Abstract
Anti-phospholipid (aPL) antibodies are important contributors to development of thrombosis in patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE). The underlying mechanism of aPL antibody-mediated thrombosis is not fully understood but existing data suggest that platelets and the complement system are key components. Complement activation on platelets is seen in SLE patients, especially in patients with aPL antibodies, and has been related to venous thrombosis and stroke. The aim of this study was to investigate if aPL antibodies could support classical pathway activation on platelets in vitro as well as in SLE patients. Furthermore, we investigated if complement deposition on platelets was associated with vascular events, either arterial or venous, when the data had been adjusted for traditional cardiovascular risk factors. Finally, we analyzed if platelet complement deposition, both C1q and C4d, was specific for SLE. We found that aPL antibodies supported C4d deposition on platelets in vitro as well as in SLE patients (p = 0.001 and p<0.05, respectively). Complement deposition on platelets was increased in SLE patients when compared with healthy individuals (p<0.0001). However, high levels of C4d deposition and a pronounced C1q deposition were also seen in patients with rheumatoid arthritis and systemic sclerosis. In SLE, C4d deposition on platelets was associated with platelet activation, complement consumption, disease activity and venous (OR = 5.3, p = 0.02), but not arterial, thrombosis, observations which were independent of traditional cardiovascular risk factors. In conclusion, several mechanisms operate in SLE to amplify platelet complement deposition, of which aPL antibodies and platelet activation were identified as important contributors in this investigation. Complement deposition on platelets was identified as a marker of venous, but not arterial thrombosis, in SLE patients independently of traditional risk factors and aPL antibodies. Further studies are needed to elucidate the role of complement deposition on platelets in development of venous thrombosis.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by systemic inflammation affecting several organ systems including joints, kidney, skin and central nervous system [1]
In this study, isolated platelets were first incubated with anti-cardiolipin antibodies, or human IgG, and P-selectin expression measured by flow cytometry as a marker of platelet activation
Using suboptimally ADP-activated platelets, this study found that aCL antibodies, but not purified human IgG, were able to amplify platelet activation (p = 0.001, Figures 1C and 1D)
Summary
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by systemic inflammation affecting several organ systems including joints, kidney, skin and central nervous system [1]. The underlying mechanism of aPL antibodymediated thrombosis is not fully understood. It is known that aPL antibodies are able to bind to platelets and amplify platelet activation and aggregation through the p38 MAPK signaling pathway [10,11,12,13,14,15]. Investigations in complement deficiency, both in mice and human, suggest that classical pathway activation of the complement system is essential in development of aPL antibody-mediated thrombosis [16,17,18,19,20,21]. Even though the exact underlying mechanism for aPL antibody-mediated development of thrombosis is still not known, existing data suggest that two of the components behind the pro-thrombotic effects are platelets and the complement system
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