Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombotic and obstetric complications in association with the persistent positivity of antiphospholipid antibodies (aPL), which include anticardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (anti-β2GPI), and lupus anticoagulant (LA) [[1], [2], [3]]. These antibodies increase thrombotic risk through various mechanisms, ranging from direct activation of coagulation factors to endothelial cell activation and the release of proinflammatory cytokines [1,[4], [5], [6]].

Thrombosis in APS most commonly affects the deep veins of the lower extremities and cerebral arteries, but it may also involve atypical sites such as visceral arteries, cerebral venous sinuses, and the microvasculature of the skin, eyes, heart, lungs, kidneys, and other organs [5]. Risk is particularly high in patients with triple positivity (positive for LA, aCL, and anti-β2GPI), with a reported 10-year thrombotic event rate of 44%, which doubles in the absence of anticoagulant therapy [7]. Obstetric manifestations primarily include recurrent miscarriage, fetal loss after the 10th week of gestation, and severe preeclampsia or placental insufficiency leading to preterm birth, the latter being among the most specific obstetric clinical manifestation for APS [8].

Although the roles of LA, aCL, and anti-β2GPI are well established, additional aPLs have been described, including antibodies against domain I of β2GPI, antiphosphatidylserine/prothrombin antibodies (anti-PS/PT), antibodies targeting lysobisphosphatidic acid/endothelial protein C receptor (anti-LBPA/EPCR), anti-β2GPI/HLA class II complex antibodies, and antibodies against neutrophil extracellular traps. However, their role in immunothrombosis remains unclear, and none of these antibodies currently has a defined role in clinical practice [6].

Classification criteria for APS have evolved significantly since their initial formulation [9], reflecting advances in the understanding and diagnosis of this complex syndrome. The 2006 Sydney criteria were based on categorical definitions with clearly delineated clinical and laboratory findings [10]. In contrast, the recently published 2023 ACR/EULAR classification criteria adopt a weighted point-based system across clinical, imaging and laboratory domains [11], aiming to improve diagnostic precision and standardization [12,13]. The 2023 ACR/EULAR criteria prioritize specificity, achieving a rate of 99% compared to 86% with the 2006 Sydney criteria [11,14,15]. However, this increased specificity in accompanied by a reduction in sensitivity, particularly in cases of obstetric APS, where the significant exclusion of patients may hinder the development of new therapies due to challenges in clinical trial recruitment [12,[16], [17], [18], [19]].

The 2006 criteria required at least one clinical and one laboratory manifestation for classification, emphasizing major thrombotic and obstetric events and requiring the presence of LA, aCL, or anti-β2GPI detected on two occasions at least 12 weeks apart [10]. By contrast, the 2023 ACR/EULAR criteria introduce more specific definitions and include new clinical domains such as microvascular involvement, valvular disease, and thrombocytopenia [11]. These changes reflect the broader spectrum of APS manifestations and assign diagnostic weight according to the strength of supporting evidence [16,20]. Key updates in the 2023 laboratory criteria include a weighted stratification of LA, aCL, and anti-β2GPI. Notably, isolated LA positivity and IgM isotypes of aCL and anti-β2GPI contribute only one point each in the new system. Thus, none of these findings alone is sufficient for APS classification in the absence of additional criteria [21].

This immunologic thrombophilia is estimated to be present in up to 5% of the general population [22]. Several studies have reported that individuals positive for aPL have an increased incidence of thrombotic events, even in the absence of previous clinical symptoms [22,23]. Persistent positivity is associated with a higher risk of arterial and venous thrombosis, especially in triple-positive patients [[23], [24], [25]] or in the presence of other risk factors [26]. However, other studies have not demonstrated an increased thrombotic risk [27]. Moreover, no additional serological thrombotic risk factors have been identified beyond triple positivity [25,28]. Given these conflicting findings, it remains unclear whether aPL carriage is associated with an increased risk of developing clinical manifestations of APS.

In addition, the recent changes in classification criteria have introduced two substantial modifications. First, the current risk stratification has abandoned the distinction between aCL and anti-β2GPI in favor of categorization by isotype (IgM vs IgG) and antibody titer. The risk profile of patients according to this new classification remains unknown, especially in individuals positive for aPL of IgM isotypes and isolated LA, both of which are no longer considered classifiable. Second, it is unclear whether these patients can develop microvascular thrombotic manifestations, which have only recently been incorporated into the classification, as well as thrombocytopenia and cardiac valve disease. Moreover, the proposed point-based classification system was designed with the aim of associating higher clinical domain scores with an increased risk of thrombotic or obstetric events; however, this risk-stratification feature of the classification has not yet been formally validated.

The primary objectives of this study were to report the incidence of clinical manifestations in individuals positive for aPL during follow-up, and to determine the time to onset of such manifestations. The secondary objectives were to evaluate the impact of specific serological domains on the development of clinical features, and to assess whether the updated 2023 ACR/EULAR scoring system effectively stratifies the risk or predicts clinical progression.