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Published in: Thrombosis Journal 1/2017

Open Access 01-12-2017 | Research

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

Authors: Nina Haagenrud Schultz, Hoa Thi Tuyet Tran, Stine Bjørnsen, Carola Elisabeth Henriksson, Per Morten Sandset, Pål Andre Holme

Published in: Thrombosis Journal | Issue 1/2017

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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.
Literature
1.
go back to reference van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968–75.CrossRefPubMed van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968–75.CrossRefPubMed
2.
go back to reference Yeh CH, Hogg K, Weitz JI. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015;35:1056–65.CrossRefPubMed Yeh CH, Hogg K, Weitz JI. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015;35:1056–65.CrossRefPubMed
3.
go back to reference Coleman CI, Antz M, Bowrin K, Evers T, Simard EP, Bonnemeier H, et al. Real-world evidence on stroke prevention in patients with atrial fibrillation in the United States: the REVISIT-US study. Curr Med Res Opin. 2016;32:2047–53.CrossRefPubMed Coleman CI, Antz M, Bowrin K, Evers T, Simard EP, Bonnemeier H, et al. Real-world evidence on stroke prevention in patients with atrial fibrillation in the United States: the REVISIT-US study. Curr Med Res Opin. 2016;32:2047–53.CrossRefPubMed
4.
go back to reference Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.CrossRefPubMed Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.CrossRefPubMed
5.
go back to reference Eerenberg ES, Middeldorp S, Levi M, Lensing AW, Büller HR. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost. 2015;13:1590–6.CrossRefPubMed Eerenberg ES, Middeldorp S, Levi M, Lensing AW, Büller HR. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost. 2015;13:1590–6.CrossRefPubMed
6.
go back to reference Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost. 2014;20:665–72.CrossRefPubMed Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost. 2014;20:665–72.CrossRefPubMed
7.
go back to reference Larsen TB, Rasmussen LH, Skjøth F, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264–73.CrossRefPubMed Larsen TB, Rasmussen LH, Skjøth F, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264–73.CrossRefPubMed
8.
go back to reference Kucher N, Aujesky D, Beer JH, Mazzolai L, Baldi T, Banyai M, et al. Rivaroxaban for the treatment of venous thromboembolism. The SWIss Venous ThromboEmbolism Registry(SWIVTER). Thromb Haemost. 2016;116:472–9.CrossRefPubMed Kucher N, Aujesky D, Beer JH, Mazzolai L, Baldi T, Banyai M, et al. Rivaroxaban for the treatment of venous thromboembolism. The SWIss Venous ThromboEmbolism Registry(SWIVTER). Thromb Haemost. 2016;116:472–9.CrossRefPubMed
9.
go back to reference Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis. 2013;106:382–93.CrossRefPubMed Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis. 2013;106:382–93.CrossRefPubMed
10.
go back to reference Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87:S141–5.CrossRefPubMed Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87:S141–5.CrossRefPubMed
11.
go back to reference Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413–24.CrossRefPubMed Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413–24.CrossRefPubMed
12.
go back to reference Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110:162–72.CrossRefPubMed Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110:162–72.CrossRefPubMed
13.
go back to reference Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.CrossRefPubMed Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.CrossRefPubMed
14.
go back to reference Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, Molina P, Reverter JC, Carné X, et al. Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers. Transfus Med Rev. 2015;29:242–9.CrossRefPubMed Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, Molina P, Reverter JC, Carné X, et al. Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers. Transfus Med Rev. 2015;29:242–9.CrossRefPubMed
15.
go back to reference Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013;11:1111–8.CrossRefPubMed Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013;11:1111–8.CrossRefPubMed
16.
go back to reference Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9.CrossRefPubMed Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9.CrossRefPubMed
17.
go back to reference Escolar G, Arellano-Rodrigo E, Lopez-Vilchez I, Molina P, Sanchis J, Reverter JC, et al. Reversal of rivaroxaban-induced alterations on hemostasis by different coagulation factor concentrates - in vitro studies with steady and circulating human blood. Circ J. 2015;79:331–8.CrossRefPubMed Escolar G, Arellano-Rodrigo E, Lopez-Vilchez I, Molina P, Sanchis J, Reverter JC, et al. Reversal of rivaroxaban-induced alterations on hemostasis by different coagulation factor concentrates - in vitro studies with steady and circulating human blood. Circ J. 2015;79:331–8.CrossRefPubMed
18.
go back to reference Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–24.CrossRefPubMed Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–24.CrossRefPubMed
19.
go back to reference Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133:671–81.CrossRefPubMed Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133:671–81.CrossRefPubMed
20.
go back to reference Korber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann C. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost. 2014;20:735–40.CrossRefPubMed Korber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann C. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost. 2014;20:735–40.CrossRefPubMed
21.
go back to reference Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015;13:S187–94.CrossRefPubMed Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015;13:S187–94.CrossRefPubMed
22.
go back to reference Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012;126:2428–32.CrossRefPubMed Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012;126:2428–32.CrossRefPubMed
23.
go back to reference Samama MM, Contant G, Spiro TE, Perzborn E, Flem LL, Guinet C, et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107:379–87.CrossRefPubMed Samama MM, Contant G, Spiro TE, Perzborn E, Flem LL, Guinet C, et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107:379–87.CrossRefPubMed
24.
go back to reference Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4–15.CrossRefPubMed Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4–15.CrossRefPubMed
25.
go back to reference Hemker HC, Al Dieri R, de Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96:553–61.PubMed Hemker HC, Al Dieri R, de Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96:553–61.PubMed
26.
go back to reference Sørensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost. 2003;1:551–8.CrossRefPubMed Sørensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost. 2003;1:551–8.CrossRefPubMed
27.
go back to reference Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2014;111:989–95.CrossRefPubMed Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2014;111:989–95.CrossRefPubMed
28.
go back to reference Kohler M, Hellstern P, Lechler E, Uberfuhr P, Müller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998;80:399–402.PubMed Kohler M, Hellstern P, Lechler E, Uberfuhr P, Müller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998;80:399–402.PubMed
29.
go back to reference Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues. Haemophilia. 2008;14:39–43.CrossRefPubMed Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues. Haemophilia. 2008;14:39–43.CrossRefPubMed
30.
go back to reference O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8.CrossRefPubMed O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8.CrossRefPubMed
31.
go back to reference Messana E, Wilson SS. Activated Pcc (Feiba) for Reversal of Rivaroxaban-Induced Life-Threatening Bleeding-a Case Series. Crit Care Med. 2015;43:303.CrossRef Messana E, Wilson SS. Activated Pcc (Feiba) for Reversal of Rivaroxaban-Induced Life-Threatening Bleeding-a Case Series. Crit Care Med. 2015;43:303.CrossRef
32.
go back to reference Maurice-Szamburski A, Graillon T, Bruder N. Favorable outcome after a subdural hematoma treated with feiba in a 77-year old patient treated with rivaroxaban. J Neurosurg Anesthesiol. 2014;26:183.CrossRefPubMed Maurice-Szamburski A, Graillon T, Bruder N. Favorable outcome after a subdural hematoma treated with feiba in a 77-year old patient treated with rivaroxaban. J Neurosurg Anesthesiol. 2014;26:183.CrossRefPubMed
33.
go back to reference Kiraly A, Lyden A, Periyanayagam U, Chan J, Pang PS. Management of hemorrhage complicated by novel oral anticoaogulantsin the emergency department: case report from the northwestern emergency medicine residency. Am J Ther. 2013;20:300–6.PubMed Kiraly A, Lyden A, Periyanayagam U, Chan J, Pang PS. Management of hemorrhage complicated by novel oral anticoaogulantsin the emergency department: case report from the northwestern emergency medicine residency. Am J Ther. 2013;20:300–6.PubMed
34.
go back to reference Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA. The role of FEIBA in reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage. Neurocrit Care. 2016;24:413–9.CrossRefPubMed Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA. The role of FEIBA in reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage. Neurocrit Care. 2016;24:413–9.CrossRefPubMed
Metadata
Title
The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor
Authors
Nina Haagenrud Schultz
Hoa Thi Tuyet Tran
Stine Bjørnsen
Carola Elisabeth Henriksson
Per Morten Sandset
Pål Andre Holme
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Thrombosis Journal / Issue 1/2017
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/s12959-017-0129-1

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