Abstract Number: OC 60.2
Meeting: ISTH 2021 Congress
Background: Protein S (PS) is a natural anticoagulant acting as a cofactor for activated protein C (APC) and tissue-factor pathway inhibitor-α (TFPI-α).
Aims: We here evaluated the antithrombotic potential of a bivalent single-domain antibody (PS003biv) found to stimulate the APC-cofactor activity of PS.
Methods: APC-cofactor activity of PS was investigated in a plasma-based clotting assay and in a FVa inactivation assay. The cofactor activity of PS on TFPIα-mediated FXa inhibition was evaluated in a purified system. PS003biv was tested in a FeCl3-induced murine thrombosis model on mesenteric vessels and in a tail bleeding model.
Results: In ELISA, PS003biv and its monovalent counterpart (PS003) bound to PS with Kd app values of 13.8 ± 5.7 nM and 26.8 ± 2.7 nM, respectively, and bound to the isolated PS SHBG-like domain. A homologous SHBG-like domain is only found in Gas6 but PS003/PS003biv did not bind to Gas6, supporting their high specificity for PS. PS003 and PS003biv enhanced the APC-cofactor activity of PS in a plasma-based clotting assay by delaying clotting times by 40% and 80%, respectively, suggesting that PS003biv might be more potent than PS003. PS003/PS003biv could not recapitulate their potentiating effects in a FVa inactivation assay, and had no effect on the TFPIα-cofactor activity of PS. We evaluated the antithrombotic effects of PS003biv in a murine thrombosis model. PS003biv (10 mg/kg IV) significantly prolonged occlusion times in venules and thrombi were unstable and highly prone to form emboli. Interestingly, mice injected with PS003biv (10 mg/kg IV) displayed normal bleeding times and blood loss volumes.
Conclusions: PS003biv enhanced APC-cofactor activity of PS in an unanticipated and complex manner as its effect was observed in plasma-based but not purified systems. However, PS003biv exhibited antithrombotic effects in vivo, suggesting that enhancement of PS with PS003biv might constitute an original therapeutic antithrombotic strategy.
To cite this abstract in AMA style:Sedzro J-, Adam F, De Carvalho A, Bianchini E, Peyron I, Gandrille S, Thomassen S, Hackeng TM, Christophe OD, Lenting PJ, Denis CV, Borgel D, Saller F. Antithrombotic Potential of a Single-domain Antibody Enhancing the Anticoagulant Activity of Protein S [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/antithrombotic-potential-of-a-single-domain-antibody-enhancing-the-anticoagulant-activity-of-protein-s/. Accessed November 30, 2023.
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