Page 54 - Haematologica March 2020

P. Pignatelli et al.
potentially used as confirmatory diagnostic markers and as indicators of the risk of thrombosis. Recently, the pres- ence of IgG and IgM aPS/PT was also detected in 9 of 17 SN-APS.25 Similar, and even stronger evidence was provid- ed by two retrospective studies on SN-APS patients that found approximately 50% of subjects were positive for aPS/PT.61,62 Nonetheless, further studies must be undertak- en before these antibodies can be included in the diagnos- tic criteria of SN-APS.
Annexin A5 antibody
Annexin A5 is a glycoprotein that binds to negative phospholipids such as PS. It has been proposed that annexin A5 forms a protective anticoagulant shield on vas- cular endothelial cells and that aβ2GPI antibodies in com- plex with ß2GPI may disturb the shield and hence predis- pose to thrombosis. Due to this marked heterogeneity, it remains controversial whether anti-annexin A5 antibodies (aANX) are associated with clinical manifestations. In a comparison of 112 APS patients with 40 healthy controls, Singh et al. found aANX positivity in 69 APS and in only 3 controls.63 On the contrary, de Laat et al. found no associ- ation between aANX and history of thrombosis in 198 patients with primary APS, SLE or lupus-like disease.64 aANX was also found to be predictive for fetal loss in a study of three groups (total 518 women) of patients with unexplained primary recurrent early fetal loss, patients with explained episodes, and mothers with no previous obstetric incident, respectively.41
Annexin A5 resistance was proposed as a mechanism for APS. The annexin A5 resistance (A5R) assay identifies patients with an antibody-mediated disruption of annexin A5 on endothelial surfaces. This is demonstrated by the resistance to the annexin A5 anticoagulant effects (i.e. annexin A5 resistance) in vitro. This test was validated in 750 patients with a history of thrombosis, pregnancy complications, and controls.65 The authors found a reduc- tion in A5 anticoagulant ratios in aPL antibody-positive patients with thrombosis and/or pregnancy complications compared with aPL antibody-negative patients and con- trols. This suggests that reduced A5R could identify patients with a propensity for thrombosis or pregnancy complications.65
Very recently, a case report described the presence of multiple annexin autoantibodies in a patient with recur- rent miscarriages, fulminant stroke, and SN-APS.66 Hence, although attractive, the evaluation of aANX or A5R in clinical practice for the management of SN-APS requires larger prospective studies.
From risk assessment to antithrombotic treatment
The first step in the assessment of thrombotic risk in APS and SN-APS patients is represented by antibody char- acterization and evaluation of cardiovascular risk factors. Thus, the thrombotic risk varies according to aPL positiv- ity and antibody titers. For example, a retrospective study on 3,088 APS patients demonstrated that single positivity for aCL or aβ2GPI was associated with low risk of event [odds ratio (OR) <5], while LA positivity alone conferred a medium risk of event (OR 5-9); this risk increased in
patients with double or triple positivity (OR >9).67
Some scores have also been proposed to stratify the risk of events in APS patients; the APL Score has no clinical items and is based exclusively on the antibody titers (Table 3).68 An aPL score of ≥30 was an independent risk factor for thrombosis (hazard ratio 3.144, 95%CI: 1.383-
7.150; P=0.006) in patients with autoimmune diseases.69 Another score is the Global Anti-Phospholipid Syndrome Score (GAPSS), which was developed in a cross-sectional study on a cohort of 211 patients with SLE. The score includes traditional cardiovascular risk factors such as hypertension and hyperlipidemia and the presence / absence of aPL70 (Table 3). Of note, both scores also
include one non-criteria aPL, such as aPS/PT.
These scores, although potentially useful in clinical
practice, require further prognostic validation.
The thrombotic risk stratification is more challenging in patients with SN-APS. It is important to identify and char- acterize the presence of non-criteria aPL, as they seem to be associated with different thrombotic complications (Table 4). Thus, aPS/PT and antibodies to vimentin/CL complex increase the risk of arterial thrombosis, while pregnancy-related complications are associated with the
presence of PE, PA, PS and PI antibodies (Table 4).
Table 3. Scores for risk stratification in antiphospholipid syndrome.
APL Score - ITEMS
APTT mixing >49 sec
CONFIRMATION TEST, ratio
KCTmixing >29sec. DRVVT mixing CONFIRMATION TEST, ratio
IgG ACL, GPL.
High titers Medium/low titers
IgG aPS/PT Hightiters >10U Medium/low titers
IgMaPS/PT >9.2U
GAPSS
CLINICAL
LABORATORY
CUT-OFF
5
POINTS
IgM ACL, MPL
>1.3 2
>1.1 1 8
>45 sec. 4
>1.3 2 >1.1 1
>30 20
>18.5 4 >7 2
20
>2.2 U 6 >6 U 1
20
>2 U 13 8
IgG Anti-β2GPI Hightiters >15U Medium/low titers
IgM anti-β2GPI
Item
Points
Hyperlipidemia 3 Arterial hypertension 1
aCL IgG/IgM 5 Anti β2GPI IgG/IgM 4 aPS/PT IgG/IgM 3 LA 4
Total 20
APTT: activated partial thromboplastin time; KCT: kaolin clotting time; dRVVT: dilute Russell’s viper venom time; aCL: anticardiolipin antibodies; β2GPI: β2-glicoprotein I; aPS/PT: phosphatidylserine prothrombin complex; aPL: antiphospholipid antibody; GPL: IgG phospholipid units; MPL: IgM phospholipid units; LA: lupus anticoagulant.
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