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.