Antibodies Directed Against the Domain 1 of Beta2-Glicoprotein 1 May be Associated with Secondary Antiphospholipid Syndrome

Background: The diagnosis of antiphospholipid syndrome (APS) is based on the persistent positivity of lupus anticoagulant (LA), IgM or IgG anticardiolipin (aCL) or IgG anti-β2 glicoprotein 1 (aβ2GP1) antibodies in patients plasma. Particularly, the role of antibodies directed against the domain 1 of β2GP1 (aβ2GP1-D1) has been described as relevant for the mechanism of immunopathogenesis in APS. However, the role of the aβ2GP1-D1 antibodies in clinical diagnosis and management of APS has not been established.  

Aim: The aim of this study was to evaluated the association of the presence of aβ2GP1-D1 antibodies with the clinical course of patients with thrombotic APS. 

Patients and methods: Patients previously diagnosed with thrombotic APS were consecutively selected for the study, from December 2013 to July 2014, in the Hemostasis Clinic of the Hematology and Hemotherapy Center of the University of Campinas. Demographic features and clinical conditions were recorded at the inclusion and during the follow-up. The clinical parameters analyzed were APS etiology (primary versus secondary to systemic autoimmune diseases), vascular bed of the thrombosis, history of multiple thrombosis, concomitant obstetrical morbidity, the presence of antinuclear antibodies (ANA) and the profile of the antiphospholipid antibodies. Anti-β2GP1-D1 antibodies were determined in patients plasma by chemiluminescence  (BioFlash/AcuStar®, Barcelona, ES). Exact Fisher test and logistic regression were performed for statistical analysis. P < 0.05 were considered statistical significant. 

Results: Eight-five patients were included in the study, all patients presented venous or arterial thrombosis. The antibodies distribution among patients was: 80% LA positive, 50% aCL positive, 54% aβ2GP1 positive and 26% triple positive. Twenty-one patients (25%) tested positive for aβ2GP1-D1, 94% of them had positive aβ2GP1 antibody, previously detected at diagnosis. The presence of aβ2GP1-D1 was not associated with age or gender. Detected clinical conditions related to APS severity, such as thrombosis recurrence, concomitant obstetrical and vascular morbidity and triple positive antiphospholipid antibodies were evaluated. The positivity for aβ2GPI-DI antibodies was not associated with thrombosis recurrence (OR=1.0, 95%CI=0.37-2.71,P=1.0), concomitant obstetrical and vascular morbidity (OR=1.5, 95%CI=0.33-7.34, P=0.58), or triple positive antibodies (OR=2.79 , 95%CI=0.76 - 8.84, P=0.13). Anti-β2GP1-D1 antibodies were associated with the diagnosis of systemic autoimmune disease, in particular with lupus, (OR= 3.49 , 95%CI=1.25-9.76, P=0.01) and with positive ANA test (OR= 3.3, 95%CI=1.08-10.1, P=0.03). 

Conclusion: In this study, aβ2GPI-DI antibody was detected mainly in patients who had already tested positive for aβ2GP1 antibody, so it is possible that aβ2GP1-D1 assay may not provide additional sensibility to the diagnosis of APS. However, our results also suggested that the presence of aβ2GP1-D1 antibody might be associated to the diagnosis of secondary APS. The diagnosis of primary APS is based on the exclusion of systemic autoimmune diseases and there are no current laboratory parameters that discriminate between primary and secondary APS. Besides the laboratory criteria for lupus diagnosis, there may be overlapping of the antibodies and hematological features between APS and lupus. Furthermore, after the diagnosis of primary APS, it may take long time of follow-up to detect the underlying autoimmune disease. Therefore, if our findings are confirmed, aβ2GP1-D1 assays may play a role as a laboratory tool for the differential diagnosis between primary and secondary APS.