Prolongation of clot lysis time by a direct thrombin inhibitor melagatran mediated by paradoxical enhancement of thrombin generation : comparison with a direct factor Xa inhibitor edoxaban
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved..
Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
|---|---|
| Enthalten in: |
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis - 32(2021), 3 vom: 01. Apr., Seite 209-215 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Morishima, Yoshiyuki [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
2A9QP32MD4 |
|---|
| Anmerkungen: |
Date Completed 23.06.2021 Date Revised 23.06.2021 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1097/MBC.0000000000001020 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM321203798 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM321203798 | ||
| 003 | DE-627 | ||
| 005 | 20231225175318.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1097/MBC.0000000000001020 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1070.xml |
| 035 | |a (DE-627)NLM321203798 | ||
| 035 | |a (NLM)33560005 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Morishima, Yoshiyuki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prolongation of clot lysis time by a direct thrombin inhibitor melagatran mediated by paradoxical enhancement of thrombin generation |b comparison with a direct factor Xa inhibitor edoxaban |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.06.2021 | ||
| 500 | |a Date Revised 23.06.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. | ||
| 520 | |a Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran | ||
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antithrombins |2 NLM | |
| 650 | 7 | |a Azetidines |2 NLM | |
| 650 | 7 | |a Benzylamines |2 NLM | |
| 650 | 7 | |a Factor Xa Inhibitors |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Thiazoles |2 NLM | |
| 650 | 7 | |a melagatran |2 NLM | |
| 650 | 7 | |a 2A9QP32MD4 |2 NLM | |
| 650 | 7 | |a Thrombin |2 NLM | |
| 650 | 7 | |a EC 3.4.21.5 |2 NLM | |
| 650 | 7 | |a edoxaban |2 NLM | |
| 650 | 7 | |a NDU3J18APO |2 NLM | |
| 700 | 1 | |a Kamisato, Chikako |e verfasserin |4 aut | |
| 700 | 1 | |a Honda, Yuko |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis |d 1992 |g 32(2021), 3 vom: 01. Apr., Seite 209-215 |w (DE-627)NLM012606456 |x 1473-5733 |7 nnns |
| 773 | 1 | 8 | |g volume:32 |g year:2021 |g number:3 |g day:01 |g month:04 |g pages:209-215 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1097/MBC.0000000000001020 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 32 |j 2021 |e 3 |b 01 |c 04 |h 209-215 | ||