This sub-analysis of a multicenter prospective study demonstrated the significant performance of DIC scores immediately after trauma for predicting a poor prognosis in severely injured trauma patients. The markedly low survival probability of DIC patients diagnosed immediately after trauma was also confirmed. The massive generation of thrombin and plasmin followed by the inhibition of fibrinolysis by PAI-1 in DIC patients also showed marked predictivity for a poor prognosis.
DIC immediately after trauma represents a fibrinolytic phenotype6,9. In this phenotype of DIC, trauma patients need massive transfusion due to trauma-related bleeding as well as DIC-induced oozing-type bleeding at surgical-site wounds, mucosal lesions, serosal surfaces, and the sites of indwelling catheters, among other points. Massive thrombin formation-induced consumption coagulopathy and the time difference between immediate plasmin generation due to tissue-type plasminogen activator (t-PA) release from the Weibel-Palde bodies and the expression of PAI-1 mRNA leading to plasmin-mediated fibrin(ogen)olysis are main causes of bleeding immediately after trauma6,9. Markedly high levels of soluble fibrin in DIC patients, as well as a reduction in platelet counts, low levels of fibrinogen, and prolonged prothrombin time and APTT, foster consumption coagulopathy. Low fibrinogen levels as well as elevated FDP levels with high FDP/D-dimer ratios in DIC patients suggest fibrin(ogen)olysis. Immediate increases in the plasmin levels followed by an increase in the PAI-1 levels at 3-h timepoints indirectly support the notion of a time difference between the immediate t-PA release and the PAI-1 mRNA expression. The administration of a median 0 mL of intravenous fluids prior to ED presentation and significant decreases in platelet counts and fibrinogen levels from the 0- to 3-h timepoints despite a large volume of platelet concentrate and FFP transfusion in DIC patients deny dilution coagulopathy.
The robustness of the present study is based on the confirmation of the results of previous studies using two prospectively obtained data points immediately after trauma. A single-center retrospective study showed that DIC with a fibrinolytic phenotype diagnosed within 4 h after arrival at the ED contributed to a poor prognosis due to massive transfusion11. A multicenter retrospective study concluded that DIC diagnosed immediately after presentation to the ED could be used to predict massive transfusion for 24 h after admission, with an association between DIC and massive transfusion within 24 h also observed (odds ratio, 4.607, P = 0.001)19. The Kaplan-Meier curves for the time from presentation to the ED to reaching critical thresholds of routine parameters for massive bleeding showed that the platelet counts, prothrombin time, and fibrinogen levels in DIC patients reached their critical level significantly earlier than those in non-DIC patients20. In addition, the time taken from the arrival at the ED to meet the definition of massive transfusion was shorter in DIC patients than in non-DIC patients. Hayakawa et al.21 showed that DIC at an early phase of trauma associated with consumption coagulopathy and increased fibrinolysis required more blood transfusions than was noted in non-DIC patients. Given these previous findings, the present results showing a good performance of DIC scores immediately after trauma to predict massive transfusion seem very reasonable.
The key point of DIC after trauma is that thrombin generation always underlies the changes in fibrinolytic systems as shown in Fig. 46,9,22. Regardless of the phenotype, DIC is always associated with massive thrombin generation; DIC with a fibrinolytic phenotype progresses to thrombotic phenotype along with the elevation of PAI-1 levels21,23. The dynamics of soluble fibrin, plasmin and antiplasmin complex and PAI-1 observed in the present study suggest that this progression occurs approximately 3 h after trauma. Despite equal severity of brain injury (as assessed by the head AIS) between the patients with and without DIC, the aggravation of the GCS during the 24-h time period in DIC patients may suggest DIC-induced secondary brain injury due to the progression of intracranial hemorrhaging or microvascular thrombosis.
The present study is significant for its confirmation that a DIC diagnosis affected the survival probability of severely injured trauma patients. Furthermore, DIC scores obtained immediately after trauma (median 49 min from injury) were proven to predict late-phase MODS and a poor outcome. MODS with a high mortality rate is characteristic of DIC6,8. Rapid progression of DIC from the fibrinolytic to the thrombotic phenotype by 3 h after arrival to the ED may be the reason for the development of MODS within 24 h after admission. Cabrera et al.24 showed that trauma patients complicated with MODS had a specific gene expression within 120 min from injury, implicating the participation of innate immune cells, such as neutrophils at this stage of trauma. In addition, previous studies showing immediate changes in mitochondrial DAMPs, histones, neutrophils, and coagulation after trauma may support the results of the present study highlighting the predictive ability of rapid-onset DIC for the later prognosis of patients7,8,10.
Another novel finding of the present study was that soluble fibrin, plasmin and antiplasmin complex, and PAI-1 were able to predict massive transfusion, MODS, and hospital mortality of severe trauma patients. DIC patients were associated with significantly higher levels of soluble fibrin, plasmin and antiplasmin complex and PAI-1 than non-DIC patients. In the main study of our series, increased levels of soluble thrombomodulin, a marker of endothelial injury, were observed in DIC patients15. Previous studies showed that MODS was more likely when markers of endotheliopathy, e.g. soluble thrombomodulin, were increased immediately after trauma25. The generation of thrombin and plasmin, inhibition of fibrinolysis by PAI-1, and endothelial injury are the main pathomechanisms of DIC6,8, supporting the significant utility of DIC for predicting a poor outcome of trauma patients in the present study.
Trauma-induced coagulopathy is defined as a pre-stage of DIC and progresses to DIC as a result of dysregulated inflammatory and coagulofibrinolytic responses to trauma26. When the trauma is sufficiently severe, therefore, DIC develops immediately after trauma without passing through the trauma-induced coagulopathy stage15. Previous studies have shown that trauma-induced coagulopathy was a significant risk factor of MODS27 and an independent predictor of MODS and mortality in cases of severe trauma28,29. These studies indirectly strengthen the present finding of the significant performance of DIC in predicting MODS and hospital mortality.
Several limitations associated with the present study warrant mention. Although this study was a sub-analysis of prospectively collected data, the data were retrospectively analyzed and included missing values. The use of tranexamic acid was equally distributed between the two groups, but the effects of tranexamic acid on the obtained results were not elucidated. The present study was a single national study conducted in a developed country, which may limit the global generalization of the obtained results.