A hypothetical mechanism of the local antithrombotic effect of protein C activators. In this model, circulating cells (eg, platelets, leukocytes) serve as delivery vehicles that carry the pharmacological PCA to the thrombus. Infused PCA is absorbed from the plasma by high-affinity cellular transmembrane receptors (R), for example, by thrombomodulin and GPIb on circulating leukocytes and platelets, respectively. Some of these PCA-loaded cells encounter the thrombogenic site where they become activated, attach, and become the building blocks, entrapped in a fibrin network, of thrombi. The thrombus is characterized by a cell density comparable with some solid tissues, which disproportionally increases the local concentration of PCA, in situ, relative to circulating blood or the intact endothelium. The abundant activated membrane surface on thrombi attracts vitamin K–dependent coagulation factors, including protein C, and provides a platform for the catalytic conversion of protein C (PC) to APC by PCA. APC concentration increases locally, with some of the APC molecules staying on the surface, either receptor or directly membrane-associated. The APC-enriched surface acts as a local anticoagulant that down-regulates thrombin generation and interrupts thrombus propagation without profound systemic anticoagulant effect.