Antithrombotic therapy is essential to prevent thrombotic reocclusion in patients with acute myocardial infarction, stroke, or venous thromboembolism. However, current antithrombotic drugs cause bleeding that limits dose and clinical effectiveness. Previously, we reported that APT102 (AZD3366), a human apyrase optimized to scavenge extracellular ADP and ATP, exhibited potent antiplatelet efficacy without bleeding in experimental myocardial infarction and stroke. Here we describe APT402, an optimized fusion of APT102 and annexin V that uniquely inhibits both platelet and coagulation components of thrombus growth. APT402 preferentially bound to injured vessels and thrombus and prevented thrombotic occlusion in arterial and venous thrombosis models, without increasing bleeding. Thus, APT402 breaks the confounding link between antithrombotic efficacy and bleeding, pioneering a safe and effective approach to prevent and treat a broad range of thrombotic diseases, and may be particularly useful in clinical conditions associated with high bleeding risks.