Introduction
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity with the persistent presence of medium or high titer of antiphospholipid antibodies (aPLs). The golden standard for APS diagnosis is the 2006 APS classification criteria (Sydney criteria), where at least one of the clinical criteria, as well as one of laboratory criteria including lupus anticoagulant (LA), high level of anti-cardiolipin (aCL), anti-β2 glycoprotein-I (aβ2GPI) immunoglobulin isotype G (IgG) or M (IgM), should be present(1). Despite its wide use in clinical practice, patients could remain persistently negative for criteria aPLs yet show typical APS clinical manifestations (defined as seronegative APS, SNAPS(2)), and a broader range of diagnostic biomarkers are required (3). Apart from standard criteria, other extra-criteria clinical and laboratory features have been found associated with APS in numerous studies, which involves heart valve disease, thrombocytopenia, neurological manifestations, anti-CL or anti-β2GpI IgA, anti-phosphatidylserine–prothrombin (aPS/PT) complex, anti-annexin A5 antibodies (aAnxV), etc(4, 5). Besides APS diagnosis, evaluation of non-criteria aPLs could also contribute to prognosis and risk assessment for associated clinical manifestations(6).
More specifically, numerous studies had been conducted to investigate the diagnostic value of aCL/aβ2GpI IgA for APS, which received contradictory results(7). Nevertheless, testing of IgA had been recommended by guidelines when criterial aPLs remained negative(8). In addition, aAnxV and aPS/PT are receiving continuous attention in recent years. AnxV is a phospholipid-binding protein highly expressed in vascular endothelial cells. It could bind tightly to exposed anionic phospholipids and assemble into a shield, which may prevent phospholipid-dependent coagulation reaction(9, 10). In a systemic review, AnxV resistance has been observed and analyzed to have a higher prevalence in APS compared to disease controls(11) and has been reported to be linked with hypercoagulable state as well as obstetric complications in APS patients(12, 13). Furthermore, its anticoagulant activity was reduced by plasmas of patients with APS and thromboembolism(14), and loss of maternal aAnxV increased the chance of placental platelet thrombosis and fetal loss(15). However, other studies found no significant association between thrombotic event or adverse pregnancy manifestations(16, 17).
Prothrombin is another phospholipid-binding protein which forms complex and is often co-detected of antibodies together with phosphatidylserine (aPS/PT). An international multi-centre study confirmed the contribution of aPS/PT IgG in APS diagnosis IgG(18). Concerning its relation with clinical features such as thrombotic events or obstetric complications, conflicting results had been shown and confirmation is still needed(19, 20). Nevertheless, numerous studies have indicated a strong correlation between aPS/PT and LA(21, 22). In addition, a higher level of aPS/PT was observed to be associated with high-risk “triple positive” patients (LA+, aCL IgG and/or IgM +, and aβ2GPI IgG and/or IgM+)(23), and may also add value to identification of SNAPS(3).
Studies design, including detection method, patient stratification, population heterogeneity, etc., may lead to contradictory results in different studies. Regarding the Chinese population, a previous study indicated an increase of both IgG and IgM aAnxV in primary APS patients and APS associated with other diseases. Significant associations were also observed between IgG aANxV and thrombotic events(24). Additionally, assessment of the diagnostic performance of aPS/PT revealed a significant correlation between thrombotic events and pregnancy loss with IgG aPS/PT(25, 26), which was confirmed by a recent study(27). Concerning aCL/aβ2GpI IgA, a study recently conducted by us in a large Chinese population revealed little added diagnostic value(28). Few studies have explored all of the above extra-criteria autoantibodies in the same patient groups, and their relations with more detailed clinical manifestations still need investigation. This study focused on evaluating the additive diagnostic value of aCL/aβ2GpI IgA, IgG and IgM for aANxV or aPS/PT to standard aPLs in a Chinese cohort. Correlation with clinical features including thrombotic events, obstetric complications, as well as microangiopathy was also explored.