Plasma Kallikrein as a Forgotten Clotting Factor

Authors: Kearney, KJ; Spronk, HM; Emsley, J; Key, NS; Philippou, H

Affiliations: Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Dept Discovery & Translat Sci, Leeds, England. Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Biochem, Lab Clin Thrombosis & Haemostasis, Maastricht, Netherlands. Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Lab Clin Thrombosis & Haemostasis, Maastricht, Netherlands. Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England. Univ N Carolina, Dept Med, Div Hematol, Chapel Hill, NC USA. Univ N Carolina, UNC Blood Res Ctr, Dept Med, Chapel Hill, NC USA. Univ Leeds, LIGHT Labs, Clarendon Way, Leeds LS2 9JT, England.

Publication: Seminars in Thrombosis and Hemostasis; 2023

Abstract: For decades, it was considered that plasma kallikrein’s (PKa) sole function within the coagulation cascade is the activation of factor (F)XII. Until recently, the two key known activators of FIX within the coagulation cascade were activated FXI(a) and the tissue factor-FVII(a) complex. Simultaneously, and using independent experimental approaches, three groups identified a new branch of the coagulation cascade, whereby PKa can directly activate FIX. These key studies identified that (1) FIX or FIXa can bind with high affinity to either prekallikrein (PK) or PKa; (2) in human plasma, PKa can dose dependently trigger thrombin generation and clot formation independent of FXI; (3) in FXI knockout murine models treated with intrinsic pathway agonists, PKa activity results in increased formation of FIXa:AT complexes, indicating direct activation of FIX by PKa in vivo. These findings suggest that there is both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation. These three recent studies are described within this review, alongside historical data that hinted at the existence of this novel role of PKa as a coagulation clotting factor. The implications of direct PKa cleavage of FIX remain to be determined physiologically, pathophysiologically, and in the context of next-generation anticoagulants in development.