Abstract

Background

Although idarucizumab is the preferred treatment for urgent dabigatran reversal, it is not always available. Prothrombin complex concentrate (PCC) may be an alternative and, with bleeding in trauma, additional hemostatic therapy may be required. The authors investigated multimodal treatment in a preclinical polytrauma model.

Methods

Dabigatran etexilate (30 mg/kg twice daily) was given orally to 45 male pigs for 3 days. On day 4, animals received a dabigatran infusion before blunt liver injury and bilateral femur fractures. After injury, animals were randomized 1:1:1:1:1 to receive placebo (control), tranexamic acid (TXA; 20 mg/kg) plus human fibrinogen concentrate (FCH; 80 mg/kg) (TXA–FCH group), PCC (25 U/kg or 50 U/kg) plus TXA plus FCH (PCC25 and PCC50 groups), or 60 mg/kg idarucizumab (IDA) plus TXA plus FCH (IDA group). Animals were monitored for 240 min after trauma, or until death.

Results

The degree of injury was similar in all animals before intervention. Control and TXA–FCH animals had the highest total postinjury blood loss (3,652 ± 601 and 3,497 ± 418 ml) and 100% mortality (mean survival time 96 and 109 min). Blood loss was significantly lower in the PCC50 (1,367 ± 273 ml) and IDA (986 ± 144 ml) groups, with 100% survival. Thrombin–antithrombin levels and thrombin generation were significantly elevated in the PCC50 group.

Conclusions

Idarucizumab may be considered the optimal treatment for emergency reversal of dabigatran anticoagulation. However, this study suggests that PCC may be similarly effective as idarucizumab and could therefore be valuable when idarucizumab is unavailable. (Anesthesiology 2017; 127:852-61)

What We Already Know about This Topic
  • Idarucizumab is an antigen-binding fragment that binds to dabigatran and is approved in many countries for urgent anticoagulation reversal. However, in certain circumstances, other hemostatic therapies, including tranexamic acid and prothrombin complex concentrates, may be administered to treat the coagulopathy after trauma and hemorrhage, or when the specific antidote is not available.

What This Article Tells Us That Is New
  • In a porcine polytrauma injury model, blood loss was lower with idarucizumab than with prothrombin complex concentrate (PCC) when administered for dabigatran reversal as part of multimodal therapy. However, survival was 100% in both groups. There were no hypercoagulability effects with idarucizumab, while PCC increased thrombin generation. Without idarucizumab or PCC, tranexamic acid and fibrinogen concentrate were ineffective at reducing bleeding in this model.

NON-VITAMIN K oral anticoagulants including dabigatran, rivaroxaban, apixaban, and edoxaban are increasingly prescribed for patients with atrial fibrillation.1–3  Although non-vitamin K oral anticoagulants carry a low risk of bleeding, the risk cannot be eliminated and immediate reversal of the anticoagulant effects is occasionally needed (e.g., emergency surgery or trauma).4  Guidelines for the management of bleeding associated with non-vitamin K oral anticoagulants are based on limited evidence.5–7 

Prothrombin complex concentrates and activated prothrombin complex concentrates are currently being used for reversing the anticoagulant effects of dabigatran.8  Preclinical experiments have shown that these products are effective,9–13  and a recent clinical study demonstrated the effectiveness of activated prothrombin complex concentrate for controlling dabigatran-associated major bleeding.14  High doses have been associated with a risk of thromboembolic complications,8,15  although clinical data indicate that the risk is no higher with prothrombin complex concentrates than with therapeutic plasma.16,17  Thromboembolic risk may persist for several days postoperatively18  and it may be higher with activated prothrombin complex concentrates than with prothrombin complex concentrates.19 

Idarucizumab, a humanized monoclonal antibody fragment, is the first specific antidote for reversing the anticoagulant activity of dabigatran.20,21  Preclinical and clinical studies have shown that it achieves immediate and sustained reversal.22  Since idarucizumab binds only to dabigatran, it has no intrinsic coagulation activity. However, in massive bleeding with complex coagulopathy, specific reversal of dabigatran may not be sufficient to achieve hemostasis; multimodal treatment with a range of hemostatic agents may be required. In central European countries, it is common for coagulation management to be based on coagulation factor concentrates (e.g., fibrinogen concentrate, prothrombin complex concentrate), administered according to point-of-care coagulation monitoring.23–25  In other countries such as the United States, there is more reliance upon treatment with allogeneic blood products (e.g., cryoprecipitate, fresh frozen plasma), potentially using a fixed-ratio approach.26,27  There is also international recognition that tranexamic acid can reduce mortality by preventing fibrinolysis.28,29 

For the current study, we hypothesized that idarucizumab is more effective in reducing blood loss than prothrombin complex concentrate when administered together with tranexamic acid and fibrinogen concentrate in a porcine polytrauma model under dabigatran anticoagulation. We also investigated the thrombogenic potential of each intervention.

Materials and Methods

The methodology for this study was similar to that of several previous studies.10,11,30  See Supplemental Digital Content (http://links.lww.com/ALN/B529) for additional details of methodology used in this study. Data from all animals were collected between March 12, 2015, and August 4, 2015.

Ethical Approval

Experiments were performed at RWTH Aachen University Hospital, Aachen, Germany, in accordance with German legislation governing animal studies following the Guide for the Care and Use of Laboratory Animals.31  The protocol was approved by the government office for animal care and use (Landesamt für Natur, Umwelt und Verbraucherschutz, Recklinghausen, Germany).

Experimental Methodology

Forty-five German landrace pigs (weight [mean ± SD]: 41 ± 3 kg) were included in the study. Animals received dabigatran etexilate orally for 3 days (30 mg/kg twice daily), with the last dose given 12 h before surgery. On day 4, animals were anesthetized and prepared for surgery. Dabigatran (Boehringer Ingelheim, Germany) was infused intravenously for 90 min (1 mg/ml; rate: 0.77 mg · kg-1 · h-1 for 30 min, then 0.2 mg · kg-1· h-1 for 60 min).

Before injury, dabigatran-treated animals were randomized using sealed envelopes (n = 9 per group) to receive: saline (control group); tranexamic acid (TXA; 20 mg/kg) plus fibrinogen concentrate (FCH; 80 mg/kg) (TXA–FCH group); prothrombin complex concentrate (PCC; 25 U/kg) plus tranexamic acid (20 mg/kg) plus fibrinogen concentrate (80 mg/kg) (PCC25 group); prothrombin complex concentrate (50 U/kg) plus tranexamic acid (20 mg/kg) plus fibrinogen concentrate (80 mg/kg) (PCC50 group); or idarucizumab (IDA; 60 mg/kg) plus tranexamic acid (20 mg/kg) plus fibrinogen concentrate (80 mg/kg) (IDA group). The following products were used: prothrombin complex concentrate, Beriplex P/N (CSL Behring, Germany; U.S. brand-name Kcentra; Lot 89270111A); tranexamic acid, Cyclocapron (Pfizer, USA; Lot Y05545); fibrinogen concentrate, Haemocomplettan P (CSL Behring; Lot 31169911A); idarucizumab, Praxbind (Boehringer Ingelheim, Germany; Lot 6001325).

A captive bolt gun (Karl Schermer and Co., Germany) was used to create bilateral femur fractures with a concomitant soft tissue injury at the midshaft, and a standardized blunt liver injury was induced. These procedures were performed by one investigator who was blinded to treatment allocation.

Five minutes after injury and after onset of hemorrhagic shock, animals were resuscitated with Ringer’s solution. Twelve minutes after injury, blood loss was measured by suctioning intraperitoneal blood. Study treatments were then administered.

Animals surviving for the 240-min observation period after injury were euthanized with pentobarbital. Immediately after death, total postinjury blood loss was determined and internal organs (heart, lungs, liver, and kidneys) were examined macroscopically and histologically.

Blood Sampling and Analytical Methods

Analysis of blood samples included conventional coagulation testing (prothrombin time; activated partial thromboplastin time; and levels of fibrinogen, fibrinopeptide A, D-dimer, and thrombin–antithrombin complex); thromboelastometry; thrombin generation; and measurement of blood gases and plasma concentrations of dabigatran (using diluted thrombin time).9,12,15  For animals that died before 240 min postinjury, the last regular assessment was evaluated.

Pathologic Examination

Immediately after death, internal organs (heart, lungs, liver, and kidneys) were removed, fixed in formalin, cut into slices (thickness: 5 mm), and examined by a pathologist who was unaware of treatment assignment.

Statistical Analysis

The primary endpoint of this study was the reduction in blood loss. The sample size was based on previous experience from a similar animal model with prothrombin complex concentrate monotherapy for the reversal of dabigatran.10  Statistical analysis was performed using SPSS 22 (SPSS, USA) and GraphPad Prism 6.0h (GraphPad Software, USA) was used for graphing purposes. Differences in total blood loss between groups were assessed using analysis of variance, with post hoc Tukey adjustment. For comparison of coagulation variables, blood cell count, and hemodynamic variables, a repeated measure analysis of variance was used with intervention as group-factor and time as repeated-factor. The group by time interaction was also included to allow the group differences to vary over time. For significant effects, the Sidak method was used post hoc. Pairwise log-rank tests were used for survival analysis. Statistical tests were performed two-tailed and P < 0.05 was considered statistically significant. Data are shown as mean ± SD.

Results

Forty-five pigs were included in the study. Until the time of death, complete data were available for all animals with respect to all study variables. Baseline laboratory and hemodynamic parameters were comparable between the groups before injury.

Blood Loss and Survival

In the control group (dabigatran plus placebo), postinjury blood loss was 3,652 ± 601 ml (P < 0.0001 vs. PCC50 and IDA) and the mean survival time was 96 min (range, 62 to 148 min) (fig. 1A and B). Treatment with tranexamic acid and fibrinogen concentrate did not reduce blood loss (3,497 ± 418 ml), while mean survival time was 109 min (77 to 156 min). The mortality rate was 100% in the control and TXA–FCH groups. Administration of prothrombin complex concentrate 25 U/kg together with tranexamic acid and fibrinogen concentrate (PCC25 group) reduced the mortality rate to 56% (fig. 1B) and the total postinjury blood loss was reduced to 2,827 ± 864 ml (P < 0.01 vs. control and TXA–FCH; fig. 1A). Treatment with prothrombin complex concentrate 50 U/kg or idarucizumab (in addition to tranexamic acid and fibrinogen concentrate) resulted in significantly lower total blood loss (1,367 ± 273 and 986 ± 144 ml) with reductions of 61 to 62% and 72 to 73% versus control and TXA–FCH animals (all P < 0.0001; P < 0.05 vs. PCC25; no significant difference between the PCC50 and IDA groups). All animals given PCC50 or idarucizumab survived to 240 min (P < 0.05 vs. control, TXA–FCH and PCC25; fig. 1B). Stabilization of hemodynamic variables and lactate levels was also observed in these groups, with significant differences from the control and TXA–FCH groups (see Supplemental Digital Content, table 1, http://links.lww.com/ALN/B529).

Fig. 1.

Blood loss and survival. Blood loss 12 min after liver injury but before intervention, and at the end of the experiment (240 min after liver injury; A). Data are presented as mean ± SD; n = 9 per group. Survival data are presented as a Kaplan-Meier curve (B); initially n = 9 per group. *P < 0.05 versus control group; †P < 0.05 versus tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) group (TXA–FCH); ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) and PCC 50 U/kg (PCC50) (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Fig. 1.

Blood loss and survival. Blood loss 12 min after liver injury but before intervention, and at the end of the experiment (240 min after liver injury; A). Data are presented as mean ± SD; n = 9 per group. Survival data are presented as a Kaplan-Meier curve (B); initially n = 9 per group. *P < 0.05 versus control group; †P < 0.05 versus tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) group (TXA–FCH); ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) and PCC 50 U/kg (PCC50) (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Plasma Levels of Dabigatran and Resulting Anticoagulation before Infliction of Injury

After the 90-min infusion of dabigatran on day 4, the overall mean plasma dabigatran level (all animals) was 522 ng/ml, and plasma-based clotting tests (activated partial thromboplastin time and prothrombin time) were prolonged (table 1). Prolongations were also seen in the EXTEM clotting time and INTEM clotting time (table 2). A further effect of dabigatran was a reduction in thrombin generation (fig. 2).

Table 1.

Dabigatran Levels, Coagulation Tests, Hemoglobin, and Platelet Counts

Dabigatran Levels, Coagulation Tests, Hemoglobin, and Platelet Counts
Dabigatran Levels, Coagulation Tests, Hemoglobin, and Platelet Counts
Table 2.

Thromboelastometry Results

Thromboelastometry Results
Thromboelastometry Results
Fig. 2.

Thrombin generation. Lag time (A), peak height (B), and endogenous thrombin potential (ETP; C) are shown. Horizontal dotted lines indicate baseline values before anticoagulation. Data are shown as mean ± SD; in each group, n = 9 animals initially. In control and tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) animals (TXA–FCH), no thrombin generation could be detected later than 60 min posttrauma. *P < 0.05 versus control group; †P < 0.05 versus TXA–FCH group; ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25); §P < 0.05 versus PCC 50 U/kg group (PCC50). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) (§‡†*) → PCC50 (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Fig. 2.

Thrombin generation. Lag time (A), peak height (B), and endogenous thrombin potential (ETP; C) are shown. Horizontal dotted lines indicate baseline values before anticoagulation. Data are shown as mean ± SD; in each group, n = 9 animals initially. In control and tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) animals (TXA–FCH), no thrombin generation could be detected later than 60 min posttrauma. *P < 0.05 versus control group; †P < 0.05 versus TXA–FCH group; ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25); §P < 0.05 versus PCC 50 U/kg group (PCC50). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) (§‡†*) → PCC50 (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Measurements after Standardized Polytrauma

Control Animals.

Despite fluid resuscitation, controls and animals treated with only tranexamic acid and fibrinogen concentrate developed severe shock after injury, with low mean arterial pressure and cardiac output attributable to ongoing blood loss (P < 0.01 vs. IDA and PCC50 within 60 min posttrauma; see Supplemental Digital Content, table 1, http://links.lww.com/ALN/B529). Controls and TXA–FCH animals also had the lowest platelet counts and hemoglobin levels (table 1). Control animals developed severe coagulopathy with deterioration over time in all coagulation parameters (significant differences vs. all other study groups except TXA–FCH; figs. 2 and 3; tables 1 and 2). EXTEM maximum clot firmness (MCF) and INTEM MCF were lowest in this group, while the plasma fibrinogen level was significantly lower than in the PCC25, PCC50, and IDA groups (table 2; fig. 3). The impairment of thrombin generation caused by dabigatran was sustained among control animals.

Fig. 3.

Fibrinogen, fibrinopeptide A, D-dimer, and thrombin–antithrombin levels. Plasma fibrinogen levels (A) and levels of fibrinopeptide A (FPA; B), D-dimer (DD; C), and thrombin-antithrombin (TAT; D), are shown. Horizontal dotted lines indicate baseline values before anticoagulation. Data are shown as mean ± SD; in each group, n = 9 animals initially. *P < 0.05 versus control group; †P < 0.05 versus tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) group (TXA–FCH); ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25); §P < 0.05 versus PCC U/kg group (PCC50). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) (§‡†*) → PCC50 (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Fig. 3.

Fibrinogen, fibrinopeptide A, D-dimer, and thrombin–antithrombin levels. Plasma fibrinogen levels (A) and levels of fibrinopeptide A (FPA; B), D-dimer (DD; C), and thrombin-antithrombin (TAT; D), are shown. Horizontal dotted lines indicate baseline values before anticoagulation. Data are shown as mean ± SD; in each group, n = 9 animals initially. *P < 0.05 versus control group; †P < 0.05 versus tranexamic acid (TXA) plus human fibrinogen concentrate (FCH) group (TXA–FCH); ‡P < 0.05 versus prothrombin complex concentrate (PCC) 25 U/kg group (PCC25); §P < 0.05 versus PCC U/kg group (PCC50). Between-group differences are presented hierarchically as follows: idarucizumab (IDA) (§‡†*) → PCC50 (‡†*) → PCC25 (†*) → TXA–FCH (*) → control.

Substitution with Fibrinogen and Tranexamic Acid (TXA–FCH Group).

Immediately after administration of fibrinogen concentrate (80 mg/kg), plasma fibrinogen levels were significantly higher in all intervention groups than in controls (P < 0.0001; fig. 3). The mean fibrinogen level subsequently decreased over time to reach comparability with controls at 120 min postinjury. All other coagulation parameters were similar to the control group.

Substitution with Fibrinogen, Tranexamic Acid, and Prothrombin Complex Concentrate (25 U/kg).

In the PCC25 group, data from 240 min onward were from the four animals surviving the whole 240-min observation period. These animals may be considered to have recovered from trauma after administration of study treatment. Hemodynamic parameters in the PCC25 group exhibited only minor deterioration after fluid resuscitation (see Supplemental Digital Content, table 1, http://links.lww.com/ALN/B529). Improvements (decreases) over time were observed in the activated partial thromboplastin time and prothrombin time (table 1) as well as in EXTEM and INTEM clotting time (table 2). Despite increased thrombin generation compared with pretrauma levels, endogenous thrombin potential and peak height remained lower than baseline values in the PCC25 group and lower than values observed in PCC50 animals (fig. 2). The lag time was significantly shorter than in the control and TXA–FCH groups (P < 0.001), although this parameter did not return to baseline levels (fig. 2). Levels of fibrinopeptide A and thrombin-antithrombin complex in the PCC25 group were higher than those in the control and TXA–FCH groups but less than those in the PCC50 group (fig. 3).

We performed a subanalysis of animals in the PCC25 group based on plasma dabigatran concentrations immediately after trauma (PCC25high, plasma dabigatran concentration 625 ± 196 ng/ml, n = 6; PCC25low, 337 ± 84 ng/ml, n = 3). Bleeding after therapy with PCC25 was lower in the PCC25low group than in the PCC25high group. Higher survival rates and greater improvements in coagulation parameters were also observed in the PCC25low group (see Supplemental Digital Content, fig. 1, http://links.lww.com/ALN/B529).

Substitution with Fibrinogen, Tranexamic Acid, and Prothrombin Complex Concentrate (50 U/kg).

PCC50 animals recovered from trauma after hemostatic intervention and fluid resuscitation as shown by significant decreases in prothrombin time (table 1), as well as in EXTEM and INTEM clotting time (table 2). EXTEM and INTEM MCF were restored close to baseline levels and the plasma fibrinogen concentration, while decreasing over time, remained higher than in all other groups except idarucizumab (fig. 3). Directly after prothrombin complex concentrate application (30 min after trauma), thrombin generation increased (fig. 2). Peak height and endogenous thrombin potential remained significantly different in the PCC50 group versus all other groups, including PCC25, throughout the study. In addition, thrombin–antithrombin complex and fibrinopeptide A concentrations were significantly higher than in all other study groups (P < 0.0001; fig. 3). Significantly higher levels of D-dimers were only observed 240 min after trauma (P < 0.002 vs. PCC25 and IDA). As expected, plasma concentrations of dabigatran were similar in the PCC50 group to those in the control, TXA–FCH, and PCC25 groups (table 1).

Substitution with Fibrinogen, Tranexamic Acid, and Idarucizumab.

Fifteen minutes after administration of idarucizumab, dabigatran activity was close to zero (table 1). Dabigatran levels in the IDA group then increased gradually, reaching a peak of 142 ng/ml at 180 min postinjury. Treatment with idarucizumab, tranexamic acid, and fibrinogen concentrate normalized plasma coagulation tests (prothrombin time and activated partial thromboplastin time), as well as EXTEM and INTEM parameters (table 2). In addition, thrombin generation was restored immediately to baseline values (fig. 2). Levels of thrombin–antithrombin complex and fibrinopeptide A were elevated after idarucizumab therapy (fig. 3), but to a lesser extent than with PCC50.

Histopathologic Analysis

The histopathologic examination of injured liver sections revealed homogeneous tissue damage and comparable lacerations in all animals. No thromboemboli or other remarkable pathologic changes were present in kidneys, lungs, heart, or nontraumatized liver tissue.

Discussion

This study demonstrates for the first time that treatment of dabigatran anticoagulation in experimental polytrauma with either idarucizumab or prothrombin complex concentrate (50 U/kg), in combination with tranexamic acid and fibrinogen concentrate, is similarly effective in reducing blood loss. Idarucizumab binds and inactivates dabigatran, thereby restoring thrombin generation. In contrast, prothrombin complex concentrate overcomes dabigatran activity by increasing the amount of prothrombin in the plasma until it exceeds the level of dabigatran, and in our study, the 50 U/kg dose increased thrombin generation above baseline (measured before administration of dabigatran). Low-dose prothrombin complex concentrate (25 U/kg) did not increase thrombin generation above baseline and was also less effective in reducing blood loss. Thromboembolic events were not observed in animals treated with idarucizumab or prothrombin complex concentrate when combined with tranexamic acid and fibrinogen concentrate during the 4-h observation time.

In our model, the causes of coagulopathy included consumption and dilution of coagulation factors and platelets and impaired thrombin generation. The mortality rate was 100% in control animals. Tranexamic acid and fibrinogen concentrate were ineffective in restoring hemostasis. Increased fibrinolysis, reduced plasma levels of fibrinogen, and reduced clot strength are hypothesized to be important contributors to trauma-induced coagulopathy.32–34  Although tranexamic acid and fibrinogen concentrate may be effective in treating these aspects, they do not enhance thrombin generation in the presence of dabigatran.

The addition of either idarucizumab or prothrombin complex concentrate to tranexamic acid and fibrinogen concentrate was effective in restoring hemostasis and reducing blood loss, enabling animals to survive. Idarucizumab restored thrombin generation potential without exceeding the baseline level seen before anticoagulation. In addition, D-dimer levels showed that idarucizumab did not increase fibrinolysis as compared to the PCC50 group. Previous animal studies of dabigatran reversal have reported similar results with idarucizumab,12,30  and clinical studies have shown a lack of procoagulant effects.35,36 

PCC50 differed from idarucizumab in that thrombin generation potential (as measured by endogenous thrombin potential and peak height) and propagation of coagulation were increased above levels seen before anticoagulation. All procoagulant markers, including thrombin–antithrombin complex levels, were increased in the PCC50 group. As expected in relation to the mechanism of action, plasma dabigatran levels were unchanged in the presence of prothrombin complex concentrate. PCC25 did not increase thrombin generation potential (endogenous thrombin potential and peak height) above levels seen before anticoagulation, but this treatment was not fully effective in reversing the anticoagulant effects of dabigatran. A subanalysis of this group showed that the effectiveness of low-dose prothrombin complex concentrate mainly depends on the level of anticoagulation: PCC25 appeared to be effective in animals with low concentrations of dabigatran. Thrombin generation may be increased as a physiologic response to trauma,37  and this may exacerbate the risk of thromboembolic complications with prothrombin complex concentrate. In trauma patients treated with prothrombin complex concentrate, a prothrombotic state has been reported to last for several days postoperatively.18  Our study did not show thromboembolic complications with prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate, although the follow-up time was limited (4 h).

Idarucizumab restores hemostasis by binding dabigatran and eliminating it from the circulation (renally as a complex). The clinical dose of idarucizumab (5 g) is, for most patients, higher than the 60 mg/kg dose used in the current study. In addition, plasma levels of dabigatran in clinical practice are lower than those achieved in the current study (e.g., in the Reversal Effects of Idarucizumab on Active Dabigatran clinical study, median plasma dabigatran levels between 100 and 150 ng/ml were reported).36  This study was intended to provide consistent, reproducible bleeding and to simulate “worst case” scenarios. Two hours after idarucizumab administration, plasma concentrations of dabigatran rebounded. This can be explained by the equilibrium of dabigatran molecules between the tissues and the blood compartment. Binding of the molecules in plasma to idarucizumab triggers a transfer of molecules from the tissues to plasma. This process is not instant and, if idarucizumab molecules in the plasma are already bound to dabigatran, the molecules arriving from the tissues remain free, causing a rise (rebound) in the plasma level of dabigatran. Each molecule of idarucizumab binds one molecule of dabigatran.35  Therefore, for full reversal of the anticoagulant effects of dabigatran, the administered dose of idarucizumab needs to be equimolar with the total quantity of dabigatran, in both blood and tissues.

Our results may be compared with a previous study using the same animal model, where prothrombin complex concentrate (25, 50, or 100 U/kg) was administered alone as hemostatic therapy.10  Lower blood loss and mortality in the current study suggests that co-administration of tranexamic acid and fibrinogen concentrate enhances the effectiveness of prothrombin complex concentrate. Comparison with data from another animal study of dabigatran anticoagulation and trauma, where idarucizumab 60 mg/kg was monotherapy,30  suggests that this product is similarly effective when administered either alone or with tranexamic acid and fibrinogen concentrate. Nevertheless, in human trauma patients, multimodal therapy may be required.

In clinical practice, idarucizumab is the preferred option for reversing dabigatran anticoagulation. However, in some cases it may not be clear whether anticoagulation is related to dabigatran or a different anticoagulant. Unlike idarucizumab, prothrombin complex concentrate may be effective for reversal of anticoagulation with a vitamin K antagonist or a factor Xa inhibitor.38–40  Thus, prothrombin complex concentrate might be a valuable first-line approach to restoring hemostasis in selected clinical circumstances. However, prothrombin complex concentrates are not currently licensed for the reversal of non-vitamin K oral anticoagulants. Although no thromboembolic events were observed in this study, we would advocate a cautious approach if choosing to use prothrombin complex concentrate for treatment of dabigatran or factor Xa anticoagulation. There are differences between prothrombin complex concentrates in their levels of anticoagulants (e.g., protein C, protein S, heparin) and these have been shown in vitro to affect the degree to which thrombin generation potential is increased.41  However, it has not been confirmed whether these findings translate into differences between the available prothrombin complex concentrates regarding clinical risk of thromboembolic complications.

There are several potential limitations to this study, including its clinical applicability. Humans and pigs are different species, meaning there could be differences in coagulation status. Our study was performed in young, healthy animals, whereas in humans, anticoagulation therapy is prescribed to patients with hypercoagulability or a risk of thromboembolic events; such patients are usually elderly with many comorbidities and concomitant medications such as antiplatelet therapy. In addition, trauma patients exhibit physiologic responses to pain/inflammation. Such factors are not represented in our animal model. Due to the limited observation period of 4 h, prediction of the longer-term postoperative effects of prothrombin complex concentrate is not possible.

Plasma concentrations of dabigatran in the study animals were intentionally higher than those usually seen clinically. Low-dose prothrombin complex concentrate (25 U/kg) might have been more effective in animals with plasma dabigatran concentrations that are encountered clinically (100 to 150 ng/ml). In the subanalysis of results from the PCC25 group, we showed that the efficacy of prothrombin complex concentrate is dependent on the level of anticoagulation. Selection of the optimal dose of prothrombin complex concentrate for dabigatran reversal is challenging in the absence of a point of care coagulation measurement that quantifies dabigatran.

Conclusions

Idarucizumab is more favorable than prothrombin complex concentrate for emergency reversal of the anticoagulant effects of dabigatran after trauma because its mode of action circumvents the risk of an overcorrection of thrombin generation. In clinical practice, determining an appropriate dose may be less challenging with idarucizumab than with prothrombin complex concentrate. However, this study shows that, in the context of multimodal therapy, high-dose prothrombin complex concentrate is similarly effective to idarucizumab for dabigatran reversal. The findings also show that prothrombin complex concentrate may be more effective as part of a multimodal approach than as monotherapy. Although prothrombin complex concentrates are not licensed for the reversal of non-vitamin K oral anticoagulants, they could be valuable when idarucizumab is unavailable or when there is uncertainty whether the patient has received dabigatran or a different oral anticoagulant.

Acknowledgments

The authors thank Renate Nadenau (Department of Anesthesiology, RWTH Aachen University Hospital, Aachen, Germany) and Johanna Schurer (Boehringer Ingelheim, Biberach, Germany) for excellent laboratory assistance. Joanne van Ryn, Ph.D. (Boehringer Ingelheim) is acknowledged for critical reading.

Research Support

Supported by the START program of RWTH Aachen University (Aachen, Germany) and by Boehringer Ingelheim (Biberach, Germany).

Competing Interests

Dr. Honickel has received travel support from Boehringer Ingelheim (Ingelheim, Germany). Dr. Rossaint has received honoraria for lectures and consultancy from CSL Behring (Marburg, Germany), Boehringer Ingelheim, and Novo Nordisk (Bagsvaerd, Denmark). Dr. ten Cate has received research funding from CSL Behring, Bayer (Leverkusen, Germany), Philips (Amsterdam, Netherlands), Pfizer (Berlin, Germany), and Boehringer Ingelheim, and honoraria for lectures and consultancy from Bayer, Leo Pharma (Neu-Isenburg, Germany), Boehringer, and Pfizer. Dr. ten Cate is a consultant to Stago (Dusseldorf, Germany) and a fellow of the Gutenberg Research Foundation, Center for Thrombosis and Haemostasis (Mainz, Germany). Dr. Grottke has received research funding from Bayer, Biotest (Dreieich, Germany), Boehringer Ingelheim, CSL Behring, Novo Nordisk, and Nycomed (Zurich, Switzerland). Dr. Grottke has also received honoraria for lectures and consultancy support from Baxalta (Unterschleißheim, Germany), Bayer Healthcare, Boehringer Ingelheim, CSL Behring, Octapharma (Lachen, Switzerland), Pfizer, Portola (San Francisco, California), and Sanofi (Berlin, Germany).

References

References
1.
Gonsalves
WI
,
Pruthi
RK
,
Patnaik
MM
:
The new oral anticoagulants in clinical practice.
Mayo Clin Proc
2013
;
88
:
495
511
2.
Saraf
K
,
Morris
PD
,
Garg
P
,
Sheridan
P
,
Storey
R
:
Non-vitamin K antagonist oral anticoagulants (NOACs): Clinical evidence and therapeutic considerations.
Postgrad Med J
2014
;
90
:
520
8
3.
Wang
Y
,
Bajorek
B
:
New oral anticoagulants in practice: Pharmacological and practical considerations.
Am J Cardiovasc Drugs
2014
;
14
:
175
89
4.
Levy
JH
,
Faraoni
D
,
Spring
JL
,
Douketis
JD
,
Samama
CM
:
Managing new oral anticoagulants in the perioperative and intensive care unit setting.
Anesthesiology
2013
;
118
:
1466
74
5.
Aronis
KN
,
Hylek
EM
:
Who, when, and how to reverse non-vitamin K oral anticoagulants.
J Thromb Thrombolysis
2016
;
41
:
253
72
6.
Levy
JH
,
Levi
M
:
New oral anticoagulant-induced bleeding: Clinical presentation and management.
Clin Lab Med
2014
;
34
:
575
86
7.
Kozek-Langenecker
SA
,
Afshari
A
,
Albaladejo
P
,
Santullano
CA
,
De Robertis
E
,
Filipescu
DC
,
Fries
D
,
Görlinger
K
,
Haas
T
,
Imberger
G
,
Jacob
M
,
Lancé
M
,
Llau
J
,
Mallett
S
,
Meier
J
,
Rahe-Meyer
N
,
Samama
CM
,
Smith
A
,
Solomon
C
,
Van der Linden
P
,
Wikkelsø
AJ
,
Wouters
P
,
Wyffels
P
:
Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
Eur J Anaesthesiol
2013
;
30
:
270
382
8.
Grottke
O
,
Aisenberg
J
,
Bernstein
R
,
Goldstein
P
,
Huisman
MV
,
Jamieson
DG
,
Levy
JH
,
Pollack
CV
Jr
,
Spyropoulos
AC
,
Steiner
T
,
Del Zoppo
GJ
,
Eikelboom
J
:
Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation.
Crit Care
2016
;
20
:
115
9.
Grottke
O
,
van Ryn
J
,
Spronk
HM
,
Rossaint
R
:
Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model.
Crit Care
2014
;
18
:
R27
10.
Honickel
M
,
Braunschweig
T
,
van Ryn
J
,
ten Cate
H
,
Spronk
HM
,
Rossaint
R
,
Grottke
O
:
Prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model.
Anesthesiology
2015
;
123
:
1350
61
11.
Honickel
M
,
Maron
B
,
van Ryn
J
,
Braunschweig
T
,
ten Cate
H
,
Spronk
HM
,
Rossaint
R
,
Grottke
O
:
Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model.
Thromb Haemost
2016
;
115
:
271
84
12.
Honickel
M
,
Treutler
S
,
van Ryn
J
,
Tillmann
S
,
Rossaint
R
,
Grottke
O
:
Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab.
Thromb Haemost
2015
;
113
:
728
40
13.
van Ryn
J
,
Schurer
J
,
Kink-Eiband
M
,
Clemens
A
:
Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation.
Anesthesiology
2014
;
120
:
1429
40
14.
Schulman
S
,
Ritchie
B
,
Nahirniak
S
,
Gross
PL
,
Carrier
M
,
Majeed
A
,
Hwang
HG
,
Zondag
M
;
Study investigators
:
Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study.
Thromb Res
2017
;
152
:
44
8
15.
Grottke
O
,
Braunschweig
T
,
Spronk
HM
,
Esch
S
,
Rieg
AD
,
van Oerle
R
,
ten Cate
H
,
Fitzner
C
,
Tolba
R
,
Rossaint
R
:
Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury.
Blood
2011
;
118
:
1943
51
16.
Goldstein
JN
,
Refaai
MA
,
Milling
TJ
Jr
,
Lewis
B
,
Goldberg-Alberts
R
,
Hug
BA
,
Sarode
R
:
Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: A phase 3b, open-label, non-inferiority, randomised trial.
Lancet
2015
;
385
:
2077
87
17.
Sarode
R
,
Milling
TJ
Jr
,
Refaai
MA
,
Mangione
A
,
Schneider
A
,
Durn
BL
,
Goldstein
JN
:
Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study.
Circulation
2013
;
128
:
1234
43
18.
Schöchl
H
,
Voelckel
W
,
Maegele
M
,
Kirchmair
L
,
Schlimp
CJ
:
Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: A 7-day observational study of trauma patients.
Crit Care
2014
;
18
:
R147
19.
Herzog
E
,
Kaspereit
FJ
,
Krege
W
,
Doerr
B
,
van Ryn
J
,
Dickneite
G
,
Pragst
I
:
Thrombotic safety of prothrombin complex concentrate (Beriplex P/N) for dabigatran reversal in a rabbit model.
Thromb Res
2014
;
134
:
729
36
20.
Burness
CB
:
Idarucizumab: First global approval.
Drugs
2015
;
75
:
2155
61
21.
Schiele
F
,
van Ryn
J
,
Canada
K
,
Newsome
C
,
Sepulveda
E
,
Park
J
,
Nar
H
,
Litzenburger
T
:
A specific antidote for dabigatran: Functional and structural characterization.
Blood
2013
;
121
:
3554
62
22.
Glund
S
,
Stangier
J
,
Schmohl
M
,
De Smet
M
,
Gansser
D
,
Lang
B
,
Moschetti
V
,
Ramael
S
,
Reilly
PA
:
A specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers.
Circulation
2013
;
128
:
A17765
23.
Innerhofer
P
,
Westermann
I
,
Tauber
H
,
Breitkopf
R
,
Fries
D
,
Kastenberger
T
,
El Attal
R
,
Strasak
A
,
Mittermayr
M
:
The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma.
Injury
2013
;
44
:
209
16
24.
Schöchl
H
,
Nienaber
U
,
Maegele
M
,
Hochleitner
G
,
Primavesi
F
,
Steitz
B
,
Arndt
C
,
Hanke
A
,
Voelckel
W
,
Solomon
C
:
Transfusion in trauma: Thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy.
Crit Care
2011
;
15
:
R83
25.
Rossaint
R
,
Bouillon
B
,
Cerny
V
,
Coats
TJ
,
Duranteau
J
,
Fernandez-Mondejar
E
,
Filipescu
D
,
Hunt
BJ
,
Komadina
R
,
Nardi
G
,
Neugebauer
EA
,
Ozier
Y
,
Riddez
L
,
Schultz
A
,
Vincent
JL
,
Spahn
DR
:
The European guideline on management of major bleeding and coagulopathy following trauma: Fourth edition.
Crit Care
2016
;
20
:
100
26.
Holcomb
JB
,
del Junco
DJ
,
Fox
EE
,
Wade
CE
,
Cohen
MJ
,
Schreiber
MA
,
Alarcon
LH
,
Bai
Y
,
Brasel
KJ
,
Bulger
EM
,
Cotton
BA
,
Matijevic
N
,
Muskat
P
,
Myers
JG
,
Phelan
HA
,
White
CE
,
Zhang
J
,
Rahbar
MH
;
PROMMTT Study Group
:
The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: Comparative effectiveness of a time-varying treatment with competing risks.
JAMA Surg
2013
;
148
:
127
36
27.
Holcomb
JB
,
Tilley
BC
,
Baraniuk
S
,
Fox
EE
,
Wade
CE
,
Podbielski
JM
,
del Junco
DJ
,
Brasel
KJ
,
Bulger
EM
,
Callcut
RA
,
Cohen
MJ
,
Cotton
BA
,
Fabian
TC
,
Inaba
K
,
Kerby
JD
,
Muskat
P
,
O’Keeffe
T
,
Rizoli
S
,
Robinson
BR
,
Scalea
TM
,
Schreiber
MA
,
Stein
DM
,
Weinberg
JA
,
Callum
JL
,
Hess
JR
,
Matijevic
N
,
Miller
CN
,
Pittet
JF
,
Hoyt
DB
,
Pearson
GD
,
Leroux
B
,
van Belle
G
;
PROPPR Study Group
:
Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial.
JAMA
2015
;
313
:
471
82
28.
Crash-trial collaborators
.
Shakur
H
,
Roberts
I
,
Bautista
R
,
Caballero
J
,
Coats
T
,
Dewan
Y
,
El-Sayed
H
,
Gogichaishvili
T
,
Gupta
S
,
Herrera
J
,
Hunt
B
,
Iribhogbe
P
,
Izurieta
M
,
Khamis
H
,
Komolafe
E
,
Marrero
MA
,
Mejia-Mantilla
J
,
Miranda
J
,
Morales
C
,
Olaomi
O
,
Olldashi
F
,
Perel
P
,
Peto
R
,
Ramana
PV
,
Ravi
RR
,
Yutthakasemsunt
S
;
Crash-trial collaborators
:
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial.
Lancet
2010
;
376
:
23
32
29.
Morrison
JJ
,
Dubose
JJ
,
Rasmussen
TE
,
Midwinter
MJ
:
Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study.
Arch Surg
2012
;
147
:
113
9
30.
Grottke
O
,
Honickel
M
,
van Ryn
J
,
ten Cate
H
,
Rossaint
R
,
Spronk
HM
:
Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation.
J Am Coll Cardiol
2015
;
66
:
1518
9
31.
Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council
:
Guide for the Care and Use of Laboratory Animals
, 7th edition.
Washington DC
,
National Academy Press
,
1996
32.
Frith
D
,
Davenport
R
,
Brohi
K
:
Acute traumatic coagulopathy.
Curr Opin Anaesthesiol
2012
;
25
:
229
34
33.
Kashuk
JL
,
Moore
EE
,
Sawyer
M
,
Wohlauer
M
,
Pezold
M
,
Barnett
C
,
Biffl
WL
,
Burlew
CC
,
Johnson
JL
,
Sauaia
A
:
Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma.
Ann Surg
2010
;
252
:
434
42
;
discussion 443–4
34.
Levy
JH
,
Welsby
I
,
Goodnough
LT
:
Fibrinogen as a therapeutic target for bleeding: A review of critical levels and replacement therapy.
Transfusion
2014
;
54
:
1389
405
35.
Glund
S
,
Moschetti
V
,
Norris
S
,
Stangier
J
,
Schmohl
M
,
van Ryn
J
,
Lang
B
,
Ramael
S
,
Reilly
P
:
A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.
Thromb Haemost
2015
;
113
:
943
51
36.
Pollack
CV
Jr
,
Reilly
PA
,
van Ryn
J
,
Eikelboom
JW
,
Glund
S
,
Bernstein
RA
,
Dubiel
R
,
Huisman
MV
,
Hylek
EM
,
Kam
CW
,
Kamphuisen
PW
,
Kreuzer
J
,
Levy
JH
,
Royle
G
,
Sellke
FW
,
Stangier
J
,
Steiner
T
,
Verhamme
P
,
Wang
B
,
Young
L
,
Weitz
JI
:
Idarucizumab for dabigatran reversal – full cohort analysis.
N Engl J Med
2017
;
377
:
431
41
37.
Dunbar
NM
,
Chandler
WL
:
Thrombin generation in trauma patients.
Transfusion
2009
;
49
:
2652
60
38.
Dzik
WH
:
Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: A re-appraisal.
J Thromb Haemost
2015
;
13 Suppl 1
:
S187
94
39.
Barco
S
,
Whitney Cheung
Y
,
Coppens
M
,
Hutten
BA
,
Meijers
JC
,
Middeldorp
S
:
In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.
Br J Haematol
2016
;
172
:
255
61
40.
Grandhi
R
,
Newman
WC
,
Zhang
X
,
Harrison
G
,
Moran
C
,
Okonkwo
DO
,
Ducruet
AF
:
Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct Factor Xa inhibitors.
World Neurosurg
2015
;
84
:
1956
61
41.
Grottke
O
,
Rossaint
R
,
Henskens
Y
,
van Oerle
R
,
ten Cate
H
,
Spronk
HM
:
Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model.
PLoS One
2013
;
8
:
e64100