RBC-MVs interact with the contact system to activate coagulation FIX. RBC-MVs that accumulate during storage of RBC units can directly activate FXII and prekallikrein (PK). FXII activation of PK forms plasma kallikrein (PKa) that reciprocally activates FXII and liberates bradykinin (BK) from high molecular weight kininogen (HK). In the canonical pathway proposed by Noubouossie et al, FXIIa activation of FXI leads to activated FIX. In an alternative pathway, PKa directly activates FIX. The sum of these activities leads to a series of proteolytic reactions and ultimately, to the generation of thrombin (FIIa). Generated BK can influence vascular smooth muscle tone, vascular permeability, and leukocyte functions.