Revised model of the tissue factor pathway of thrombin generation: Role of the feedback activation of FXI.
coagulation factor XI
feedback regulation
systems biology
thrombin
tissue factor pathway inhibitor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
26
02
2022
received:
24
11
2021
accepted:
16
03
2022
pubmed:
31
3
2022
medline:
25
5
2022
entrez:
30
3
2022
Statut:
ppublish
Résumé
Biochemical reaction networks are self-regulated in part due to feedback activation mechanisms. The tissue factor (TF) pathway of blood coagulation is a complex reaction network controlled by multiple feedback loops that coalesce around the serine protease thrombin. Our goal was to evaluate the relative contribution of the feedback activation of coagulation factor XI (FXI) in TF-mediated thrombin generation using a comprehensive systems-based analysis. We developed a systems biology model that improves the existing Hockin-Mann (HM) model through an integrative approach of mathematical modeling and in vitro experiments. Thrombin generation measured using in vitro assays revealed that the feedback activation of FXI contributes to the propagation of thrombin generation based on the initial concentrations of TF or activated coagulation factor X (FXa). We utilized experimental data to improve the robustness of the HM model to capture thrombin generation kinetics without a role for FXI before including the feedback activation of FXI by thrombin to construct the extended (ext.) HM model. Using the ext.HM model, we predicted that the contribution of positive feedback of FXI activation by thrombin can be abolished by selectively eliminating the inhibitory function of tissue factor pathway inhibitor (TFPI), a serine protease inhibitor of FXa and TF-activated factor VII (FVIIa) complex. This prediction from the ext.HM model was experimentally validated using thrombin generation assays with function blocking antibodies against TFPI and plasmas depleted of FXI. Together, our results demonstrate the applications of combining experimental and modeling techniques in predicting complex biochemical reaction systems.
Sections du résumé
BACKGROUND
Biochemical reaction networks are self-regulated in part due to feedback activation mechanisms. The tissue factor (TF) pathway of blood coagulation is a complex reaction network controlled by multiple feedback loops that coalesce around the serine protease thrombin.
OBJECTIVES
Our goal was to evaluate the relative contribution of the feedback activation of coagulation factor XI (FXI) in TF-mediated thrombin generation using a comprehensive systems-based analysis.
MATERIALS AND METHODS
We developed a systems biology model that improves the existing Hockin-Mann (HM) model through an integrative approach of mathematical modeling and in vitro experiments. Thrombin generation measured using in vitro assays revealed that the feedback activation of FXI contributes to the propagation of thrombin generation based on the initial concentrations of TF or activated coagulation factor X (FXa). We utilized experimental data to improve the robustness of the HM model to capture thrombin generation kinetics without a role for FXI before including the feedback activation of FXI by thrombin to construct the extended (ext.) HM model.
RESULTS AND CONCLUSIONS
Using the ext.HM model, we predicted that the contribution of positive feedback of FXI activation by thrombin can be abolished by selectively eliminating the inhibitory function of tissue factor pathway inhibitor (TFPI), a serine protease inhibitor of FXa and TF-activated factor VII (FVIIa) complex. This prediction from the ext.HM model was experimentally validated using thrombin generation assays with function blocking antibodies against TFPI and plasmas depleted of FXI. Together, our results demonstrate the applications of combining experimental and modeling techniques in predicting complex biochemical reaction systems.
Identifiants
pubmed: 35352494
doi: 10.1111/jth.15716
pmc: PMC9590754
mid: NIHMS1840383
pii: S1538-7836(22)00203-3
doi:
Substances chimiques
Factor XI
9013-55-2
Thromboplastin
9035-58-9
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1350-1363Subventions
Organisme : NHLBI NIH HHS
ID : R01HL101972
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL158079
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30HL158079
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL101972
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35HL140025
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL140025
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL144113
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144113
Pays : United States
Informations de copyright
© 2022 International Society on Thrombosis and Haemostasis.
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