Ticagrelor reversal:in vitroassessment of four haemostatic agents.
OBJECTIVE
Management of ticagrelor-induced bleeding is challenging as platelet transfusion is ineffective. An effective strategy is needed. This study aimed to investigatein vitrothe efficacy of four haemostatic drugs (HDs), namely recombinant activated factor VII (rFVIIa), fibrinogen concentrate (Fib), tranexamic acid (TXA) and factor XIII concentrate (FXIII) to improve the haemostatic capacity in the presence of ticagrelor.


METHODS
Blood was spiked with ticagrelor then supplemented by either HD or control. Several assays were performed: ADP-induced platelet aggregation measured by impedance aggregometry, light transmission and two global assays, thrombolastography with the platelet mapping device (TEG-PM) and a platelet-dependent thrombin generation assay (TGA).


RESULTS
Ticagrelor inhibited ADP-induced platelet aggregation and decreased the clot strength maximum amplitude (MA) in TEG-PMADP. None of the HDs corrected these parameters. However, rFVIIa shortened the coagulation time R using TEG-PMthrombinand the time to peak prolonged by ticagrelor in TGA. Fib increased MAthrombinand FXIII decreased LY30. TXA had no effects.


CONCLUSIONS
Whereas none of the HDs corrected ticagrelor-induced platelet inhibition, rFVIIa shortened coagulation times, Fib increased clot firmness and FXIII decreased fibrinolysis. Consequently, they may bypass ticagrelor effects by acting on fibrin formation or fibrinolysis. Further studies are needed to confirm these datain vivo.
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Hématologie, AP-HP, Hôpital Cochin, Paris, France.
Leyla
L
Calmette
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service de Cardiologie, Hôpital Val de Grâce, Paris, France.
Anne-Céline
AC
Martin
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Bernard
B
Le Bonniec
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Diane
D
Zlotnik
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire d'Hématologie, AP-HP, Hôpital Cochin, Paris, France.
Isabelle
I
Gouin-Thibault
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Christilla
C
Bachelot-Loza
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service d'Hématologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
Pascale
P
Gaussem
Faculté de Pharmacie, Inserm UMR-S1140, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service d'Anesthésie-Réanimation, Fondation Rothschild, Paris, France.
Anne
A
Godier
D000241:Adenosine / Q000031:analogs & derivatives* / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000494:pharmacology; D005340:Fibrinogen / Q000494:pharmacology; D005341:Fibrinolysin / Q000494:pharmacology; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000633:toxicity*; D010979:Platelet Function Tests; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D000077486:Ticagrelor; D013997:Time Factors; D014148:Tranexamic Acid / Q000494:pharmacology
D006490:Hemostatics; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D014148:Tranexamic Acid; D005340:Fibrinogen; C103587:recombinant FVIIa; D015942:Factor VIIa; D005341:Fibrinolysin; D000077486:Ticagrelor; D000241:Adenosine
ANTICOAGULANTS; BLEEDING DISORDERS; HAEMOSTASIS; PLASMA VISCOSITY