Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease

Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular-weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events. Prekallikrein-deficient mice have reduced thrombosis risk and plasma kallikrein (PKa) inhibition is associated with reduced experimental gastroenterocolitis and arthritis in rodents. In sum, prekallikrein and its enzyme PKa are major targets in HAE providing much opportunity to improve the acute and chronic management of HAE. PKa inhibition also may be a target to ameliorate cardiovascular disease, thrombosis risk, and inflammation as in enterocolitis and arthritis.