Mechanistic Differences of Prothrombin Complex Concentrate and Idarucizumab in a Trauma Model Under Dabigatran Anticoagulation
Authors: Honickel Markus , van Ryn Joanne , Grottke Oliver 
Published: October 2019

Abstract
Background: A proportion of trauma patients presenting with coagulopathy also receive anticoagulant therapy, which can exacerbate coagulopathy and increase bleeding. Emergency reversal of anticoagulation therapy may require therapy with specific reversal agents, as with idarucizumab for dabigatran or non-specific reversal agents, such as prothrombin complex concentrates (PCC).
Methods: Using a lethal polytrauma model under dabigatran anticoagulation, we investigated the mechanism and procoagulant properties of a four-factor PCC or idarucizumab in dabigatran-anticoagulated pigs following multiple injuries. Blood markers of coagulation associated with procoagulant effects, platelet activation and hyperfibrinolysis were determined over time and related to blood loss.
After ethical approval, dabigatran etexilate was given orally for 3 days and iv on day 4 to 18 pigs after anesthesia. Animals were randomized to receive idarucizumab (60 mg/kg), PCC (50 IU/kg) or saline (control), administered 15 minutes after bilateral femur fracture and blunt liver injury. Plasma dabigatran was determined using diluted thrombin time. Thrombin-antithrombin (TAT) complexes and fibrinopeptide A (FPA) were quantified using ELISA and D-Dimer with a clotting assay. Thrombin generation (ETP) in plasma was measured using Calibrated Automated Thrombogram. Platelet function was evaluated as aggregation using platelet-rich plasma in response to tissue factor, collagen, or adenosine diphosphate (ADP) agonism using light transmission aggregometry.
Results: Mean dabigatran levels were 543±186 ng/ml prior to injury. Blood loss was 4056±537 mL after saline treatment (control), 1822±222 mL after PCC (P<0.0001 vs. control) and 1086±134 mL after idarucizumab (P<0.0001 vs. all). All controls developed severe coagulopathy and exsanguinated with a mean survival time of 93 min (range: 62-146 min). Post-injury and after PCC infusion, TAT, D-dimers and FPA were significantly increased vs idarucizumab and control and remained elevated over 300 minutes. Similarly thrombin generation (baseline ETP 267±84 nM*min) increased immediately after PCC administration and persisted elevated 848±114 nM*min at 120 min. In contrast, following therapy with idarucizumab ETP was restored to baseline values. Thrombin-dependent tissue factor-induced platelet aggregation was inhibited with dabigatran, partially restored with PCC and fully restored with idarucizumab. There was no effect with thrombin-independent collagen- and ADP-induced aggregation.
Conclusion: Although four-factor PCC (50 IU/kg) is effective in reducing blood loss, its efficacy is less than therapy with idarucizumab (60 mg/kg). Most importantly the activation of coagulation is explained by different mechanisms. Supernormal activation of coagulation (e.g. TAT, FPA, ETP) was evident after PCC administration, whereas idarucizumab normalized ETP to baseline values. Since thrombin is a potent activator of platelets via PAR, restoration of active thrombin after PCC also partially restored aggregation. In contrast, idarucizumab binds dabigatran and forms an irreversible complex, inactivating dabigatran in plasma, thereby restoring hemostatic function. This difference may influence the choice of therapy when idarucizumab is clinically available.

Disclosures
van Ryn: Boehringer Ingelheim: Employment. Grottke:NovoNordisk: Research Funding; Portola Pharmaceuticals: Consultancy; CSL Behring: Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Biotest: Research Funding.