The Acute Coagulopathy of Trauma: Mechanisms and Tools for Risk Stratification
Maegele, Marc*†; Spinella, Philip C.‡§; Schöchl, Herbert∥¶
*Department of Traumatology and Orthopedic Surgery and †Institute for Research in Operative Medicine, Cologne-Merheim Medical Center, University of Witten/Herdecke, Cologne, Germany; ‡St Louis Children’s Hospital and Critical Care Translational Research Program, Washington University School of Medicine, St Louis, Missouri; §US Army Institute of Surgical Research, Fort Sam Houston, Texas; and ∥Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg; and ¶Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
Received 2 Jun 2012; first review completed 21 Jun 2012; accepted in final form 6 Aug 2012
Address reprint requests to Marc Maegele, MD, PhD, Department of Traumatology and Orthopedic Surgery, Cologne-Merheim Medical Center, University of Witten/Herdecke, Ostmerheimerstr 200, D-51109 Cologne, Germany. E-mail: Marc.Maegele@t-online.de.
Conflict of interest and source of funding: None are declared.
Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.shockjournal.com).
ABSTRACT: Trauma remains the leading cause of death, with bleeding as the primary cause of preventable mortality. When death occurs, it happens quickly, typically within the first 6 h after injury. The principal drivers of the acute coagulopathy of trauma have been characterized, but another group of patients with early evidence of coagulopathy both physiologically and mechanistically distinct from this systemic acquired coagulopathy has been identified. This distinct phenotype is present in 25% to 30% of patients with major trauma without being exposed to the traditional triggers and is associated with higher morbidity and a 4-fold increase in mortality. Despite improvements in the resuscitation of exsanguinating patients, one of the remaining keys is to expeditiously and reproducibly identify the patients most likely to require transfusion including massive transfusion with damage control resuscitation principles. Several predictive scoring systems/algorithms for transfusion including massive transfusion in both civilian and military trauma populations have been introduced. The models developed usually suggest combinations of physiologic, hemodynamic, laboratory, injury severity, and demographic triggers identified on the initial evaluation. Many use a combination of dichotomous variables that are readily accessible after the patient’s arrival to the trauma bay, but others rely on time-consuming mathematical calculations and may thus have limited real-time application. Weighted and more sophisticated systems including higher numbers of variables perform superiorly. A common limitation to all models is their retrospective nature, and prospective validations are needed. Point-of-care viscoelastic testing may be an alternative to early recognize trauma-induced coagulopathy with the risk of ongoing hemorrhage and transfusion.
Trauma is the leading cause of death worldwide in persons younger than 40 years (1) and accounts for approximately 10% of all deaths in general (2). Despite substantial improvements in acute trauma care, uncontrolled hemorrhage is still responsible for more than 50% of all trauma-related deaths in both civilian and military settings within the first 48 h after hospital admission (3). Hemorrhage has also been determined to be the most common cause of preventable deaths (4–6). Clinical observations together with recent research emphasize the central role of coagulopathy in acute civilian and military trauma care (7–15), but rapid identification of patients with active ongoing bleeding requiring transfusion or even massive transfusion (MT) remains unsatisfactory. Vice versa, the early identification of trauma patients at risk for ongoing bleeding and transfusion is of fundamental clinical importance to rapidly address and correct the acute coagulopathy of trauma including potential triggers via early activation of damage control resuscitation strategies, MT protocols (MTPs), and timely adequate mobilization of resources, for example, blood bank resources in the civilian setting as well as activation of whole-blood donation in the military setting (16–19).
To date, several authors have shown that early recognition of the acute coagulopathy of trauma accompanied by adequate and aggressive management including the balanced use of blood components can correct coagulopathy, control bleeding, reduce blood product use, and improve outcome in severely injured patients (20–22). However, the optimum ratio of packed red blood cell concentrates, fresh frozen plasma concentrates, and platelet concentrates is still under investigation (Prospective Randomized Optimum Platelet and Plasma Ratios Study). As an alternative approach, other groups have reported improved survival rates by using thromboelastometry-guided, individualized coagulation therapy based on the administration of coagulation factor concentrates (23). But also here, no randomized controlled study has been performed to date assessing this concept, and safety data are still lacking. In this review, we present the current understanding and concepts of the acute coagulopathy of trauma as well as clinically relevant strategies for its early detection. These concepts, in principle, are based on the constructive discussions among key opinion leaders in the field during the eighth Wiggers-Bernard Conference on “Trauma-Induced Coagulopathy” held in Salzburg (Austria), February 16 to 18, 2011 (see also Shock Volume 38, Supplement 1,availableatwww.shockjournal.org).
THE ACUTE COAGULOPATHY OF TRAUMA
The principal triggers to drive the acute coagulopathy of trauma are summarized in Figure 1 (7, 24, 25). Direct loss and the consumption of coagulation factors, dilution, hypothermia, acidosis and fibrinolysis, and the release of anticoagulation factors, e.g., activated protein C, all interfere with coagulation and diminish hemostasis. There seems to be an additive effect among the clinical drivers of the process as the probability of life-threatening coagulopathy increases with the number of triggers present. Cosgriff and coworkers (26), for example, have shown that the conditional probability of developing coagulopathy after trauma was 1% in moderate injury without the presence of additional triggers but increased to 39% in severe injury (Injury Severity Score [ISS] >25) combined with hypotension, to 58% when injury occurred with acidosis (pH <7.1), and to 98% in cases of ISS greater than 25 together with hypotension (systolic blood pressure <70 mmHg), hypothermia (<34°C), and acidosis (pH <7.1).
Dilution may occur both physiologically and iatrogenically. In trauma-associated physiologic hemodilution, the unopposed osmotic activity of plasma in states of hypotension is prompted by a water shift into the intravascular space, thus diluting plasma proteins until equilibrium is reestablished. In this scenario, each protein is diluted to the same amount, and their interactions, e.g., the intrinsic “tenase complex” comprising combined factors IXa, VIIIa, and X, are reduced proportionally to their individual factor concentrate changes. In this model, Monroe calculated a 37% reduction in single factor concentration to result in a 75% reduction in overall complex activity (27).
Iatrogenic dilution is caused by unguided and often overadministration of fluids in the acute phase of trauma care. In patients from the TR-DGU (Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie/German Trauma Society) database, coagulopathy upon emergency room (ER) admission was observed in greater than 40% of patients with more than 2,000 mL, in greater than 50% with more than 3,000 mL, and in greater than 70% with more than 4,000 mL of fluids administered during the prehospital phase of care (13). More recently, a prehospital intravenous colloid/crystalloid ratio of 1:2 or greater and the amount of prehospital intravenous fluids of 3,000 mL or greater have been identified as independent contributors to the acute coagulopathy of trauma (25). This dilution is accompanied by consumption and inactivation of not only coagulation factor substrates but also coagulation enzymes with magnitudes matching the degree of individual injury (28).
Wolberg et al. (29) and Meng et al. (30) have frequently demonstrated the effects of temperature and pH on coagulation factor and complex activity. Both, temperature and acidosis, contribute to coagulopathy by reducing the pace of plasma coagulation factor biochemical reactions. This activity is slowed down by approximately 5% with each 1°C drop in temperature. The von Willebrand factor–glycoprotein Ib interaction, which activates platelets, is absent in 75% of individuals at 30°C (31, 32). Similarly, drops in pH to values of 7.2 have been shown to reduce coagulation factor complex activities by half and down to 20% of normal activity at pH 6.8 (30). Figure 2 shows an example for reduced plasma coagulation factor and complex activity if pH drops to values of 7.0. The correlation between the activity or activation of different coagulation factors and negative base excess (BE) assuming nonrespiratory acidosis is demonstrated in Figure 3.
Under physiological conditions, the coagulation system modulates fibrinolysis in that blood clots are maintained stable for a given time to control bleeding and to promote adequate wound healing. High concentrations of thrombin inhibit plasmin activation via the activation of TAFI (thrombin-activated fibrinolysis inhibitor) and PAI-1 (plasminogen activator inhibitor 1). Vice versa, if the thrombin burst is weak, TAFI remains unactivated. Furthermore, if thrombin encounters thrombomodulin on endothelial cells, protein C may be activated, which then inactivates PAI-1.
Hyperfibrinolysis (HF) has been identified as a major contributor of mortality in bleeding trauma patients (33, 34). For example, Schöchl and coworkers (33) have reported a mortality rate of approximately 88% in trauma patients with HF present upon ER admission as detected by viscoelastic testing. Even a small reduction of the maximum amplitude (MA) in thromboelastography (TEG >15%) is likely to be associated with higher transfusion requirements including MT, coagulopathy, and hemorrhage-related death (34).
ACUTE COAGULOPATHY IN TRAUMA AND SHOCK
More recently, it has been recognized that another group of trauma patients presents to the ER with early evidence of coagulopathy both physiologically and mechanistically distinct from this above referenced traditional systemic acquired coagulopathy. Several studies have identified an acute traumatic coagulopathy, according to standard coagulation tests, present in 25% to 30% of patients with major trauma without being exposed to the traditional triggers of coagulopathy. For example, Brohi and colleagues (12) have reported a series of patients who had received less than 500 mL of fluids during prehospital care, of whom one of four presented coagulopathic upon arrival to the trauma bay as indicated by global coagulation testing. This finding was confirmed by other investigators reporting even larger patient series (13, 14) and also in children (35). Our own group has reported the presence of coagulopathy upon admission even in trauma patients who had received no fluid resuscitation at all during their prehospital phase of care (13). In all studies, the presence of coagulopathy was associated with a higher magnitude of injury sustained as reflected by higher ISS as well as a dramatic increase in mortality up to 2- to 4-fold (12–14, 35, 36) (Fig. 4). In the study of Brohi et al., increasing injury severity predicted a stepwise increasing fraction of patients with increased PT upon admission with presence in 45% of all patients with an ISS of greater than 45 (12). Abnormalities in other conventional tests such as fibrinogen levels and platelet counts showed a similar stepwise increase together with increased injury severity (36). Among the 28% of the 20,000 trauma center admissions with any initial PT prolongation reported by MacLeod and colleagues (14), there was a 35% increase in the risk of in-hospital death; among the 8% of patients with prolonged partial thromboplastin time (PTT), the increase in risk of dying was 42%. Noteworthy, all of these deaths occurred within the first 5 h after admission and were due to uncontrolled primary hemorrhage.
In their analysis from data from the German TR-DGU database, Wafaisade and coworkers (25) reported an ongoing state of shock after trauma (on scene and upon admission to the trauma bay) to be associated with an almost 3-fold increase in risk for the development of coagulopathy. Figure 5 shows an increasing frequency of coagulopathy upon ER arrival with increasing levels of shock as reflected by BE. This finding corresponds to other reports (7, 15) and has also been described in children (35). Hypoperfused tissue inducing acidemia may be one potential mechanism underlying this shock/trauma–induced coagulopathy, as acidemia interferes with the coagulation enzyme activity (see above). More recently, several authors have shown that shock may also activate anticoagulant and hyperfibrinolytic pathways. In this context, Brohi and colleagues (8) have suggested that, in the presence of shock and hypoperfusion, the endothelium releases thrombomodulin, which complexes with thrombin to divert it into an anticoagulant function. Thus, reduced amounts of thrombin are available to cleave fibrinogen, and thrombin complexed to thrombomodulin may also activate protein C, which inhibits the extrinsic pathway and antifibrinolytic factors (Fig. 6). Of course, this relatively new identified pathway still needs further and more detailed investigation.
Thus, direct tissue trauma and shock/hypoperfusion may represent the primary drivers responsible for the development of this distinct form of coagulopathy apart and independent from the traditional factors. This coagulopathy is, in addition, associated with a higher transfusion requirement, a greater incidence of multiorgan dysfunction syndrome, and longer intensive care unit and overall in-hospital length of stay as well as a 4-fold increase in mortality compared with those patients with normal coagulation. The early undetected presence of this distinct coagulopathy almost certainly contributes to the development and aggravation of the previously mentioned coagulopathy, which is considered systemically acquired and frequently observed after severe injury.
STRATEGIES AND TOOLS FOR EARLY DETECTION AND STRATIFICATION OF RISK
Perturbations in blood coagulation are common after major trauma and are associated with poor outcomes. A substantial proportion of trauma patients is already coagulopathic upon admission (11–14), and incidence rates up to 60% have been reported according to definition (37). The human coagulation system can be rapidly overwhelmed by severe injury (38), and death from traumatic exsanguination usually occurs early, typically within the first 6 to 12 h after initial impact but heavily weighted toward the first 1 to 2 h (15, 39–41). Approximately 10% of all trauma patients are transfused with at least one unit of blood, and up to 30% of these require MT as defined by transfusion of 10 or more units within the first 24 h after ER admission (42, 43). Even with improved triage, evacuation, early surgical intervention (e.g., damage control surgery), the problems associated with bleeding, and the inability to control it remain challenging. The classic definition of MT is being changed by some to reflect the changing practice of early blood use with damage control resuscitation (44), and some prefer to instead focus on defining massive bleeding instead of MT. Until massive bleeding can be more accurately characterized or quantified, we will continue to determine the risk of hemorrhagic death by using transfusion requirement as a surrogate.
Despite substantial improvements in the knowledge on how to adequately resuscitate the exsanguinating patient, one of the fundamental issues to improve the outcome still remains the early identification of patients in need of transfusion including those requiring MT. Although the criteria that trigger the activation of MTPs remain highly center and provider dependent, the benefits of timely MTP activation have been frequently demonstrated given the identification of the appropriate patient (45, 46). However, not all investigators were able to show improved survival after MTP implementation or activation (47). Allogeneic blood transfusion increased significantly without being associated with mortality. A similar observation was made by Simmons and colleagues (48). Therefore, early and reliable prediction of the need for MT is highly demanded.
The inappropriate use of MTPs in patients not in need of MT may result in a higher incidence of adverse effects of fresh frozen plasma and platelet concentrate transfusions without an improvement in survival (49–51). Although blood transfusion has the obvious benefit of volume restoration and improved oxygen-carrying capacity in the injured patient, there are quite a few risks and immunosuppressive and infectious consequences associated with blood products including transfusion reaction, transmission of blood-borne pathogens, and the impact of limited supply (52–55). For these reasons, there has been a trend to restrict transfusion in nonurgent clinical settings and to limit transfusion to ongoing and imminently life-threatening situations. However, the hazards of transfusion may appear somewhat trivial relative to the need of care for an exsanguinating patient.
Substantial problems in the use of conventional coagulation testing for the early identification of patients in need of transfusion including those requiring MT include delayed turnaround times, incomplete characterization, and their poor predictive nature not accurately reflecting the patient’s true coagulation status (12, 56, 57). Although international normalized ratio (INR) and base deficit (BD) are good predictors of mortality, by themselves, they cannot discriminate between patients to go or not go on for MT (58). Second, surgical relevant bleeding due to thoracic and/or retroperitoneal/intraperitoneal organ injury is difficult to detect and often requires time-consuming diagnostics (59). Thus, significant hemorrhage and coagulopathy may be underestimated or even missed during early resuscitation (14, 60).
Scoring systems and algorithms
Over the past few years, a considerable number of scoring systems has been developed and introduced for the initial evaluation of the bleeding trauma patient in both civilian (17, 45, 61–69) and military settings (70–73). The authors have just recently published a comprehensive overview of the most commonly discussed scoring systems and algorithms for the need of transfusion including MT in severely injured patients (74). These systems may provide clinically useful information that potentially gives freedom to providers to deviate from established algorithms toward the more aggressive and early use of blood products with the assumption that early product use improves outcome. These scoring systems may be used to guide the activation of MTPs and could help providers of all experience levels know when it is likely that the patient will require a MT.
The scoring systems developed to date usually suggest combinations of physiologic, hemodynamic, laboratory, injury severity, and demographic triggers identified on the initial evaluation of the bleeding trauma patient. Many of them use a combination of dichotomous variables that are obtained rapidly after the patient’s arrival to the trauma bay, but others rely on time-consuming mathematical calculations or complex scoring algorithms that are required to determine the patients who will need MT and may thus have limited real-time application.
The most commonly proposed triggers that were correlated with the need for transfusion including MT in the civilian setting are shown in Table 1 and include systolic blood pressure, which is present in 9/9 scoring systems, followed by heart rate (present in 6/9 scoring systems), hemoglobin/hematocrit (present in 5/9 scoring systems) and positive Focused Assessment Sonography for Trauma (FAST+; present in 4/9 scoring systems). Parameters that can be quickly obtained via point-of-care arterial blood gas analyzers, e.g., BE/BD, lactate, and pH, are included in 6/9 civilian scoring systems. Six of nine systems consider anatomical injury including its magnitude or mechanism of injury as components of their assessment. However, the severity of injury as reflected by the ISS or the overall pattern of the anatomical injury may be difficult to calculate and to assess during initial assessment.
A major and common limitation to all scoring systems and algorithms with one exception is their retrospective nature. All systems have been developed retrospectively based on data sets derived from single-center or multicenter civilian or military databases. Some models have been developed using a classic data-split approach, with half of the data set for development and the other half for internal validation. Meanwhile, some scores and algorithms have been internally revalidated on data from the same database, e.g., the Trauma-Associated Severe Hemorrhage score (TASH score; 62). The only score that has been prospectively validated on data from a subset of 481 ER patients is the Emergency Transfusion Score (69).
To date, several systems and algorithms have been applied onto other external but also retrospective data sets and have thus been externally validated. In developing their ABC score, Nunez and coworkers (45), for example, have applied both the TASH and the McLaughlin scores onto their local trauma center database including 596 trauma patients for score comparison. In result, all three scores (TASH AUROC [area under receiver operating characteristic] = 0.842, McLaughlin AUROC = 0.846, ABC AUROC = 0.842) were considered as equally good predictors for MT without a statistically significant difference between the scores. In another retrospective study, Cotton and colleagues (75) have applied the ABC score onto adult trauma data sets from three different Level I trauma centers in the United States (n = 513 from trauma center 1, n = 373 from trauma center 2, and n = 133 from trauma center 3) and compared the predictive ability of the score at each institution. The sensitivity and specificity for the ABC score to predict MT ranged from 75% to 90% and from 67% to 88%, respectively. Correctly classified patients and AUROCs, however, were 84% to 87% and 0.83 to 0.90, respectively. Recently, Mitra and coworkers (76) compared the performance of the PWH score (63) to the ABC (45) and TASH scores (61, 62) by a retrospective review of a subgroup of major trauma patients (n = 1.234) derived from the Alfred Trauma Registry (Victoria, Australia). In this analysis, the performance of the TASH score was best with an AUROC of 0.8986, followed by the PWH score (AUROC = 0.8419) and the ABC score.
Our own group has recently applied a total of six scores and algorithms to predict transfusion in trauma patients, i.e., ABC, Larson, PWH, Schreiber, TASH, and Vandromme, onto a large subset of trauma patients derived from the most updated database of the German TR-DGU (n = 5.047; unpublished observation, manuscript in preparation by Brockamp et al.). This extract included data from adult severely injured trauma patients (ISS >16), with all variables present from each patient to calculate all six scores. Although we had initially attempted to validate all scores on our database, the remaining scores had to be excluded from this analysis because of missing or noncaptured data within our registry for model calculation. For the TASH score, this analysis served again as an internal validation, whereas all other scores were externally validated by being subjected onto our data sets. Not surprisingly, the TASH score performed best (AUROC = 0.889) followed by the PWH score (AUROC = 0.860), which is also a weighted score with structure and content variables very similar to the TASH score (Fig. 7). In this analysis, the nonweighted and more simple scores performed less accurate (AUROCs for Vandromme score: 0.840; Larson score: 0.823; Schreiber model: 0.800; and ABC score: 0.763).
Viscoelastic testing methods
An alternative to scoring systems and algorithms to early recognize trauma-induced coagulopathy with the risk of ongoing hemorrhage and transfusion requirement is the early use of viscoelastic testing methods. To date, similar to the above referenced scoring systems and algorithms, prospective data are also limited for this approach. However, low maximum clot firmness (MCF) in thromboelastometry EXTEM (activates hemostasis via the physiological activator tissue factor), INTEM (activates the contact phase of hemostasis), and FIBTEM (an EXTEM-based assay for the fibrin part of the clot) or MA (the equivalent TEG parameter) has been identified as an important determinant of packed red blood cell transfusion (57, 58, 77–79). Cotton and colleagues (77) recently presented results from a pilot study in which they had prospectively evaluated the timeliness of real-time rapid TEG (r-TEG) results, their correlation with conventional coagulation tests, and the ability of r-TEG to predict early blood transfusion in 272 consecutive major trauma activations over a 5-month time period. Early r-TEG values (activated clotting time [ACT], r value [reaction time = time to first evidence of a clot], and k time [time from the end of r until the clot reaches >20 mm, represents the speed of clot formation]) were available within 5 min; late r-TEG values (maximal amplitude [reflects clot strength] and α angle [tangent of the curve made as the k is reached]) were available within 15 min, in contrast to results from conventional coagulation testings with turnaround times of 48 min on average. Activated clotting time, r value, and k time showed strong correlations with later incoming results from conventional testings, and linear regression demonstrated ACT to predict the need for red blood cells, plasma, and platelet transfusions within the first 2 h of arrival. In addition, an ACT of less than 105 s predicted patients who did not receive any transfusions during the first 24 h of admission. Similar results have been reported by Davenport and colleagues (57). In their study, a threshold of clot amplitude of 35 mm or less at 5 min of rotational thromboelastometry was indicative of acute traumatic coagulopathy and the need for transfusion including MT. These findings are in concert with reports by Leemann and coworkers (78), who demonstrated low INTEM MCF along with low hemoglobin levels to be an independent risk factor for MT. An overview of the most relevant studies conducted to date on the use of viscoelastic testing in the context of the acute coagulopathy of trauma including main conclusions is provided in Table 2.
Point-of-care viscoelastic testing may offer the unique potential to predict transfusion even faster as compared with scoring systems involving conventional coagulation testing and to activate and guide resuscitations more objectively. A recent retrospective analysis of major trauma patients revealed low FIBTEM amplitudes (<4 mm) and/or low EXTEM amplitudes at 10 min to be highly predictive of MT (79). Independent from the viscoelastic test used, time to effective clot formation, clot strength, and sustained stability of the clot appear to have the highest clinical value. The authors have recently published a comprehensive review on the early and individualized goal-directed therapy for the acute coagulopathy of trauma including their local hospital algorithm for managing this potentially life-threatening disorder based on the use of viscoelastic testing (80). Other algorithms have been published elsewhere (81, 82).
Trauma remains the leading cause of death, and bleeding is the primary cause for this mortality usually occurring quickly within the first 6 h after impact. Even with improved triage, evacuation, and early surgery, bleeding-associated problems and the inability to control it remain challenging. The principal drivers of the acute coagulopathy of trauma have been identified. More recently, it has been recognized that another group of trauma patients presents with early evidence of coagulopathy both physiologically and mechanistically distinct from this systemic acquired coagulopathy and with worse outcome. One of the remaining keys is to expeditiously and reproducibly identify the patients most likely to require transfusion including MT. The scoring models developed so far usually suggest combinations of physiologic, hemodynamic, laboratory, injury severity, and demographic triggers identified on the initial evaluation. Weighted and more sophisticated systems including higher numbers of variables perform superiorly over simple nonweighted models. A major and common limitation to all models is their retrospective nature, and prospective validations are urgently needed. Point-of-care viscoelastic testing may be an alternative to these systems to early recognize trauma-induced coagulopathy with the risk of ongoing hemorrhage and transfusion.
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Trauma; coagulopathy; mechanisms; scoring; stratification
©2012The Shock Society
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