In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.
Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0.03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.|Department of Internal Medicine, IRCCS Policlinico "San Matteo" Foundation, University of Pavia, Pavia, Italy.
Stefano
http://orcid.org/0000-0002-2618-347X
S
Barco
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Y
Y
Whitney Cheung
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Michiel
M
Coppens
Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Barbara A
BA
Hutten
Department of Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.|Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.
Joost C M
JC
Meijers
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Saskia
S
Middeldorp
D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001780:Blood Coagulation Tests / Q000379:methods; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D000069552:Rivaroxaban / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis; D055815:Young Adult
D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; C025667:prothrombin complex concentrates; D000069552:Rivaroxaban; D013917:Thrombin
anticoagulant reversal; prothrombin complex concentrate; prothrombin time; rivaroxaban; thrombin generation