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Plasma Kallikrein as a Forgotten Clotting Factor
Katherine J Kearney1, Henri M H Spronk2, Jonas Emsley3
1Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.
Seminars in Thrombosis and Hemostasis
|April 18, 2023
Summary
Plasma kallikrein (PKa) has a newly discovered role in activating Factor IX (FIX), independent of Factor XI. This finding reveals a non-canonical pathway in blood coagulation, with implications for future anticoagulant therapies.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Plasma kallikrein (PKa) was traditionally recognized solely for activating Factor XII.
- Factor IX (FIX) activation was primarily attributed to Factor XIa and the TF-FVIIa complex.
Purpose of the Study:
- To review recent findings identifying a novel, direct activation pathway of FIX by PKa.
- To discuss the implications of this PKa-dependent FIX activation in the coagulation cascade.
Main Methods:
- Review of three independent studies using biochemical and in vivo murine models.
- Analysis of FIX/FIXa binding to prekallikrein (PK)/PKa.
- Assessment of thrombin generation and FIXa:AT complex formation in human plasma and FXI knockout mice.
Main Results:
- PKa directly activates FIX, independent of FXI.
- PKa binds with high affinity to PK/PKa.
- PKa triggers thrombin generation and clot formation in human plasma and in vivo.
- Evidence supports both canonical (FXIa-dependent) and non-canonical (PKa-dependent) FIX activation pathways.
Conclusions:
- A novel, PKa-dependent pathway for FIX activation has been identified, expanding the understanding of blood coagulation.
- This discovery opens new avenues for investigating physiological and pathophysiological roles of PKa in hemostasis.
- The findings have potential relevance for the development of next-generation anticoagulants.
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