The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor

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Abstract

Background

An increasing number of patients are treated with direct-acting oral anticoagulants (DOACs), but the optimal way to reverse the anticoagulant effect is not known. Specific antidotes are not available and prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are variously used as reversal agents in case of a major bleeding. We aimed to determine the most effective haemostatic agent and dose to reverse the effect of rivaroxaban in blood samples from patients taking rivaroxaban for therapeutic reasons.

Methods

Blood samples from rivaroxaban-treated patients ( n = 50) were spiked with PCC, aPCC and rFVIIa at concentrations imitating 80%, 100% and 125% of suggested therapeutic doses. The reversal effect was assessed by thromboelastometry in whole blood and a thrombin generation assay (TGA) in platelet-poor plasma. Samples from healthy subjects ( n = 40) were included as controls.

Results

In thromboelastometry measurements, aPCC and rFVIIa had a superior effect to PCC in reversing the rivaroxaban-induced lenghtening of clotting time (CT). aPCC was the only haemostatic agent that shortened the CT down to below the control level. Compared to healthy controls, patients on rivaroxaban also had a prolonged lag time and decreased peak concentration, velocity index and endogenous thrombin potential (ETP) in platelet-poor plasma. aPCC reversed these parameters more effectively than rFVIIa and PCC. There were no differences in efficacy between 80%, 100% and 125% doses of aPCC.

Conclusions

aPCC seems to reverse the anticoagulant effect of rivaroxaban more effectively than rFVIIa and PCC by evaluation with thromboelastometry and TGA in vitro.

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Most cited references 26

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Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.

Elise S Eerenberg, Pieter Kamphuisen, Meertien K Sijpkens … (2011)

Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration- URL: http://www.trialregister.nl. Unique identifier: NTR2272.

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Calibrated Automated Thrombin Generation Measurement in Clotting Plasma

H. Coenraad Hemker, Peter L A Giesen, Raed Al Dieri … (2003)

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Thrombin generation, a function test of the haemostatic-thrombotic system.

Raed Al-Yamori, S Béguin, Erik De Clercq … (2006)

By the use of a fluorogenic thrombin substrate and continuous calibration of each individual sample, it is now possible to obtain a thrombin generation (TG) curve (or thrombogram) in plasma, with or without platelets, in an easy routine procedure at high throughput and with an acceptable experimental error (<5%). Evidence is growing that the parameters of the thrombogram, and notably the area under the curve (endogenous thrombin potential, ETP), are useful in assessing bleeding- or thrombotic risk and its modification by antithrombotic- or haemostatic treatment. Available data strongly suggest that conditions (congenital, acquired, drug-induced) that increase TG all cause a thrombotic tendency and that conditions that decrease TG prevent thrombosis but, beyond a limit, cause bleeding. Diminution of TG is a common denominator of all antithrombotic treatment, including anti-platelet drugs. The thrombogram can also be used as a tool in the search for new antithrombotics and reflects the haemorrhagic or thrombotic side effects of other drugs (e.g. oral contraceptives). The thrombogram thus is a promising new approach to clinical management of bleeding and thrombotic disease as well as a tool in drug research and epidemiology. Our experience at this moment is insufficient, however, to already clearly define its limits.

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Author and article information

Contributors

Nina Haagenrud Schultz: schultzj@online.no

Hoa Thi Tuyet Tran: htra@ahus.no

Stine Bjørnsen: stine.bjornsen@medisin.uio.no

Carola Elisabeth Henriksson: carola.henriksson@medisin.uio.no

Per Morten Sandset: p.m.sandset@medisin.uio.no

Pål Andre Holme: pholme@ous-hf.no

Journal

Journal ID (nlm-ta): Thromb J

Journal ID (iso-abbrev): Thromb J

Title: Thrombosis Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-9560

Publication date (Electronic): 20 February 2017

Publication date PMC-release: 20 February 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 6

Affiliations

[1 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Research Institute of Internal Medicine, , Oslo University Hospital, ; Box 4950, Nydalen, N-0424 Oslo, Norway

[2 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Haematology, , Oslo University Hospital, ; Box 4950, Nydalen, N-0424 Oslo, Norway

[3 ]ISNI 0000 0000 9637 455X, GRID grid.411279.8, Department of Haematology, , Akershus University Hospital, ; N-1478 Lørenskog, Norway

[4 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Institute of Clinical Medicine, Faculty of Medicine, , University of Oslo, ; Box 1171, Blindern, N-0318 Oslo, Norway

[5 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Medical Biochemistry, , Oslo University Hospital, ; Box 4950, Nydalen, N-0424 Oslo, Norway

Article

Publisher ID: 129

DOI: 10.1186/s12959-017-0129-1

PMC ID: 5319105

PubMed ID: 28239301

SO-VID: 356aef57-114a-4105-b468-9f2160286f4f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 November 2016

Date accepted : 14 February 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000801, Bayer HealthCare;

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ScienceOpen disciplines: Cardiovascular Medicine

Keywords: rivaroxaban,reversal,prothrombin complex concentrate,activated prothrombin complex concentrate,recombinant afviia

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ScienceOpen disciplines: Cardiovascular Medicine

Keywords: rivaroxaban, reversal, prothrombin complex concentrate, activated prothrombin complex concentrate, recombinant afviia

The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor

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Most cited references 26

Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.

Calibrated Automated Thrombin Generation Measurement in Clotting Plasma

Thrombin generation, a function test of the haemostatic-thrombotic system.

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