Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis.
BACKGROUND
As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis.


METHODS
After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min.


RESULTS
Apixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs.


CONCLUSIONS
rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.
INSERM UMR S765, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Cardiology, Hôpital du Val de Grâce, Paris, France.
Anne-Céline
AC
Martin
Bernard
B
Le Bonniec
Anne-Marie
AM
Fischer
Catherine
C
Marchand-Leroux
Pascale
P
Gaussem
Charles-Marc
CM
Samama
Anne
A
Godier
D000818:Animals; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015942:Factor VIIa / Q000627:therapeutic use*; D005340:Fibrinogen / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011728:Pyridones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D001779:Blood Coagulation Factors; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; C522181:apixaban; D005340:Fibrinogen; C103587:recombinant FVIIa; D015942:Factor VIIa
Animal model; Apixaban reversal; Haemorrhage; New oral anticoagulants; Thrombosis