**3. Trauma**

DIC has been well known to occur in trauma since the 1960s, especially in relation to head trauma (**Table 1**). Coagulopathy in trauma was believed to originate as a consequence of fluid administration and hypothermia [27]. However, in the 2000s, the concept of acute traumatic coagulopathy (ATC) first appeared [27] with the demonstration that an organ and/or cell injury itself caused the coagulopathy. Using coagulation biomarkers such as PT, APTT and thrombin time (TT), acute traumatic coagulopathy was shown to be associated with mortality and severe trauma.

Initially, the concept of ATC was reported mainly in severe trauma, because PT, APTT and TT were found to have normal values in lightly and mildly traumatized patients. However, using fibrinolytic coagulation biomarkers such as FDP and D-dimer, we also detected ATC in lightly and mildly traumatized patients. This has been described in our first report on the clinical usefulness of coagulation biomarkers [28].

#### **3.1. The relationship between coagulation biomarkers and trauma severity**

Our study reported that of all coagulation biomarkers, FDP and D-dimer were associated with the severity of trauma [28]. We have previously demonstrated an association between FDP and D-dimer, and a trauma score such as the Injury Severity Score (ISS) [29]. The ISS has been one of the most common and useful scoring systems to evaluate the severity of trauma and is used widely throughout the world. In clinical practice, the ISS is calculated for each anatomical injury according to the results of physical examinations, surgery and imaging studies; therefore, the ISS cannot be calculated in an initial emergency field. However, we can predict ISS using FDP and D-dimer.

In this study, the area under receiver operating characteristics curves (AUROCs) of FDP and D-dimer for predicting an ISS ≥ 9 were 0.757 and 0.756, and the sensitivity and specificity of FDP and D-dimer based on the Youden's index were 75.9 and 68.4%, and 75.9 and 73.7%, respectively. This demonstrated that we could predict mild to severe injury (ISS ≥ 9) with about 70% sensitivity and specificity; this finding signaled to trauma physicians and surgeons that minor injury was not to be overlooked. Because several minor injuries, such as minute spinal column and rib fractures, are sometimes hard to detect, FDP and D-dimer can be used as supplementary diagnostic tools.

In addition, we have adopted this finding to more severe trauma. In the previous study, we investigated the association between FDP and D-dimer, and an ISS ≥ 9. In a similar setting, we calculated the AUROCs of FDP and D-dimer for predicting ISS ≥ 9, ISS ≥ 16 and ISS ≥ 25 (**Figure 2**).

predict an ISS over 25 were 73.3 and 82.7%, and 76.7 and 78.4%, respectively. These findings are novel because they are based on a patient's trauma severity, allowing the development of

**Figure 2.** (a) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury severity score (ISS) of a patient with trauma ≥9 points. FDP, fibrin degradation products. (b) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury severity score (ISS) of a patient with trauma ≥16 points. FDP, fibrin degradation products. (c) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury

> 0.691 (0.624–0.759) 0.694 (0.628–0.761)

32.1 μg/mL 12.8 μg/mL

67.8 65.6

64.9 66.1

CI, confidence interval; FDP, fibrin degradation product; AUROC, area under the receiver operating characteristic curve;

**Table 2.** Area under the receiver operating characteristic curve and cut-off points of FDP and D-dimer to predict whether

0.818 (0.735–0.901) 0.813 (0.732–0.894)

Clinical Application of Coagulation Biomarkers http://dx.doi.org/10.5772/intechopen.76589 87

101.4 μg/mL 28.2 μg/mL

73.3 76.7

82.7 78.4

severity score (ISS) of a patient with trauma ≥25 points. FDP, fibrin degradation products.

0.751 (0.689–0.814)

6.5 μg/mL

73.1

66.7

**FDP D-dimer ISS ≥ 9 ISS ≥ 16 ISS ≥ 25**

In the section of the relationship between coagulation biomarkers and trauma severity the ability of FDP and D-dimer to predict trauma severity was demonstrated. Therefore, we also applied this to pelvic fracture [30]. Pelvic fracture is an independent risk factor for death after blunt trauma. It is associated with increased mortality in blunt trauma, with rates up to 30%

**3.2. The prediction of extravasation in pelvic fracture using coagulation biomarkers**

definitive treatment more rapidly.

AUROC (95% CI) 0.743 (0.681–0.806)

Cut-off point 32.1 μg/mL

Sensitivity, % 59.4

Specificity, % 79.8

ISS, injury severity score.

the ISS is over 9, 16 or 25.

These figures demonstrated that the predictivity of FDP and D-dimer for ISS was more accurate, especially in severe trauma. In **Table 2**, the AUROC and cut-off points of FDP and D-dimer to predict whether the ISS was over the 25 were the highest at 0.818 and 0.813, respectively. The sensitivities and specificities, based on the Youden's index, of FDP and D-dimer to

**3. Trauma**

86 Biomarker - Indicator of Abnormal Physiological Process

and severe trauma.

clinical usefulness of coagulation biomarkers [28].

predict ISS using FDP and D-dimer.

as supplementary diagnostic tools.

(**Figure 2**).

DIC has been well known to occur in trauma since the 1960s, especially in relation to head trauma (**Table 1**). Coagulopathy in trauma was believed to originate as a consequence of fluid administration and hypothermia [27]. However, in the 2000s, the concept of acute traumatic coagulopathy (ATC) first appeared [27] with the demonstration that an organ and/or cell injury itself caused the coagulopathy. Using coagulation biomarkers such as PT, APTT and thrombin time (TT), acute traumatic coagulopathy was shown to be associated with mortality

Initially, the concept of ATC was reported mainly in severe trauma, because PT, APTT and TT were found to have normal values in lightly and mildly traumatized patients. However, using fibrinolytic coagulation biomarkers such as FDP and D-dimer, we also detected ATC in lightly and mildly traumatized patients. This has been described in our first report on the

Our study reported that of all coagulation biomarkers, FDP and D-dimer were associated with the severity of trauma [28]. We have previously demonstrated an association between FDP and D-dimer, and a trauma score such as the Injury Severity Score (ISS) [29]. The ISS has been one of the most common and useful scoring systems to evaluate the severity of trauma and is used widely throughout the world. In clinical practice, the ISS is calculated for each anatomical injury according to the results of physical examinations, surgery and imaging studies; therefore, the ISS cannot be calculated in an initial emergency field. However, we can

In this study, the area under receiver operating characteristics curves (AUROCs) of FDP and D-dimer for predicting an ISS ≥ 9 were 0.757 and 0.756, and the sensitivity and specificity of FDP and D-dimer based on the Youden's index were 75.9 and 68.4%, and 75.9 and 73.7%, respectively. This demonstrated that we could predict mild to severe injury (ISS ≥ 9) with about 70% sensitivity and specificity; this finding signaled to trauma physicians and surgeons that minor injury was not to be overlooked. Because several minor injuries, such as minute spinal column and rib fractures, are sometimes hard to detect, FDP and D-dimer can be used

In addition, we have adopted this finding to more severe trauma. In the previous study, we investigated the association between FDP and D-dimer, and an ISS ≥ 9. In a similar setting, we calculated the AUROCs of FDP and D-dimer for predicting ISS ≥ 9, ISS ≥ 16 and ISS ≥ 25

These figures demonstrated that the predictivity of FDP and D-dimer for ISS was more accurate, especially in severe trauma. In **Table 2**, the AUROC and cut-off points of FDP and D-dimer to predict whether the ISS was over the 25 were the highest at 0.818 and 0.813, respectively. The sensitivities and specificities, based on the Youden's index, of FDP and D-dimer to

**3.1. The relationship between coagulation biomarkers and trauma severity**

**Figure 2.** (a) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury severity score (ISS) of a patient with trauma ≥9 points. FDP, fibrin degradation products. (b) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury severity score (ISS) of a patient with trauma ≥16 points. FDP, fibrin degradation products. (c) Receiver operating characteristic (ROC) curve of coagulation biomarkers to predict the injury severity score (ISS) of a patient with trauma ≥25 points. FDP, fibrin degradation products.


CI, confidence interval; FDP, fibrin degradation product; AUROC, area under the receiver operating characteristic curve; ISS, injury severity score.

**Table 2.** Area under the receiver operating characteristic curve and cut-off points of FDP and D-dimer to predict whether the ISS is over 9, 16 or 25.

predict an ISS over 25 were 73.3 and 82.7%, and 76.7 and 78.4%, respectively. These findings are novel because they are based on a patient's trauma severity, allowing the development of definitive treatment more rapidly.

#### **3.2. The prediction of extravasation in pelvic fracture using coagulation biomarkers**

In the section of the relationship between coagulation biomarkers and trauma severity the ability of FDP and D-dimer to predict trauma severity was demonstrated. Therefore, we also applied this to pelvic fracture [30]. Pelvic fracture is an independent risk factor for death after blunt trauma. It is associated with increased mortality in blunt trauma, with rates up to 30% [31–33]. In pelvic fracture, retroperitoneal hemorrhage may induce hemodynamic instability, with 5–20% originating from arterial bleeding [34].

In a clinical situation, the standard tool to detect arterial bleeding in a pelvic fracture has been computed tomography (CT) using contrast material; however, several problems exist with CT scanning. One problem is the specificity of CT scanning to detect arterial bleeding in pelvic fracture [35] is decreased. Another problem is that the quality of the CT scanning may be related to the scanning protocol and can be affected by interference caused by vasospasm, consequently affecting the diagnostic ability of physicians [36, 37]. Thus, we evaluated the predictive ability of coagulation biomarkers to detect arterial bleeding and whether these could be used as alternative tools for CT scanning.

Our report highlighted the highly accurate ability of FDP and D-dimer to detect arterial bleeding in a pelvic fracture; the AUROCs of FDP and D-dimer were 0.900 and 0.882, respectively (**Table 3**) [30]. In addition, in this study we calculated the ratios of FDP to fibrinogen, and of D-dimer to fibrinogen. Fibrinogen is said to be an independent risk factor of mortality and severity in blunt trauma patients [38–40], and a predictor of transfusion [41, 42]. We combined the high FDP and D-dimer, and the low fibrinogen, to the ratio of FDP to fibrinogen and the ratio of D-dimer to fibrinogen, this was a novel finding. This ratio was subsequently developed to the next stage [43, 44].

especially, the ratio of FDP to fibrinogen, were found to be the most accurate markers for

AUROC, area under the receiver operating characteristic curve; CI, confidence interval; ABC, assessment of blood consumption score; GCS, Glasgow Coma Scale; Ht, hematocrit; PT-INR, international normalized ratio of prothrombin

**AUROC (95% CI) Cut-off point Sensitivity (%) Specificity (%)**

Clinical Application of Coagulation Biomarkers http://dx.doi.org/10.5772/intechopen.76589 89

In recent decades, the science of cardiac pulmonary arrest (CPA) has been improving due to the widespread adoption of guidelines by the International Liaison Committee on Resuscitation (ILCOR). The 2015 guidelines by the Japan Resuscitation Council, which is one of the subsidiary organizations of ILCOR, enumerates predictive candidates for outcomes of patients with an outof-hospital cardiac arrest (OHCA), such as S-100B, neuron specific enolase, imaging findings, brain waves, among others. However, it is presently difficult to predict favorable neurological outcomes or the survival of patients with OHCA [52]. Recently, several reports have suggested that blood coagulation makers reflected the prognosis of patients with CPA. The occurrence of fibrinolysis in patients with CPA has been noticed for a long time [53]; however, coagulation biomarkers has not been clinically applied to CPA until recently, with clinical applications with

**AG ACAG FDP D-dimer**

AUROC (95% CI) 0.664 (0.514–0.815) 0.667 (0.516–0.818) 0.714 (0.571–0.858) 0.707 (0.561–0.853) Cut-off point 27.8 mmol/L 31.7 mmol/L 29.4 μg/mL 10.2 μg/mL Sensitivity, % 84.4 78.1 87.5 87.5 Specificity, % 45.0 55.0 50.0 55.0

AG, anion gap; ACAG, albumin-corrected anion gap; CI; confidence interval; FDP, fibrin degradation products; AUROC,

**Table 5.** Areas under receiver operating characteristic curves and cut-off points of parameters that predict whether a patient with cardiopulmonary arrest can achieve a return of spontaneous circulation after effective cardiopulmonary

predicting the need for packed red blood cell transfusions (**Table 4**) [43].

**Table 4.** Results of receiver operating characteristic curves analysis.

time; APTT, activated partial thromboplastin time; Fib, fibrinogen; FDP, fibrin degradation product.

ABC 0.591 (0.420–0.763) 0.5 21.4 96.7 GCS 0.716 (0.547–0.885) 12.5 96.4 42.9 Ht 0.667 (0.503–0.830) 31.3% 97.3 35.7 PT–INR 0.859 (0.760–0.958) 1.065 71.4 90.1 APTT 0.684 (0.501–0.866) 36.45 s 42.9 96.4 Fib 0.877 (0.808–0.947) 245.5 mg/dL 64.3 100 FDP 0.874 (0.784–0.963) 45.65 μg/dL 78.6 80.4 FDP/Fib ratio 0.899 (0.819–0.979) 0.202 × 10−3 85.7 82.3

**4. Cardiac pulmonary arrest**

areas under receiver operating characteristic curves.

resuscitation.

#### **3.3. Prediction of the need for packed red blood cell transfusions using coagulation biomarkers**

We applied coagulation biomarkers to the prediction of the need for packed red blood cell transfusions [43]. For a long time, many investigators have discussed how to predict massive transfusion requirements in blunt trauma patients [45–51]. The characteristics of FDP and D-dimer were correlated with the trauma severity: from relatively light to severe trauma [28]. This feature has been utilized to predict not only patients requiring massive transfusions, but also whether patients needed packed red blood cells or not. Coagulation biomarkers,


CI, confidence interval; FDP, fibrin degradation product; AUROC, area under the receiver operating characteristic curve.

**Table 3.** Area under the receiver operating characteristic curves and cut-off points of parameters to predict arterial extravasation in pelvic fracture patients.


AUROC, area under the receiver operating characteristic curve; CI, confidence interval; ABC, assessment of blood consumption score; GCS, Glasgow Coma Scale; Ht, hematocrit; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; Fib, fibrinogen; FDP, fibrin degradation product.

**Table 4.** Results of receiver operating characteristic curves analysis.

especially, the ratio of FDP to fibrinogen, were found to be the most accurate markers for predicting the need for packed red blood cell transfusions (**Table 4**) [43].

## **4. Cardiac pulmonary arrest**

[31–33]. In pelvic fracture, retroperitoneal hemorrhage may induce hemodynamic instability,

In a clinical situation, the standard tool to detect arterial bleeding in a pelvic fracture has been computed tomography (CT) using contrast material; however, several problems exist with CT scanning. One problem is the specificity of CT scanning to detect arterial bleeding in pelvic fracture [35] is decreased. Another problem is that the quality of the CT scanning may be related to the scanning protocol and can be affected by interference caused by vasospasm, consequently affecting the diagnostic ability of physicians [36, 37]. Thus, we evaluated the predictive ability of coagulation biomarkers to detect arterial bleeding and whether these

Our report highlighted the highly accurate ability of FDP and D-dimer to detect arterial bleeding in a pelvic fracture; the AUROCs of FDP and D-dimer were 0.900 and 0.882, respectively (**Table 3**) [30]. In addition, in this study we calculated the ratios of FDP to fibrinogen, and of D-dimer to fibrinogen. Fibrinogen is said to be an independent risk factor of mortality and severity in blunt trauma patients [38–40], and a predictor of transfusion [41, 42]. We combined the high FDP and D-dimer, and the low fibrinogen, to the ratio of FDP to fibrinogen and the ratio of D-dimer to fibrinogen, this was a novel finding. This ratio was subsequently devel-

**3.3. Prediction of the need for packed red blood cell transfusions using coagulation** 

**FDP D-dimer Ratio of** 

0.882 (0.728–1.000)

We applied coagulation biomarkers to the prediction of the need for packed red blood cell transfusions [43]. For a long time, many investigators have discussed how to predict massive transfusion requirements in blunt trauma patients [45–51]. The characteristics of FDP and D-dimer were correlated with the trauma severity: from relatively light to severe trauma [28]. This feature has been utilized to predict not only patients requiring massive transfusions, but also whether patients needed packed red blood cells or not. Coagulation biomarkers,

> **FDP to fibrinogen**

0.918 (0.797– 1.000)

Cut-off point 126.8 μg/mL 46.0 μg/mL 0.656 0.215 11.0 g/dL 2.75 mmol/L

CI, confidence interval; FDP, fibrin degradation product; AUROC, area under the receiver operating characteristic curve.

**Table 3.** Area under the receiver operating characteristic curves and cut-off points of parameters to predict arterial

Sensitivity, % 94.1 94.1 94.1 94.1 61.1 58.8 Specificity, % 90.0 90.0 90.0 80.0 0.0 85.7

**Ratio of D-dimer to fibrinogen**

0.900 (0.773– 1.000)

**Hemoglobin level**

0.815 (0.656–0.974) **Lactate level**

0.765 (0.563–0.967)

with 5–20% originating from arterial bleeding [34].

88 Biomarker - Indicator of Abnormal Physiological Process

could be used as alternative tools for CT scanning.

oped to the next stage [43, 44].

0.900 (0.765–1.000)

extravasation in pelvic fracture patients.

**biomarkers**

AUROC (95% CI) In recent decades, the science of cardiac pulmonary arrest (CPA) has been improving due to the widespread adoption of guidelines by the International Liaison Committee on Resuscitation (ILCOR). The 2015 guidelines by the Japan Resuscitation Council, which is one of the subsidiary organizations of ILCOR, enumerates predictive candidates for outcomes of patients with an outof-hospital cardiac arrest (OHCA), such as S-100B, neuron specific enolase, imaging findings, brain waves, among others. However, it is presently difficult to predict favorable neurological outcomes or the survival of patients with OHCA [52]. Recently, several reports have suggested that blood coagulation makers reflected the prognosis of patients with CPA. The occurrence of fibrinolysis in patients with CPA has been noticed for a long time [53]; however, coagulation biomarkers has not been clinically applied to CPA until recently, with clinical applications with


AG, anion gap; ACAG, albumin-corrected anion gap; CI; confidence interval; FDP, fibrin degradation products; AUROC, areas under receiver operating characteristic curves.

**Table 5.** Areas under receiver operating characteristic curves and cut-off points of parameters that predict whether a patient with cardiopulmonary arrest can achieve a return of spontaneous circulation after effective cardiopulmonary resuscitation.

regard to CPA having appeared since the 2010s. For example, FDP and D-dimer are associated with the return of spontaneous circulation (ROSC) and have been useful for predicting ROSC [54] (**Table 5**) [54]. Other reports have demonstrated that a high D-dimer concentration on admission predicts a poorer outcome [55], and that the FDP level predicts neurological outcomes [56].

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