In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers.
BACKGROUND
Four-factor prothrombin complex concentrate (PCC) (Cofact; Sanquin Blood Supply) 50 IU kg(-1) increased thrombin generation beyond baseline values in healthy, rivaroxaban-treated subjects.


OBJECTIVE
To assess whether infusion with doses of 37.5 IU kg(-1) and 25 IU kg(-1) PCC reverses the anticoagulant effect of high-dose apixaban, another oral direct factor Xa inhibitor.


METHODS
In a randomized, double-blind, placebo-controlled, crossover study, six healthy subjects received twice-daily apixaban 10 mg for 3.5 days followed by a single bolus of 37.5 IU kg(-1) PCC, 25 IU kg(-1) PCC, or placebo. The primary outcome was the effect of PCC 15 min after infusion on thrombin generation (endogenous thrombin potential [ETP]); secondary outcomes were the immediate effect of PCC on prothrombin time (PT) and the effect of PCC as compared with placebo over a period of 24 h on ETP and PT.


RESULTS
Fifteen minutes after infusion of 37.5 IU kg(-1) and 25 IU kg(-1) PCC, ETP increased from 41% ± 11% to 56% ± 23% (P = 0.06) and from 44% ± 12% to 51% ± 15% (P = 0.03), respectively. ETP significantly differed over time between 37.5 IU kg(-1) PCC and placebo during 24 h after infusion (P < 0.01). Both PCC doses restored apixaban-induced PT prolongation after 15 min (P < 0.01), and this was sustained over a period of 24 h.


CONCLUSIONS
Both 37.5 IU kg(-1) PCC and 25 IU/kg PCC improved coagulation parameters in healthy subjects, suggesting partial reversal of the anticoagulant effect of apixaban. This implies that PCC might be considered in patients with apixaban-associated bleeding. However, ETP was not immediately restored to pre-apixaban levels, suggesting that these doses are too low to instantly and fully restore hemostasis at peak apixaban levels.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Y W
YW
Cheung
Department of Internal Medicine, IRCCS Policlinico 'San Matteo' Foundation, University of Pavia, Pavia, Italy.
S
S
Barco
Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.
B A
BA
Hutten
Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.
J C M
JC
Meijers
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
S
S
Middeldorp
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
M
M
Coppens
D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000008:administration & dosage*; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors / Q000008:administration & dosage*; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009426:Netherlands; D011720:Pyrazoles / Q000008:administration & dosage*; D011728:Pyridones / Q000008:administration & dosage*; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
D015415:Biomarkers; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C025667:prothrombin complex concentrates; C522181:apixaban; D013917:Thrombin
anticoagulants; apixaban; factor Xa inhibitors; hemorrhage; prothrombin complex concentrates; randomized controlled trial