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

Abstract

Introduction Besides distinctive respiratory and digestive hallmarks, COVID-19 has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “COVID-19 Associated Coagulopathy” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipid antibodies (aPLs) and viral infections has long been suggested. APLs are assessed for anti-phospholipid syndrome (APS) diagnosis, characterized by thrombocytopenia, thrombosis, and coagulopathy. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cell damage and thrombotic complications. Method We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti-annexin-V on two COVID-19 patient groups (early and late infection time), and a negative control group. IgG CIC analysis followed to evaluate inflammatory status, through a possible complement system activation. Results Our results showed low positive case percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, and 4.55%; in early infection group, late infection group, and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V immunoassays; and no IgG CIC positivity in any patient. Conclusions In conclusion, our data show a low aPL prevalence, likely excluding an involvement in the pathogenesis of CAC. Interestingly, IgG/IgM anti-prothrombin and anti-annexin-V positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “COVID-19-induced-APS-like-syndrome” in predisposed patients. Key Points•To our knowledge, anti-prothrombin (aPT) antibodies, anti-annexin-V antibodies and CICs in COVID-19 patients have not been reported in the scientific literature.•Lack of uniformity and the low percentage of aCL/aβ2GP1 positivity preclude a putative role in CAC pathogenesis.•IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V data show that distribution of positive case number increases in late infection patients, significantly in anti-annexin-V results, suggesting a possible role for these anti-phospholipid antibodies in disease course.•aPLs can arise transiently in some patients with critical illness and SARS-CoV-2 infection (disappearing in a few weeks), as well as in other genetically predisposed patients; they could trigger a “COVID-19-induced-APS-like-syndrome”.

Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19

“…Misdirected, or defective IFN I responses were reported as a key factor for inefficient immune responses in patients with COVID-19 ( 13) , ( 14) , (15). Moreover, exuberant B-cell responses were regularly found in COVID-19 ( 36) , (37), along with a high prevalence of antiphospholipid- (38), anti-Ro/La- (39)or anti-annexin-V-antibodies (40). It is noteworthy that PGRN-autoantibodies were first identified in plasma from patients with different forms of primary small vessel vasculitis.…”

Antiphospholipid Antibodies and Infection: Non Nova Sed Nove

“…From this perspective, as a limit to their analysis, they acknowledged that the LA test was not performed given lack of access to fresh plasma samples. When considering solid-phase aPL assays, methods that are in principle insensitive to anticoagulation and other confounding agents, the presence of aPL in patients with COVID-19 was recently reported in a handful of case reports and small cohorts of patients ( 7 , 8 ). While encouraging, these data are limited and its interpretation remains controversial, with some investigators proposing an important role of aPL in COVID-19 patients ( 7 , 8 ) while others suggesting no association between aPL and thrombotic events ( 9 , 10 ).…”

COVID-19 and Antiphospholipid Antibodies: Time for a Reality Check?

“…Few studies identified a statistical difference in thrombotic risk for aPL-positive versus aPL-negative patients or substantial aPL positivity in their thrombosis cohorts (LA only 45,50 ), 55,[57][58][59]63 whereas most did not. 31,[41][42][43][44][47][48][49]52,54,56,61,62,64,[69][70][71][72]74,75 There are many potential confounders to consider, and it is unlikely that such confounders were considered in all published comparisons. Thus, transient aPL positivity may develop in the sickest patients, who will then be most at risk of thrombosis, and therefore aPL may just reflect an association with, rather than be responsible for, the pathophysiological events.…”