Tissue factor (TF) on the luminal surface of blood vessels initiates thrombin generation by forming a complex with FVII/FVIIa (left). However, thrombus growth away from the vessel wall depends on activation of FXI to amplify the process (center). In most cases, FXI is likely to be activated by thrombin, but in some situations, particularly those in which blood is exposed to artificial surfaces (right), FXIIa may be the major activator of FXI. Italics indicate cofactors. NETs = neutrophil extracellular traps; PP = polyphosphate.