Diagnosis and management of the antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy complications in the presence of persistent antiphospholipid antibodies (APLA). Laboratory diagnosis of APLA depends upon the detection of a lupus anticoagulant, which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin (aCL) and anti-β2-glycoprotein-1 (β2GPI) antibodies. APLA are primarily directed toward phospholipid binding proteins. Pathophysiologic mechanisms underlying thrombosis and pregnancy loss in APS include APLA induced cellular activation, inhibition of natural anticoagulant and fibrinolytic systems, and complement activation, among others. There is a high rate of recurrent thrombosis in APS, especially in triple positive patients (patients with lupus anticoagulant, aCL and anti-β2GPI antibodies), and indefinite anticoagulation with a vitamin K antagonist is the standard of care for thrombotic APS. There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOAC) in thrombotic APS. Aspirin with low molecular weight or unfractionated heparin may reduce the incidence of pregnancy loss in obstetric APS. Recent insights into the pathogenesis of APS have led to the identification of new potential therapeutic interventions, including anti-inflammatory and immunomodulatory therapies. Additional research is needed to better understand the effects of APLA on activation of signaling pathways in vascular cells, to identify more predictive biomarkers that define patients at greatest risk for a first or recurrent APLA-related clinical event, and to determine the safety and efficacy of DOACs and novel anti-inflammatory and immune-modulatory therapies for refractory APS.

Keywords: Anti-β2-glycoprotein-1; Antiphospholipid antibody; Antiphospholipid syndrome; Domain 1 anti-β2-glycoprotein-1; Thrombosis.

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. Adapted from Agar et al, Blood 116:1336, 2010 with permission.