Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.

Keywords: Antiphospholipid syndrome; Neutrophil extracellular traps; Thrombosis; Vasculopathy.

Fig. 1

Neutrophil extracellular promote thrombosis. Activated neutrophils release decondensed chromatin decorated with nuclear (histones), granule (proteases that degrade antithrombotic molecules such as TFPI and antithrombin), and cytoplasmic proteins that promote inflammation and coagulation (tissue factor, factor XI and XII). Together, NETs form a scaffold for cell aggregation and thrombus formation. TFPI = tissue factor pathway inhibitor. Illustration credit: Ethan Tyler (NIH)

Fig. 2

Potential mechanisms contributing to thrombotic APS. A Endothelial cells increase expression of tissue factor (TF) and adhesion molecules. Complement damages the endothelium via the membrane attack complex (MAC) and acts as a chemoattractant via C5a. Monocytes express TF and cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and type I interferons (IFNs), and release microparticles. Neutrophils produce reactive oxygen species and release neutrophil extracellular traps (NETs). B NETs form an intravascular scaffold that promotes thrombus accretion. C Chronic activation of the endothelium by aPL can result in progressively occlusive vasculopathy. aPL = antiphospholipid antibodies; ApoER2 = apolipoprotein E receptor 2; β₂GPI = beta-2 glycoprotein I; NF-κB = nuclear factor kappa B; KLFs = Kruppel-like factors. Illustration credit: Ethan Tyler (NIH)