Pathways of initiation of coagulation by storage lesion–induced RBC-MVs. RBC-MVs directly promote FXII and PK activation, leading to FXIIa and PKa formation, respectively. By reciprocal activation, FXIIa further activates PK, whereas PKa further activates FXII. In addition, formation of these 2 enzymes leads to FIX activation via 2 independent pathways. The canonical pathway (in blue) in which FXIIa indirectly activates FIX after FXI activation, and an alternative pathway (in red) in which PKa directly activates FIX. Both pathways ultimately lead to thrombin formation via the common pathway.