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

Dysfunctional Coagulation Cascade

Clinical and biological evidence suggests the existence of extensive connections between haemostasis and inflammation.[90] Thus, not surprisingly, alterations in the deployment of the coagulation cascade constitute a distinctive feature of patients with inflammatory diseases such as SLE (Figure 5).[81,103–105] Intuitively, enhanced activation of TF pathway can be linked to increased inflammation-induced TF expression on endothelial cells, neutrophils, eosinophils and other cells[89,101] and has been consistently detected in SLE.[106] However, impaired TFPI function has also been proposed as a potential prothrombotic mechanism in patients with SLE and in patients with APS. Circulating TFPI levels are affected by disease activity[105,107] and by the generation of NETs.[90] In addition, TFPI can be inhibited by aβ2GPI.[108] Nevertheless, conflicting results have been reported for TFPI concentrations in SLE under resting conditions compared with healthy subjects.[105,107,109] In addition to TFPI, the plasmin system and the thrombomodulin/protein C/protein S system physiologically regulate the coagulation cascade. Activation of protein C during the coagulation cascade is crucial to counterbalance the prothrombotic effects of TG, with factor Va and VIIIa inactivation by activated protein C (APC) effectively preventing thrombin formation.[110] Interestingly, in addition to its role as an anticoagulant, protein C is also an anti-inflammatory mediator. APC exerts an endothelial protein C receptor–dependent cytoprotective effect on the endothelium (as well as on glomerular podocytes) through cleavage of protease activated receptor 1.[111] Furthermore, it inhibits the formation of NETs.[112]

Figure 5.

The coagulation cascade in SLE
An active interplay links the coagulation cascade with inflammation in SLE. Inflammation induces the expression of TF on the endothelium and on circulating platelets, leucocytes and platelet-derived and endothelial-derived microparticles (yellow and red dots, respectively). NETting neutrophils constitute additional sources of TF, activate factor XII and neutralize TFPI. TF, in combination with phospholipids (provided by activated cells), activated factor VII and calcium, constitutes the main trigger of the coagulation cascade in vivo. Thrombin can interact with multiple cellular and humoral immune mediators, including complement. SLE can impair the regulation of the coagulation cascade at different levels including TFPI and protein C.

TG via the TF pathway is integral to the blood coagulation process and TG analysis provides a global measure of coagulation dynamics and an individual's thrombogenic potential.[113–115] Two studies reported that the generation of thrombin in SLE patients under platelet-free conditions was either delayed[103] or less extensive[104] than in controls, which apparently contrasts with the increased thrombotic risk of these patients. Notably, in the latter study the results were not affected by the aPL profile, thus ruling out an exclusive LA effect and supporting the idea that multiple biological factors might account for the unique SLE haemostatic phenotype.[104] In contrast, Pereira et al.[81] took into consideration the amount of PMP in platelet-free plasma and found that TG was dependent on PMP. In addition, the levels of PMP correlated with the ability of plasma to generate thrombin. Since patients with SLE had higher concentrations of circulating PMP, they also showed a higher endogenous thrombin potential. More recently, Arachchillage et al.[67] demonstrated that high-avidity anti-protein C antibodies are associated with greater resistance to both endogenous and exogenous protein C and with a severe APS thrombotic phenotype (defined as the development of recurrent venous thromboembolism while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis), suggesting their potential use as prognostic markers in APS.

Besides APS, acquired APC resistance (APCR) has also been reported in SLE. In particular, Oosting et al.[62] described the ability of some aPLs extracted from patients with SLE to dampen APC-mediated inactivation of activated factor V with variable dependency on the presence of protein S. Nojima et al.[65] later reported a 34.4% prevalence of acquired APCR in patients with SLE and found a strong association with venous thromboembolism and with coexisting LA and anti-prothrombin antibodies. The same group also described additional associations with aPS/PT, aβ2GPI and anti-protein S antibodies.[63,64] Little is known about the role of anti-protein C antibodies and APCR in SLE.

Besides being favoured by inflammation, the generation of thrombin, in turn, affects the activation state of a wide range of cells involved in inflammation, such as the endothelium, circulating platelets and even mast cells.[116–118] Thrombin is also able to bypass the conventional ways of initiation of the complement cascade and to favour the generation of C5a and C5b.[119] High levels of anaphylotoxins, such as C5a, affect the activation status of the endothelium, platelets and leucocytes, ultimately promoting thrombosis through the expression of TF and increasing vascular permeability. Thrombin-induced shredding of C5 also leads to formation of the complement membrane attack complex, which either causes direct endothelial damage or promotes long-term inflammation through its inactive form.[120] Accordingly, anticoagulation prompts substantial changes in complement activation status.[121] Similarly, C1 inhibitor, one of the main physiological regulators of the complement cascade can also inhibit the coagulation system.[122] Patients with SLE and thrombotic events constitutionally show reduced C1 inhibitor–activated factor XII complexes, suggesting the presence of disease-related alterations in the activation of the contact system.[123] The presence of shared activation pathways between the coagulation cascade and other key cellular of humoral players in the pathophysiology of SLE suggests that imbalances in haemostasis could, epiphenomenally, represent or pathogenically affect SLE-related manifestations other than overt thrombosis.