Prothrombin Complex Concentrate in Combination with Fibrinogen Plus Tranexamic Acid Is More Effective Than Mono-Therapy with Prothrombin Complex Concentrate in a Dabigatran Anticoagulation Experimental Polytrauma Model
Authors: Grottke Oliver , Honickel Markus , Spronk Henri M.H. , ten Cate Hugo , van Ryn Joanne , Rossaint Rolf 
Published: October 2019

Abstract
Background: Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of the direct thrombin inhibitor dabigatran. As no specific reversal agent in situations of life-threatening bleeding with dabigatran is currently available, this study assessed the ability of a four-factor prothrombin complex concentrate (PCC) as mono-therapy as well as PCC in combination with tranexamic acid (TX) and fibrinogen in an experimental polytrauma pig model.
Methods: After ethical approval dabigatran etexilate (30 mg/kg p.o. twice daily, n=24) was administered to male pigs for 3 days. On day 4, the pigs were anesthetized and given a 90 min infusion of active dabigatran to achieve consistent, supratherapeutic plasma levels. A standardized polytrauma including bilateral femur fractures and a blunt liver injury was induced. Animals underwent hemorrhagic shock and were resuscitated using Ringer’s solution (1 L). Twelve min after polytrauma, animals received either placebo (control group, n=6); TX, 20 mg/kg plus fibrinogen (80 mg/kg; TX+F group, n=6); PCC alone (PCC group, 50 U/kg, n=6); or TX (20 mg/kg) plus fibrinogen (80 mg/kg) plus PCC (50 U/kg; TX+F+PCC group, n=6) according to randomized group allocation. Coagulation was assessed by thromboelastometry, coagulation parameters and diluted TT. Blood loss (BL) was measured over the observation period of 240 min. Data were analyzed by ANOVA (± SD).
Results: Dabigatran levels were 504 ± 171 ng/mL prior to injury and plasma levels remained significantly elevated in all animals throughout the observation period. The degree of injury was similar among animals with comparable BL of 803 ± 46 mL 12 min post injury. Anticoagulation with dabigatran without intervention resulted in a total BL of 3521 ± 600 mL, with 100% mortality and mean survival time of 101 ± 34 min (range: 67 - 148 min; p<0.05 vs PCC-treated groups). In contrast, treatment with 50 U/kg PCC (1712 ± 147 mL) resulted in a significant reduction in BL (p<0.05 vs. controls, TX+F group) and 100% survival. Blood loss was further reduced by adding TX and F with PCC (TX+F+PCC group: 1234 ± 215 mL, p<0.05 vs. all groups). In contrast total BL in animals treated with only TX plus F was 3601 ± 410 mL and comparable to control animals receiving only dabigatran, mortality was 100%, although the onset of bleeding was slightly reduced. Likewise, coagulation parameters improved substantially in animals from PCC and TX+F+PCC groups. Despite a significant increase of fibrinogen after substitution (196 ± 22 mg/dL) in the TX+F group, only moderate effects were measured on coagulation parameters including clot strength and kinetics of clot formation. Clinically and macroscopically no adverse events were observed.
Conclusions: This study shows that bleeding in a lethal trauma model can be reduced with mono-therapy using a four-factor PCC. Prior correction of hypofibrinogenanemia with fibrinogen concentrate and tranexamic acid further improves PCC efficacy. Although the effects of PCCs on dabigatran reversal are not well understood, one possible explanation is that by elevating thrombin concentrations through PCC administration, (i.e. PCCs contain prothrombin) this may competitively bind to dabigatran, thereby reducing its anti-thrombin anticoagulant activity. This hypothesis is supported by the lack of effect on blood loss by mono-therapy with TX plus fibrinogen in this study.

Disclosures
Grottke: Boehringer Ingelheim: Consultancy, Research Funding; CSL Behring: Research Funding. Honickel:Boehringer Ingelheim: Travel support Other. Spronk:Boehringer Ingelheim: Research Funding. van Ryn:Boehringer Ingelheim Pharma: Employment. Rossaint:CSL Behring: Honoraria.