title: More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate.
abstract: The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa®). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 μg/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2™ and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2™. Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 μg/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis' correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients.
authors.affiliation: Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Dept. of Clinical Chemistry and Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Electronic address: tomas.lindahl@liu.se.
authors.forename: Tomas L
authors.initials: TL
authors.lastname: Lindahl
authors.affiliation: Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Wallstedt
authors.affiliation: Dept. of Clinical Chemistry and Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Gustafsson
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark.
authors.forename: Egon
authors.initials: E
authors.lastname: Persson
authors.affiliation: Dept. of Clinical Chemistry, Halmstad Hospital, Halmstad, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hillarp
mesh_terms: D000991:Antithrombins / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D000069604:Dabigatran / Q000494:pharmacology*; D015942:Factor VIIa / Q000494:pharmacology*; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D053657:Platelet-Rich Plasma / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D001779:Blood Coagulation Factors; D006490:Hemostatics; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; C103587:recombinant FVIIa; D015942:Factor VIIa; D000069604:Dabigatran