Mechanism for tPA-mediated activation of plasma prekallikrein (PPK). A therapeutic dose of tPA converts plasminogen in plasma to plasmin (yellow arrow) in a suitably high concentration to facilitate generation of the protease factor XIIa (FXIIa) from its precursor FXII. FXIIa then initiates reciprocal activation of PPK to PKal, as indicated by the red arrows. PKal may contribute to the adverse side effects associated with tPA therapy through several mechanisms, including cleavage of high molecular weight kininogen (HK) to cleaved kininogen (HKa), liberating bradykinin (BK, green arrow), activation of the matrix metaloproteinase-9 (MMP-9) system (blue arrow), and sustained FXII activation. Professional illustration by Somersault18:24.