Abstract 10: Systemic Administration of an Optimized Human Apyrase Inhibits Acute Thrombosis and Neointima Formation in Vein Grafts

Abstract

Introduction. Occlusion of vein grafts (VGs) after bypass surgery is a major clinical problem. Apyrase (CD39) plays a key role in inhibiting thrombosis and vascular inflammation by scavenging ADP and ATP at sites of vascular injury. We examined the capacity of APT102, a recombinant mutant human apyrase with enhanced activity and prolonged half-life, to inhibit thrombosis and intimal hyperplasia in VGs. Methods and Results. Segments of inferior vena cava from C57BL/6J donor mice were grafted into carotid arteries of recipient mice. APT102 (1 mg/kg) or saline was delivered by intraperitoneal (IP) injection every 2 days after surgery. To determine if APT102 inhibits VG thrombosis, VGs were exposed 6 days after surgery, injured with ferric chloride, and formation of thrombi was assessed by monitoring blood flow. Within 60 minutes after injury an occlusive thrombus formed in 1 of 7 mice treated with APT102 vs. 5 of 6 mice treated with vehicle control (P<0.05). No abnormal bleeding was observed in APT102-treated mice. To examine the effect of APT102 on neointima formation, mice received APT102 or vehicle control by IP injection for 2 weeks after surgery. Intimal hyperplasia in VGs was measured 2 weeks later (i.e. 4 weeks after surgery). Mean intima thickness was significantly less (P<0.05) in VGs of APT102-treated mice (26±8.4 μm, n=4) than in VGs of saline-treated mice (48±9.4 μm, n=5). Conclusions. Systemic administration of a recombinant human apyrase inhibits thrombosis and intimal hyperplasia in VGs without increasing bleeding. These results suggest that APT102 has the potential to become a novel treatment strategy to prevent thrombotic occlusion and adverse remodeling of VGs.