Impact of initial coagulation and fibrinolytic markers on mortality in patients with severe blunt trauma: a multicentre retrospective observational study

Haemorrhage plays a critical role in deaths caused by trauma, accounting for approximately 30–40% of trauma-related deaths [1]. Coagulopathy occurring in early phases of trauma leads to systemic haemorrhage that cannot be controlled using surgical procedures; patients who present with coagulopathy following trauma have an approximately four-fold higher mortality [2‐4]. These patients are considered to require ‘damage control strategy’ including damage control surgery, restrictive fluid administration, massive transfusion and use of antifibrinolytic drugs. Therefore, detection of coagulopathy in patients with trauma is crucial for providing adequate management.

Prolonged prothrombin time has been defined as coagulopathy that increases risk of death in patients with severe trauma [2‐5]. Decreased platelet counts and fibrinogen levels are also considered important signals because those represent coagulopathy that is potentially amendable with blood transfusions, including platelet concentrate (PC), fresh frozen plasma (FFP), fibrinogen concentrate and cryoprecipitate [4, 6‐10]. Additionally, recent studies have reported that elevated D-dimer, which suggests the existence of hyperfibrinolysis, is a significant predictor of poor outcomes [11‐13]. Other than those standard laboratory-based coagulation tests, viscoelastic methods are reportedly effective for rapid assessment of coagulopathy [14, 15]; however, several systematic reviews indicate limited evidence to support their utility [16, 17]. Therefore, the European guidelines regarding coagulopathy after trauma still recommend early and repeated monitoring of standard laboratory-based coagulation tests as well as parameters of viscoelastic testing [18].

From these perspectives, traditional coagulation and fibrinolytic markers play important roles in the management of patients with trauma. However, which of these markers best contributes to detecting coagulopathy and stratification of trauma patients at risk for mortality has been poorly investigated. Moreover, huge variations in the cut-off values have been reported to predict mortality of these markers in previous studies [2‐5, 9‐12]. Thus, how can one best stratify patients with trauma and predict their mortality using coagulation and fibrinolytic markers remains to be established.

The purpose of this study was to investigate the impact of initial coagulation and fibrinolytic markers on mortality in patients with severe trauma. Specifically, we identified preferential markers profitable for prediction of mortality and determined their optimal cut-off values. We hypothesised that combination of coagulation markers (platelet counts, prothrombin time or fibrinogen) and a fibrinolytic marker (D-dimer) would be profitable for predicting mortality.

In the present study, we investigated the impact of initial coagulation and fibrinolytic markers including platelet counts, PT-INR, fibrinogen and D-dimer on 28-day mortality in patients with severe blunt trauma. CART analysis revealed that fibrinogen and D-dimer are the most profitable discriminators among these markers for predicting 28-day mortality. Although there were significant difference in platelet count and PT-INR between survivors and non-survivors, CART analysis did not identified these two markers suggesting that the combination of fibrinogen and D-dimer predicted 28-day mortality the best. Furthermore, low fibrinogen and high D-dimer were the useful for predicting mortality even after adjustment of the patient severity calculated by the TRISS Ps.

Fibrinogen is essential for clot formation and platelet aggregation; during major blood loss, fibrinogen decreases to critically low levels earlier than the other coagulation factors [25] and the early phase of severe trauma [26]. Although several studies report the benefits of fibrinogen concentrate or cryoprecipitate transfused in patients with hypofibrinogenaemia, because these productions contain abundant fibrinogen [8, 27, 28], the optimal threshold for treating fibrinogen depletion remains variable and opinion-based. The 2015 guidelines from the American Society of Anaesthesiologists suggested a threshold of 80–100 mg/dL [29], whereas the 2016 European guidelines recommended initiating fibrinogen supplementation when fibrinogen level is < 150–200 mg/dL [18]. Our results proposed a cut-off value of 130 mg/dL; the 28-day mortality was 5.3% in patients with initial fibrinogen levels ≥130 mg/dL, whereas 56.1% of the patients died when initial fibrinogen levels were <  130 mg/dL. These results suggested that fibrinogen supplementation should be initiated at least before the plasma fibrinogen level decreases to a critical level of 100 mg/dL. Further studies are warranted to evaluate the validity of early fibrinogen supplementation, including fibrinogen concentrates and cryoprecipitate activated by initial fibrinogen levels of 100–150 mg/dL.

The second discriminator in the CART analysis was the D-dimer. In the subgroup analysis, we found that all patients with high a D-dimer without fibrinogen depletion died of TBI. Because the D-dimer is generated as a result of fibrin formation and sequential fibrinolysis [30], it is considered a useful marker for excessive fibrinolysis in patients with trauma [12]. Thus, hyperfibrinolysis should be corrected in patients with high D-dimer to prevent death due to TBI. An important treatment option in such a situation is an antifibrinolytic drug, including tranexamic acid [31]. Although recent trials have failed to demonstrate the efficacy of tranexamic acid on clinical outcomes in patients with TBI [32, 33], it is possible that selective use of the drug in the TBI patients with hyperfibrinolysis provides benefits. Our results suggested that patients with high D-dimer levels and TBI are potential candidates for TXA administration, because they have evidence of hyperfibrinolysis and are at high risk for mortality from TBI. Thus, the efficacy of selective use of TXA should be investigated in future studies.

The association between the types of coagulation and fibrinolytic abnormalities and cause of death in trauma patients has not been extensively investigated. We found that patients with sustained fibrinogen and high D-dimer died due to TBI, whereas majority of patients with decreased fibrinogen without elevated D-dimer died from exsanguination. The coagulation system is usually activated in patients with severe trauma, converting fibrinogen to fibrin to form blood clots [34]. TBI predisposes patients to hyperfibrinolysis following activation of the coagulation system, known as secondary hyperfibrinolysis, that degrades fibrin to D-dimer [13]. Severe haemorrhagic shock causes tissue hypoxia/ischemia injury that leads to increased release of tissue-plasminogen activator from endothelial cells [35]. This excessive fibrinolysis breaks down not only fibrin but also fibrinogen. We speculate that patients with sustained fibrinogen and elevated D-dimer had secondary hyperfibrinolysis that worsened the TBI and that patients with decreased fibrinogen without elevated D-dimer had primary hyperfibrinolysis caused by haemorrhagic shock that resulted in death from exsanguination.

Our study includes several limitations that might cause a bias in the results or interpretations. First, this was a retrospective cohort study conducted at only two tertiary care hospitals. In particular, optimal cut-off values of these markers can differ according to patient characteristics and background of each study cohort. External validation should be performed to confirm the results. Second, in the two hospitals, the D-dimer level was quantified using different reagents at the two companies. The difference may affect the results in this study; however, we could not adjust the difference because there is no established method. Third, we could not investigate effects of anticoagulant/platelet agents on mortality as small number of patients used these drugs before injury. Against our expectations, the proportion of patients who used these drugs was slightly lower in non-survivors than survivors; however, the association of antithrombotic agents with outcomes in patients should be explored separately. Fourth, we examined only the initial coagulation and fibrinolytic markers measured upon ED arrival and did not routinely examine other important markers, such as fibrinogen and fibrin degradation products (FDP), thrombin–antithrombin complex and plasminogen activation inhibitor. As FDP reflects primary hyperfibrinolysis as well as secondary hyperfibrinolysis, it may be a better predictor than D-dimer. The impact of FDP on mortality should also be investigated. Finally, only patients with severe blunt trauma were included. As a result, most patients in this study cohort had TBI. It was thus not possible to conduct a subgroup analysis to evaluate the impact of the tested markers on death from exsanguination in patients without TBI. Further studies are warranted to examine whether our findings are applicable to severe haemorrhagic shock patient population including many penetrating injuries and/or fewer TBI.

Fibrinogen and D-dimer were the principal markers for stratification of the risk of death in patients with severe blunt trauma. Even after adjustment for TRISS Ps, fibrinogen depletion and D-dimer elevation were independently associated with mortality; they might play critical roles in haemostatic abnormalities in the early phase of trauma and could be the therapeutic targets and predictive variables of mortality.