Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency
Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) was recently implicated as a modifying factor in individuals with bleeding of unknown cause.
OBJECTIVES: To determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals.
METHODS: The effects of TFPI on thrombin generation and clot formation, structure, and fibrinolysis in FXI-deficient plasma were measured in vitro in the absence or presence of inhibitory anti-TFPI antibody or exogenous recombinant TFPIα. Total plasma TFPI concentration was measured in 2 independent cohorts of controls and FXI-deficient individuals classified as bleeders or nonbleeders (cohort 1: 10 controls and 16 FXI-deficient individuals; cohort 2: 48 controls and 57 FXI-deficient individuals) and correlated with ex vivo plasma clot formation and fibrinolysis parameters associated with bleeding risk.
RESULTS: In an in vitro FXI deficiency model, inhibition of TFPI enhanced thrombin generation and clot formation, increased the network density, and decreased fibrinolysis, whereas an increase in TFPI had the opposite effects. Compared with controls, plasma from FXI-deficient bleeders had higher TFPI concentration. Total plasma TFPI concentrations correlated with parameters from ex vivo clotting and fibrinolysis assays that differentiate FXI-deficient bleeders and nonbleeders.
CONCLUSION: Coagulation and fibrinolysis parameters that differentiate FXI-deficient nonbleeders and bleeders were altered by plasma TFPIα. Total plasma TFPI was increased in FXI-deficient bleeders. TFPI may modify the bleeding risk in FXI-deficient individuals.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 21(2023), 3 vom: 25. März, Seite 467-479 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Reitsma, Stéphanie E [VerfasserIn] |
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| Links: |
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| Themen: |
9013-55-2 |
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| Anmerkungen: |
Date Completed 03.03.2023 Date Revised 02.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jtha.2022.10.005 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352067470 |
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| 100 | 1 | |a Reitsma, Stéphanie E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 02.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) was recently implicated as a modifying factor in individuals with bleeding of unknown cause | ||
| 520 | |a OBJECTIVES: To determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals | ||
| 520 | |a METHODS: The effects of TFPI on thrombin generation and clot formation, structure, and fibrinolysis in FXI-deficient plasma were measured in vitro in the absence or presence of inhibitory anti-TFPI antibody or exogenous recombinant TFPIα. Total plasma TFPI concentration was measured in 2 independent cohorts of controls and FXI-deficient individuals classified as bleeders or nonbleeders (cohort 1: 10 controls and 16 FXI-deficient individuals; cohort 2: 48 controls and 57 FXI-deficient individuals) and correlated with ex vivo plasma clot formation and fibrinolysis parameters associated with bleeding risk | ||
| 520 | |a RESULTS: In an in vitro FXI deficiency model, inhibition of TFPI enhanced thrombin generation and clot formation, increased the network density, and decreased fibrinolysis, whereas an increase in TFPI had the opposite effects. Compared with controls, plasma from FXI-deficient bleeders had higher TFPI concentration. Total plasma TFPI concentrations correlated with parameters from ex vivo clotting and fibrinolysis assays that differentiate FXI-deficient bleeders and nonbleeders | ||
| 520 | |a CONCLUSION: Coagulation and fibrinolysis parameters that differentiate FXI-deficient nonbleeders and bleeders were altered by plasma TFPIα. Total plasma TFPI was increased in FXI-deficient bleeders. TFPI may modify the bleeding risk in FXI-deficient individuals | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a TFPI | |
| 650 | 4 | |a factor XI | |
| 650 | 4 | |a fibrin | |
| 650 | 4 | |a fibrinolysis | |
| 650 | 4 | |a tissue factor pathway inhibitor | |
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| 650 | 7 | |a EC 3.4.21.5 |2 NLM | |
| 650 | 7 | |a lipoprotein-associated coagulation inhibitor |2 NLM | |
| 650 | 7 | |a Factor XI |2 NLM | |
| 650 | 7 | |a 9013-55-2 |2 NLM | |
| 700 | 1 | |a Holle, Lori A |e verfasserin |4 aut | |
| 700 | 1 | |a Bouck, Emma G |e verfasserin |4 aut | |
| 700 | 1 | |a Monroe, Dougald M |e verfasserin |4 aut | |
| 700 | 1 | |a Mast, Alan E |e verfasserin |4 aut | |
| 700 | 1 | |a Burthem, John |e verfasserin |4 aut | |
| 700 | 1 | |a Bolton-Maggs, Paula H B |e verfasserin |4 aut | |
| 700 | 1 | |a Gidley, Gillian N |e verfasserin |4 aut | |
| 700 | 1 | |a Wolberg, Alisa S |e verfasserin |4 aut | |
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