New considerations on pathways involved in acute traumatic coagulopathy: the thrombin generation paradox

Abstract

Background: An acute traumatic coagulopathy (ATC) is observed in about one third of severely traumatized patients. This early, specific, and endogenous disorder is triggered by the association of trauma and hemorrhage. The early phase of this condition is characterized by the expression of a bleeding phenotype leading to hemorrhagic shock and the late phase by a prothrombotic profile leading to multiple organ failure. The physiopathology of this phenomenon is still poorly understood. Hypotheses of disseminated intravascular coagulation, activated protein C-mediated fibrinolysis, fibrinogen consumption, and platelet functional impairment were developed by previous authors and continue to be debated. The objective of this study was to observe general hemostasis disorders in case of ATC to confront these hypotheses.

Method: Four groups of 15 rats were compared: C, control; T, trauma; H, hemorrhage; and TH, trauma and hemorrhage. Blood samples were drawn at baseline and 90 min. Thrombin generation tests, platelet aggregometry, and standard hemostasis tests were performed.

Results: Significant differences were observed between the baseline and TH groups for aPTT (17.9 ± 0.8 s vs 24.3 ± 1.4 s, p < 0.001, mean ± SEM), MAP (79.7 ± 1.3 mmHg vs 43.8 ± 1.3 mmHg, p < 0.001, mean ± SEM), and hemoglobin (16.5 ± 0.1 g/dL vs 14.1 ± 0.3 g/dL, p < 0.001, mean ± SEM), indicating the presence of an hemorrhagic shock due to ATC. Compared to all other groups, coagulation factor activities were decreased in the TH group, but endogenous thrombin potential was (paradoxically) higher than in group C (312 ± 17 nM/min vs. 228 ± 23 nM/min; p = 0.016; mean ± SEM). We also observed a subtle decrease in platelet count and function in case of ATC and retrieved an inversed linear relationship between fibrinogen concentration and aPTT (intercept, 26.53 ± 3.16; coefficient, - 3.40 ± 1.26; adjusted R²: 0.1878; p = 0.0123).

Conclusions: The clinical-biological profile that we observed, combining normal thrombin generation, fibrinogen depletion, and a hemorrhagic phenotype, reinforced the hypothesis of activated protein C mediated-fibrinolysis. The key role of fibrinogen, but not of the platelets, was confirmed in this study. The paradoxical preservation of thrombin generation suggests a protective mechanism mediated by rhabdomyolysis in case of major trauma. Based on these results, we propose a new conception concerning the pathophysiology of ATC.

Keywords: Coagulation; Model; Platelet; Shock; Thrombin; Trauma.

Fig. 1

Experimental protocol. Group C, without trauma without hemorrhage; T, trauma without hemorrhage; H, hemorrhage without trauma; TH, hemorrhage with trauma (n = 15 in each group)

Fig. 2

Markers of ATC and coagulation factors. Baseline, pooled values from all groups at 0 min; C₉₀, control at 90 min; T₉₀, trauma at 90 min; H₉₀, hemorrhage at 90 min; TH₉₀, trauma and hemorrhage at 90 min. Data are presented as mean ± SEM. *ANOVA I significance was designated at the p < 0.05 level of confidence. ^†Significantly different from baseline. Letter differences indicate statistical differences between groups at 90 min

Fig. 3

Evolution of MAP during the time in each group. C, control; T, trauma; H, hemorrhage; TH, trauma and hemorrhage, n = 15 per group. Values represent mean ± SEM. ^†Significantly different from baseline. Letter differences indicate statistical differences between groups at 90 min

Fig. 4

New considerations on pathways involved in acute traumatic coagulopathy. Hemorrhage leads to fibrinogen depletion and decreases its competitive inhibition on the thrombin/thrombomodulin complex, enhancing protein C activation. In addition, shock induces a decrease in thrombin clearance, also increasing thrombin/thrombomodulin interactions and protein C activation. The result is a hyperfibrinolysis triggered by aPC. Shock also lead to an increase in endogenous epinephrine, leading to heparan sulfate exposition on endothelial cells, activating antithrombin. The repression on coagulation mediated by antithrombin and activated protein C is counteracted by increases in tissue factor and myoglobin triggered by tissular damages, explaining the preservation of thrombin generation despite the expression of a hemorrhagic phenotype due to hyperfibrinolysis.