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More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate

Lindahl, Tomas L ; Wallstedt, Maria ; Gustafsson, Kerstin M ; Persson, Egon and Hillarp, Andreas LU (2015) In Thrombosis Research 135(3). p.7-544
Abstract

The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa®). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 μg/L. We measured clotting time being induced by... (More)

The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa®). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 μg/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2™ and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2™. Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 μg/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis' correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Antithrombins/pharmacology, Blood Coagulation/drug effects, Blood Coagulation Factors/pharmacology, Dabigatran/pharmacology, Factor VIIa/pharmacology, Hemostatics/pharmacology, Humans, Platelet-Rich Plasma/drug effects, Recombinant Proteins/pharmacology
in
Thrombosis Research
volume
135
issue
3
pages
7 - 544
publisher
Elsevier
external identifiers
  • pmid:25596769
  • scopus:84925823784
ISSN
1879-2472
DOI
10.1016/j.thromres.2014.12.019
language
English
LU publication?
no
additional info
Copyright © 2014 Elsevier Ltd. All rights reserved.
id
7dea7bcf-d7ad-4e3e-88f0-3b2bf19b8dff
date added to LUP
2022-08-29 10:55:29
date last changed
2024-04-04 11:08:59
@article{7dea7bcf-d7ad-4e3e-88f0-3b2bf19b8dff,
  abstract     = {{<p>The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa®). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 μg/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2™ and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2™. Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 μg/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis' correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients.</p>}},
  author       = {{Lindahl, Tomas L and Wallstedt, Maria and Gustafsson, Kerstin M and Persson, Egon and Hillarp, Andreas}},
  issn         = {{1879-2472}},
  keywords     = {{Antithrombins/pharmacology; Blood Coagulation/drug effects; Blood Coagulation Factors/pharmacology; Dabigatran/pharmacology; Factor VIIa/pharmacology; Hemostatics/pharmacology; Humans; Platelet-Rich Plasma/drug effects; Recombinant Proteins/pharmacology}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{7--544}},
  publisher    = {{Elsevier}},
  series       = {{Thrombosis Research}},
  title        = {{More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate}},
  url          = {{http://dx.doi.org/10.1016/j.thromres.2014.12.019}},
  doi          = {{10.1016/j.thromres.2014.12.019}},
  volume       = {{135}},
  year         = {{2015}},
}