Inhibition of Thrombosis after Vascular Injury with a Novel Tissue Factor-Targeted Thrombomodulin Fusion Protein

Abstract number: OR077

Abendschein¹ D, Wang² Y-X, Light² D, Hoefelmann¹ C, Citkowicz² A, Riffel² A, McLean² K

¹¹Washington University School of Medicine, St. Louis, MO, USA ¹¹Washington University School of Medicine, St. Louis, MO, USA ²²Berlex Biosciences, Richmond, CA, USA

Thrombotic occlusion often complicates surgical and vascular recanalization procedures. Tissue factor initiates coagulation while thrombomodulin binds thrombin and activates protein C to attenuate coagulation. This study was designed to compare the antithrombotic efficacies of a targeted fusion protein comprised of human tissue factor antibody linked to soluble thrombomodulin (TFTM) and low molecular weight heparin (LMWH) in arteries and veins after deep injury simulating surgery or angioplasty. Cynomolgus macaques were anesthetized and instrumented with blood flow probes and transmural needle electrodes on a femoral artery and contralateral vein. Fifteen minutes after an intravenous bolus of either TFTM (0.01 mg/kg, n= 5, 0.03 mg/kg, n= 5, 0.15 mg/kg, n= 5), LMWH (enoxaparin, 0.5 mg/kg, n= 5, 2.5 mg/kg, n= 5), or saline as a control (n= 6), direct anodal current was applied to the electrodes. After 2 h, only 17% of arteries and 33% of veins were patent in controls while low dose TFTM increased patency to 60% of arteries and 75% of veins and increased venous blood flow compared with controls (P= 0.04) and low dose LMWH (P= 0.02). The 0.03 mg/kg dose of TFTM was most efficacious increasing patency to 100% of arteries (P= 0.02 vs control) and 80% of veins (P= 0.03 vs low dose LMWH) and venous blood flow compared to low dose LMWH (P= 0.002). Only high dose LMWH trended to increase venous, but not arterial, patency and blood flow compared with controls. Thrombus weight was reduced in the arteries from animals given 0.03 mg/kg of TFTM (P < 0.05 vs control) and trended towards a reduction in veins from all groups given TFTM, but not LMWH. Bleeding time was prolonged less than 2-fold baseline by either TFTM or LMWH. We conclude that TFTM, which effectively targets anticoagulation to the injured vessel wall, improves the antithrombotic efficacy compared with LMWH without increasing the potential for bleeding.