Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.
Blood Coagulation
/ physiology
Bradykinin
/ chemistry
Calcium
/ chemistry
Cations, Divalent
Factor IX
/ chemistry
Factor XI
/ chemistry
Factor XII
/ chemistry
Fibrin
/ chemistry
Humans
Kallikreins
/ chemistry
Kinetics
Phosphatidylcholines
/ chemistry
Phosphatidylethanolamines
/ chemistry
Phosphatidylserines
/ chemistry
Protein Binding
Thrombin
/ chemistry
Factor IX
Factor XII
intrinsic pathway
plasma kallikrein
prekallikrein
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
19 01 2021
19 01 2021
Historique:
entrez:
5
1
2021
pubmed:
6
1
2021
medline:
13
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33397811
pii: 2014810118
doi: 10.1073/pnas.2014810118
pmc: PMC7826336
pii:
doi:
Substances chimiques
Cations, Divalent
0
Phosphatidylcholines
0
Phosphatidylethanolamines
0
Phosphatidylserines
0
dioleoyl phosphatidylethanolamine
2462-63-7
1,2-dioleoylphosphatidylserine
70614-14-1
Factor IX
9001-28-9
Factor XII
9001-30-3
Fibrin
9001-31-4
Factor XI
9013-55-2
Kallikreins
EC 3.4.21.-
Thrombin
EC 3.4.21.5
1,2-oleoylphosphatidylcholine
EDS2L3ODLV
Bradykinin
S8TIM42R2W
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : British Heart Foundation
ID : SP/14/1/30717
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110373
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R35 HL140025
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_14109
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_18053
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001502
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17165
Pays : United Kingdom
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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