Semin Thromb Hemost
DOI: 10.1055/s-0043-57034
Review Article

Plasma Kallikrein as a Forgotten Clotting Factor

1   Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
2   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
3   Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
4   Division of Hematology and UNC Blood Research Center, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
1   Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
› Author Affiliations
Funding H.P. acknowledges funding from the British Heart Foundation (SP/14/1/30717), the Wellcome Trust (110373), the Medical Research Council Confidence in Concept (MC_PC_14109), and Innovate UK (30084). J.E. acknowledges funding from the British Heart Foundation Program Grant no. RG/12/9/29775. N.S.K. acknowledges funding support from the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (Grant # UO1HL117659).


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.

Publication History

Article published online:
18 April 2023

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