Figure 1: Model proposed to describe the biological function and binding of HK, HK-PK complex, and their metabolites to vascular endothelium. Under physiological conditions, high molecular weight kininogen (HK), in the absence of prekallikrein (PK), activates bradykinin (BK) B2 receptors on endothelial cells to stimulate nitric oxide (NO) and prostacyclin (PGI2) production without an accompanying increase in endothelial permeability, suggesting that HK plays a cytoprotective role (1). In the presence of PK, the HK-PK complex assembles on endothelial cells via binding to a multi-protein complex consisting of urokinase plasminogen activator receptor (uPAR), complement C1q receptor (gC1qR) and cytokeratin 1 (CK1) (2). The membrane bound serine protease, prolylcarboxypeptidase (PRCP) or heat shock protein 90 (HSP90), activates PK to kallikrein, which in turn cleaves HK to produce BK and cleaved HK (HKa) (3). BK acting via its constitutively expressed B2 receptors induces NO and PGI2 production (4). Under physiological conditions, the small amount of BK produced serves as an antithrombotic, proangiogenic and cytoprotective peptide. The release of BK from HK increases the binding affinity of HKa to uPAR(5). The tight association between HKa and uPAR inhibits cell proliferation and angiogenesis via disruption of vitronectin-uPAR and uPA-uPAR interaction. Under pathological conditions, robust generation of kallikrein and BK promotes inflammation. Further, during endothelial damage, FXII can be autoactivated to FXIIa upon contact with negatively charged surfaces (e.g. components of the subendothelial matrix) (6). Besides PRCP, FXIIa can also activate PK to kallikrein, which can then amplify FXII activation several times. FXIIamediated activation of FXI then leads to activation of the intrinsic pathway of the coagulation system leading to thrombus formation at the site of injury.