BackgroundReports of severe COVID-19 MESHD being associated with thrombosis MESHD, anti-phospholipid antibodies (APLA), anti- phospholipid syndrome MESHD ( APS MESHD) have yielded disparate conclusions. Studies comparing COVID-19 MESHD patients with contemporaneous controls of similar severity are lacking. Methods22 COVID+ and 20 COVID- patients with respiratory failure MESHD admitted to intensive care were studied longitudinally. Demographic and clinical data were obtained from the day of admission. APLA testing included anti-cardiolipin (aCL), anti-{beta}2glycoprotien 1 ({beta}2GP1), anti-domain 1 beta2 glycoprotein 1 HGNC ({beta}2GP1) and anti-phosphatidyl serine/prothrombin complex (PS/PT). Anti-nuclear antibodies (ANA) were detected by immunofluorescence and antibodies to cytokines by a commercially available multiplexed array. ANOVA was used for continuous variables and Fishers exact test was used for categorical variables with =0.05 and the false discovery rate at q=0.05. ResultsAPLA were predominantly IgG aCL (48%) followed by IgM (21%) in all patients, with a tendency toward higher frequency among the COVID+. aCL was not associated with surrogate markers of thrombosis MESHD but IgG aCL was strongly associated with worse disease severity and higher ANA titers regardless of COVID-19 MESHD status. An association between aCL and anti-cytokine autoantibodies tended to be higher among the COVID+. ConclusionsPositive APLA serology was associated with more severe disease regardless of COVID-19 MESHD status. KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LI COVID-19 MESHD is associated with coagulopathy MESHD and high morbidity and mortality. C_LIO_LI COVID-19 MESHD shares some of these clinical features with anti- phospholipid syndrome MESHD. C_LIO_LIReports of an association of anti-phospholipid antibodies with high risk COVID-19 MESHD have yielded disparate conclusions, but they lacked longitudinal follow up and control groups of similar severity. C_LI What does this study add?O_LIAnti-phospholipid syndrome serology assessed longitudinally was predominantly anticardiolipin IgG autoantibodies, in 48% of patients. C_LIO_LIAnticardiolipin serology was associated with worse disease severity in both COVID-19 MESHD positive and negative patients. C_LI How might this impact on clinical practice or future developments?O_LIThe use of anti-phospholipid antibodies tests in the COVID-19 MESHD clinical setting needs to be taken in context; whereas they are associated with more serve disease, they do not discriminate between COVID-19 MESHD positive and negative patients. C_LI

Background: Vascular thrombosis MESHD is common in patients with coronavirus disease 2019 MESHD ( COVID-19 MESHD). Etiologies underlying this complication are unclear. Purpose: To determine the prevalence of antiphospholipid (aPL), including lupus anticoagulant, anti-cardiolipin and anti-{ beta}2-glycoprotein-1 HGNC antibodies, and its possible association with thrombotic MESHD manifestations of COVID-19 MESHD. Data Sources: We searched MEDLINE indexed journals on September 24, 2020 using the tool LitCovid and the pre-print server medRxIV. Study Selection: Original investigations (cross-sectional studies, cohort studies, case series, and research letters) on COVID-19 MESHD and thrombosis MESHD were included. Data Extraction: Data were independently extracted, and compiled into spreadsheets based on the PRISMA principles. Data Synthesis: Hospitalized patients with COVID-19 MESHD showed a higher prevalence of lupus anticoagulant compared to non- COVID-19 MESHD patients. Temporally, lupus anticoagulant was generally positive early in the course of illness, whereas anti-cardiolipin and anti-{ beta}2-glycoprotein-1 HGNC antibodies appeared to emerge later in the disease. Some patients who were aPL-negative at an early time-point after disease onset became aPL-positive at a later time-point. Lupus anticoagulant was independently associated with thrombosis MESHD in 60 COVID-19 MESHD patients in New York had who had 32 thrombotic MESHD events (8 arterial and 24 venous). In 88 patients in Wuhan, who had more than 20 each of arterial and venous thrombotic MESHD events, medium/high positivity for multiple aPL MESHD was significantly associated with arterial thrombosis MESHD. However, the association of aPL with thrombosis MESHD was not evident in reports that had an overall lower number of or predominantly venous thrombotic MESHD events. Analysis of pooled patients revealed that aPL were significantly more frequent in COVID-19 MESHD patients with stroke MESHD than stroke MESHD patients in the general population. Furthermore, injection of IgG aPL fractions from COVID-19 MESHD patients into mice accelerated venous thrombosis MESHD. Limitation: Limited data and paucity of prospective studies. Conclusion: The aPL are prevalent in patients with COVID-19 MESHD and their presence is associated with thrombosis MESHD. Importantly, these antibodies may be a key mechanism of thrombosis MESHD in COVID-19 MESHD. Follow-up studies are required to understand the relationship between aPL and the spectrum of vascular thrombosis MESHD during and after infection with SARS-CoV-2.

Introduction: Besides distinctive respiratory and digestive hallmarks, COVID-19 MESHD has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “ COVID-19 MESHD Associated Coagulopathy MESHD” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipids antibodies (aPLs) and viral infections MESHD has long been suggested. APLs are assessed for Anti-phospholipid Syndrome MESHD ( APS MESHD) diagnosis, characterized by thrombocytopenia MESHD, thrombosis MESHD and coagulopathy MESHD. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cells damage and thrombotic complications MESHD.Method: We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti- annexin-V HGNC on two COVID-19 MESHD patient groups (early and late infection time) and a negative control group. IgG CICs analysis followed to evaluate inflammatory status, through a possible complement system activation.Results: Our results showed low positive cases percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, 4.55%; in early infection group, late infection MESHD group and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti- annexin-V HGNC immunoassays; no IgG CICs positivity in any patient.Conclusions: In conclusion, our data show a low aPLs prevalence, likely excluding an involvement in the pathogenesis of CAC.Interestingly, IgG/IgM anti-prothrombin and anti- annexin-V HGNC positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “ COVID-19 MESHD-induced- APS-like-syndrome MESHD” in predisposed patients.Finally, even though aPLs are transient, they may still have a thrombotic MESHD potential in genetically predisposed COVID-19 MESHD patients.

Background: While the pathogenesis of coronavirus disease 2019 MESHD ( COVID-19 MESHD) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense. Objective: To determine, whether COVID-19 MESHD is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic MESHD events are frequent in severe COVID-19 MESHD and resemble hypercoagulation of antiphospholipid syndrome MESHD ( APS MESHD), our approach focused on antiphospholipid antibodies (aPL). Materials and methods: In this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 MESHD from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits. Results: Clinical records of the 64 patients with COVID-19 MESHD were reviewed and divided into a cohort with mild illness (mCOVID, n=26 [41%]), a discovery cohort with severe illness (sdCOVD, n=14 [22%]) and a confirmation cohort with severe illness (scCOVID, n=24 [38%]). Severe illness MESHD was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, P<0.001). Total IgG levels were similar in both cohorts. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID, P<0.001), anti-Cardiolipin IgM (sdCOVID, P=0.003; scCOVID, P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID, P<0.001). Systemic lupus erythematosus MESHD was excluded from all patients as a potential confounder of APS MESHD. Conclusions: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity MESHD.

Patients with coronavirus disease MESHD 19 ( COVID-19 MESHD) are at high risk for thrombotic arterial and venous occlusions MESHD. At the same time, lung histopathology often reveals fibrin-based occlusion of small vessels in patients who succumb to the disease. Antiphospholipid syndrome MESHD ( APS MESHD) is an acquired and potentially life-threatening thrombophilia MESHD in which patients develop pathogenic autoantibodies (aPL) targeting phospholipids and phospholipid-binding proteins. Small case series have recently detected aPL in patients with COVID-19 MESHD. Here, we measured eight types of aPL (anticardiolipin IgG/IgM/IgA, anti-beta-2 glycoprotein I IgG/IgM/IgA, and anti- phosphatidylserine/prothrombin (PS/PT) IgG/IgM) in the sera of 172 patients hospitalized with COVID-19 MESHD. We detected anticardiolipin IgM antibodies in 23%, anti-PS/PT IgG in 24%, and anti-PS/PT IgM in 18%. Any aPL was present in 52% of patients using the manufacturer's threshold and in 30% using a more stringent cutoff (>40 units). Higher levels of aPL were associated with neutrophil hyperactivity (including the release of neutrophil extracellular traps/NETs), higher platelet count, more severe respiratory disease MESHD, and lower glomerular filtration rates. Similar to patients with known and longstanding APS MESHD, IgG fractions isolated from patients with COVID-19 MESHD promoted NET release from control neutrophils. Furthermore, injection of these COVID-19 MESHD IgG fractions into mice accelerated venous thrombosis MESHD. Taken together, these studies suggest that a significant percentage of patients with COVID-19 MESHD become at least transiently positive for aPL and that these aPL are potentially pathogenic.

Background and aims: Cerebral infarction MESHD in COVID-19 MESHD patients might be associated with a hypercoagulable state related to a systemic inflammatory response. Its diagnosis might be challenging. We present two critically ill patients with COVID-19 MESHD who presented acutely altered mental status as the main manifestation of multiple strokes MESHD.Methods:Clinical presentation and diagnostic work-up of the patients.Results:Two patients in their sixties were hospitalized with a bilateral pneumonia COVID-19 MESHD. They developed respiratory failure MESHD and were admitted to ICU for mechanical ventilation and intense medical treatment. They were started on low-molecular-weight heparin since admission. Their laboratory results showed lymphopenia MESHD and increased levels of C-reactive protein and D-dimer. Case 1 developed hypofibrinogenemia and presented several cutaneous lesions with biopsy features of thrombotic vasculopathy MESHD. Case 2 was performed a CT pulmonary angiogram at ICU showing a bilateral pulmonary embolism MESHD. When waking up, both patients were conscious but with a remarkable global altered mental status without focal neurological deficits MESHD. A brain MRI revealed multiple acute bilateral ischemic lesions MESHD with areas of hemorrhagic MESHD transformation in both patients (Case 1: affecting the left frontal and temporal lobes MESHD and both occipital lobes; Case 2: affecting both frontal and left occipital lobes). Cardioembolic source and acquired antiphospholipid syndrome MESHD were ruled out. COVID-19 MESHD-associated coagulopathy MESHD was suspected as the possible main etiology of the strokes MESHD.Conclusion:Acutely altered mental status might be the main manifestation of multiple brain infarctions MESHD in critically ill COVID-19 MESHD patients. It should be specially considered in those with suspected COVID-19 MESHD-associated coagulopathy MESHD. Full-dose anticoagulation and clinical-radiological monitoring might reduce their neurological consequences.

Background The most severely COVID-19 MESHD patients need intensive care and show increased risk of thromboembolic MESHD events. Although some patients meet the diagnostic criteria for the Disseminated Intravascular Coagulation, the pathogenesis of the diffuse thrombotic MESHD status remains unclear. The aim of the present study is to evaluate the presence of antiphospholipid antibodies (aPL) in sera of deceased patients with autoptic proven thrombotic microangiopathy MESHD to evaluate if some patients may have developed Catastrophic Antiphospholipid Syndrome MESHD ( CAPS MESHD CAPS HGNC). Methods Thirty-five patients were enrolled. The available medical history, comorbidities, therapies, laboratory and autopsy findings were collected post-mortem from clinical records. IgA, IgG and IgM anti cardiolipin (ACA) and anti { beta}2 glycoprotein 1 HGNC ({beta}2GP1) antibodies, IgG and IgM anti phosphatidylserine/prothrombin (PS/PT) antibodies were tested for all the patients. Results 3/35 (8.6%) patients were slightly positive for aPL: one for ACA IgG and two for ACA IgM but values were low (< 3X the cut off). No patients tested positive for ACA IgA neither for {beta}2GP1 isotypes. 3/35 (8.6%) patients were positive for PS/PT, one for IgG and two for IgM, but values were less than 2X the cut off. No patients showed simultaneous positivity for ACA and PS/ PT. Conclusions It is difficult to categorize the vascular events into a conventional disease: we did not find significant association with anti-phospholipid antibodies. It is most likely that several factors contribute to trigger the hypercoagulability MESHD status and the thromboembolism MESHD but, on the basis our results, CAPS MESHD CAPS HGNC is probably not involved into the pathogenesis of these phenomena.