Page 52 - Haematologica March 2020

P. Pignatelli et al.
cardiolipin); 4) prothrombin (forming complex with PS – anti-PS/PT); and 5) the anticoagulant protein Annexin A5 (Table 2). In addition, the IgA isotype aβ2GPI is under investigation in APS and SN-APS patients.
A collaborative USA/UK study analyzed a comprehen- sive panel of ‘non-criteria’ aPL tests in a series of 175 con- secutive patients matching the criteria for APS and 68 SN- APS patients with clinical manifestations suggestive of APS but having negative serology. The Authors found that one-third of the ‘seronegative’ sera gave positive results.24 The study concluded that patients with clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria bio- markers.24
A recent study evidenced that positivity for the extra- criteria aPL was <1% in SN-APS (thrombotic or obstetric); however, the lack of clear inclusion and exclusion criteria does not allow a precise estimation of the prevalence to be made.25
Similarly, non-criteria antibodies were detected in 18.8% of SN-APS patients also in a Chinese cohort com- posed of APS and patients with only clinical criteria for APS.26 This is also confirmed in obstetric SN-APS patients, in whom 68% were positive for non-conventional aPL.27
Here we will provide an overview of current evidence on the most studied non-criteria aPL that, although not validated in large cohort studies, may have a potential role in the pathogenesis of APS.
IgA antibody isotype anti-β 2 glycoprotein-I and anticardiolipin antibodies
There is a growing body of evidence to suggest a poten- tial usefulness of IgA in the context of APS.28 Very recent evidence suggested that, while IgG/M isotypes recognize an epitope in domain 1, the epitopes recognized by IgA are the domains 3, 4 and 5.29 However, as reported by the 13th International Congress on Antiphospholipid Antibodies, testing for IgA-aβ2GPI should be considered only in patients negative for IgG and IgM isotypes with APS symptoms.30
Studies investigating the prevalence of IgA aPL reported
a variable prevalence ranging from 14% to 72% according
to different reports;28 however, these studies have a retro-
spective design, used different assays to measure IgA aPL,
and used different cut-off values to define aPL positivi- ty.31,32
A large study including 5,892 patients (803 with SLE and 5,089 from the Antiphospholipid Standardization Laboratory sent for evaluation for APS) found that IgA aβ2GPI isotype was positive in 255 (4.3%) patients, in 198 cases in association with other aPL, while only aPL was detectable in 57.33 Isolated IgA aβ2GPI positivity was asso- ciated with an increased risk of arterial thrombosis (P<0.001), venous thrombosis (P=0.015), and all thrombo- sis (P<0.001).33
A second study evaluated, in addition to IgM and IgG, the positivity and predictivity of IgA aCL and IgA aβ2GPI in 430 patients: 111 with APS, 119 with SLE, and 200 healthy controls.34 Positivity for IgA aCL was 38%; IgA aβ2GPI was 46% in patients with APS. All three antibody isotypes (IgM, IgG and IgA) were significantly associated with a diagnosis of APS, with high specificity but not good sensitivity, based on receiver operating characteristic (ROC) analysis. Looking at likely hazard ratios, the IgA aβ2GPI (HR 33.9, 95%CI: 10.5-109.5) was similarly asso-
ciated to APS as compared to IgG aβ2GPI (HR 33.4, 95%CI: 13.0-86.1), but showed a higher association com- pared to IgM aβ2GPI (HR 9.2, 95%CI: 4.6-18.4) and was associated with thrombotic but not obstetric complica- tions in patients with APS.34
Indeed, IgA aβ2GPI levels seem to be associated with thrombotic events in patients without other aPL.33,35 Thus, a case-control study including 244 asymptomatic patients screened for aPL and positive only for IgA aβ2GPI and 221 negative patients followed for five years showed that the presence of IgA aβ2GPI was associated with an increased risk for developing clinical thrombotic APS events (OR 5.15; P<0.001).36
Although attractive, these data were not confirmed by another study evaluating the presence of IgA aβ2GPI anti- bodies in SN-APS.25
Based on this evidence, it is not clear whether testing for IgA aCL and IgA aβ2GPI antibodies in addition to the rou- tine tests may improve thrombotic risk stratification. Thus, the use of IgA antibodies to identify a SN-APS needs to be further investigated.
Antibodies to phosphatidylethanolamine
Phosphatidylethanolamine is mainly found in the inner
leaflets of plasma membranes and contributes to 20-50%
of total phospholipids. It works as an anticoagulant by
enhancing activated protein C (APC) activity. Other
investigators have demonstrated that PE inhibits coagula-
tion activity interfering with the factor Xa-prothrombin
37 system.
Several studies reported that antibodies against PE (aPE) are significantly associated with major clinical events such as fetal loss and/or thrombosis, and are mainly pres- ent in the absence of the laboratory criteria of APS. Bérard et al. showed that aPE were the only aPL found in 6 of 34 patients suffering from thrombotic events and with a neg- ative screening for antibodies to anionic phospholipids, including LA.38 A second study focused on patients with unexplained thrombosis and no criteria for APS. Thus, in 98 patients with unexplained thrombosis, 142 with thrombophilia, 67 with APS, 75 with hereditary hemo- static defects and 110 without thrombosis, the authors found that aPE prevalence was significantly higher both in patients with APS (43%; P<0.0001) and in those with unexplained thrombosis (18%; P=0.001) compared to patients without thrombosis.39 Subsequently, in a large multicenter study including 317 patients with deep venous thrombosis and 52 with arterial events, aPE were found in 15% of the thrombotic patients, most of whom were only positive for aPL.40 Some interesting data were also reported regarding the association between aPE and obstetric complications. Gris et al. measured various aPL in a large cohort of 518 women with unexplained or explained early fetal losses and a control group of healthy mothers. IgM-aPE were found to be independent risk fac- tors for unexplained early fetal loss.41
A retrospective study on 228 SN-APS demonstrated a positivity for aPE in 10% of the patients.42 In contrast, a recent study on a Chinese population composed of APS and patients with only clinical criteria for APS failed to demonstrate any aPE positivity in SN-APS.26
The above reported results suggest that aPE could be considered as markers of a variant of APS when they are associated with thrombosis and a potential tool to define the SN-APS subjects.
566
haematologica | 2020; 105(3)