Under Crossfire

Thromboembolic Risk in Systemic Lupus Erythematosus

Giuseppe A. Ramirez; Maria Efthymiou; David A. Isenberg; Hannah Cohen


Rheumatology. 2019;58(6):940-952. 

In This Article

Platelets, Leucocytes and the Endothelium

Endothelial cells, leucocytes and platelets interact productively to ensure vessel integrity. These first-line innate immune cells sense the presence of potential septic and non-septic threats within the circulating blood and activate a complex set of stereotyped responses, which in turn promote inflammation and thrombosis.[78,79] Platelets, in particular, are involved in a wide range of inflammatory tasks beyond their most obvious role in haemostasis (Figure 4). After recognition of invading pathogens through innate (TLR) or adaptive (Fcγ, εR) immune receptors, platelets promote endothelial and leucocyte activation locally, through direct cell–cell interactions, or systemically, due to release of microparticles. Platelet-derived microparticles (PMPs) are shed from the platelet cell surface following activation and constitute the bulk of circulating microparticles in humans.[80] Constitutive activation of platelets and persistently high levels of PMP are thought to characterize autoimmune diseases and affect disease activity, vessel integrity and thrombotic risk.[81–84] Platelets further contribute to long-term vessel remodelling by releasing growth factors and mitogens.[85]

Figure 4.

Platelet–leucocyte–endothelial interactions in SLE
Upon activation, neutrophils are able to promote thrombosis by expressing TF and by generating NETs. The activation of neutrophils can be induced by several stimuli, including interactions with activated platelets by cell–cell contact or by microparticles (yellow dots). IFN-α can also promote NETosis and affect endothelial turnover. The endothelium also plays a crucial role in triggering coagulation through tissue factor and by providing leucocytes with the access to tissues. Besides exerting a role in the control of local inflammation and haemostasis, the endothelium can also extend its functions systemically, through microparticles (red dots).

Platelets may have a fundamental role as inflammatory partners of neutrophils.[86] In fact, platelets can trigger neutrophil activation, extend neutrophil lifespan and prompt the generation of neutrophil extracellular traps (NETs).[87,88] These aggregates of decondensed chromatin concentrate high amounts of crucial autoantigens for the pathogenesis of SLE and coagulation triggers such as TF or von Willebrand factor.[89] NETs further contribute to thrombosis by neutralizing tissue factor pathway inhibitor (TFPI) and activating factor XII.[90] Recently a non-canonical mechanism of vascular occlusion due to uncontrolled NET formation has been described.[91] Interestingly, this phenomenon was dependent on DNAses, which are preferential SLE autoantigens.[92] Neutrophils from patients with SLE have also been shown to undermine endothelial integrity under inflammatory conditions and to contribute to atherosclerosis by enhancing cholesterol-induced innate responses and by promoting IFN-α production.[31,93–95] Deranged platelet–leucocyte interactions and/or NETosis are also detectable in RA, ANCA-associated vasculitides, APS and even diabetes, which all share an enhanced thrombotic risk.[96–98] Intriguingly, aPLs induce NETs, which in turn are also able to promote thrombin generation (TG). This phenomenon is apparently more evident with aβ2GPI and is dependent on the formation of reactive oxygen species and platelet/endothelial TLR4.[99] Conversely, heparin prevents the formation of NETs.[100] NETs have also been detected within coronary thrombi and can contribute to plaque destabilization in atherosclerosis.[101]

Activation of the endothelium is a pivotal pathogenic event at the crossroads between inflammation and thrombosis, as it involves the expression of leucocyte adhesion molecules such as P-selectin and, later on, E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecules as well as coagulation triggers such as TF and von Willebrand factor. Furthermore, similar to platelets and other circulating cells, the endothelium is endowed with the ability to release signalling quanta through microparticles and has a major role in control of the vascular tone. Endothelial activation and vasomotor dysfunction, possibly favoured by IFN-α-prominent responses, are hallmarks of SLE and may account for part of the SLE-related cardiovascular risk.[76] Moreover, endothelium-derived microparticles constitute the prevalent microparticle subset in patients with SLE and can promote dendritic cell activation and NETosis.[83,102]