Background SLE patients are at risk for diverse organ systems involvement, which increases the challenges for diagnosis and predictions for the development of specific clinical features. In recent studies we have compared traditional and novel serologic markers and identified profiles that correlate with levels of overall clinical disease activity, and for specific organ system involvement (1). In the current studies we extended our studies to surveys of levels of Protein S, a vitamin K dependent factor implicated both in the coagulation cascade and as a ligand for the TAM receptor tyrosine kinase family that regulates inflammatory responses and apoptotic cell clearance.
Objectives To determine whether levels of Protein S can identify sets of SLE patients with distinct clinical features.
Methods In cross-sectional surveys of the well-characterized Hopkins SLE cohort, we assessed levels of free Protein S with a commercial immunoassay. All clinical and experimental data was imported into a customized database where multivariate methods were used to seek natural divisions in the sample set based on a panel of IgM and IgG lupus/apoptosis-associated natural autoantibodies and to relate them to various clinical parameters. Systems analyses with both laboratory assays and clinical data were performed using Mathworks Matlab V.7.12.
Results In surveys of 90 SLE patients, low Protein S levels correlated with a history of DVT/PE (N=12, Spearman, P<0.00074, R=0.4054) (Sens. 0.92, Spec.0.56). These correlations had greater significance than for well known lab correlates, that include high levels of IgG anti-cardiolipin (P=0.0065, R=-0.285), IgG anti-β2 gp I (P=0.0271, r= -0.23300), RVVT (P=0.0011, R=-0.3381). Patients with a hx of MI/CVA also had significantly lower levels of free Protein S (N=17, P=0.0011, R=-0.337) (Sens. 0.76, Spec.0.56). We found no correlations between protein S and overall SLE disease activity levels by SELENA-SLEDAI, physician’s global assessment, or organ damage by the SLICC index, or for nephritis. There were also no significant correlations with natural antibodies to PC and MDA that have been implicated in lupus-associated global disease activity and MI/CVA events, or with autoantibodies to dsDNA or C1q. There were no correlations with C3 or C4. Although the vitamin K antagonist, coumadin, is reported to affect Protein S levels, we found no difference in Protein S levels between those with and without coumadin. For MI/CVA affected patients not treated with coumadin, we found significantly lower levels of Protein S compared to clinically unaffected SLE pts (P<0.01).
Conclusions Levels of free Protein S were shown to correlate with the SLE subset with clinical DVT/PE and for MI/CVA events. These patients did not have profiles associated with higher overall disease activity and greater systemic inflammation. These findings support the hypothesis that disturbance in levels of the anti-coagulant Protein S may plays roles in both venous thrombopathy and cardiovascular events, which is relevant to the development of better personalized evaluation and therapy. Collectively, this study describes a potential biomarker, free Protein S, which identifies a SLE subgroup that may be at risk for events linked to a Protein S-associated pathogenic mechanism.
Gronwall et al. Clinical Immunology 2012 (in press)
Disclosure of Interest None Declared