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disease, and recurrent venous thromboembolism (VTE) in patients with systemic lupus erythematosus (SLE) and serum positivity for anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC).3 Recently, Duarte-Garcia et al. found an annual incidence of APS of 2.1 per 100,000 per year, with a prevalence of 50 APS patients per 100,000, equally distributed between males and females.4
A more clinically challenging scenario is represented by patients with a clinical history characterized by episodes of thrombosis (especially if recurrent) without cardiovas- cular risk factors, and more in general, in absence of an identifiable cause of thrombosis, suggestive of a throm- bophilic condition, such as APS, but in absence of any pos- itivity of aPL. For these patients, the definition of seroneg- ative APS (SN-APS) was proposed.5 In the context of SN- APS, several non-criteria aPL have been investigated with divergent results.
In this review, we will discuss criteria for defining the SN-APS, the new potential non-criteria antibodies implied in SN-APS and its clinical management.
Antiphospholipid syndrome
Diagnosis of antiphospholipid syndrome
Antiphospholipid syndrome is a systemic autoimmune disorder characterized by arterial and venous thrombotic manifestations and/or pregnancy morbidity in patients with persistently high levels of aPL.6 APS may be classified as primary or secondary, the latter being present in 30- 40% of patients with SLE.7 The 2006 Sapporo criteria are those currently recommended to diagnose APS.8 They include the presence of one clinical criterion and high val- ues of at least one aPL among IgM/IgG aCL in serum or
Seronegative antiphospholipid syndrome
plasma, IgM/IgG anti-β2 glycoprotein-I (aβ2GPI) antibod- ies in serum or plasma, and LAC in plasma. Clinical and laboratory criteria are listed in Figure 1.7
The persistence of high antibody values should be test- ed at least 12 weeks apart, and, in addition, the antibody titers should be dosed at least 12 weeks after the throm- botic event but no more than five years afterwards.7,8 Of note, not all patients remain positive over time, and fac- tors associated with persistence of aPL positivity are not well known, but may include inflammation and oxidative stress.9
Subjects positive for aPL have a low risk of developing thrombotic events (<1%/year), but after a first episode, the risk of recurrence increases by 10-67%.10 This finding was supported by a recent study performed by Kearon et al.,11 in which 307 patients with a first unprovoked VTE were tested for aPL. In this study, the persistence of aPL on ≥2 occasions was associated with an increased risk of recurrent thrombosis, despite negative D-Dimer values (HR 4.5: 95%CI: 1.5-13.0; P=0.006).11
Clinical presentation of antiphospholipid syndrome
Antiphospholipid syndrome can be broadly classified in venous, arterial or obstetric APS, which are, however, not mutually exclusive. In a retrospective analysis of a cohort of 160 patients with a definite APS, VTE was the most common manifestation (47.5%), followed by arterial thromboembolism (43.1%), while obstetrical complica- tions was found in only 9.7% of patients; in this study, catastrophic APS (C-APS) represented 2.5% of the cases.12
Stroke and transient ischemic attack often involve APS patients, but also lower limb ischemia and myocardial infarction can occur.12 In this context, the relationship between aPL and myocardial infarction seems to be bidi-
Figure 1. Summary of criteria for antiphospholipid syndrome (APS) diagnosis according to Sapporo criteria. GPL: glycopeptidolipid; MPL: monophosphoryl lipid A.
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