Is Lupus Anticoagulant a Significant Feature of COVID-19? A Critical Appraisal of the Literature

Abstract

The term “lupus anticoagulant (LA)” identifies a form of antiphospholipid antibodies (aPLs) causing prolongation of clotting tests in a phospholipid concentration-dependent manner. LA is one of the laboratory criteria identified in patients with antiphospholipid (antibody) syndrome (APS). The presence of LA in patients with APS represents a significant risk factor for both thrombosis and pregnancy morbidity. There have been several reports of similarities between some of the pathophysiological features of COVID-19 and APS, in particular the most severe form, catastrophic APS. There have also been many reports identifying various aPLs, including LA, in COVID-19 patients. Accordingly, a very pertinent question arises: “Is LA a feature of COVID-19 pathology?” In this review, we critically appraise the literature to help answer this question. We conclude that LA positivity is a feature of COVID-19, at least in some patients, and potentially those who are the sickest or have the most severe infection. However, many publications have failed to appropriately consider the many confounders to LA identification, being assessed using clot-based assays such as the dilute Russell viper venom time, the activated partial thromboplastin time (aPTT), and the silica clotting time. First, most patients hospitalized with COVID-19 are placed on anticoagulant therapy, and those with prior histories of thrombosis would possibly present to hospital already on anticoagulant therapy. All anticoagulants, including vitamin K antagonists, heparin (both unfractionated heparin and low-molecular-weight heparin), and direct oral anticoagulants affect these clot-based assays. Second, C-reactive protein (CRP) is highly elevated in COVID-19 patients, and also associated with severity. CRP can also lead to false-positive LA, particularly with the aPTT assay. Third, persistence of aPL positivity (including LA) is required to identify APS. Fourth, those at greatest risk of thrombosis due to aPL are those with highest titers or multiple positivity. Most publications either did not identify anticoagulation and/or CRP in their COVID-19 cohorts or did not seem to account for these as possible confounders for LA detection. Most publications did not assess for aPL persistence, and where persistence was checked, LA appeared to represent transient aPL. Finally, high titer aPL or multiple aPL positivity were in the minority of COVID-19 presentations. Thus, at least some of the reported LAs associated with COVID-19 are likely to be false positives, and the relationship between the detected aPL/LA and COVID-19-associated coagulopathy remains to be resolved using larger and better studies.

The Impact of SARS-CoV-2 Infection on Blood Coagulation and Fibrinolytic Pathways: A Review of Prothrombotic Changes Caused by COVID-19

“…[73][74][75] A role for lupus anticoagulant and antiphospholipid antibodies has been suggested for pathogenesis of COVID-19-associated coagulopathy. 52,[76][77][78][79][80] In severely infected patients, immobility under conditions of quarantine or hospitalization is another predisposing factor of thrombosis. 81,82 Modification of the equilibrium between clot formation and degradation in favor of hypercoagulability and hypofibrinolysis, impaired endothelial function, platelet hyperactivation, and excessive immune response are emerging as major contributors to the thrombotic complications.…”

COVID-19 Induced Coagulopathy (CIC): Thrombotic Manifestations of Viral Infection

“… 73 This finding is significant in the light of COVID-19 as formation of antiphospholipid antibodies, like anti-β2 glycoprotein IgG antibodies, are associated with thrombosis in patients with COVID-19. 74 A cohort studied from France has demonstrated that a large percent of severe COVID-19 patients exhibits a detectable lupus anticoagulant. 75 However, it still remains to be established whether the presence of antiphospholipid antibodies in SARS- CoV-2 patients plays a role in infection-associated thrombosis or represents merely an association.…”

COVID‐19 coagulopathies: Human blood proteins mimic SARS‐CoV‐2 virus, vaccine proteins and bacterial co‐infections inducing autoimmunity

“…The obvious conclusion, which has been reached previously in studies of other autoimmune diseases, is that molecular mimicry may be necessary to induce auto-reactive B and T cells but is clearly not sufficient to induce autoimmune disease. [22,[83][84][85][86] This point is essential for understanding how many hospitalized COVID-19 patients are found transiently to express anti-phospholipid antibodies (aPL), anti-PL4, b2GPI, and other blood cell antibodies [7,[21][22][23][24][25][26][27]87,88] but only a fraction of these develop coagulopathies [25,30,87,88] and also why SARS-…”

“…The obvious conclusion, which has been reached previously in studies of other autoimmune diseases, is that molecular mimicry may be necessary to induce auto‐reactive B and T cells but is clearly not sufficient to induce autoimmune disease . [ 22 , 83 , 84 , 85 , 86 ] This point is essential for understanding how many hospitalized COVID‐19 patients are found transiently to express anti‐phospholipid antibodies (aPL), anti‐PL4, b2GPI, and other blood cell antibodies [ 7 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 87 , 88 ] but only a fraction of these develop coagulopathies [ 25 , 30 , 87 , 88 ] and also why SARS‐CoV‐2 vaccines (to be discussed in “Implications of bacterial and viral coinfections for understanding vaccine‐induced coagulopathies”) often induce autoantibodies but rarely autoimmune disease. Mimicry may frequently induce autoantibody production but rarely leads to overt autoimmune disease or, alternatively, mimics may be perceived by the immune system as “self” antigens resulting in T cell tolerance.…”

“…Autoantibodies directed at phospholipids and phospholipid‐binding proteins have been identified in the majority of COVID‐19 patients affected by coagulopathies but rarely in mild cases [ 21 ] ; these include lupus anticoagulant, antibodies against cardiolipin (CL), and antibodies against the cardiolipin‐binding proteins phosphatidylserine/prothrombin (Factor 2) and beta‐2 glycoprotein I (β2GPI). [ 7 , 21 , 22 , 23 , 24 ] However, these antibodies are also found transiently in many COVID‐19 patients who do not develop coagulopathies, calling their causal relationship into question, [ 25 ] a point of great significance to be discussed below. Autoantibodies against platelet factor 4 (PF4), a platelet activating factor that binds heparin (as well as bacterial antigens), have also been documented in thrombotic COVID‐19 patients [ 26 , 27 ] as well as in vaccinees who have developed thrombotic thrombocytopenia [ 28 , 29 ] but, again, are found in many patients who do have not developed clinically‐evident coagulopathies.…”