Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay.
BACKGROUND
In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI).


METHODS
Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation.


RESULTS
When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM®thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV-t), and with all measured thrombin generation parameters. In vivo, CT, MaxV-t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax(+461% for PCC, +87.5% for aPCC).


CONCLUSIONS
Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents.


BACKGROUND
EudracCT trial no. 213-00474-30.
Department of General and Surgical Intensive Care Medicine bettina.schenk@i-med.ac.at.
B
B
Schenk
Central Institute for Medical and Chemical Laboratory Diagnostics.
P
P
Würtinger
Department of Paediatrics.
W
W
Streif
Department of Internal Medicine, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria.
W
W
Sturm
Department of General and Surgical Intensive Care Medicine.
D
D
Fries
Department of General and Surgical Intensive Care Medicine.
M
M
Bachler
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests / Q000379:methods; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069552:Rivaroxaban / Q000494:pharmacology*; D013916:Thrombelastography / Q000379:methods*; D013917:Thrombin / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban; D013917:Thrombin
blood, anticoagulants; complications, haemorrhage; thromboelastography