Thrombotic complications in patients with end-stage kidney disease are frequent. While being a lifesaving treatment for these patients, hemodialysis introduces a thromboinflammatory environment. Additionally, the extracorporeal hemodialysis circuit itself is prone to clotting because of an interaction between different activation mechanisms of the coagulation system, platelets, and the immune system. Anticoagulation of the patient and the machine is frequently complicated by bleeding. We discuss the factors important in this balancing act and touch on potential strategies that are on the horizon to target thromboinflammation.