Department of Physiology, Favaloro University, Division of Hematology, Thrombosis and Haemostasis, University Hospital, Favaloro Foundation, Buenos Aires, Argentina
Received date: July 25, 2013; Accepted date: July 27, 2013; Published date: July 29, 2013
Citation: Forastiero R (2013) Trends in the Antiphospholipid Syndrome Criteria. J Hematol Thromb Dis 1:e103 doi: 10.4172/2329-8790.1000e103
Copyright: © 2013 Forastiero R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The Antiphospholipid Syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of either venous or arterial thrombosis in different vascular beds, and/or recurrent miscarriages in the first trimester, or fetal death in the second or third trimesters, or severe pre-eclampsia requiring delivery of a premature infant before 34 weeks of gestation. Cerebrovascular infarction is the most common clinical feature within the arterial circulation, whereas lower limb deep venous thrombosis and pulmonary embolism are the main locations within the venous circulation . The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS. The positivity for at least one aPL test: lupus anticoagulant (LA) by clotting assays and/or IgG/IgM anticardiolipin (aCL) and/ or IgG/IgM anti-β2 glycoprotein I antibodies (aβ2GPI) by Enzyme-Linked Immunosorbent (ELISA) assays must be detected. aPL must be found on two or more occasions at least 12 weeks apart. In the 2006 updated APS criteria it is advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL present alone; IIc, aβ2GPI present alone .
aPL can occur in isolation or in association with other autoimmune conditions, particularly Systemic Lupus Erythematosus (SLE). The catastrophic APS is a rare variant of APS characterized by microthrombi in multiple organs. It is commonly triggered by several factors including infection, trauma, surgery, and the withdrawal of oral anticoagulation. Less than 1% of patients with the APS develop the catastrophic complication but it has a life-threatening clinical course. Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, factor VIII inhibitor, or prothrombin deficiency is present.
According to the 2006 criteria for the classification of APS, a single positivity of any of the three aPL tests mentioned before fulfill the serologic criteria. More recently, however, several studies have shown that the risk of thrombosis increases with the number of positive tests in APS patients and also in asymptomatic carriers of persistent aPL. The concept of triple positivity (LA/aCL/aβ2GPI) conferring a higher risk for thromboembolic events and pregnancy losses has been proposed taking into account several retrospective and prospective studies. One recent study showed that this combination of aPL retrospectively increased the risk for thrombotic recurrences in patients without SLE . With respect to thrombosis, triple aPL positivity conferred an odds ratio (OR) that ranges from 5.2 to 33.3. In contrast, none of the other combinations of aPL results reached statistical significance. A large, prospective multicentre study on triple aPL-positive APS patients reported a cumulative incidence of thrombosis of 12.2, 26.1, and 44.2% after 1, 5, and 10 years of follow-up, respectively . In addition, it was reported that the annual incidence of the first thrombotic event was 5.3% per year among 104 triple aPL-positive patients with no history of thrombosis (aPL carriers) followed-up for a mean of 4.5 years . Multivariate analysis also showed that male sex and other risk factors for VTE were independent predictors of a first thrombotic event. Thus, the likely occurrence of a first thrombotic event in carriers of a high-risk aPL-profile is considerable and is more frequent among male subjects and in the presence of additional risk factors for VTE. The risk of recurrent thrombosis is even higher in triple aPL-positive patients who were not on oral anticoagulation. Regarding obstetric complications, triple aPL positivity conferred an OR of 16.2 for late pregnancy loss and an OR of 34.4 for a subsequent pregnancy loss [6,7]. These findings reinforce the concept that patients with LA and the triple positive population have a more severe course of the disease. It is likely that the presence of triple positivity is due to antibodies directed against the Gly40-Arg43 epitope in the first domain of β2GPI. At the present time, the detection of aβ2GPI-D1 seems to be a promising biomarker in diagnosis/risk assessment of APS, but more studies are needed to clearly define the clinical utility of its evaluation.
A number of studies have also suggested that testing for other aPL than those recommended in the last APS criteria may help to identify the syndrome. Among them, antibodies to prothrombin and the complex of prothrombin with phosphatidylserine (aPS/PT) have been proposed to be relevant to APS. In our prospective study in, 2005  we showed that the triple positivity for LA, IgG aβ2GPI, and IgG antiprothrombin antibodies gave the highest annual rate of thrombosis (8.4%), that was statistically significant in multivariate analysis (OR, 2.6; 95% CI, 1.35- 5.01). In a recent retrospective study, a large series of SLE patients was analyzed, and assessed the potential clinical usefulness of combining routinely tested aPL with new aPL specificities in an attempt to find a profile that will identify patients at higher risk of APS . Among the 23 possible combinations of the six aPL tested, LA+aβ2GPI+aPS/ PT had the best diagnostic accuracy for APS as a whole, and for both thrombosis and pregnancy loss. When comparing it to the combination suggested by the current criteria and all the other tested combinations, positivity for LA/aβ2GPI/aPS/PT had the best diagnostic performance in terms of specificity and predictive value in this SLE cohort.
Pengo et al.  proposed a modification of the categorization proposed in the last APS criteria, which takes into account the type (clotting tests or ELISA) and the number of positive assays:
a. Triple aPL positivity (positivity of LA, aCL, and aβ2GPI)
b. Double aCL and aβ2GPI positivity (in the absence of LA)
c. Single aPL positivity
Taken into account this increasing knowledge, it is now proposed that the definition of APS should include a different clinical risk to develop APS-related events:
1. definite APS in those patients with triple aPL positivity (high risk group).
2. probable APS in those patients with double aPL positivity (medium risk group).
3. non-APS in those patients with single aPL positivity (low risk group).
Likely this risk stratification would improve the clinical management of patients with aPL.