Antiphospholipid syndrome: an update for clinicians and scientists

Abstract

Purpose of review: Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is unlikely to be made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology.

Recent findings: How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells is being increasingly defined. Although established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In-vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, and rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data.

Summary: As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.

Figure 1

Recent mechanistic insights into the pathophysiology of antiphospholipid antibodies (aPL) and APS. Starting at the bottom of the figure and moving roughly clockwise: In the vessel wall of atherosclerotic plaques, beta-2 glycoprotein I (β₂GPI)-specific T_H1 cells trigger cell death and release interferons (IFNs). Endothelial cells (ECs) release vesicles (like microparticles) that activate TLR7 in other ECs by delivery of single-stranded RNA. aPL-mediated platelet activation relies on phosphoinositide 3-kinase (PI3K). Type I IFNs reduce the function of restorative circulating endothelial progenitors, which may lead to the accrual of endothelial damage over time. Cofactor-independent aPL activate monocytes via endosomal reactive oxygen species (ROS), resulting in increased expression of tissue factor (TF). In response to aPL, neutrophils release neutrophil extracellular traps (NETs), which help facilitate thrombin activation. Complement activation, especially through the classical pathway, leads to the assembly of the membrane attack complex (MAC) on the endothelial surface, while also facilitating the recruitment and activation of inflammatory cells.