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Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution

BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its...

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Autores principales: Grottke, Oliver, van Ryn, Joanne, Zentai, Christian, Gan, Guanfa, Honickel, Markus, Rossaint, Rolf, ten Cate, Hugo, Spronk, Henri M. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322768/
https://www.ncbi.nlm.nih.gov/pubmed/30615630
http://dx.doi.org/10.1371/journal.pone.0209350
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author Grottke, Oliver
van Ryn, Joanne
Zentai, Christian
Gan, Guanfa
Honickel, Markus
Rossaint, Rolf
ten Cate, Hugo
Spronk, Henri M. H.
author_facet Grottke, Oliver
van Ryn, Joanne
Zentai, Christian
Gan, Guanfa
Honickel, Markus
Rossaint, Rolf
ten Cate, Hugo
Spronk, Henri M. H.
author_sort Grottke, Oliver
collection PubMed
description BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer’s solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.
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spelling pubmed-63227682019-01-19 Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution Grottke, Oliver van Ryn, Joanne Zentai, Christian Gan, Guanfa Honickel, Markus Rossaint, Rolf ten Cate, Hugo Spronk, Henri M. H. PLoS One Research Article BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer’s solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran. Public Library of Science 2019-01-07 /pmc/articles/PMC6322768/ /pubmed/30615630 http://dx.doi.org/10.1371/journal.pone.0209350 Text en © 2019 Grottke et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Grottke, Oliver
van Ryn, Joanne
Zentai, Christian
Gan, Guanfa
Honickel, Markus
Rossaint, Rolf
ten Cate, Hugo
Spronk, Henri M. H.
Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title_full Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title_fullStr Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title_full_unstemmed Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title_short Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution
title_sort volume replacement strategies do not impair the binding of dabigatran to idarucizumab: porcine model of hemodilution
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322768/
https://www.ncbi.nlm.nih.gov/pubmed/30615630
http://dx.doi.org/10.1371/journal.pone.0209350
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