Anti-phospholipid antibodies in severely ill patients not distinctive to COVID-19, says study

Recent research indicates the occurrence of thromboembolic complications involving anti-phospholipid antibodies (APLA) and the anti-phospholipid syndrome (APS) in severe coronavirus disease 2019 (COVID-19). However, conflicting reports have emerged.

A new study by researchers at the University of Toronto and the University of Calgary in Canada indicates that the presence of these antibodies correlates with more severe COVID-19 symptoms and signs.

The team have released their findings as a preprint on the medRxiv* server.

Anti-phospholipid antibodies

APLA are markers for the APS, which includes a constellation of features involving multiple organs, caused by venous and arterial thrombosis. APLA include those that form a part of the diagnostic criteria for APS, such as IgG and/or IgM anti-cardiolipin (aCL), -β2-glycoprotein1 (GP1), and the lupus anticoagulant (LAC). Others that may also be considered diagnostic in a minor context include anti-phosphatidylserine/prothrombin (PS/PT) complex, -PT, and -domain 1 of β2-GP1.

APLA have gained attention in the background of COVID-19-associated thrombosis-mediated events, leading to severe disease and death, because of the occurrence of systemic inflammation and the cytokine storm. This fails to take into consideration the fact that APLA are also found in many other infectious diseases.

Another confounding factor is the high rate of thromboembolism in non-APS patients with critically ill patients, in the absence of APLA.

Study aims

The current study aims to provide preliminary evidence of APLA in patients with severe COVID-19, compared to controls with similar clinical features but without COVID-19.

An observational study of adult patients admitted to a single center was carried out, with all patients being admitted to the intensive care unit (ICU) with acute respiratory failure. There were 22 COVID-19 patients and 20 controls, with a mean ICU stay of two weeks.

About a third of the patients died. The number of clotting events in both cohorts were comparable, as were platelet counts. None of the patients had a history of APS in the past, or other APS-associated conditions, including systemic lupus erythematosus (SLE). The medical history was also similar for patients and controls.

Anticardiolipin antibodies

About half of all patients showed the presence of IgG aCL by 10 days after ICU admission, irrespective of age or sex.

The presence of IgG aCL corresponded to a trend for adverse outcomes in both patient groups, despite the absence of significant differences in platelet counts, or the ratio of platelets to neutrophils, or indications for therapeutic anticoagulation. Only a fifth showed IgM aCL.

One patient was positive for IgM anti-PS/PT, with seroconversion being observed during days 5-7 of ICU stay. None of the other patients tested positive for IgM/IgG anti-β2-GP1, anti-PS/PT domain 1 or IgG β2-GP1.

Other antibody associations

The presence of IgG aCL antibodies were associated with higher ANA titers, in patients with and without COVID-19. Anti-cytokine autoantibodies were also associated with IgG aCL positivity across the spectrum, with anti-interferon-γ, anti-IL10 and anti-IL-17f being the most common.

However, COVID-19 patients had markedly higher levels of anti-cytokine antibodies. Conversely, IgG aCL was not found to be associated with antigen-specific autoantibodies, such as those in SLE or myositis.

What are the implications?

The study shows that the presence of IgG aCL tends to be associated with more severe disease, in both COVID-19 patients and controls. The trend towards poor respiratory outcomes in COVID-19 patients was less significant, but aCL status was an independent predictor of more severe disease in both groups.

The absence of significant differences in platelet counts or clotting events between the two groups makes it difficult to pinpoint the contribution of aCL antibodies in severe illness. This is the first time a controlled study shows high aCL autoantibodies among COVID-19 patients as well as controls.

The finding of aCL without other antigen-specific autoantibodies “suggest that aCL positivity in the setting of acute severe respiratory illness may be a marker of a unique phenotype with variable temporal expression of aCL and anti-cytokine antibodies.”

Thus, conflicting findings about aCL and other APLA in COVID-19 may be partly due to the development of these antibodies at different times during the clinical course of the illness, and also the cross-sectional nature of most studies on inflammatory disease conditions that show changes over time.

The researchers conclude that COVID-19 and APS share features like impaired coagulation function, severe disease and death. APS tests in severe illness in both groups of patients (COVID-19-positive or negative) showed aCL IgG autoantibodies in about half the cases. Thus, the presence of APLA is not discriminant for COVID-19.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.