Systemic lupus erythematosus (SLE) is a broad-spectrum autoimmune disease that affects more than 1.5 million people in the United States. The etiology of SLE remains unclear and disease manifestations often extend beyond the systemic autoimmune response. For example, thrombosis is frequently observed in SLE patients and constitutes one of the leading causes of mortality and morbidity. However, whether thrombosis directly contributes to the etiology of a subset of SLE remains unknown. We and others have identified a significant association between reduced amounts of the anticoagulant protein, Protein S (PROS1) in the plasma and a diagnosis of autoimmune diseases in humans, including SLE. Rare variants of PROS1 have been identified in SLE patients. Some of these variants have been previously described in patients with thrombosis and are known to impair the anticoagulant function of PROS1. These data suggest that PROS1 mutations leading to thrombosis may be a risk factor in SLE. We have recently identified that PROS1 is also a potent anti-inflammatory molecule. Whether any of these mutations also alter the anti-inflammatory function, and thereby contribute to autoimmunity in SLE is unknown. We hypothesize that the loss of PROS1 anticoagulant function, and the loss of its anti-inflammatory signaling role can independently contribute to SLE etiology, but together exacerbate the risk of SLE. We will (1) characterize the anticoagulant and anti-inflammatory functions of PROS1 rare variants identified in SLE patients and (2) determine the direct contribution of the loss of PROS1 anticoagulant and/or anti-inflammatory function to SLE in mouse models. Unraveling the relative contributions of the two distinct biological properties of PROS1 may help guide stratification of SLE patients and the design of future therapeutic interventions in this disease.