COVID-19 and aPL Antibodies: Frequently Asked Questions
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(Version 1.1; last updated February 2, 2022)
Input from Geoffrey Wool, MD, PhD; Morayma Reyes Gil, MD, PhD; Agnes Y. Y. Lee, MD, MSc; Nigel Key, MD; Dan Sabath, MD; Cindy Leissinger, MD; Oksana Volod, MD; Lisa Baumann Kreuziger, MD.
Note: Please review ASH's disclaimer regarding the use of the following information.
Is there a relationship between COVID-19 and antiphospholipid antibodies (aPL Ab)?
Clinical laboratories may increasingly encounter aPL Ab testing from COVID-19 patients and be requested to interpret results.
Early in the pandemic, Dr. Yan Zhang and colleagues described three severely ill COVID-19 patients with multisystem thrombosis and ischemic strokes and prior risk factors for cardiovascular disease who were found to have aPL Abs, specifically anticardiolipin IgA and anti-beta-2 glycoprotein-I IgG and IgA antibodies. The degree of antibody positivity (e.g. titer) was not reported. No lupus anticoagulants were detected in these three patients. The authors did not report if other aPL Ab antigenic assays were performed.
Different patterns have subsequently emerged in patients with COVID-19 throughout the past two years. From two of our institutions, 27 total COVID-19 patients had antiphospholipid syndrome testing. Twenty of 27 (74%) had positive dilute Russell Viper Venom assays, often significantly so. Only four of 27 (15%) had a positive Staclot Lupus Anticoagulant (aPTT-based system). Zero of 27 (0%) had positive IgM or IgG antigenic aPL Ab studies (anticardiolipin and anti-beta-2 glycoprotein-I), and six of these additionally had negative extended antigenic studies (IgA anticardiolipin and anti-beta-2 glycoprotein-I; IgG/IgM antiphosphatidylserine/prothrombin). These findings are in contrast to those previously reported by Dr. Zhang and colleagues.
Similarly, multiple other reports have shown that lupus anticoagulant testing is much more frequently positive than antigenic aPL Ab studies in patients with COVID-19 (Table). This is variably confounded by anticoagulation depending on the study and reagents used. The association between aPL Ab and thrombosis or other clinical outcomes is variable. It remains uncertain whether aPL Ab are an epiphenomenon or are involved in the pathogenesis of COVID-19.
Should all COVID-19 patients be tested for antiphospholipid antibodies (aPL Ab)?
No. It is well described that aPL Ab can arise transiently at times of acute infection, inflammation, or thrombosis. This is the reason for the 12-week interval recommended by ISTH guidelines for repeat confirmatory laboratory testing to diagnose the antiphospholipid syndrome. At the current time, it remains unclear if aPL Ab represent an epiphenomenon or are actually involved in any hemostatic abnormalities seen in COVID-19 disease. Thus we strongly recommend against routine testing for aPL Ab in COVID-19 patients, unless clinically indicated by prior history or as part of a research protocol.
Patients with specific clinical sequelae suggestive of antiphospholipid syndrome (APS), such as thrombosis or pregnancy loss, where anticoagulation management would be changed based on testing, should be investigated with a guideline-based battery of aPL Ab.
Are there potential caveats to accurately measuring aPL Ab in COVID-19 patients?
C-reactive protein (CRP) can bind phospholipid and thus very high CRP levels can result in false positivity when using functional lupus anticoagulant assays, specifically aPTT-based assays rather than DRVVT-based assays (Schouwers et al). Anticoagulation, particularly therapeutic anticoagulation, can also cause false positivity in LA testing (Pavoni et al). In contrast, very high FVIII and fibrinogen levels can result in false negative functional lupus anticoagulant testing. Thus, interpretation of lupus anticoagulant testing in critically ill patients with COVID-19 may be challenging, and written interpretive report by a laboratorian or expert user is recommended.
What other laboratory markers of inflammation and thrombophilia are commonly observed in patients with COVID-19?
Severe COVID-19 is a profound pro-inflammatory state. Patients with COVID-19 commonly have marked hyperfibrinogenemia, together with other elevated acute-phase reactants such as CRP and ferritin. These patients also commonly have elevated D-dimer levels, reflecting crosslinked fibrin formation with subsequent lysis. Protein C, protein S, and antithrombin levels may be abnormal in the presence of severe inflammation and should not be routinely measured unless there is an indication for a specific patient.
Should we give therapeutic anticoagulation to COVID-19 patients with aPL Ab?
The presence of aPL Ab alone is not a specific indication for therapeutic anticoagulation. Similarly, the presence of aPL Ab does not represent a clinical diagnosis of antiphospholipid syndrome (APS) unless the patient also fits standard syndrome criteria. It should not be assumed that a patient with COVID-19 and an aPL Ab has catastrophic antiphospholipid syndrome (CAPS), unless the patient meets diagnostic criteria for CAPS. CAPS and COVID-19 coagulopathy may share some features, but likely have very different underlying pathophysiology, and different optimal treatment.
For additional information, see:
- Zhang et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):e38.
- Schouwers SM et al. Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res. 2010 125(1):102-4. PubMed PMID: 19782388).
- Pavoni V etal. Antiphospholipid antibodies and thrombosis in severe COVID-19 pneumonia: A difficult relationship. Thromb Res. 2020 Oct;194:190-191.