**Abstract**

Patients infected with COVID-19 are at higher risk of thrombosis, suggesting an important role of COVID-19 induced coagulopathy. Abnormal coagulation parameters such as elevation in D-dimer are found in patients, with frequent thrombotic events ranging from peripheral ischemia, pulmonary thromboembolism to disseminated intravascular coagulation. Recently, the role of antiphospholipid antibodies (aPL) in the pathophysiology of COVID-19 have been questioned but it remains unclear whether they contribute to coagulopathy. We aim to evaluate the presence of aPL, including LAC, aCL (IgG, IgM), aβ2GPI (IgG, IgM) in a cohort of patients with SARS-CoV-2, study clinical associations and discuss the relevance. The relevance of aPLs in patients with COVID-19 is yet to be determined. Inflammation is closely associated to thrombosis and the presence of inflammatory mediators in COVID-19 infection can lead to thrombosis. Further studies are needed before to determine the role of aPL in COVID-19 patients and their relationship with thrombosis. The presence of aPL should be carefully interpreted as it is important to evaluate the persistence of aPL positivity in patients infected with COVID-19.

**Keywords:** antiphospholipid antibodies, covid-19, thrombotic, cardiolipin, lupus anticoagulant

## **1. Introduction**

COVID-19 has swept through the world in the last 6 months with 28,584,158 confirmed cases, including 916,955 deaths, being reported to the World Health Organization (WHO), on September 13th 2020 [1].

COVID-19 is caused by SARS-CoV2-virus, a member of coronaviridae that includes MERS-CoV2 which is responsible for severe respiratory illness and causes acute respiratory distress syndrome [2]. Many patients infected with COVID-19 develop a hyperinflammatory response due to cytokine storm syndrome which associates with high mortality [3]. Recent studies demonstrated an association between COVID-19 severity and inflammatory biomarkers such as C-reactive protein, procalcitonin, IL-6 and ferritin. In addition, a high incidence of thrombotic events suggests an important role of COVID-19-induced coagulopathy, despite the use of prophylactic doses of low molecular weight heparin [4]. Advanced age and comorbidities are predictors of increased mortality in COVID-19, which may facilitate thrombosis in these individuals [5].

Several hemostasis laboratory parameters are altered in patients with COVID-19 which constitutes an argument in favor of coagulopathy [6–10]. Abnormal

coagulation parameters such as prolonged aPTT coagulation times, D-dimer elevation and fibrinogen degradation products correlate with COVID-19 severity and are risk factors for higher mortality [10–12].

There are increasing cases of thrombotic events ranging from venous thromboembolic disease, pulmonary thromboembolism to disseminated intravascular coagulation, as well as reports of arterial thrombosis including strokes and myocardial infarctions [13–15]. The activation of leukocytes, endothelium and plaquettes due to cytokine storm, as well as hypoxic vaso-occlusion and direct activation of cells by viral transduction are several mechanisms by which COVID-19 infection may lead to thrombosis [16].

Recently studies have been published about the role of antiphospholipid antibodies (aPL) in SARSCoV-2 patients, leading investigators to start measuring aPL in these patients because of the hypercoagulable state [17–21].

Antiphospholipid syndrome is an autoimmune condition that leads to autoantibodies creation. These autoantibodies react against phospholipids and phospholipid-binding proteins such as beta-2-glycoprotein I (β2GPI) and activate endothelial cells, platelets, and neutrophils, leading to thrombosis [22, 23]. The ability to promote thrombosis in arterial and venous circuits is a defining characteristic of antiphospholipid syndrome. The catastrophic variant of antiphospholipid syndrome is sometimes fatal and resembles to diffuse coagulopathy seen in patients with COVID-19 [24]. Classification criteria for APS includes lupus anticoagulant (LAC), anticardiolipin (aCL) and antibeta2-glycoprotein I antibodies (aβ2GPI) IgG or IgM, if persistently present [25].

The theory involving aPL in COVID-19 infected patients is intriguing however, most studies published so far only include one point of measurement, usually during the acute phase, without confirmation after at least three months, as defined in laboratory criteria of antiphospholipid syndrome [26].

Lupus anticoagulant (LA) is a well-known case of aPTT prolongation, which can be detected in a significant percentage of COVID-19 infected patients. Several biological causes such as high fibrinogen, factor VIII levels and biomarkers such as elevated C-reactive protein (CRP) and the presence of antiphospholipid antibodies may affect the aPTT [27].

We should also keep in mind that aPL can arise transiently in patients with critical illness and various infections [28]. The presence of these antibodies can lead to thrombotic events, making it difficult to differentiate from other types of thrombosis. Viral infections, such as VIH, hepatitis C and parvovirus B19 are triggers of transient aPL, due to a mechanism of molecular mimicry mechanism [29].

To investigate the role of aPL in COVID-19, it is important to evaluate all criteria of aPL, including LAC, aCL and aβ2GPI antibodies with their isotype and to obtain confirmation after at least 3 months, in concordance with the laboratory criteria of APS.

In this report, we illustrate the presence of aPL, including LAC, aCL (IgG, IgM) and aβ2GPI (IgG, IgM) in a cohort of patients with SARS-CoV-2 and discuss the relevance.
