REVIEW URRENT C OPINION

Acute coagulopathy in pediatric trauma Pamela M. Choi and Adam M. Vogel

Purpose of review To summarize our current understanding of the pathophysiology, diagnosis, and management of acute traumatic coagulopathy in children. Recent findings Traumatic coagulopathy is a complex process that leads to global dysfunction of the endogenous coagulation system and results in worse outcomes and increased mortality. Although the cause is multifactorial, it is common in severely injured patients and is driven by significant tissue injury and hypoperfusion. Viscoelastic coagulation tests have been established as a rapid and reliable method to assess traumatic coagulopathy. Additionally, massive transfusion protocols have improved outcomes in adults, but limited studies in pediatrics have not shown any difference in mortality. Summary Prospective studies are needed to determine how to best diagnose and manage acute traumatic coagulopathy in children. Keywords coagulopathy, resuscitation, thromboelastography, transfusion, trauma

INTRODUCTION Trauma is a leading cause of morbidity and mortality in children, and is a significant public health concern [1]. Acute coagulopathy of trauma is an ill-defined but well-described phenomenon of multifactorial cause that is very common in severely injured patients and is strongly associated with increased morbidity and mortality [2–5,6 ]. The identification and management of this coagulopathy is a critical component of the resuscitative effort. Although traumatic coagulopathy has been established as an indicator of poor outcomes, many questions remain regarding its pathophysiology, diagnosis, and treatment. Unfortunately, the majority of literature on this subject is a product of the adult trauma population. Children are not ‘little adults’ and have unique and age-dependent physiologic hemodynamic and hemostatic characteristics that may make translating the results of adult data on traumatic fluid resuscitation and massive transfusion to children challenging. With respect to hemostasis, pediatric patients exhibit agedependent variation in coagulation factor profiles and function that has been termed ‘developmental hemostasis’ [7]. Although a child’s coagulation system is fully functional at birth, these variations may lead to confusion when interpreting laboratory &

results from the adult trauma literature. Despite these limitations, the adult literature forms the backbone of our understanding of coagulopathy of trauma and must be considered in order to provide a more complete discussion of coagulopathy in pediatric trauma. The purpose of this review is to describe the recent developments in our understanding of acute traumatic coagulopathy in both adults and children, and how these developments impact the management of critically ill pediatric trauma patients.

EPIDEMIOLOGY AND SIGNIFICANCE Acute traumatic coagulopathy is extremely common. One prospective single-center study found that 56% of 45 adult trauma patients had coagulopathy within 25 min after injury, whereas another

Division of Pediatric Surgery, Department of Surgery, St Louis Children’s Hospital, Washington University School of Medicine, St Louis, Missouri, USA Correspondence to Adam M. Vogel, MD, St Louis Children’s Hospital, One Children’s Place, Suite 5S40, St Louis, MO 63110, USA. Tel: +1 314 454 6022; fax: +1 314 454 2442; e-mail: vogelam@wudosis. wustl.edu Curr Opin Pediatr 2014, 26:343–349 DOI:10.1097/MOP.0000000000000086

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KEY POINTS  Traumatic coagulopathy is a complex process of multifactorial cause that is commonly seen in critically ill patients, especially in those with acidosis, shock, severe injuries, and traumatic brain injury, and is independently associated with mortality.  The benefits of viscoelastic coagulation tests such as thromboelastography are its point-of-care availability and the ability to convey rapid and reliable data that aids in goal-directed hemostatic resuscitation.  Massive transfusion protocols with high ratios of plasma and platelets to packed red blood cells have improved outcomes in adult trauma patients; however, further prospective trials are needed in the pediatric population.

study found that 77% of 102 pediatric patients had abnormal prothrombin time (PT) or partial thromboplastin time (PTT) levels upon arrival at the hospital [6 ,8]. A 10-year retrospective review of 803 pediatric trauma patients found that 37.9% of those admitted to the ICU had coagulopathy [defined as an International Normalization Ratio (INR) 1.2] [9 ]. Several adult studies have identified the risk factors for acute traumatic coagulopathy, including penetrating injury, traumatic brain injury (TBI), injury severity, and shock [4,10 ]. Similar risk factors are seen in the pediatric population. A review of 200 pediatric patients from a European trauma registry showed that coagulopathy was present in 44% of patients with severe isolated TBI [11 ]. Similarly, a single-center retrospective review showed that coagulopathy is present in 42% of children presenting with severe TBI [12]. Injury Severity Score (ISS), hypotension, acidosis, and nonaccidental trauma were also associated with coagulopathy in pediatric trauma [5,6 ,9 ]. Traumatic coagulopathy is an independent predictor of mortality. Coagulopathic (defined as admission INR >1.5) adult patients in a combat hospital were found to have an increased mortality rate of 24%, compared with 4% in noncoagulopathic patients, and had an increased relative risk of death of 5.4 [4]. Coagulopathy is also associated with higher transfusion requirements, greater incidence of multiorgan dysfunction syndrome, and longer ICU and hospital length of stay as well as a four-fold increase in mortality [10 ]. A review of 744 pediatric combat casualties with early coagulopathy (defined as admission INR >1.5) had a mortality rate of 22% compared with 3.9% in those who did not have an early coagulopathy [5]. &

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Studies in civilian trauma centers have found similar results. In a 10-year retrospective review of pediatric trauma patients, a direct relationship was found between mortality rate and initial INR, as mortality reached nearly 70% in those with an admission INR greater than 1.8. Another study found a similar relationship between increased PT and mortality, and also found that 96% of all deaths occurred in pediatric trauma patients with abnormal coagulation studies on presentation to the emergency department [6 ]. Coagulopathy was also found to be independently associated with longer ventilator days as well as longer ICU and hospital length of stay [6 ,9 ]. &

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PATHOPHYSIOLOGY OF TRAUMATIC COAGULOPATHY The pathophysiology of acute traumatic coagulopathy is a result of an imbalance between procoagulant factors, anticoagulant factors, platelets, endothelial components, and fibrinolysis [13 ]. Hemorrhage and tissue damage are the initiating factors for the coagulation cascade and thrombin formation, but are also believed to be the causative factors behind trauma-induced coagulopathy. Tissue injury results in the exposure of collagen as well as tissue factor to initiate the intrinsic and extrinsic pathways, resulting in the consumption of factors (Fig. 1). However, traumatic coagulopathy does not occur with tissue injury alone [15] and requires hypoperfusion. Hypoperfusion stimulates the endothelium to release thrombomodulin, which interacts with thrombin to activate protein C [16]. Activated protein C inactivates factors V and VIII, leading to hypocoagulation, and consumes plasminogen activator inhibitor-1 (PAI-1), which is an antagonist of tissue-type PAI-1 (t-PA). The resulting increase in tPA leads to hyperfibrinolysis [16,17]. This is evident clinically as fibrinogen concentrations decrease after injury [18,19]. A review of pediatric trauma patients requiring transfusions found hypofibrinogenemia in 52% [6 ]. Hemorrhagic shock results in an increased intravascular osmotic pressure and a shift of fluid into the intravascular space. This physiologic dilution of coagulation factors results in a net reduction in coagulation activity [10 ]. An iatrogenic dilution may also be caused by overadministration of fluids in the acute treatment of trauma. Tissue hypoperfusion also leads to metabolic acidosis, which contributes to coagulopathy by decreasing the rate of coagulation factor biochemical reactions. An acidosis of a pH of 7.2 decreases the coagulation factor and complex activity by 50% [14]. Animal models of hemorrhagic shock have also shown that resuscitation with normal saline worsens &&

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Acute coagulopathy in pediatric trauma Choi and Vogel

Contact activation (intrinsic) pathway

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VIIa

XIIa XI

Tissue factor

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Thrombin (II) Fibrinogen (I)

Fibrin (Ia)

t-PA

PAI-1 Plasminogen

Plasmin Fibrin degradation products (d-dimers)

Cross linked fibrin clot

FIGURE 1. Coagulation cascade and impairments caused by acidemia. Boxed figures represent factors and complexes in which activity is significantly decreased by acidemia. Dashed lines represent inhibition of reactions. Adapted and modified from [14]. PAI-1, plasminogen activator inhibitor-1; tPA, tissue-type PAI-1.

acidosis by contributing to a nonanion gap metabolic acidosis over lactated Ringer’s, which is pH neutral [20]. Animals treated with normal saline were also more coagulopathic with greater overall blood loss than those treated with lactated Ringer’s [21]. Hypothermia, caused by shock, exposure, and large volume resuscitation, also exacerbates coagulopathy by a similar mechanism. For every 18C drop in temperature, clotting activity is slowed by approximately 5% [10 ]. Although platelet counts are mildly reduced by trauma, they do not fall to levels that would be expected to significantly contribute to coagulopathy [13 ,22]. However, platelet function as determined by viscoelastic monitoring was found to be significantly impaired in trauma patients [23]. Prospective data has shown that platelet dysfunction is an independent predictor of mortality despite reassuring platelet counts [24]. &&

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DETECTION OF COAGULOPATHY The majority of research conducted on traumatic coagulopathy is based on conventional coagulation tests (CCTs) such as PT, INR, or PTT. However, these CCTs have come under scrutiny as they were originally designed for the management of hemophilias as well as to guide anticoagulation therapy. CCTs have been shown not to adequately characterize the

complex disequilibrium of traumatic coagulopathy [25–27]. A recent prospective study showed that INR values did not adequately reflect coagulopathy in stable adult trauma and surgical patients [28]. These tests also require more time to process before results are available [2,29 ]. Goal-directed hemostatic resuscitation utilizing near real-time assessment of hemostasis and coagulopathy along with massive transfusion protocols (MTPs) has gained widespread acceptance in the management of coagulopathic adult trauma patients [30–33]. Thromboelastography (TEG), a point-of-care measure of hemostasis that evaluates the global viscoelastic mechanical properties of whole blood, has been shown to be an accurate measure of the acute coagulopathy of trauma [2,34]. The two most commonly used assays are TEG and rotational thromboelastometry (ROTEM). In TEG, a small sample of whole blood is pipetted into a cuvette and activated with a reagent (most commonly kaolin). The sample is placed into the thromboelastograph machine, in which the cuvette oscillates. A pin suspended in the blood sample transduces the viscoelastic mechanical properties into a graphical tracing, and computational algorithms generate individual data points. In ROTEM, the pin oscillates instead of the cuvette [35 ]. Rapid TEG (rTEG) uses tissue factor in addition to accelerate activation of the clotting cascade and has been

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found to be the most rapid coagulation study available, as meaningful results may be available within 5–15 min as opposed to CCTs, which take approximately 30–48 min [34,36]. The TEG tracing provides information regarding multiple aspects of the coagulation cascade (Fig. 2). The r-value or activated clotting time (in rTEG) is the time between test initiation and fibrin formation (representative of clotting factor function). The k-time is indicative of hypofibrinogenemia or platelet deficiency. The a-angle is the rate of clot formation and decreases with hypofibrinogenemia or platelet deficiency. The maximal amplitude (MA) represents the platelet contribution to clot strength, whereas the percentage of clot lysis at 30 min (LY30) represents fibrinolysis. Detailed reviews of viscoelastic monitoring have been previously published [26–28,29 ,30–34,35 ,36,37 ,38 ]. In adults, TEG values have been shown to be rapidly available, to correlate with CCTs, and to be predictive of early blood cell, plasma, and platelet transfusion [29 ,34,37 ]. TEG values are also useful in predicting substantial bleeding and the need for massive transfusion, and are independent predictors of early mortality. Adult patients sustaining penetrating trauma who have received TEG-guided resuscitation have been found to have decreased mortality compared with those who received a standardized MTP [38 ]. As mentioned earlier, hyperfibrinolysis has also been determined to be a component of traumatic coagulopathy. The clinical randomization of an antifibrinolytic in significant hemorrhage study, a large randomized controlled trial of adult trauma patients with significant hemorrhage, established &

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the significance of fibrinolysis in coagulopathy as treatment with tranexamic acid (a synthetic antifibrinolytic agent) significantly reduced mortality [39]. However, CCTs do not adequately reflect fibrinolysis, although this is represented by the LY30 value of TEG. Adult patients with abnormal LY30 values have been associated with increased injury severity, acidosis, increased transfusion, and mortality [40,41 ]. In children, a recent retrospective study reviewed the use of rTEG in 86 severely injured pediatric patients. Admission rTEG values were found to be predictive of the need for packed red blood cells (PRBCs) and fresh frozen plasma (FFP) transfusion within 6 h, life-saving interventions, as well as increased odds of mortality [35 ]. Unfortunately, a prospective evaluation of goal-directed hemostatic resuscitation in traumatically injured children at risk for acute coagulopathy of trauma has not yet been performed. &

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RESUSCITATION A timely, appropriate, and adequate hemodynamic and hemostatic resuscitation is required to minimize morbidity and mortality in critically ill traumatically injured patients. The pathology of traumatic coagulopathy implies that this resuscitative effort should be directed to correct specific impaired or depleted factors. The comprehensive nature of viscoelastic monitoring tests such as TEG allows a more specific goal-directed hemostatic resuscitation. However, these tests have yet to be adopted in many centers. Additionally, the fact that infusion of crystalloid products or PRBCs without co-infusion of platelets or FFP worsens coagulopathy may further complicate resuscitative efforts [10 ]. With this in mind, the use of MTP has become widespread in an effort to minimize coagulopathy, as it allows the replacement of coagulation factors and platelets early in the resuscitation process. A retrospective review of adult combat patients who received massive transfusions found that patients who received a high ratio of FFP to PRBC (1 : 1.4) were associated with the lowest mortality rate [42]. Another military study of 466 civilian trauma patients also found increased survival in patients with high plasma and platelet-to-PRBC transfusion ratios (1 : 2) as well as increased ICU, ventilator, and hospital-free days [43]. This study ultimately recommended a plasma : platelet : PRBC ratio of 1 : 1 : 1. Since then, research in the adult civilian population has consistently shown improved outcomes when plasma and platelets are transferred in higher ratios with PRBCs [44–46].

Clot strength

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Time

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R K

ACT Coagulation

Fibrinolysis

FIGURE 2. Rapid TEG tracing. TEG, thromboelastography. Data from Vogel et al. [35 ]. &

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Acute coagulopathy in pediatric trauma Choi and Vogel

Unlike adults, children are better able to tolerate blood loss because of their substantial physiologic reserve. As such, the needs of massive transfusion are believed to be different than in adults [47]. Compared with the adult literature, there is limited data on the use of MTP in pediatric trauma. A singlecenter prospective study compared pediatric patient outcomes before and after MTP was initiated. The MTP was designed with a goal FFP : PRBC ratio of 1 : 1. Although MTP patients received twice the ratio of platelets compared with the pre-MTP cohort, the actual ratio MTP patients received was 1 : 1.8. Additionally, there were no differences in overall mortality [48 ]. Another single-center prospective study in children described the use of an MTP with a 1 : 1 : 1 ratio of PRBC, FFP, and platelets with broad therapeutic goals of maintaining platelets greater than 50 000/ ml, hemoglobin greater than 10 mg/dl, and normalization of PT, PTT, fibrinogen, and fibrin degradation products. The MTP group was likely to be more severely injured and consumed a higher overall amount of blood products. The non-MTP group had a higher thromboembolic complication rate; however, there were no differences in mortality. The cohort included 55 patients and the investigators noted that the actual ratio of FFP to PRBC was 1 : 3. This ratio was presumably the result of a delay in obtaining thawed FFP compared with the more readily available rapidly warmed PRBCs. As such, there was actually no difference in the FFP-to-PRBC ratio in the MTP group and the non-MTP group [47]. A recent retrospective review examined the impact of blood product ratios in pediatric trauma patients requiring massive transfusions, defined as greater than 50% total blood volume within 24 h of admission. Over a 7-year study period, 105 massive transfusion patients were identified. Ultimately, the ratios of FFP to PRBC and platelets to PRBC were not found to impact mortality. In other words, high ratios of plasma and platelets were not found to increase survival. However, as a retrospective study, patients received a wide range of ratios as transfusions were determined by physician choice rather than protocol. Additionally, all patients who died suffered from severe head trauma, and so these deaths were secondary to brain injury rather than hemorrhage [49 ]. Adult studies have shown that factor VII has decreased blood product requirement without demonstrating any change in mortality [50–53]. In pediatrics, factor VII has been found to be well tolerated [54,55] and has resulted in decreased hemorrhage in cardiac surgery patients with preexisting congenital coagulopathies [56,57]. The use of factor VII in pediatric trauma patients has been limited to a &

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few case reports of cerebral injury, in which administration of factor VII corrected the coagulopathy fast enough to proceed with invasive neurosurgical procedures [58,59]. A case report of a 5-year-old boy with a grade 4 liver injury and right common hepatic artery laceration also describes successful TEG-guided resuscitation, including factor VII administration, which resulted in discharge of the patient from the hospital within 13 days [60].

CONCLUSION Traumatic coagulopathy is the result of severe injury and hemorrhage, and is an independent indicator of poor outcomes. The use of viscoelastic monitoring such as TEG offers a promising new diagnostic modality, but its ability to improve the outcomes in pediatric trauma has not yet been proven. Additionally, although MTP have decreased mortality in adults, the same benefits have not been shown in children. Incorporating ‘real-time’ viscoelastic hemostatic monitoring into MTP in a hybrid resuscitation model may represent an optimal treatment paradigm for managing coagulopathic, critically ill trauma patients. Given the limitations of present research on traumatic coagulopathy in the pediatric population, prospective studies are needed to better determine the guidelines for diagnosis and management. Acknowledgements None. Conflicts of interest There are no conflicts of interest.

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Acute coagulopathy in pediatric trauma.

To summarize our current understanding of the pathophysiology, diagnosis, and management of acute traumatic coagulopathy in children...
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