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

Abstract and Introduction


Cerebral and cardiovascular ischaemic events are frequent complications of SLE and constitute primary causes of permanent damage. However, the pathogenic determinants of an increased thromboembolic risk in patients with SLE are only partially understood. Atherosclerosis constitutes fertile soil for the development of thrombosis and shows disproportionately high prevalence and progression rates in patients with SLE. aPLs are independent risk factors for acute thrombosis but can also prompt long-term vascular inflammation. Aberrant interactions among immune cells and dysfunctions in the deployment of the coagulation cascade have historically been less explored in SLE, but recent evidence suggests they can also play a critical role at the crossroads between inflammation and haemostasis. In this review we discuss how different prothrombotic mechanisms can be prompted by and synergize with SLE-specific pathogenic events and speculate about novel potential directions for research and drug development.


SLE is a multifactorial, autoimmune rheumatic disease with a peak incidence in females during early adulthood. From a pathogenic perspective, SLE results from a wide range of inherited and acquired factors that combine to disturb the physiological immune response at different levels. Clinically this complexity is evident from the significant phenotype heterogeneity, which in turn impairs the capacity to develop effective treatments for large numbers of patients. Thus, despite significant advances in the control of inflammatory manifestations, which are usually identified as hallmarks of the disease, we still lack knowledge of key individual pathogenic mechanisms that link SLE to increased overall mortality and reduced quality of life.[1,2]

Cerebral and cardiovascular ischaemic events are major causes of irreversible damage and death in patients with SLE.[3–5] SLE-associated pregnancy complications and non-cerebrovascular neurological features constitute additional major causes of morbidity and, interestingly, potential manifestations of vascular dysfunction.[6,7] Patients with SLE show an increased cardiovascular risk and develop thromboembolic events earlier[8–10] compared with age-matched controls from the general population and patients with other immune-mediated diseases.[11,12] Furthermore, SLE constitutes an independent risk factor for mortality and impaired recovery after an ischaemic event.[4,13] Cerebral and cardiovascular events can complicate the underlying inflammatory disease at any time, but the early stages of the disease seem to be associated with a higher age-adjusted risk of vascular complications.[14–16] Nonetheless, the excess prevalence of ischaemic manifestations in patients with SLE increases with time compared with control subjects.[17] Arterial ischaemic events are more frequent[18] and occur with an estimated probability of 5.1–8.5% within 5 years of diagnosis.[19] In addition, venous events are relatively frequent in patients with SLE (5 year probability 3.7–10.3% according to ethnicity[19]), who show a 4.5- to 12.7-fold increased risk of deep vein thrombosis and a 3.0- to 19.7-fold increased risk of pulmonary embolism compared with the general population.[20,21] The reasons for a disproportionate thromboembolic risk in patients with SLE are only partially understood, but seem to involve different pathogenic mechanisms such as accelerated atherosclerosis, aPLs, abnormal interactions between platelets, leucocytes and the endothelium and aberrant activation of the coagulation cascade (Figure 1). Aseptic endocarditis and, in particular, Libman–Sacks endocarditis can affect up to 31% of patients with SLE and constitute additional potential causes of embolism.[22] In this review we discuss the most recent evidence describing the susceptibility of patients with SLE to the development of thromboembolic ischemic events and speculate about possible future directions for investigation of pathogenic mechanisms and therapeutic intervention.

Figure 1.

Main pathogenic determinants of thromboembolic risk in SLE
Accelerated atherosclerosis; aPLs; abnormal interactions between platelets, leucocytes and the endothelium and aberrant activation of the coagulation cascade account for increased thromboembolic risk in patients with SLE.