The role of polyP/FXII in thrombosis. (A) Initially, the TF/FVIIa-driven “extrinsic” coagulation pathway triggers fibrin formation at sites of injury. FXII has no function during this stage. Tissue factor pathway inhibitor (TFPI) is released from endothelial cells and adherent platelets and blocks TF activity. (B) In the developing thrombus, activated platelet–released polyP triggers fibrin production via activation of FXII that drives the “intrinsic” coagulation cascade. polyP/FXII-driven fibrin formation operates distant from the injured vessel wall and, hence, does not contribute to hemostasis.