Circulating Immune Complexes of IgA Bound to Beta 2 Glycoprotein are Strongly Associated with the Occurrence of Acute Thrombotic Events

Abstract

Aim: Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and/or gestational morbidity in patients with antiphospholipid autoantibodies (aPL). Over recent years, IgA anti-beta2-glycoprotein I (B2GPI) antibodies (IgA aB2GPI) have reached similar clinical relevance as IgG or IgM isotypes. We recently described the presence of immune complexes of IgA bounded to B2GPI (B2A-CIC) in the blood of patients with antecedents of APS symptomalology. However, B2A-CIC's clinical associations with thrombotic events (TEV) have not been described yet.Methods: A total of 145 individuals who were isolate positive for IgA aB2GPI were studied: 50 controls without any APS antecedent, 22 patients with recent TEV (Group-1), and 73 patients with antecedents of old TEV (Group-2).Results: Mean B2A-CIC levels and prevalence in Group-1 were 29.6 ± 4.1 AU and 81.8%, respectively, and were significantly higher than those of Group-2 and controls (p < 0.001). In a multivariable analysis, positivity of B2A-CIC was an independent variable for acute thrombosis with a 22.7 odd ratio (confidence interval 5.1 –101.6, 95%, p < 0.001). Levels of B2A-CIC dropped significantly two months after the TEV. B2A-CIC positive patients had lower platelet levels than B2A-CIC-negative patients (p < 0.001) and more prevalence of thrombocytopenia (p < 0.019). Group-1 had no significant differences in C3 and C4 levels compared with other groups.Conclusion: B2A-CIC is strongly associated with acute TEV. Patients who did not develop thrombosis and were B2A-CIC positive had lower platelet levels, which suggest a hypercoagulable state. This mechanism is unrelated to complement-fixing aPL. B2A-CIC could potentially select IgA aB2GPI-positive patients at risk of developing a thrombotic event.

Pretransplant IgA-Anti-Beta 2 Glycoprotein I Antibodies As a Predictor of Early Graft Thrombosis after Renal Transplantation in the Clinical Practice: A Multicenter and Prospective Study

“…Since not all IgA-aB2GP1 positive patients develop thrombotic complications ( 18 ), the next step should be to find a marker that would identify the patients with a higher risk of thrombosis among those are IgA-aB2GP1 positive ( 28 ). We recently described that the presence of circulating immune complexes (CIC) of IgA bounded to B2GP1 was associated with occurrence of recent thrombotic events ( 29 ) and are a predictor of acute thrombotic events, including graft thrombosis after renal transplantation ( 30 ). However, we have not been able to detect the presence of CIC as, unfortunately, although the conditions of preservation of serum samples were adequate for the determination of IgA-aB2GP1, these conditions were not consistent with the maintenance of stable CIC and they had not been reliably determined in the present group of patients in some centers.…”

Immune Complexes of Beta-2-Glycoprotein I and IgA Antiphospholipid Antibodies Identify Patients With Elevated Risk of Thrombosis and Early Mortality After Heart Transplantation

“…The presence of CIC would indicate that the aPL are of high affinity and therefore more pathogenic (22). However, this hypothesis does not explain the observation that the presence of CICs vary throughout the evolution of the disease while the antibody titers remain stable (23).…”

“…Its study has allowed us to recognize that there is no simple mechanism by which obstetric complications are triggered in the pathogenesis of PHC but rather diverse pathologic pathways (TLR, NADPHox, LRP8) are being linked to aPL (39,40). In this way, a new pathophysiological pathway of APL is studied through the presence of immune complexes of B2GP1 and aPL (IgG, IgM, or IgA isotype) and its association with acute events (23) and with extra-criteria manifestations of APS (41).…”

“…Although the presence of IgA aB2GP1 identifies many patients at risk of developing thrombotic events after kidney transplantation, its predictive value is too low to justify applying preventive treatments to patients who express this biomarker. Searching for new biomarkers that would allow a better identification of the population at risk, circulating immune complexes (CIC) of IgA bound to B2GP1 (B2A-CIC) were described in the blood of patients with APS symptomatology (22) and its presence was associated with the occurrence of acute thrombotic events (23).…”

Presence of Immune Complexes of IgG/IgM Bound to B2-glycoprotein I Is Associated With Non-criteria Clinical Manifestations in Patients With Antiphospholipid Syndrome

“…Currently, several authors have been emphasizing the need for new APS biomarkers to improve sensitivity and specificity in the diagnosis of the syndrome ( 19 , 20 ). Presence of immune complexes of IgA aB2GPI antibodies bound to B2GPI (B2A-CIC) has been described recently in the blood of patients with clinical thrombotic manifestations for APS ( 21 , 22 ). The prevalence of B2A-CIC has been found to be significantly higher in patients with acute thrombotic event ( 22 ).…”