Hematological, coagulation, metabolic, and hemodynamic data obtained before liver injury and treatment are shown in Tables 1 and 2. There were no significant differences among the 4 treatment groups in any of the study variables at baseline or any of the other time points before administration of study treatment.
Blood Loss and Survival
As shown in Figure 2, total blood loss after the second liver injury, the primary endpoint of the study, was lower in the TXA–FC and TXA–FC–PCC groups (1012 ± 86 mL and 1037 ± 118 mL, respectively) than in the TXA and control groups (1579 ± 306 mL and 2376 ± 478 mL, respectively; P < 0.001 for all 4 comparisons). Total blood loss in the TXA group was lower than in the control group (P < 0.001).
All animals in the TXA–FC and TXA–FC–PCC groups survived the complete observational period, whereas 5 of 9 (56%) and 2 of 9 animals (22%) died after the second trauma in the control and TXA-only groups, respectively (for both these groups, P < 0.05 versus TXA–FC and TXA–FC–PCC).
Hemoglobin Levels, Platelet Counts, Hemodynamic Variables, and Shock
Decreasing values for MAP and cardiac output were observed in the control group after the second liver injury (Table 1). MAP was higher in the TXA–FC and TXA–FC–PCC groups than in the control and TXA groups from 45 to 240 minutes after the second trauma (P < 0.05). Cardiac output was higher in the TXA–FC and TXA–FC–PCC groups than in the control group from 90 to 240 minutes after the second trauma. Lactate increased over time in the control and TXA groups (Table 1). At 180 and 240 minutes after the second trauma, lower levels of lactate were observed in the TXA–FC and TXA–FC–PCC groups than in the TXA and control groups (P < 0.05).
Hemoglobin concentrations decreased below baseline levels after the administration of study treatment in all groups (Table 2). The most pronounced reduction was noted in control animals. At 180 and 240 minutes after the second trauma, higher levels of hemoglobin were observed in the TXA–FC and TXA–FC–PCC groups than in the TXA and control groups (P < 0.05). Similarly, the lowest platelet counts were observed in the control group. However, the only significant difference in platelet count was between the TXA–FC group and the control group, at 180 and 240 minutes after the second trauma (P < 0.05).
Fibrinogen Concentration, Coagulation Tests, and Thromboelastometry
After administration of study treatment, PT and aPTT increased in the control group (Table 2). In the TXA–FC and TXA–FC–PCC groups, PT was lower than in the control and TXA groups at 90, 180, and 240 minutes after the second trauma (P < 0.05). Lower values for aPTT were observed in the TXA–FC and TXA–FC–PCC groups than in the control group (P < 0.05) at the same 3 time points.
The administration of study intervention rapidly increased plasma fibrinogen levels in the TXA–FC and TXA–FC–PCC groups; no such increase was seen with control or TXA (Fig. 3A). Plasma fibrinogen levels were significantly higher in the TXA–FC–PCC group than in the control and TXA groups from 45 to 240 minutes after the second trauma (P < 0.05). The fibrinogen level in the TXA–FC group was significantly higher than in the control group at 45 and 90 minutes (P < 0.05). An increase in the FPA level was evident in the TXA–FC–PCC group compared with the control and TXA groups (P < 0.05; Fig. 3B). However, no significant difference in FPA level was evident between the TXA–FC group and the control or TXA group.
In the control group, EXTEM CT increased over time, and there was a gradual decline in MCF (Fig. 4, A and B). Treatment with TXA was associated with a lower EXTEM CT than in the control group at 180 minutes (P = 0.005), and MCF was higher than in the control group from 45 to 240 minutes after the second trauma (P < 0.05). In the fibrinogen-treated groups (TXA–FC and TXA–FC–PCC), CT was shorter than in the control group at 180 minutes (P < 0.05) and shorter than in the control and TXA groups at 240 minutes (P < 0.05). The fibrinogen-treated groups exhibited higher EXTEM MCF than in the control group at 45 and 90 minutes (P < 0.05) and higher MCF than in the control and TXA groups at 180 and 240 minutes (P < 0.05).
The tissue plasminogen activator ROTEM analysis showed low LI30 values (<10%) throughout the study in the control group. In all TXA-treated animals, LI30 was <35% before study intervention but exceeded 90% at all time points after study intervention (P < 0.05 versus control).
Thrombin Generation, Activation of Coagulation, and Platelet Activity
Thrombin generation data showed a clear response to study intervention in the TXA–FC–PCC group but not in any of the other groups. Peak height and endogenous thrombin potential were higher 45 minutes after the second trauma in the TXA–FC–PCC group than in any of the other 3 study groups (P < 0.05; Fig. 5, A and B). Values for these 2 variables remained higher in the TXA–FC–PCC group than in the TXA group and the control group from 90 to 240 minutes. No significant between-group differences were observed in lag time (data not shown).
TAT complex levels were higher in the TXA–FC–PCC group than in all the other study groups from 90 to 240 minutes after the second trauma (P < 0.05; Fig. 6A). At 180 and 240 minutes, higher D-dimer levels were observed in the control group than in all the other study groups (P < 0.05; Fig. 6B).
The binding of fluorescent labels to platelets (P-selectin and fibrinogen) after stimulation with adenosine diphosphate showed no significant between-group differences in platelet activation (data not shown).
The extent of tissue damage resulting from the liver injuries was not different among the 4 study groups. Macroscopic and histological evaluation of tissue samples from all organs showed no evidence of thromboembolic events.
Using a porcine model of severe trauma and trauma-induced coagulopathy, we have shown that combination therapy in the TXA and FC groups was effective for reducing blood loss and improving coagulation variables compared with either the TXA group or the control group. Total blood loss in the TXA–FC and TXA–FC–PCC groups was approximately half that in the control group. Additional treatment with PCC enhanced thrombin generation, but there was no further reduction of blood loss compared with the TXA–FC group. Coagulopathy worsened over time in the control group, and 56% of animals died before the end of the observation period. In contrast, all animals in the TXA–FC and TXA–FC–PCC groups survived to the end of the observation period and our data indicate a lack of deterioration in the coagulation status of these animals after the administration of study treatment.
Despite extensive clinical and laboratory research, the optimal approach to treating patients with trauma and massive hemorrhage and/or acute coagulopathy is under debate. This is attributable, in part, to the biological complexity resulting from injury, hemorrhagic shock, and hemostatic therapy. Hypothesized mechanisms for trauma-induced coagulopathy implicate a central role of upregulation of fibrinolysis and poor clot strength.3–5,25–28 Thus, one would speculate that antifibrinolytic therapy would lead to reduced coagulopathy in the setting of trauma. Published data on the incidence of hyperfibrinolysis in patients after severe trauma are variable, ranging between approximately 2% and 20%.29–33
In our study, we administered TXA to the massively bleeding pigs early (i.e., 15 minutes after the second trauma) in the absence of major changes from baseline in a ROTEM indicator of fibrinolysis or D-dimer levels. The resulting reduction in blood loss and the stabilization or improvement of ROTEM variables suggest that early administration of TXA may be beneficial in either occult or suspected hyperfibrinolysis. Systemic inflammation can make a significant contribution to the deleterious effects of trauma.34 In addition to its effects of fibrinolysis, TXA functions as an anti-inflammatory agent by inhibiting the effects of plasmin.35 It is possible that the impact of TXA on inflammation contributes to its effects on blood loss and mortality in patients with trauma.26,35
The benefits of early TXA treatment versus no treatment were increased when FC was administered as an additional therapy. This finding is concordant with the survival benefits of combined therapy with TXA and cryoprecipitate in the recent MATTERs II (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) study.36
Fibrinogen depletion occurs early after trauma.11,15,37–40 Low plasma levels of fibrinogen are associated with worsened injury severity score, shock, blood loss, transfusion requirements, and mortality.15,41,42 In our study, the administration of FC rapidly achieved plasma levels recommended by current European trauma guidelines.1 This was associated with enhancement of viscoelastic measurements and a reduction in blood loss compared with both control and TXA-treated animals. These data are consistent with a 2012 prospective cohort study investigating the time course of fibrinogen depletion in 517 trauma patients,15 where the authors advocated fibrinogen replacement as a means of improving outcomes. This is in line with the conclusions of previous studies.43–46
We observed that the administration of PCC in addition to TXA and FC produced no further reduction in blood loss. We suspect that thrombin generation is reduced only in the later stages of trauma-induced coagulopathy such as when coagulation factor II is decreased by two-thirds or more as is expected with blood loss of 150% to 200%.17,47,48 Nevertheless, previous studies have indicated a role for PCC in the treatment of trauma-induced coagulopathy when administered selectively to patients with prolonged EXTEM CT or high international normalized ratio and continued bleeding after fibrinogen supplementation.39,49,50 This use of PCC, in conjunction with fibrinogen supplementation, appears to reduce patients’ exposure to allogeneic blood products.49–51
It has been shown that thrombin generation may be upregulated as a physiological response to trauma.48 The potential risk of thromboembolic complications has been identified as a substantial shortcoming with PCC.48,52 For example, in a porcine model of liver injury, our group observed thromboembolism among animals receiving a PCC dose of 50 IU*kg−1, attributable to an imbalance of pro- and anticoagulant proteins.24 A clinical study has also reported a potential prothrombotic state lasting for several days after PCC therapy in trauma patients.53 In our study, there was no evidence of thromboembolic complications, but increased thrombin generation and enhanced fibrinogen activation indicated the potential for a prothrombotic state in the TXA–FC–PCC group. We would therefore advocate caution if considering the use of PCC for bleeding management in trauma patients.
A strength of our study is that promoters of coagulopathy such as hypothermia, acidosis, and hemodilution caused by intravascular volume replacement were included, mimicking the injury and treatment phases of severe trauma. There are also some limitations to our study. We investigated the effects of human and not porcine coagulation factors because of the unavailability of the latter. Although animal models enable a high degree of standardization, the results cannot necessarily be considered as fully transferable to humans because of species differences. In the clinical setting, coagulation factor concentrates are typically administered in response to clinical bleeding in the setting of abnormal coagulation test results. In contrast, in this study, these products were administered according to a fixed protocol independent of each animal’s coagulation data. Also, before the investigated treatment approach could be applied in humans, safety studies would be needed, particularly regarding the risk of thromboembolic events. The present study was too small to provide reliable insight into the risk of adverse events with the combinations of hemostatic agents administered. The posttreatment follow-up period was relatively short, and it is possible that prothrombotic complications might have occurred if the animals had been observed for a longer period of time. Finally, in accordance with clinical practice, we administered TXA, FC, and PCC sequentially. Consequently, our study provides no information regarding the possible benefits of administering these treatments simultaneously.
In conclusion, our data show that the early administration of TXA combined with FC reduces blood loss and improves coagulation test results after blunt liver injury and prolonged shock compared with no treatment and TXA administration alone. These effects could be related to the prevention of hyperfibrinolysis and rapid correction of hypofibrinogenemia. Sufficient thrombin generation was observed in this model, potentially explaining the lack of benefit with additional PCC therapy.
Name: Christian Zentai, MD.
Contribution: This author performed the experimental laboratory work.
Attestation: Christian Zentai approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Paola E. J. van der Meijden, PhD.
Contribution: This author performed the CAT assays and platelet analyses.
Attestation: Paola E. J. van der Meijden approved the final manuscript.
Conflicts of Interest: None.
Name: Till Braunschweig, MD.
Contribution: This author accomplished the pathological assessment.
Attestation: Till Braunschweig approved the final manuscript.
Conflicts of Interest: None.
Name: Nicolai Hueck, MD.
Contribution: This author performed the experimental laboratory work.
Attestation: Nicolai Hueck approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Markus Honickel, MD.
Contribution: This author performed the statistical analysis.
Attestation: Markus Honickel approved the final manuscript and attests to the integrity of the original data and the analyses reported in this manuscript.
Conflicts of Interest: Markus Honickel has received travel support from Boehringer Ingelheim (Germany).
Name: Henri M. H. Spronk, PhD.
Contribution: This author performed the CAT assays and platelet analyses.
Attestation: Henri M. H. Spronk approved the final manuscript.
Conflicts of Interest: Henri M. H. Spronk has received research funding from Boehringer Ingelheim (Germany) and honoraria for consultancy from Bayer (Germany).
Name: Rolf Rossaint, MD.
Contribution: This author participated in the study design.
Attestation: Rolf Rossaint approved the final manuscript.
Conflicts of Interest: Rolf Rossaint has received honoraria for lectures and consultancy from CSL Behring (Germany) and Novo Nordisk (Denmark).
Name: Oliver Grottke, MD, PhD, MPH.
Contribution: This author conceived and conducted the experimental laboratory work.
Attestation: Oliver Grottke approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is also the archival author.
Conflicts of Interest: Oliver Grottke has received research funding from Novo Nordisk (Denmark), Biotest (Germany), CSL Behring (Germany), and Nycomed (Germany). He has also received honoraria for consultancy and/or travel support from CSL Behring (Germany), Boehringer Ingelheim (Germany), Bayer Healthcare (Germany), and Portola (USA).
Charles W. Hogue, MD.
The authors thank Renate Nadenau (Department of Anaesthesiology) for her excellent support.
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