How we diagnose the antiphospholipid syndrome

Abstract

IntroductionThe antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia and recurrent miscarriages. This narrativestyle review discusses the key laboratory and clinical aspects of APS. Particular focus is given to antibodies against beta 2-glycoprotein I (␤ 2 GPI), in view of their recent inclusion in the APS laboratory classification criteria 1 (Figure 1). The evidence for assessing antiprothrombin and antiphosphatidylethanolamine antibodies to diagnose APS is also examined.The utility of the ␤ 2 GPI enzyme-linked immunosorbent assay (ELISA), when used in conjunction with the cardiolipin (CL) ELISA and the lupus anticoagulant (LA) assays, in risk-stratifying APS patients is explored. Work undertaken by many groups over the years, ours included, in delineating the key characteristics of anti-␤ 2 GPI antibodies that associate with APS is presented.Miscarriages are a major feature of APS. The relative importance of the LA assays, the CL-ELISA, and the ␤ 2 GPI-ELISA in diagnosing APS in the context of early and late gestation miscarriages is assessed. The value of recent epidemiologic and basic science insights in refining our understanding of obstetric APS pathophysiology is examined, particularly with regards to considering the possibility that distinct mechanisms may be responsible for early and late miscarriages. The clinical implications arising from these observations are discussed. Clarification of the nomenclatureAntiphospholipid antibodies is a term applied to antibodies detected traditionally by 2 types of assays, the CL-ELISA, which stems from the earlier work of Harris et al, 2 and the LA assays. 3 The first report of a cofactor requirement for antibodies to bind cardiolipin (an anionic phospholipid) from patients with APS was by McNeil et al in 1989. 4 This was subsequently confirmed by Galli et al 5 and Matsuura et al 6 in 1990. Purification and sequencing of the cofactor as ␤ 2 GPI was reported by McNeil et al in 1990. 7 It was noted that anionic phospholipid is not an absolute requirement for antibodies to bind ␤ 2 GPI, 8 negating the notion that ␤ 2 GPI is a "cofactor" for antibody binding. Antibodies from these patients can bind to ␤ 2 GPI immobilized on an irradiated plate in the absence of anionic phospholipids. 9 A negatively charged surface serves a 2-fold role. It enables ␤ 2 GPI clustering, allowing divalent binding by the low affinity antibodies. 10,11 It also enables the ␤ 2 GPI molecule to undergo a conformational change, 9 exposing a cryptic epitope on the first domain. 12 Positivity on the CL-ELISA is not directed against ␤ 2 GPI in the context of a number of infections. 13 However, this is not true for all types of infections, as elevated anti-␤ 2 GPI antibodies in patients with leishmaniasis, leptospirosis, 14 and leprosy 15 have been noted. A key distinguishing feature between anti-␤ 2 GPI antibodies occurring in the context of leprosy and those that strongly associate with thrombosis is that in the former instance they are directed against an epitope on dom...

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study

“…We recommend systematic dichotomization of pregnancy loss according to the 10 WG threshold, as in the clinical criteria of APS. 4 Our APS women developed more late pregnancy complications (mainly PE) than controls. Adverse pregnancy outcomes, including PE and SGA, were observed for 19.4% of 144 treated APS patients, but only the minority of these women had prior pregnancy loss, such that this factor could not predict adverse pregnancy outcomes.…”

“…[1][2][3][4] The defining laboratory criterion for APS is repeated positive test results for the antiphospholipid antibodies (aPLAbs) lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-b2 glycoprotein I antibody (ab2GP1) of immunoglobulin G (IgG) and/or IgM isotype at moderate or high titers. 2,4 Obstetric APS without a history of thrombosis is currently managed by administering low-dose aspirin (LDA) and either low-dose unfractionated heparin (twice daily) or low-molecular-weight heparin (LMWH, once daily) pending large, multicenter randomized controlled trials directly comparing the 2 treatments. 5,6 Currently, LMWH is preferred for practical and safety reasons.…”

How I treat the antiphospholipid syndrome

“…3,4 The concept of prognosis involves consideration of whether the detection of the autoantibodies alters the probability of thrombotic recurrence or death compared with not having the antibodies in patients who have otherwise had a similar initial thrombotic event and have received identical secondary prophylaxis. This is a theme explored in this review (see supplemental material for the literature search strategy used).…”

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

“…Although once thought to directly recognize anionic phospholipids, most of these aPLs actually recognize phospholipid binding proteins, such as ß 2 -glycoprotein I (ß 2 GPI) and prothrombin. ß 2 GPI has emerged as a particularly common antigen for these autoantibodies (5). Anti-ß 2 GPI antibodies are found frequently in the plasma of patients, suggesting their important roles in APS.…”