Prothrombotic antiphospholipid antibodies in COVID-19

Abstract

Patients with coronavirus disease 19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. At the same time, lung histopathology often reveals fibrin-based occlusion of small vessels in patients who succumb to the disease. Antiphospholipid syndrome (APS) is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies (aPL) targeting phospholipids and phospholipid-binding proteins. Small case series have recently detected aPL in patients with COVID-19. Here, we measured eight types of aPL (anticardiolipin IgG/IgM/IgA, anti-beta-2 glycoprotein I IgG/IgM/IgA, and anti- phosphatidylserine/prothrombin (PS/PT) IgG/IgM) in the sera of 172 patients hospitalized with COVID-19. We detected anticardiolipin IgM antibodies in 23%, anti-PS/PT IgG in 24%, and anti-PS/PT IgM in 18%. Any aPL was present in 52% of patients using the manufacturer's threshold and in 30% using a more stringent cutoff (>40 units). Higher levels of aPL were associated with neutrophil hyperactivity (including the release of neutrophil extracellular traps/NETs), higher platelet count, more severe respiratory disease, and lower glomerular filtration rates. Similar to patients with known and longstanding APS, IgG fractions isolated from patients with COVID-19 promoted NET release from control neutrophils. Furthermore, injection of these COVID-19 IgG fractions into mice accelerated venous thrombosis. Taken together, these studies suggest that a significant percentage of patients with COVID-19 become at least transiently positive for aPL and that these aPL are potentially pathogenic.

Anti-phospholipids antibodies and immune complexes in COVID-19 patients: a putative role in disease course for anti-annexin-V antibodies

“…Interestingly, IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V data show that distribution of positive cases number increases in late infection patients, signi cantly in anti-annexin-V results, suggesting a possible role for these anti-phospholipids antibodies in disease course. In fact, it has been reported that aPLs can arise transiently in some patients with critical illness and SARS-CoV-2 infection (disappearing in a few weeks) [22]; as well as in other genetically predisposed patients they could trigger a "COVID-19-induced-APS-like-syndrome" or other autoimmune diseases [27][28]. Unfortunately, we could not perform a longer-term follow up.…”

Rheumatic Musculoskeletal Diseases and COVID-19 A Review of the First 6 Months of the Pandemic

“…Additionally, in a population of COVID-19 patients on the intensive care unit (ICU) 87% of the patients tested had a positive LAC ( 101 ). In contrast, antiphospholipid antibodies were commonly detected to a substantially lower degree with a preponderance of antibodies, which are not part of the official classification criteria for APS [IgA aCL; IgA ab2gp1; antibodies against phosphatidylserine/prothrombin (aPS/PT)] ( 102 – 104 ). Due to their disputed role in APS in general, the significance of these antibodies for COVID-19 is not yet clear.…”

“…The occurrence of APL in viral infection is a well-known phenomenon, however, in most cases these are of IgM or IgG aCL subtypes with an antigen recognition differing from classical APS and are less thrombogenic in nature ( 105 ); in COVID-19 the latter finding has also been observed, casting a doubt on the clinical relevance of the characterized antibodies ( 102 ). Nevertheless, the pathogenicity of APL from COVID-19 patients was proven elegantly in a pre-publication by Zuo et al, in which IgG aPS/PT antibodies led to NETosis in vitro , thus contributing to thrombus formation, and increased thrombus extension in vivo in a mouse model ( 104 ). This finding is corroborated by the observation that APL occur preferably in critically ill patients ( 103 ).…”

Bilateral Renal Artery Thrombosis in a Patient With COVID-19

“…The incidence of thrombotic disease in COVID-19 patients has been reportedly as high as 31% 6 . Zuo et al 7 even found that 52% of hospitalized COVID-19 patients had antiphospholipid antibodies. A rare condition seen in patients in a prothrombotic state is renal artery thrombosis.…”