The availability of novel nonfactor therapeutics is revolutionizing the management of hemophilia in individuals with inhibitory antibodies, as well as making prophylaxis more convenient even in the absence of inhibitors. Unfortunately, the use of these products has been associated with thrombotic events that are not typically seen with factor replacement. These are primarily seen when a patient on a nonfactor therapy experiences breakthrough bleeding and concomitantly receives another hemostatic agent. This video addresses thrombotic complication in 3 nonfactor products: (1) emicizumab, a bispecific antibody that mimics the cofactor activity of factor VIII; (2) fitusiran, an small interfering RNA that knocks down synthesis of antithrombin; and (3) concizumab, an antibody that blocks inhibition of factor Xa by tissue factor pathway inhibitor. The latter 2 agents were developed on the premise that hemostasis in hemophilia could be “rebalanced” by reducing the levels of anticoagulant activity to compensate for the defect in procoagulant activity. Each of these approaches increases peak levels of thrombin achieved in assays on plasma from treated subjects and reduces bleeding rates in individuals with or without inhibitors. However, we do not yet have a good mechanistic model for precisely how these approaches affect hemostasis in vivo. It is not only the total amount of active thrombin produced that determines the effectiveness of hemostasis but also how thrombin generation is regulated. Therefore, it is currently difficult to predict how these new agents will interact with other perturbations or therapeutic manipulations of the coagulation system.