Background/Purpose: 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.

Methods:  In cross-sectional surveys of 90 SLE patients, 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.

Results: Low Protein S levels correlated with a history of DVT/PE (N=12, Spearman, P<0.0007, R=0.41)(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=0.007, R=-0.29), IgG anti-β2-GPI (P= 0.03, r= -0.23), and RVVT (P=0.001, R=-0.34). Patients with a hx of MI/CVA also had significantly lower levels of free Protein S (N=17, P=0.001 R=-0.34) (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. Although the vitamin K antagonist, coumadin, is reported to affect Protein S levels, we found no significant 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).

Conclusion:  Significantly lower levels of free Protein S were found in the subsets of SLE patients with clinical DVT/PE and for MI/CVA events. These findings support the hypothesis that disturbance in levels of the anti-coagulant Protein S may play roles in both venous thrombopathy and cardiovascular events.

Collectively, this study describes a potential biomarker, free Protein S, which identifies a specific SLE subgroup that may be at increased risk for pathogenic mechanisms responsible for thrombotic events and serious CV events. Further investigations of this topic may allow for the development of better diagnostic and prognostic tests and personalized therapies in patients afflicted by SLE.

References: (1) Grönwall et al. Clinical Immunology 2012 142(3):390-8

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-free-protein-s-levels-may-be-linked-to-cardiovascular-events-and-venous-thrombosis-in-sle/