(743a) Targeted Anticoagulation Therapy for the Prevention of Venous Thrombosis

Background: Deep vein thrombosis (DVT) and its complications are a leading cause of cardiovascular morbidity and mortality. Despite recent advances in anticoagulation therapy, the rate of bleeding complication remains high, especially for patients with two or more risk factors. In this study, we constructed a fusion protein SCE5-TAP that combines potent FXa inhibition with platelet targeting. Using this unique approach, we illustrate enrichment of targeted TAP at sites of venous thrombosis without altering systemic coagulation profiles.

Method and Results: We used genetic engineering to fuse an activation-specific single chain antibody (scFv) with a potent, direct FXa inhibitor, tick ant-coagulant peptide (TAP). Specific antibody binding of the fusion molecules SCE5-TAP to activated platelets was proven in flow cytometry and anti-FXa activity was demonstrated in chromogenic assays. Intravital microscopy of localized laser-induced injury was used to demonstrate the capacity of SCE5-TAP to target and prevent thrombus formation to murine cremaster venules. Furthermore, anticoagulation efficacy was evaluated in a murine model of inferior vena cava (IVC) thrombosis induced by electrolytic injury, as representative of non-occlusive thrombus. SCE5-TAP was effective in limiting acute venous thrombosis event, by decreasing 32% of thrombus weight, 75% of neutrophil, and 55% of monocyte infiltration. In contrast to Enoxaparin (LMWH) and Rivaroxaban, SCE5-TAP revealed anti-thrombotic effects at low doses at which bleeding time was not prolonged and anti-FXa activity in the plasma was below 0.1 IU/mL.

Conclusions: We present in vivo data suggesting unique properties of SCE5-TAP in limiting thrombosis burdens associated with DVT. In summary, SCE5-TAP represents a promising therapeutic candidate that reduce the risk of DVT without an attendant risk of bleeding.