Reality Check on Antiphospholipid Antibodies in COVID‐19–Associated Coagulopathy

Abstract

To the Editor: Thromboses are severe complications of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory system coronavirus 2 (SARS–CoV-2). The mechanism of COVID-19–associated thrombophilia is unknown; increasing global reports of positivity for antiphospholipid antibody (aPL) in COVID-19 suggest that the virus may induce antiphospholipid syndrome (APS), a separate autoimmune thrombotic illness (1). Because laboratory criteria used to diagnose APS are neither highly specific nor sensitive, and because clinical circumstances, including anticoagulation therapy, alter the laboratory results, international committees have published strict guidelines for aPL testing (2, 3). The hypothesis that SARS–CoV-2 induces APS requires demonstrating that COVID-19 patients fulfill both the clinical and laboratory criteria for APS (4). We reviewed recent publications (see Supplementary Methods, available on the Arthritis & Rheumatology website at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41472/​abstract) in order to assess the likelihood that aPL contributes to thromboses in COVID-19 patients. As of June 1, 2020, we identified 23 studies, in which 250 COVID-19 patients were tested for aPL; 145 of 250 (58%) were aPL positive (Table 1 and Supplementary Table 1 available on the Arthritis & Rheumatology website at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41472/​abstract). Lupus anticoagulant (LAC) was present in 64% of tested COVID-19 patients, anticardiolipin antibody (aCL) in 9%, and anti–β2 glycoprotein I (anti-β2GPI) antibody in 13%. When aCL isotypes were reported, IgM was the most frequent. Relevant clinical information (whether patients were receiving anticoagulation therapy at the time of LAC testing or had a history of aPL positivity/APS) was rarely provided. In studies with aPL test details, 65% of the patients (135 of 209) had a clinically meaningful aPL profile (LAC and/or moderate-to-high titers of aCL/anti-β2GPI). No reports of studies included information on confirmatory aPL testing at 12 weeks. No. of studies (%) No. of aPL-positive patients (%) Similar to patients with severe COVID-19–associated coagulopathy, in a subtype of APS, patients develop multiorgan thromboses over very short periods of time (catastrophic APS [CAPS]) (1). In both COVID-19–associated coagulopathy and CAPS, acute inflammatory response, cytokine storm, and highly elevated ferritin levels occur (5, 6). In patients with definite CAPS, along with a clinically meaningful aPL profile (7), aPL test results remain positive over long periods of time. Infection-induced aPL, in contrast, may be transient. The persistence of aPL in COVID-19 is unknown. As seen in CAPS, a subgroup of patients with severe COVID-19 develop retiform purpura and livedoid rashes. Biopsy findings include thrombotic microvascular injury of the skin as well as lungs, with endothelial damage and cytokine reaction, propagated by complement activation and deposition that predisposes to thrombosis (8). Unlike CAPS, thrombocytopenia is relatively uncommon in COVID-19 (9). The question of whether transient aPL positivity may be pathogenic for the development of incident thromboses and lead to APS, particularly in critically ill patients or during infection, has been poorly understood. Reports to date suggest clinical and laboratory similarities between severe COVID-19 and CAPS; however, the studies suggesting an aPL-related mechanism for thrombosis in COVID-19 are only hypothesis generating. A starting point for future research is to adhere to the criteria for defining clinically important aPL profiles (see Supplementary Table 2, http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41472/​abstract) in COVID-19 patients, including detailed information regarding LAC test results and immunoassays, and serial studies of aPL to demonstrate persistence. In conclusion, there is an opportunity to discover potentially common mechanisms that will inform our understanding of both COVID-19 and APS. However, this will require correct use and measurement of aPL. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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