-two patients were followed-up and screened for antiphospholipid antibodies and ANAs at least 3 months and up to 6 months after first LA identification (Table 1) In conclusion, LA is frequent in COVID-19 patients in the acute phase, but its signification is controversial. Herein we show that LA is transient. Based on our study and others, LA with aCLs of 

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