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Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI

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Title: Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI
Authors: Kearney, KJ
Butler, J
Posada, OM
Wilson, C
Heal, S
Ali, M
Hardy, L
Ahnstrom, J
Gailani, D
Foster, R
Hethershaw, E
Longstaff, C
Philippou, H
Item Type: Journal Article
Abstract: Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.
Issue Date: 28-Jan-2021
Date of Acceptance: 1-Jan-2021
URI: http://hdl.handle.net/10044/1/86429
DOI: 10.1073/pnas.2014810118
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: 1
End Page: 9
Journal / Book Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 118
Issue: 3
Copyright Statement: © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
plasma kallikrein
prekallikrein
Factor IX
intrinsic pathway
Factor XII
MOLECULAR-WEIGHT KININOGEN
HUMAN-PLASMA PREKALLIKREIN
DEFICIENCY
MECHANISM
MICE
IDENTIFICATION
HEMOSTASIS
COFACTOR
PROTEASE
BINDING
Factor IX
Factor XII
intrinsic pathway
plasma kallikrein
prekallikrein
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
plasma kallikrein
prekallikrein
Factor IX
intrinsic pathway
Factor XII
MOLECULAR-WEIGHT KININOGEN
HUMAN-PLASMA PREKALLIKREIN
DEFICIENCY
MECHANISM
MICE
IDENTIFICATION
HEMOSTASIS
COFACTOR
PROTEASE
BINDING
Publication Status: Published
Open Access location: https://www.pnas.org/content/118/3/e2014810118.long
Article Number: ARTN e2014810118
Online Publication Date: 2021-01-04
Appears in Collections:Department of Immunology and Inflammation



This item is licensed under a Creative Commons License Creative Commons