Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial

Bettina Schenk; Stephanie Goerke; Ronny Beer; Raimund Helbok; Dietmar Fries; Mirjam Bachler

doi:10.1186/s12959-017-0158-9

Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial

Thromb J. 2018 Jan 10:16:1. doi: 10.1186/s12959-017-0158-9. eCollection 2018.

Authors

Bettina Schenk¹, Stephanie Goerke^{2

3}, Ronny Beer⁴, Raimund Helbok⁴, Dietmar Fries¹, Mirjam Bachler^{1

5}

Affiliations

¹ 1Department of General and Surgical Intensive Care Medicine, Medical University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
² 2Department of Neurosurgery, Medical University of Innsbruck, Anichstr. 35, Innsbruck, 6020 Austria.
³ 3Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Anichstr. 35, Innsbruck, 6020 Austria.
⁴ 4Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
⁵ 5Institute for Sports Medicine, Alpine Medicine and Health Tourism, UMIT - University for Health Sciences, Medical Informatics and Technology, Eduard Wallnöfer Zentrum 1, 6060 Hall in Tirol, Austria.

Abstract

Background: Direct oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent.

Methods: Patients with life-threatening bleeding events during rivaroxaban treatment were included and administered 25 U kg^-1 of PCC. Blood samples were collected immediately prior to as well as after PCC treatment at predefined time intervals. The primary endpoint was defined as the difference in thrombin generation (TG) parameters ETP (endogenous thrombin potential) and C_max (peak thrombin generation) prior to and ten minutes subsequent to PCC treatment.

Results: Thirteen patients, of whom the majority suffered from intra-cranial haemorrhage (ICH) or subdural haemorrhage (SDH), were included and administered PCC. The results show that the ETP (TG) significantly (p = 0.001) improved by 68% and C_max (TG) by 54% (p = 0.001) during PCC treatment. In addition, the Quick value (prothrombin time: Quick^PT) significantly improved by 28% and the activated partial thromboplastin time (aPTT) was decreased by 7% ten minutes after PCC administration. C_max was reduced at baseline, but not ETP, aPTT or Quick^PT. Lag time until initiation (TG, t_lag), thromboelastometry clotting time (CT_EXTEM) and time to peak (TG, t_max) correlated best with measured rivaroxaban levels and were out of normal ranges at baseline, but did not improve after PCC administration. In 77% of the patients bleeding (ICH/SDH-progression) ceased following PCC administration. During the study three participants passed away due to other complications not related to PCC treatment. The possibility of thrombosis formation was also evaluated seven days after administering PCC and no thromboses were found.

Conclusions: This study shows that use of PCC improved ETP, C_max, Quick^PT and aPTT. However, of these parameters, only C_max was reduced at the defined baseline. It can be concluded that CT_EXTEM, t_lag and t_max correlated best with the measured rivaroxaban levels. The study drug was found to be safe. Nonetheless, additional studies specifically targeting assessment of clinical endpoints should be performed to further confirm these findings.

Clinical trial registration: EudraCT trial No. 2013-004484-31.