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High D-Dimer Levels Predict a Poor Outcome in Patients with Severe Trauma, Even with High Fibrinogen Levels on Arrival

A Multicenter Retrospective Study

Hayakawa, Mineji; Maekawa, Kunihiko; Kushimoto, Shigeki; Kato, Hiroshi; Sasaki, Junichi; Ogura, Hiroshi; Matauoka, Tetsuya; Uejima, Toshifumi; Morimura, Naoto; Ishikura, Hiroyasu; Hagiwara, Akiyoshi; Takeda, Munekazu; Kaneko, Naoyuki; Saitoh, Daizoh; Kudo, Daisuke; Kanemura, Takashi; Shibusawa, Takayuki; Furugori, Shintaro; Nakamura, Yoshihiko; Shiraishi, Atsushi; Murata, Kiyoshi; Mayama, Gou; Yaguchi, Arino; Kim, Shiei; Takasu, Osamu; Nishiyama, Kazutaka

Author Information
doi: 10.1097/SHK.0000000000000542

Abstract

INTRODUCTION

In patients with severe trauma, trauma-induced coagulopathy is observed during the early phase, frequently develops into severe haemorrhage due to coagulation abnormalities, and contributes to a poor outcome (1–4). Although trauma-induced coagulopathy is mainly caused by tissue injuries and shock with complex underlying mechanisms, consumptive coagulopathy and hyperfibrinolysis are the predominant mechanisms (1, 5–9).

During the early phase of trauma, fibrinogen plays an important role in clot formation (10, 11). Therefore, many previous studies have indicated that low fibrinogen levels were associated with haemostatic impairment and induced massive bleeding as well as predicted a poor outcome (7, 12–17). Furthermore, fibrinogen levels tend to deteriorate more quickly than other coagulation factors during the early phase of trauma (14, 18, 19).

Previous studies have indicated that elevated D-dimer levels are also associated with a poor outcome (5–7, 20), as well as the severity of tissue damage (21–23). Gando and colleagues recently reported that high D-dimer levels on arrival at the emergency department (ED) indicated hyperfibrinolysis and predicted massive bleeding and death (5–7).

Although low fibrinogen levels on arrival at the ED have been shown to be associated with coagulopathy and a poor outcome (7, 10–17), the predictive value of the interaction between fibrinogen and D-dimer levels in the early phase of severe trauma has never been evaluated. Therefore, we hypothesized that high D-dimer levels would predict trauma-induced coagulopathy and a poor outcome in patients with severe trauma, even with high fibrinogen levels on arrival at the ED. The aim of the present study was to investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the ED for massive transfusion and mortality in patients with severe trauma in a multicenter retrospective study.

MATERIALS AND METHODS

This retrospective study was conducted at 15 tertiary emergency and critical care centers in Japan (Japanese Observational Study for Coagulation and Thrombolysis in Early Trauma, J-OCTET) and was approved by the Institutional Review Board of each hospital. No consent was needed because of the retrospective study.

Patient selection and data collection

J-OCTET was a retrospective multicenter study to investigate disorders of coagulation and thrombolysis in patients with severe trauma. J-OCTET recruited consecutive trauma patients with an injury severity score (ISS) ≥16 admitted to EDs from January to December 2012. Patients were excluded if they were younger than 18 years or complicated with cardiac arrest, burn, cervical spine injury not caused by a high-energy accident, pregnancy, or liver cirrhosis. The clinical backgrounds, laboratory test results (i.e., complete blood counts, coagulation, and biochemistry variables), treatments, and outcomes of the patients were retrospectively collected.

Definitions

Trauma-induced coagulopathy may induce massive bleeding during the early phase of trauma and may be associated with death before massive transfusion (1–4). Furthermore, in patients with severe brain injuries, trauma-induced coagulopathy may induce early death unrelated to massive bleeding and massive transfusion (24, 25). Therefore, we defined a poor outcome associated with trauma-induced coagulopathy as patients with more than 10 units of red cell concentrate transfusion or death during the first 24 h; all other patients were defined as having a good outcome.

Statistical analysis

All variables are expressed as median and interquartile range (i.e., first to third quartile) or number (percentage). Intergroup comparisons were made using the Mann–Whitney U test or chi-square test. To compare more than two groups, the Kruskal–Wallis test was applied with a Bonferroni correction. The receiver operating characteristic (ROC) curves of fibrinogen and D-dimer were constructed to determine the relationship to a poor outcome. Cut-off values were defined on the basis of the Youden Index. On the basis of the cut-off values for fibrinogen and D-dimer to differentiate the outcomes, patients were divided into four groups, and the amount of transfusion, haemostatic procedures, and survival rates were compared. Kaplan–Meier analyses were performed to evaluate survival time, and the log-rank test was used to compare differences between groups. SPSS 15.0J (SPSS Inc, Chicago, IL) was used for all statistical analyses. The level of significance was set at P < 0.05.

RESULTS

Patient characteristics

A total of 796 severe trauma patients were enrolled in J-OCTET (see Supplemental Table, Supplemental Digital Content 1 at http://links.lww.com/SHK/A356). Of these, 277 patients, in whom fibrinogen and/or D-dimer levels were not measured on arrival at the ED, were excluded from the present analysis; thus 519 patients were analyzed (Fig. 1). The patient characteristics are shown in Table 1. Patients with a poor outcome were anatomically, physiologically, and haematologically more severe than those with a good outcome. Time from accident to sample collection was statistically different between the two groups. Patients with a more severe condition may promptly transfer to the ED and have blood samples taken immediately after arrival. The precise duration from accident to sample collection was not indicated in some patients, because the time of the accidents was unclear.

Fig. 1
Fig. 1:
Receiver operating characteristic (ROC) curves for predicting a poor outcome based on fibrinogen and D-dimer levels.Dotted line indicates D-dimer; solid line, fibrinogen.
Table 1
Table 1:
Patient characteristics

Division of patients based on D-dimer and fibrinogen levels

Figure 2 shows the ROC curves for predicting a poor outcome according to fibrinogen and D-dimer levels as fibrinolytic variables, and the results of the ROC curve analysis are shown in Table 2. The optimal cut-off values for fibrinogen and D-dimer were 1.9 g/L and 38 mg/L, respectively. On the basis of the cut-off values for fibrinogen and D-dimer, 519 patients, who had both fibrinogen and D-dimer levels measured on arrival at the ED, were divided into the following four groups: 267 patients in low D-dimer (<38 mg/L)/high fibrinogen (>190 mg/dL), 53 patients in low D-dimer/low fibrinogen (≤190 mg/dL), 113 patients in high D-dimer (≥38 mg/L)/high fibrinogen, and 86 patients in high D-dimer/low fibrinogen. The characteristics of the patients in the four groups are shown in Table 3. Although Glasgow Coma Scale scores were statistically different among the four groups, anatomical severities of head trauma (abbreviated injury score of the head) were not different. Table 4 shows haemostatic procedures (including emergency surgery and interventional radiology for haemostasis) and transfusion data. The rate of haemostatic procedures and amount of transfusion increased gradually from group (1) to (4). Furthermore, the mortality rate increased gradually from group (1) to (4) (Fig. 3). Kaplan–Meier survival curves in the four groups are presented in Figure 4. The survival rate in group (4) was lower than that in the other three groups (P < 0.001 vs. group (1), P < 0.001 vs. group (2), and P = 0.011 vs. group (3)). Moreover, the survival rate in group (3) was statistically lower than that in groups (1) and (2) (P < 0.001 and P = 0.007, respectively).

Fig. 2
Fig. 2:
Mortality rate 24 and 48 h after arrival at the emergency department.The mortality rate 24 and 48 h after arrival at the emergency department was statistically different among the groups (P < 0.001 and <0.001, respectively). Low and high D-dimer levels were defined as <38 mg/L and ≥38 mg/L, respectively, on arrival at the emergency department. Low and high fibrinogen levels were defined as ≤1.9 g/L and >1.9 g/L, respectively, on arrival at the emergency department. Fbg indicates fibrinogen. * P < 0.0083 (after Bonferroni correction) versus the low D-dimer/high fibrinogen group. P < 0.0083 (after Bonferroni correction) versus low D-dimer/low fibrinogen group. P < 0.0083 (after Bonferroni correction) versus high D-dimer/high fibrinogen group.
Table 2
Table 2:
Receiver operating characteristic (ROC) curve analysis of fibrinolytic variables
Table 3
Table 3:
Patient characteristics
Table 4
Table 4:
Hemostatic procedures and transfusions
Fig. 3
Fig. 3:
Kaplan–Meier survival curves.The survival rate in the (4) high D-dimer/low fibrinogen group was lower than that in the other three groups (P < 0.001 vs. (1), P < 0.001 vs. (2), and P = 0.011 vs. (3) based on log-rank tests). The survival rate in the (3) high D-dimer/high fibrinogen group was lower than that in (1) and (2) groups (P < 0.001 and P = 0.007, respectively based on log-rank tests). Low D-dimer (<38 mg/L) and high D-dimer (≥38 mg/L) and low Fbg (≤1.9 g/L) and high Fbg (>1.9 g/L) levels are values on arrival at the emergency department. Fbg indicates fibrinogen.
Fig. 4
Fig. 4:
Kaplan-Meier survival curves in the four groups.The survival rate in group (4) was lower than that in the other three groups (P < 0.001 vs. group (1), P < 0.001 vs. group (2), and P = 0.011 vs. group (3). Moreover, the survival rate in group (3) was statistically lower than that in groups (1) and (2) (P < 0.001 and P = 0.007, respectively).

DISCUSSION

In the present study, the outcome of patients with high D-dimer/low fibrinogen was poorest among the severe trauma patients. Moreover, mortality was significantly higher in patients with high D-dimer levels than in those with low D-dimer levels among patients without fibrinogen deficiency on arrival at the ED.

D-dimer is a fibrin degradation product and reflects fibrinolysis after coagulation activation in the vessels before blood sampling (26). Fibrinolysis is induced by plasmin, which is activated from plasminogen by tissue type-plasminogen activator (t-PA) (26). Recent studies have indicated that hyperfibrinolysis, detected as clot lysis using thromboelastometry, was an important component in trauma-induced coagulopathy and induced haemostatic impairments and a poor outcome (27–30). Traumatic shock and tissue hypoperfusion induce acute release of t-PA from endothelial cells (1, 2, 31). The released t-PA causes hyperfibrinolysis, which is detected as clot lysis using thromboelastometry, in severe trauma patients (1, 2). In thromboelastometry, the clot lysis is observed when fibrinolytic activation by t-PA overrides fibrinolytic suppression by α2-antiplasmin in the blood sample after the start of thromboelastometry (30, 32). Therefore, hyperfibrinolysis indicated by elevation of D-dimer levels is different from that indicated by thromboelastometry. Moreover, several studies have suggested that elevation of D-dimer levels is usually observed in trauma patients with thromboelastometry-indicated hyperfibrinolysis (30, 33, 34), but thromboelastometry-indicated hyperfibrinolysis may not always be observed in trauma patients with elevation of D-dimer levels (30). Raza et al. (30) indicated that thromboelastometry-indicated hyperfibrinolysis was observed in only 5% of patients with severe trauma, although elevation of D-dimer levels was observed in most patients with severe trauma. Therefore, elevated D-dimer level may indicate hyperfibrinolysis and predict massive transfusion, which is an important outcome of this study.

Previous reports have indicated that high D-dimer levels on arrival at the ED were associated with a poor outcome in patients with traumatic brain injury (21–23). However, several studies demonstrated that high D-dimer levels were associated with a poor outcome in all trauma patients regardless of brain injury complications (5–7, 30, 33, 34). In the present study, anatomical severities of head trauma were not different among the four groups (Table 3). Although Glasgow Coma Scale scores were statistically different among groups, physiological factors might affect the consciousness levels regardless of the anatomical severities of head trauma.

Gando and colleagues previously reported a relationship between fibrin/fibrinogen degradation products (FDP) and outcome in trauma patients (5–7). FDP levels reflect not only fibrinolysis, but also fibrinogenolysis, unlike D-dimer levels (26). Therefore, FDP levels are more ideal for evaluating hyperfibrinolysis during the early phase of trauma than D-dimer levels (5–7). However, in the present multicenter study, we could not analyze FDP levels because they were not measured on arrival at the ED in many patients.

There has been much discussion in recent years regarding ratios of packed red cells and plasma in massive transfusion, with debate over whether a 1 : 1 ratio should be achieved (35). In the present study, almost all of the physicians adopted the transfusion practice, which was close to a 1 : 1 ratio of red cells to plasma, in the involved centers. Thus, the transfusions were close to a 1 : 1 ratio of red cells to plasma (Table 4).

The present retrospective study has several limitations. First, although 796 patients with severe trauma were included, some patients did not have fibrinogen and D-dimer levels measured on arrival at the ED. Therefore, in the analysis comparing the four groups based on fibrinogen and D-dimer levels, 227 patients were excluded because of missing values. Second, time from accident to sample collection varied in each patient, and the time was statistically different between the poor and good outcome groups (Table 1). Patients with a more severe condition may have been promptly transferred to the ED to have blood samples taken immediately after arrival. However, there was no statistically significant difference among the four groups (those separated by D-dimer and fibrinogen levels) in the timing following accident (Table 3). During the early phase of trauma, coagulation and fibrinolytic variables change dramatically; thus differences in the time from injury to blood collection may have some effect on the results. This is especially true in patients with hyperfibrinolysis, as fibrinogen levels may decrease gradually just after injury owing to consumption by coagulation activation and degradation by hyperfibrinolysis. Third, in the participating institutions, D-dimer level was measured using the latex coagulating method, which employed different reagents at the three companies. The sensitivity and range differ among the three reagents and may affect the results of the present study.

In conclusion, high D-dimer levels on arrival at the ED are a strong predictor of early death or a requirement for massive transfusion in severe trauma patients, regardless of fibrinogen levels, which may indicate hyperfibrinolytic status. This indicates the need to recognize patients with high D-dimer levels to allow better preparation for immediate haemostatic resuscitation.

Acknowledgments

The following Institutional Review Board of each hospital approved the present study: Institutional Review Board of Hokkaido University Hospital for Clinical Research; Ethics Committee of Tohoku University School of Medicine; Institutional Review Board of National Hospital Organization Disaster Medical Center; Keio University School of Medicine, ETHICS COMMITTEE; Ethics Committee of Osaka University Medical School; Institutional Review Board of Rinku General Medical Center; Ethics Committee of Kinki University Faculty of Medicine; Institutional Review Board of Yokohama City University Medical Center; Institutional review board of Fukuoka University Hospital; Ethical committee of National Center for Global and Medicine; Ethics Committee of Tokyo Women's Medical University; Medical Research Ethics Committee of Tokyo Medical and Dental University; Nippon Medical School Hospital Institutional Review Board; The Ethical Committee of Kurume University; Ethics Committee, Juntendo University, Urayasu Hospital.

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Keywords:

Coagulopathy; disseminated intravascular coagulation; fibrin fibrinogen degradation products; fibrinolysis; multiple trauma; transfusion

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