The polyP/FXII axis in thrombosis. At a site of vessel injury, tissue factor–initiated coagulation mechanisms mediate hemostasis, and deficiency in these pathways results in bleeding. In thrombosis, activated platelets expose polyP nanoparticles that induce FXII contact activation driving coagulation within the thrombus. The polyP/FXII specifically contributes to pathologic coagulation, and targeting polyP or FXII interferes with thrombosis but has no impact on hemostasis, suggesting use of this strategy for safe thromboprotection.