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Antiphospholipid syndrome (APS) is a clinical-biological entity defined by the combination of thrombotic events and/or obstetric complications and the presence of persistent antiphospholipid antibodies (APLAs) detected by coagulation tests (lupus anticoagulant, LAC) and/or immunological assays (anticardiolipin and anti-glycoprotein-beta-I antibodies). The increased use of direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) poses a challenge for hematology laboratories when it comes to diagnosing APS. DOACs interfere with LAC screening and confirmation tests, resulting in a risk of false positive results. To avoid these interferences, several solutions are suggested. Some of them rely on the use of DOAC-reversal systems (activated charcoal tablet, filter system); others on the use of reagents insensitive to DOAC presence in the sample. Detection of anti-phosphatidylserine/prothrombin antibodies may be helpful because they are strongly associated with the presence of LAC and are increasingly recognized as a useful tool in the diagnosis and prognosis of APS. Finally, positivity of LA in the context of a viral infection is frequent and not specific to APS. During the Covid-19 pandemic, many patients developed arterial and/or venous thromboembolism that could suggest testing for APLAs. The link between LAC and a risk of VTE or in-hospital mortality in hospitalized Covid-19 patients was not demonstrated. Moreover, APLAs do not persist after Covid-19. Currently, testing for APLAs in Covid-19 patients is not recommended.