Complement deposition, C4d, on platelets is associated with vascular events in systemic lupus erythematosus

Abstract

Objective Complement components, including C4d, can be found on activated platelets, a process associated with vascular disease in SLE. We investigated whether platelet C4d (PC4d) adds additional value to traditional and known lupus-associated risk factors when identifying SLE patients with vascular disease. Methods This cross-sectional study included 308 well-characterized SLE patients and 308 matched general population controls. PC4d deposition was analysed using flow cytometry. Values >95% of controls were considered as PC4d positive (+). aPL were determined by Luminex, and the LA test was performed by DRVVT. History of vascular disease (composite and as separate outcomes) was defined at inclusion. Results SLE patients had increased PC4d deposition as compared with population controls (50 vs 5%, P < 0.0001). PC4d+ positively associated with any vascular events, and separately with venous and cerebrovascular events, and also with all investigated aPL profiles. The association for any vascular event remained statistically significant after adjustment for traditional and SLE-associated risk factors (odds ratio: 2.3, 95% CI: 1.3, 4.3, P = 0.008). Compared with patients negative for both PC4d and LA, patients with double positivity were more likely to have vascular disease (odds ratio: 12.3, 95% CI: 5.4, 29.3; attributable proportion due to interaction 0.8, 95% CI: 0.4, 1.1) Conclusion PC4d+ is associated with vascular events in SLE, independently of traditional and SLE-associated risk factors. Concurrent presence of PC4d and LA seem to interact to further increase the odds for vascular events. Prospective studies should examine whether the aPL/PC4d combination can improve prediction of vascular events in SLE and/or APS.

A Review of Complement Activation in SLE

“…Association of PC4d with history of thrombosis was recently found also by another group that analyzed PC4d by flow cytometry utilizing frozen platelet-rich plasma [ 27 •] instead of fresh blood. Comparison of PC4d in patients with SLE to controls in the general population showed that PC4d was associated with venous thromboembolism and ischemic stroke, but not with ischemic heart disease or subclinical atherosclerosis.…”

“…Comparison of PC4d in patients with SLE to controls in the general population showed that PC4d was associated with venous thromboembolism and ischemic stroke, but not with ischemic heart disease or subclinical atherosclerosis. Interestingly, this study found not only a negative correlation between PC4d and C3 or C4 but also a positive correlation between PC4d and C3dg and, to a lesser extent, with soluble C5a-9 [ 27 •]. This suggests that both soluble and cell-bound complement split products may be useful biomarkers in SLE and may be associated with thrombosis.…”

Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus

“…A split product of C4, C4d, has been found in increased levels on SLE patient platelet surfaces and is associated with increased disease activity, thrombosis and antiphospholipid antibodies. 52 SLE nor differed from SLE low in significantly higher immunoglobulin levels, and it is tempting to speculate that this at least partially reflects levels of circulating ICs, potentially bound by the FcγRIIA. Since increased levels of ICs are considered a leading cause of acquired complement deficiency in SLE, 53 we would expect to find an association with circulating complement.…”

“…Despite that patients in this study had a low median disease activity, their platelet proteome showed increased levels of C4 and future studies will have to determine if this can be related to exposure to immune complexes or an ongoing activation of the classical pathway. A split product of C4, C4d, have been found in increased levels on SLE patient platelet surfaces and is associated with increased disease activity, thrombosis and anti-phospholipid antibodies 52 .…”

The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies

“…Platelet depositions of C4d, a marker of complement activation, and LA positivity have been shown to interact synergistically leading to higher rates of thrombotic events in SLE. 41,42 Warfarin could possibly partly explain this interaction through a more pronounced reduction in C4BPt that may lead to enhanced complement activation. Nevertheless, warfarin is to date considered the best documented and the first-choice treatment for thrombotic APS, 43 although recurrent thrombotic events may still occur during warfarin treatment.…”