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


aPLs are part of the spectrum of SLE-related serological abnormalities and detectable in up to 40% of patients.[19] Clinically significant aPLs are those that are persistently positive, i.e. present on two occasions at least 12 weeks apart. APS is defined as persistent aPLs associated with thrombosis (arterial, venous or microvascular) or pregnancy morbidity according to the International Consensus Criteria.[45] Catastrophic APS (CAPS) is defined as the simultaneous occurrence of APS manifestations in three or more organs, systems or tissues and confirmed by finding microthrombosis at biopsy.[46] APS occurs in ~15% of SLE patients[47] and can also be found in other inflammatory diseases or as a stand-alone disorder (primary APS). CAPS has a 1% prevalence in patients with APS.[46] Routine aPL screening conventionally[45] involves testing for LA and measuring the titres of IgG and IgM aCL and anti-β2-glycoprotein I (aβ2GPI) antibodies. β2GPI constitutes the main antigenic counterpart of aPLs, although other potential ligands have been identified (Figure 3). The physiological role of β2GPI is only partially understood and includes scavenging microparticles and pyrogens from the circulation, trimming the activation of the coagulation cascade and interacting with the endothelium and circulating cells.[48,49] In particular, in vitro studies suggest that Toll-like receptor 4 (TLR4) and annexin A2 (a phospholipid-binding protein involved in endothelial activation and in the regulation of the coagulation cascade), possibly through reciprocal interactions, behave as β2GPI cell surface receptors and promote activation of the endothelium as well as of circulating leucocytes and platelets.[50] TLR1, 2 and 6 and apolipoprotein E receptor 2 might also redundantly recognize β2GPI on the cell surface.[50–52]

Figure 3.

Pathogenic effects of aPLs
aPLs jeopardize physiological haemostasis through several mechanisms, which include facilitation of the coagulation cascade, activation of the endothelium and promotion of long-term vessel remodelling, complement activation, recruitment of inflammatory cells and inhibition of the scavenger, anti-inflammatory or antithrombotic properties of their antigenic targets. Most aPLs recognize the linearized form of β2GPI as their ligand and affect cellular activation through TLR1, 2, 4 and 6; Anx A2; ApoER2 and other yet unknown receptors. Nonetheless, other antigens such as phosphatidylserine/prothrombin complexes or AnxA5 might be relevant targets for aPLs. Anx: annexin; AnxA5: annexin A5; ApoER2: apolipoprotein E receptor 2.

aPLs can bind to different epitopes on the pentameric tridimensional structure of β2GPI. Domain I of β2GPI contains the immunodominant epitope for clinically relevant aPLs. However, this epitope is only exposed when β2GPI binds to anionic surfaces, losing its default closed circular conformation and enabling antibody binding.[49] Among the non-criteria aPLs, anti-annexin A5 antibodies have also been detected in patients with APS.[53] Annexin A5 forms organized structures on surface phospholipids, providing an anticoagulant shield against tissue factor (TF)-dependent coagulation progression.[50] Anti-annexin A5 antibodies might interfere with this mechanism, thus favouring thrombosis, but their clinical significance is controversial.[54] Antibodies targeting prothrombin or the phosphatidylserine–prothrombin complex (aPS/PT) may show better promise as diagnostic and prognostic markers in APS. In particular, the aPS/PT appears to be associated with increased thrombotic risk,[55–58] SLE-related neuropsychiatric manifestations[59] and pregnancy morbidity.[57,60,61] The pathogenic mechanism underlying these clinical manifestations is also unknown. Recently, following previous evidence of impaired protein C activity in association with aPL positivity and APS,[62–66] anti-protein C antibodies have been added to the APS serological repertoire.[67]

Thromboembolic events do not occur in all persistently positive aPL patients. In fact, although aPLs induce a prothrombotic environment, additional factors are required to trigger and sustain activation of the coagulation cascade leading to thromboembolic events. Constitutional variables include congenital abnormalities in coagulation factors or acquired prothrombotic conditions such as neoplasia. Situational, environmental and host-related factors such as infections, traumas, surgery, pregnancy, exogenous oestrogens, smoking and flares of an underlying inflammatory disease can provide the so-called second hit for aPL-mediated progression to thrombosis. Endothelial priming plays a crucial role in the recruitment of clotting factors. Inflammatory stimuli such as lipopolysaccharide are able to provide this initiating input. Interestingly, lipopolysaccharide-induced upregulation of TLR4 favours β2GPI docking to the vessel walls, possibly also enhancing aPL/β2GPI binding.[50] Linearization of β2GPI and exposure of domain I is another rate-limiting step in the pathogenesis of aPL-induced thrombosis. Oxidation might play a role in this setting,[68] as oxidized β2GPI is bound more strongly by aβ2GPI in vitro.[69] Accordingly, patients with APS at higher clinical risk show increased levels of oxidized β2GPI, higher titres of anti-domain I antibodies and higher markers of oxidative stress.[70] Complement is also crucial to foster endothelial as well as platelet and leucocyte activation towards thrombosis.[71] Thrombotic microangiopathy, characterized by extensive endothelial injury, decreased coagulation factors and platelet levels, traumatic haemolysis and multi-organ injury, constitutes an extreme phenotype in the spectrum of deranged complement activation and can be part of the clinical manifestations of APS.[72]

Acute thrombosis represents the most devastating manifestation of aPLs in patients with APS, with or without SLE. However, mechanistic studies suggest that aPLs also promote long-term vessel remodelling.[55,73] These pathogenic events have a prominent role in aPL-related nephropathy,[73,74] which can account for up to 14% of cases of SLE with renal involvement and eventually cause nephrovascular hypertension.[75] Furthermore, chronic aPL-induced vascular injury is a potential cofactor in the development of atherosclerosis in patients with SLE.[31] Similar to patients with SLE,[76] patients with APS also show an IFN-mediated impairment of endothelial turnover that might promote plaque destabilization.[77]