Abstract 18403: Effect of Dabigatran on the Ability to Generate Fibrin at a Wound site and its Reversal by Idarucizumab, the Antidote to Dabigatran, in Healthy Volunteers: An Exploratory Marker of Blood Loss

Background: Idarucizumab is a humanized antibody fragment (Fab) that specifically and potently binds dabigatran to neutralize its anticoagulant activity. Assessing whether reversal of anticoagulation also reverses bleeding is challenging. This healthy volunteer (HV) study explored dabigatran’s ability to inhibit fibrin formation in blood at a non-penetrating wound site by measuring fibrinopeptide A (FPA) generation and to test whether idarucizumab restores wound site fibrin formation. Methods: The study followed the Declaration of Helsinki with HV written informed consent. Dabigatran etexilate (DE, 220 mg bid) was given for 4 days. FPA was assessed before DE and on day 3 and 4 at 2.5 and 6 hrs post morning DE dose. On day 4, HV received 5 min infusion of 1, 2 or 4 g of Fab or placebo 2 hrs post morning DE dose (n=8-9/group). Incisions were made with a scalpel device (Surgicutt®) on the forearm volar surface. Blood was collected from the wound at each time point over 4 min into vials containing stop solution and frozen until assayed. FPA was measured via commercial ELISA, ecarin clotting time (ECT) and diluted thrombin time (dTT) using standard methods. Plasma dabigatran levels were measured by LC-MS/MS. Data expressed as mean ± SE and analyzed using two way ANOVA, p<0.05 as significant. Results: Fab and dabigatran were well tolerated. Mean FPA before DE was 3980 ± 1735 ng/ml (n=35). There was almost complete inhibition of FPA to 208 ± 28 ng/mL 2.5 hrs post DE day 3, corresponding to peak dabigatran levels (210 ± 17 ng/mL). Six hrs post DE, levels were 127 ± 10 ng/mL and FPA was still significantly reduced to 328 ± 35 ng/mL (pooled day 3 data). There was a significant, dose-dependent return of fibrin formation with increasing doses of Fab to 24, 45 and 63% of pre DE values 30 min after 1, 2 and 4 g Fab, respectively (p<0.05). Anticoagulation (ECT and dTT) was significantly prolonged with dabigatran and reversed to control levels after dosing with 2 and 4 g Fab. Discussion: This study demonstrates that idarucizumab reverses dabigatran-induced inhibition of wound site fibrin formation in HV and this correlated with reversal of systemic anticoagulation. Translation into reversal of bleeding in patients requires further clinical investigations, which are currently ongoing.