The antiphospholipid syndrome: still an enigma

Abstract

Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being β2-glycoprotein 1 (β2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-β2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.

Figure 1. Proposed structures of the open and closed forms of β2GPI DI-DV represent the 5 domains of β2GPI

(A) β2GPI structure in the “open” form, as identified by its crystal structure. In this conformation, often referred to the “fish hook” conformation, an epitope containing Lys19, Arg39, and Arg43 that is recognized by anti-β2GPI domain 1 antibodies is exposed. β2GPI incubated at high pH adopts this conformation, and it is proposed that binding of anionic phospholipid results in similar conformational changes. (B) The “circular” form of β2GPI. This conformation is suggested by electron microscopy of circulating plasma β2GPI. In this conformation, the epitopes recognized by anti-β2GPI domain 1 antibodies are not available, which is thought to explain the fact that circulating immune complexes are not present in patients with antiphospholipid antibodies. This conformation is proposed to be maintained by interactions between domain 1 and domain 5. Reprinted with permission from Agar et al.

Figure 2. Approach to the asymptomatic patient with antiphospholipid antibodies

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