Antiphospholipid Syndrome: An Antibody-Mediated Disease With Emerging Therapeutic Opportunities

Abstract

Antiphospholipid syndrome (APS) is an autoimmune thromboinflammatory disease characterized by vascular thrombosis, pregnancy morbidity, and other manifestations driven by antiphospholipid autoantibodies. In this review, we present a clinical case that illustrates some diagnostic and therapeutic challenges in managing severe, relapsing APS manifestations, including microvascular injury and diffuse alveolar hemorrhage. We then discuss recent advances in our understanding of APS pathophysiology, emphasizing the critical role of anti-β-2 glycoprotein I antibodies in triggering cell-specific inflammatory and thrombotic pathways. Finally, we speculate that achieving definitive disease control will ultimately require strategies that eliminate or effectively neutralize these pathogenic antibodies.

Figure 1

Antiphospholipid antibody testing and relevant clinical associations. The diagram highlights the relationship among commonly available laboratory tests, the autoantigens driving their positivity, and relevant clinical associations. Dashed lines indicate associations that remain incompletely understood. APS, antiphospholipid syndrome; β₂GPI, β‐2 glycoprotein I; LBPA, lysobisphosphatidic acid; PS/PT, phosphatidylserine/prothrombin. Source: The diagram's concept is adapted from lectures by Dr Robert Roubey (University of North Carolina).

Figure 2

Mechanisms of prothrombotic cell activation by anti‐β₂GPI IgG. The diagram highlights the receptors most commonly linked to cell activation by β₂GPI/anti‐β₂GPI IgG surface complexes, as well as some effectors known to be downstream of that activation. β₂GPI, β‐2 glycoprotein I; KLF2/4, Krüppel‐like factor 2 or 4; LRP, low‐density lipoprotein receptor‐related protein; mTOR, mechanistic target of rapamycin; ROS, reactive oxygen species; TF, tissue factor; TLR, Toll‐like receptor; VWF, von Willebrand factor. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.43258/abstract.