Protein S as a therapeutic target.

Protein S (PS) is a key anticoagulant with additional roles in cell signaling through its interaction with Tyro3-Axl-MerTK family receptor tyrosine kinases Tyro3 and MerTK. Therapeutic targeting of PS-either enhancing or inhibiting its activity-has emerged as a promising strategy to modulate coagulation and inflammation. Approaches include nanobodies, monoclonal antibodies, and RNA interference, aiming to restore hemostatic balance or prevent bleeding, depending on the clinical context. Severe PS deficiency (homozygous or compound heterozygous) causes life-threatening conditions such as disseminated intravascular coagulation and purpura fulminans. Heterozygous deficiency is associated with an elevated venous thromboembolic risk. These insights highlight the need for tailored modulation of PS activity. A PS-enhancing nanobody has demonstrated potent antithrombotic effects in murine models, establishing proof-of-concept for a novel, safe anticoagulant strategy. Conversely, PS inhibition is being pursued to treat bleeding disorders such as von Willebrand disease and hemophilia. Both monoclonal antibodies and small-interfering RNAs targeting PS have shown safety and efficacy in preclinical models. Notably, a monoclonal antibody has demonstrated safety and preliminary efficacy in a phase 1/2 trial in patients with von Willebrand disease. Beyond coagulation, PS exerts protective effects on joint and bone tissues via Tyro3 and MerTK receptor signaling, further broadening its therapeutic potential. These findings support the continued development of PS-targeted therapies, with implications for both thrombotic and bleeding disorders, as well as for mitigating tissue damage in chronic bleeding conditions.