Christiaans, Sarah C.*†; Duhachek-Stapelman, Amy L.‡; Russell, Robert T.†; Lisco, Steven J.‡; Kerby, Jeffrey D.†; Pittet, Jean-François*†
Trauma remains the leading cause of morbidity and mortality in the United States among children aged 1 to 21 years (1, 2). Compared with adults, children seem to sustain higher rates of blunt than penetrating trauma (3). Children may also be victims of nonaccidental trauma that is often associated with traumatic brain injury (TBI).
Perturbations in blood coagulation have been commonly observed in trauma and are associated with adverse outcomes in adults and children (3–9). Attempts to define the perturbations in blood coagulation after trauma have been hindered by inadequate measures of coagulation; also, there is no common laboratory parameter that defines coagulopathy appropriately. Acute traumatic coagulopathy (ATC) has been described by Davenport (10) as an early endogenous process driven by a combination of tissue injury and shock that is associated with increased mortality and worse outcome in the severely injured trauma patient. In adults, endothelial activation of protein C (PC) is a central mechanism of ATC, which produces rapid anticoagulation and fibrinolysis after severe trauma (10). Trauma-induced coagulopathy (TIC) includes not only ATC but also other mechanisms of iatrogenic coagulopathy (IC), such as dilution, acidosis, and hypothermia. It is a global failure of the coagulation system to sustain adequate hemostasis after major trauma. Derangements in coagulation screens identifying hypocoagulation or hypercoagulation are detectable in the hyperacute phase after severe trauma (10). As early as 1982, Miner et al. (11) described the presence of at least one coagulation abnormality in 71% of children with head trauma. However, only a limited number of studies have been performed on the incidence of TIC after pediatric trauma. The incidence of coagulation abnormalities on admission reported in these retrospective pediatric studies ranges widely from 10% to 77% (Table 1). Expanded knowledge on coagulation status of severely injured children is critical to further improvement of pediatric trauma care. In adults, damage control resuscitation strategies have been developed to achieve early aggressive correction of TIC in conjunction with other interventions designed to achieve early hemostasis (12). These strategies have been accompanied by improved outcomes (13–15). In contrast to adults, massive bleeding is less common after pediatric trauma. Traumatic brain injury seems to be the common trigger of TIC and mortality in children (16, 17). The complex pathophysiological mechanisms of the coagulation abnormalities associated with TBI are not yet fully understood but might differ from coagulation disturbances associated with massive systemic bleeding.
The goal of this review is to summarize the current knowledge on the incidence and potential mechanisms of coagulopathy after pediatric trauma as well as the role of rapid diagnostic testing for early identification of TIC. Finally, we discuss different options for treating coagulopathy after severe pediatric trauma.
COAGULOPATHY AFTER PEDIATRIC TRAUMA
During the past decade, a better understanding of TIC and its mechanistic explanations has led to a new therapeutic approach requiring earlier and more aggressive management in adults. Although TIC has long been associated with trauma in children (11), the pediatric population has been understudied and few investigations have been performed to date (Table 1). Recent data from combat support hospitals in Iraq and Afghanistan where children with traumatic injuries were treated revealed an independent association between TIC and shock on admission and higher in-hospital mortality than patients without shock or TIC (8). The authors used a trauma registry capturing 744 patients younger than 18 years across a 7-year period. The incidences of early TIC and shock were 27% and 38.3%, with associated mortality rates of 22% and 16.8%, respectively. Coagulopathy was defined as an International Normalized Ratio (INR) of 1.5 or higher and shock as a base deficit of 6 or higher. Strengths of this study include the use of a comprehensive registry from multiple centers, the size of the study population, and the analysis of many covariates. The authors acknowledged that the retrospective nature of the analysis potentially introduced a selection bias because only patients with full data sets on coagulation studies and shock were included. Furthermore, one could argue that the distribution of mechanisms of injury in this population differ widely from pediatric trauma patients treated in civilian hospitals and are therefore not representative: 43% of children in the studied cohort suffered from injuries resulting from explosion, 26% from gunshot wounds, and only 10% of patients sustained a motor vehicle accident. Regardless, this study illustrates an association between TIC and worse outcomes for pediatric patients who sustain severe traumatic injury.
Several studies have evaluated the relationship between TIC and outcome in the civilian pediatric trauma population. A prospective study performed by Hendrickson et al. (9) evaluated TIC in 102 civilian pediatric trauma patients and found a high prevalence of coagulation abnormalities in children requiring a least one blood product in the first 24 h of admission. The prothrombin time (PT) was abnormal in 72%, partial thromboplastin time in 38%, fibrinogen in 52%, hemoglobin in 58%, and platelet count in 23%. Furthermore, abnormal PT, partial thromboplastin time, and platelet count were strongly associated with mortality and remained significantly associated in the multivariate analysis after adjusting for the Injury Severity Score (ISS). As TIC is particularly prevalent in pediatric patients with TBI, several studies have examined the relationship between TIC and outcome in this patient population. For example, Vavilala et al. (18) reported that fibrin degradation product levels greater than 1,000 μg/mL on admission predicted a poor outcome in children younger than 16 years with a Glasgow Coma Scale (GCS) score between 7 and 12 with isolated head injury. Chiaretti et al. (19) also showed that coagulation abnormalities were associated with poor outcome, including both mortality and long-term neurologic deficit. Furthermore, Talving and colleagues (20) reported an incidence of TIC exceeding 40% in a retrospective study of 320 children sustaining isolated TBI. The mortality rate was 17.5% vs. 0.5% in coagulopathic versus noncoagulopathic patients, respectively. However, after logistic regression to adjust for confounders, no statistically significant mortality difference in patients with and without TIC was noted. The Talving study concluded that a low GCS, a high ISS, and increasing age were independently associated with TBI coagulopathy. This age-related factor suggests that physiological derangements occurring early after TBI and contributing to TIC may be better tolerated in early childhood. These results were not replicated in subsequent studies. Peiniger et al. (15), in a retrospective analysis of 200 data sets from the German trauma registry, found that the GCS score was predictive of hemocoagulative disorders after blunt head trauma. Children with an initial GCS score of 8 or less who presented with TIC on admission to the hospital showed an increased risk for mortality (15). Finally, our research group has recently shown in a retrospective 10-year review of 803 children after severe trauma that early coagulopathy, defined as an INR of 1.2 or higher at presentation, is an independent predictor of mortality (3). The increase in mortality was particularly significant in patients with TBI, either isolated or combined with other injuries. Although these studies describe an association between severe TIC and increased mortality after severe pediatric trauma, the retrospective nature of these studies precludes statements of causality. Whether TIC is simply a marker of severe trauma (particularly brain trauma) or, in fact, contributes to secondary injury is uncertain. Several mechanisms have been evoked to explain the coagulation abnormalities associated with TBI (Fig. 1). Traumatic brain injury causes a combination of both hypocoagulable and hypercoagulable states caused by the traumatized brain tissue (21). In addition, it has been hypothesized that TBI causes a local release of tissue factor from the injured neurons that is associated with activation of the PC pathway, thus triggering the release of anticoagulant mediators (4). However, none of these hypotheses has yet been proven in prospective clinical studies. In summary, the mechanisms behind the development of TIC in pediatric trauma patients have not been fully elucidated, and no study to date has shown evidence for outcome improvement after correction of the TIC in children.
DIFFERENCES BETWEEN THE ADULT AND PEDIATRIC HEMOSTATIC SYSTEMS
Determining the extent of TIC requires reliable testing and an understanding of the physiology of hemostasis in pediatric patients. The hemostatic system develops in utero and evolves during the first few months of life, leading up to maturational differences of many levels of coagulation factors. This inevitably also leads to differences in the normal ranges of coagulation screening tests for very young infants compared with adults. A series of articles by Andrew et al. (22–25) in the late 1980s describes the differences between the pediatric and adult hemostatic systems and how age-related changes occur as the hemostatic system matures.
In healthy children aged 1 to 16 years, the hemostatic system has reached a higher degree of maturation. The screening tests consisting of PT, activated partial thromboplastin time (aPTT), and fibrinogen are almost identical to those of adults. However, mean values of seven coagulant proteins (II, V, VII, IX, X, XI, XII) in children might still be significantly lower than adult values (22, 26, 27), and the PT might be slightly prolonged because plasma prothrombin concentrations during childhood can be 10% to 20% lower than for adults, along with factor VII levels (25, 26). Plasma concentrations of antithrombin (AT), PC, and protein S, all major inhibitors of the coagulation system, show low levels at birth. The mean values for protein S and AT are similar to those in adults by 3 and 6 months of age, respectively, whereas PC is still markedly lower at 6 months of age (23, 24). Lower values of tissue factor pathway inhibitor have been observed in newborns (28).
Although all key components of the fibrinolytic system are present at birth, important age-dependent quantitative and qualitative differences can be observed in children. The major age-dependent differences include decreased plasma concentrations of plasminogen, tissue plasminogen activator (t-PA), and α-antiplasmin (α2-AP); increased plasma concentrations of plasminogen activator inhibitor-1 (PAI-1); and a decrease in both plasmin generation and overall fibrinolytic activity (29).
Limited studies are available on platelet count and function in children; most have been performed in neonates or young infants. Platelet counts have been studied in young healthy infants of varying ages, and it seems that they are significantly higher at 2 months and lower at both 5 and 13 months (30). Differences in platelets between healthy neonates and adults with regard to their response to platelet agonists have also been described. Initial platelet aggregation using flow cytometry consistently demonstrated that platelets from neonatal cord blood were less responsive than adult platelets to agonists such as adenosine 5′-diphosphate, epinephrine, collagen, thrombin, and thromboxane analogs (31). The mechanism(s) underlying these differences are still poorly understood, although it has been suggested that the hyporesponsiveness to epinephrine is probably because of the presence of fewer α2-adrenergic receptors (32). In addition, the reduced response to collagen likely reflects the impairment of calcium mobilization (33), and the decreased response to thromboxane may result from differences in signaling downstream from the receptor in neonatal platelets (34).
Studies of primary hemostasis revealed significantly shorter bleeding times in healthy neonates compared to adults (22). Other studies using a platelet function analyzer found a shorter closure time in neonates than that in adults (35). This apparently paradoxical finding of enhanced primary hemostasis in the face of platelet hypoactivity has been attributed to the higher hematocrit levels, higher mean corpuscular volumes, and higher von Willebrand factor concentrations in the blood of neonates (22). Whether this in vitro platelet hyporeactivity of neonates translates into poor platelet reactivity under in vivo conditions is not well known.
The thrombin hemostasis system might also differ in children. It has been observed that the capacity to generate thrombin in vitro by a chromogenic assay is decreased by 26% in plasma from children aged 1 to 16 years compared with that in adults; this would justify the lower prevalence of thromboembolic complications in this period (36). When compared with adult reference ranges, children aged 1 to 5 years might display higher values of soluble thrombomodulin, thrombin-AT complex, and d-dimer (37).
Taken together, the results of these studies indicate some variability in the maturation of the different coagulation proteins and of the functional activity of platelets in young children. However, the susceptibility to bleeding is based on the contextuality of the entire hemostatic system as evaluated by coagulation monitoring devices assessing the viscoelastic properties of whole blood and platelet function testing and not just on coagulation factor and anticoagulation factor balance changes over time.
EARLY DETECTION OF TIC AFTER PEDIATRIC TRAUMA
The basic precondition for adequate management of a coagulation problem in the acute phase after trauma is timely recognition. Scoring systems and algorithms have been developed to evaluate severely injured patients to help guide activation of massive transfusion protocols (MTPs). These systems are limited by their retrospective design. An alternative for early identification of TIC is through point-of-care evaluation of coagulation status (38). A number of tests are available to assess coagulation in the pediatric population; standard coagulation monitoring is composed of the early and repeated determination of conventional coagulation tests (CCTs) such as PT, aPTT, INR, and fibrinogen. It is frequently assumed that these CCTs monitor coagulation; however, these tests monitor only the initiation phase of blood coagulation and represent only the first 4% of thrombin production (39). It is, therefore, possible that the conventional coagulation screen appears normal, whereas the overall state of blood coagulation is abnormal (40–42). Moreover, CCTs, originally developed for the guidance of anticoagulation therapy or management of certain disease states, assess only plasma-based components of the coagulation system and do not account for the contribution of the endothelium and cellular components of blood. Also, the detection of hypercoagulability is limited by the use of CCTs. As the majority of trauma patients become hypercoagulable, it would be important to use coagulation monitoring devices, such as thromboelastography (TEG), that have been shown to accurately assess hypercoagulation in other conditions (43).
Increasing emphasis focuses on the importance of coagulation monitoring devices assessing the viscoelastic properties of whole blood and platelet function testing, that is, TEG, rotation thrombelastometry (RoTEM), and impedance aggregometry (Multiplate; DiaPharma, West Chester, Ohio) (Table 2; Fig. 2). Thromboelastography/RoTEM measures and graphically displays the changes in viscoelasticity at all stages of the developing and resolving clot, starting with fibrin formation and continuing on through clot retraction and fibrinolysis with minimal delays. Furthermore, the coagulation status of patients is assessed in whole blood, providing a functional assay that allows the plasma-based coagulation system to interact with platelets, red blood cells (RBCs), and white blood cells, thereby providing useful information on platelet function (44). In addition, with the development of the Multiplate device and FDA clearance for two of its tests, a rapid point-of-care platelet function testing will soon become available clinically and has successfully been used in research studies to identify platelet dysfunction in adult trauma patients (45). A major benefit of these assays is their ability to evaluate the coagulation system in whole blood, which may improve the accuracy of monitoring hemostasis.
Early variables of clot firmness assessed by viscoelastic testing, such as TEG, have been shown to be good predictors for the need for massive transfusion, the incidence of thrombotic/thromboembolic events, and mortality in adult surgical and trauma patients (42, 46–55). The delay in detection of TIC can influence outcome, and the turnaround time of viscoelastic devices (TEG/RoTEM) has been shown to be significantly shorter by 30 to 60 min compared with conventional laboratory testing in both adult and pediatric patient populations (42, 56, 57). Data on the measurement of viscoelastic properties of whole blood in children after trauma are limited. An initial study detailing the use of viscoelastic devices has recently been described in 86 children sustaining severe trauma (58). Interestingly, rapid TEG was used in that study that produced faster results than conventional TEG measurements. Similarly, the use of interim ROTEM values (A10) has been shown to provide an early and specific assessment of coagulation status after trauma in adult patients to guide resuscitation (59). These investigators described results comparable to adult studies (50, 60), with admission data correlating with CCT and predicting early transfusion and outcome. Thus, although normal values of viscoelastic properties of whole blood have been established in healthy children of all ages for TEG, thromboelastometry, and impedance aggregometry (61–64), carefully designed prospective trials on the use of these global measurements of hemostasis are warranted to obtain a more detailed description of the coagulation abnormalities that occur after trauma in this special population.
POTENTIAL MECHANISMS OF TIC AFTER PEDIATRIC TRAUMA
There are several potential mechanisms that contribute to the development of TIC. Much adult trauma literature details mechanisms and drivers of TIC, but there are only limited descriptions characterizing these mechanisms in pediatric trauma. The principal mechanistic drivers are summarized in Figure 3. As the number of aforementioned drivers of TIC mount after injury, the probability of life-threatening coagulopathy increases exponentially. Previous studies have shown that the conditional probability of developing TIC with moderate injury without the presence of additional triggers for coagulopathy is 1%. However, with increased ISS, higher than 25, and hypotension, the probability increases to almost 40%, and in cases with ISS higher than 25, hypotension, hypothermia, and acidosis, the probability of developing TIC increases to 98% (65).
Physiologic and iatrogenic dilution in trauma patients when present can act as an additional mechanistic driver of TIC. In times of hypotension, physiologic or iatrogenic dilution potentiates the osmotic activity of plasma, leading to a shift of extravascular water into the intravascular space. Until equilibrium is reestablished, this osmotic activity causes a proportional dilution of plasma proteins and coagulation factors adversely affecting their subsequent interactions. Monroe et al. (66) modeled the action of factor VIIa in dilutional coagulopathy and demonstrated a calculated reduction in single factor concentration of 37%, resulting in a 75% reduction in overall factor complex activity. The effects of iatrogenic dilution in trauma were nicely demonstrated in a study of patients from the German Trauma Society Database (TR-DGU). Investigators observed TIC on emergency room (ER) admission in greater than 40% of patients receiving more than 2,000 mL in transport, in greater than 50% of patients with more than 3,000 mL in transport, and in 70% of patients with more than 4,000 mL of fluid administered in the prehospital phase of care (67). This dilution is accompanied by consumption and inactivation of coagulation factor substrates and coagulation enzymes of varying magnitudes depending on the degree of individual injury (68).
In addition to dilutional mechanisms of TIC, the effects of temperature and pH on coagulation factor and complex activity have also been well described. The pace of coagulation factor reactions is affected by hypothermia and acidosis. Kermode et al. (69) and Jurkovich et al. (70) have demonstrated that coagulation interactions are slowed down by approximately 5% with each degree Celsius drop in temperature. Similarly, the critical interactions between factors and glycoproteins that activate platelets are absent in 75% of individuals at 30°C (69, 70). A reduction in pH to 7.2 has been shown to reduce coagulation factor complex activities by 50%, with activity falling to 20% of normal at a pH of 6.8 (71).
Fibrinolysis is another important mechanism controlled by the coagulation system, which plays a role in TIC. The coagulation system modulates fibrinolysis, maintaining stable blood clots for the time necessary to control bleeding. In the normal setting, high concentrations of thrombin inhibit plasmin activation by the activation of thrombin-activated fibrinolysis inhibitor and PAI-1. However, hypothetically, in the setting of trauma, if the thrombin burst is not robust, thrombin-activated fibrinolysis inhibitor remains inactivated, allowing thrombin to bind to thrombomodulin on endothelial cells, leading to PC activation, subsequent factor V and VII and PAI-1 inactivation, and increased fibrinolysis. Hyperfibrinolysis has been identified as a significant risk factor for mortality in bleeding trauma patients (72, 73).
More than one fourth of adult trauma patients demonstrate detectable coagulopathy on arrival to the emergency department before the development of the classic triad of hypothermia, dilution, and acidosis. Brohi and colleagues (5), in a large prospective study of 209 patients presenting with severe trauma (ISS ≥ 16) and meeting the criteria for the highest trauma activation, documented the development of TIC within 1 h after injury in approximately 30% of patients. In this study, patients arriving coagulopathic had significantly increased mortality of 40%. Other authors subsequently reported similar findings (6). In the study by Brohi et al. (4), potential mechanisms for TIC were also evaluated. In this cohort of severely injured adult patients, plasma levels of PC zymogen were found to be depleted on admission to the hospital. More recent data from the same investigators showed that, in a similar group of 200 adult trauma patients, the combination of tissue injury, elevated ISS, and shock was associated with TIC nearly immediately after their injury (74). They found that TIC was strongly correlated with the activation of the PC pathway. Further evidence for PC activation is demonstrated by the fact that they also found a strong inverse correlation between plasma levels of activated PC (aPC), factor Va and VIIIa inactivation, and the derepression of fibrinolysis. Activated PC directly inhibits PAI-1, which usually serves to limit t-PA activity. Without the limitation of PAI-1, t-PA is free to enhance the conversion of plasminogen to plasmin and thereby enhance fibrinolysis. In summary, aPC exerts its profound anticoagulant activity by inhibiting coagulation and through derepression of fibrinolysis (4).
The possible mechanistic role of the PC pathway in the development of TIC was also demonstrated in a mouse model of trauma-hemorrhage (75). Mice subjected to pressure-controlled hemorrhage to a mean arterial pressure of 40 mmHg for 60 min developed severe metabolic acidosis (base deficit, >10), were hypocoagulable (had an increase in their aPTT), and had a significant increase in their plasma levels of aPC. The aPTT returned to normal values 12 h later. When mice were pretreated with an antibody that blocks the anticoagulant domain of aPC, it reversed the coagulopathy induced by severe trauma, indicating that the activation of the PC pathway might play a mechanistic role in TIC.
Another potential driver of TIC is the disruption of the vascular endothelium and its glycocalyx after trauma because of hypoperfusion, tissue trauma, inflammation, and sympathoadrenal activation. Significant levels of heparin-like compounds exist in the noncirculating plasma of the glycocalyx and may be released with its disruption (76). Evidence supporting this mechanism was revealed in a prospective study of 77 adult trauma patients with autoheparinization by TEG, which was likely related to endothelial glycocalyx degradation, as exhibited by increased syndecan-1, thrombomodulin, and interleukin-6 levels (77).
One would assume that certain physiologic drivers would be similar between children and adults, including hypothermia, acidosis, dilutional effects, and consumption of coagulation factors. However, on a more detailed level, minimal literature exists on a pediatric patient’s response to significant traumatic tissue injury and the release of inflammatory markers and anticoagulation factors, like aPC, which may interfere with coagulation and hemostasis. A detailed description of the mechanistic changes in the coagulation system associated with severe trauma has not been performed in the pediatric population and will require further investigation.
TREATMENT OPTIONS FOR TIC IN PEDIATRIC TRAUMA
Administration of procoagulant concentrates
In adults, damage control resuscitation strategies have been developed to achieve an early aggressive correction of TIC (12, 78). This strategy has been accompanied by improved outcomes (13–15). We hypothesize that, in pediatric patients with coagulopathy that is rapidly identified and amenable to correction, a goal-directed approach to resuscitation may be more appropriate than an empiric blood product approach. The most important procoagulant concentrates include fibrinogen concentrate, prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), and antifibrinolytics such as the tranexamic acid (TXA). The effect of these adjuvant interventions has not been systematically studied in the pediatric population. The use of these hemostatic agents in a goal-directed fashion guided by TEG/RoTEM monitoring to assess effectiveness and avoid potential thromboembolic complications makes for a compelling therapeutic strategy (Table 3; Fig. 4).
Fibrinogen concentrate (HaemocomplettanP/RiaSTAP; CSL Behring, USA) has been marketed for a number of years for the treatment of congenital hypofibrinogenemia but has been advocated as a fibrinogen replacement therapy for patients requiring massive transfusion (79). It is produced from pooled human plasma by fractionation and undergoes inactivation steps; it has a fibrinogen concentration of approximately 20 mg/mL. Despite the evidence supporting maintenance of adequate fibrinogen levels in bleeding patients, little data are available on the administration of fibrinogen concentrate to trauma patients. In pediatric trauma, the use of a fibrinogen concentrate was recently reported in a 7-year-old patient with severe abdominal and pelvic trauma (80). On arrival to the emergency department, he received 250 mL RBC, 250 mL crystalloid, and 0.5 g fibrinogen concentrate, which were given preemptively. He then underwent goal-directed hemostatic therapy using RoTEM. A total of 2 g fibrinogen was administered, whereas fresh-frozen plasma (FFP) and platelets were avoided. Despite an estimated blood loss of more than 70 mL/kg, the patient received only 3 units of RBC. The ratio of intraoperative fibrinogen concentrate (g) to RBC (U) was 0.7, which is similar to the ratio of 0.9 described by Schochl when looking at thromboelastometry-guided coagulation factor concentrate–based therapy versus FFP in adult trauma (81). Fibrinogen or cryoprecipitate (for fibrinogen replacement) received a grade 1C recommendation in a recent European guideline for management of traumatic bleeding in adult patients with thromboelastometric signs of fibrinogen deficiency or a fibrinogen level of less than 1.5 to 2.0 g/L and significant bleeding (82).
Recombinant factor VIIa
Recombinant factor VIIa was initially developed for the treatment of hemophilia and acquired inhibitors, but off-label use of rFVIIa has become increasingly prevalent. Recombinant factor VIIa has a more developed presence in the pediatric literature than that of the other factor concentrates. Its effectiveness in neonates, infants, and children with TIC and clinically significant bleeding, as well as complications after its administration in pediatric patients, has been described in several reports. A retrospective case series of 135 pediatric patients receiving rFVIIa for off-label use revealed its potential for clinical utility in the setting of surgery and trauma. In this case series, 15 patients received rFVIIa for trauma, 19 patients for surgical bleeding, 16 patients for procedural prophylaxis, and 28 patients for bleeding resulting from disseminated intravascular coagulation/sepsis. There was a decrease in 24-h median transfusion volume after rFVIIa administration. Surgical patients had control of life-threatening bleeding with low associated mortality. Indeed, the mortality rate was significantly lower in the surgical/trauma patients (16%) in comparison with that in medical patients (58%). Major thrombotic events were seen in three patients after rFVIIa, resulting in two deaths and one leg amputation (83). Another case review study on pediatric patients with severe TIC after cerebral injury reports a rapid correction of hemostatic abnormalities after administration of a bolus of 90 μg/kg rFVIIa in three children aged 5 weeks, 20 months, and 11 years (84).
Dosing recommendations in the pediatric patient are extrapolated, in part, from the adult literature, supplemented by the pediatric hemophiliac population. Bolus doses have ranged from 40 to 100 μg/kg in the nonhemophiliac pediatric population. With ongoing bleeding or risk for bleeding, repeat doses at intervals of 2 to 6 h have been administered. In addition to bolus dosing, continuous infusion (20–30 μg/kg per h) after the bolus to maintain hemostatic levels of rFVIIa has been reported. Compared with adults, the pharmacokinetics in pediatric patients demonstrates a shorter half-life and an increased clearance (85). In addition to its effects on coagulation function, recent data report enhanced platelet function (84), suggesting a potential role in patients with qualitative platelet disorders, which may include severely injured pediatric trauma patients, more specifically, brain-injured children. However, some limitations in the use of rFVIIa have been observed in adults. Data from 21 institutions and 380 patients were collected from the Western Trauma Association Web-based registry and revealed several indicators of poor response to rFVIIa, including acidosis (pH <7.2), thrombocytopenia (platelets, <100,000), and hypotension (systolic blood pressure, ≤90 mmHg). Based on these results, maximal benefit cannot be achieved with administration late in the treatment of a hemorrhaging trauma patient (86).
Prothrombin complex concentrate
Prothrombin complex concentrate, also referred to as factor IX complex, is derived from pooled human plasma and contains 25 to 30 times the concentration of clotting factors as FFP. Four-factor PCCs contain factors II, VII, IX, and X, whereas 3-factor PCCs contain little or no factor VII. Depending on the formulation, PCCs may additionally contain PC, protein S, AT, and low-dose heparin (87). Most formulations available in the United States are 3-factor PCCs and are approved for prevention and control of bleeding in patients with hemophilia B. However, because of the availability of highly purified and recombinant factor IX products, PCCs are rarely used for this indication. There have been no controlled clinical trials evaluating the use of PCC in massive bleeding; recommendations are generally based on retrospective or observational studies, case reports, and expert opinion (87). Literature regarding use of PCC in the pediatric trauma patient is scarce. One case report described an 8-kg infant with liver trauma and severe hemorrhage who was acidotic (pH 6.67) and severely anemic with a hemoglobin count of 4 mg/dL (88). The patient underwent two surgical procedures and transfusion of packed RBCs, platelets, and FFP. After the second operation, the infant continued to bleed despite the administration of FFP, platelets, and RBCs. Vitamin K and 30 IU/kg PCC were administered because of ongoing hemorrhage, at which point there was rapid cessation of bleeding and the INR decreased from 2.9 to 1.5.
The variability in factor concentration between formulations creates challenges in standardization of dosing. When using the package information regarding dosing recommendations for hemophilia B, an expected increase in factor IX between 20% and 50% would occur with a dose of 20 to 50 units/kg (89). Similarly, Australasian guidelines recommend a dose of 25 to 50 units/kg of 3-factor PCC to reverse INR after administration of vitamin K antagonists (90). Caution must be exercised in administration of these agents because of their activity as potent procoagulants (91). Patanwala recommended a maximum cumulative dosage of less than 50 units/kg because of the risk of thromboembolism (89). Although some studies have shown benefits of PCC, there is currently only level 2C evidence (GRADE working group) for its usage in patients with massive bleeding in concert with FFP (87). In the European guidelines for management of traumatic bleeding, it is only recommended for the emergent reversal of vitamin K–dependent anticoagulation (grade 1B recommendation) (92). For stronger recommendations to be developed for use in hemorrhage secondary to trauma, there is a need for randomized studies to evaluate outcomes after administration, especially in children.
Tranexamic acid, an antifibrinolytic agent, is a synthetic lysine analog that functions by competitive inhibition of the enzymatic activation of plasminogen to plasmin, responsible for the degradation of fibrin. The Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) investigators revealed a significant decrease in death secondary to bleeding when TXA was administered early after trauma. Despite this favorable outcome, several gaps in knowledge regarding the use of TXA in trauma were identified in a recent review by a US Department of Defense Committee. Many issues raised are important in the pediatric population as well, including the need for a more clear-cut identification of which patients might benefit from TXA, the development of animal models to establish efficacy and safety, and further evaluation of the safety profile of TXA given the increased risk for thrombotic events and the lack of data regarding safety in children (93). A 2008 systematic review analyzing the use of TXA in pediatric patients undergoing spine surgery revealed six studies. Tranexamic acid led to a modest decrease in volume of blood transfused, but not the number of patients requiring transfusion. No deaths or major adverse events were reported; however, the number of patients was too small and follow-up duration was too brief to draw conclusions regarding safety (94). Similar results have been found in pediatric cardiac literature (95).
The Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group Medicines Committee published an evidence statement in November 2012 addressing the use of TXA for major trauma in children in response to CRASH-2. This evidence statement strongly encouraged the need for ongoing research into the use of TXA in the pediatric population but offered pragmatic dosing guidelines based on extrapolation from adult literature because published use of TXA in pediatric patients has revealed wide variability in dosing. The recommendation by this group was a 15-mg/kg loading dose (maximum, 1 g) for 10 min followed by 2 mg/kg per h for at least 8 h or until bleeding stops. Because no indication recommendations were given, the group urged caution with administration of TXA in the pediatric trauma population because a potential risk of thrombosis exists (96). This stance was supported by Reade and colleagues (97) who encouraged the further evaluation of the safety and efficacy of TXA in trauma patients before its universal protocolized use.
Transfusion of blood and plasma
Massive blood transfusion
In the adult trauma setting, resuscitation strategies have evolved with a trend toward the early and liberal use of blood products, including RBC, FFP, and platelets in patients with hemorrhagic shock. Several studies have supported the use of a 1:1:1 platelet/FPP/RBC ratio when transfusing severely injured patients (13, 14, 98, 99). However, the results of these studies may have been affected by survival bias (100–103). Other published studies have not shown any improvement in survival using this approach (104–106). In contrast, two recent studies have still shown a benefit of using a high FFP-blood ratio after adjusting for survival bias (107, 108). Regardless of these results, a higher ratio transfusion approach has been adopted at the majority of level 1 adult trauma centers, and prospective, randomized, controlled trials are currently underway to determine optimal ratios for patients with severe hemorrhagic blood loss (109).
Massive transfusion in children is uncommon, and in non-neonatal pediatric patients, transfusion guidelines are similar to those in adults. In children, because blood volume varies per age, gender, and weight (110–112), it is unclear as to what constitutes a massive transfusion. Moreover, the response to massive bleeding in children is thought to differ from the adult response because of their greater physiological reserve and an improved tolerance of blood loss (113). Data analyzing the effects of a balanced ratio of blood product component administration in massive transfusion are limited in pediatric populations. To date, only three single-center studies have been reported on experience with MTP in pediatric patients (Table 3). A prospective study on 102 pediatric trauma patients was completed after the institution of a pediatric MTP and outcomes compared with a period before protocol implementation (110). After MTP institution, the median FFP/RBC transfusion ratio was 1:1.8 compared with a ratio of 1:3.6 in the pre-MTP patient population. Although this study was not powered to show improvement in outcome, there were two important findings. First, the majority of patients had at least one coagulation value abnormality. Second, implementation of a pediatric MTP with early and aggressive use of plasma transfusion in children with TIC was feasible. In the same year, Chidester et al. (113) performed a prospective cohort study of 55 children, of whom 22 patients received transfusions according to MTP whereas the other 33 patients received blood at physician discretion. Similar to results reported by Hendrickson et al. (110), mortality was not significantly different between the two groups. However, the MTP group received a greater overall amount of blood products and was more likely to be severely injured. Thromboembolic events were observed exclusively in the non-MTP group, which the authors attributed to undertransfusion in those patients. Importantly, despite using an MTP, neither study was able to reach the protocols’ goal of 1:1 ratio for FFP/RBC transfusion because of the lack of availability of thawed plasma. Recently, a retrospective study on 105 pediatric trauma patients receiving massive transfusion found no association between blood product ratios and survival (114). Interestingly, all casualties suffered from severe TBI (head AIS, ≥3) and not hemorrhage. Taken together, additional prospective randomized clinical trials are needed to fully evaluate the effectiveness of varying ratios of blood component therapies in the pediatric trauma population.
Fresh-frozen plasma is the most common blood component transfused to treat coagulopathy. Fresh-frozen plasma is plasma produced from whole blood and frozen to -40°C to preserve labile coagulation factors. Fresh-frozen plasma typically contains coagulation factors close to normal blood levels as well as other plasma proteins, including immunoglobulins and albumin. Volume is a potential disadvantage of using FFP in the pediatric trauma setting where TIC may be present and rapidly progressing, but no volume expansion is needed. Most guidelines suggest that plasma should be only transfused in the case of active bleeding and not based on abnormal coagulation screens alone (115, 116).
There are inherent risks to the transfusion of FFP. These risks include, but are not limited to, exposure to pathogens, transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload, and adverse immunological reactions. In a retrospective study, Karam et al. (117) found a 3-fold increase in risk of new or progressive multiple organ dysfunction syndrome in pediatric patients receiving one or more plasma transfusions. Those patients receiving plasma also had an increase in nosocomial infections and intensive care unit length of stay. Another retrospective study compared trauma patients receiving FFP alone versus coagulation factor concentrates (fibrinogen and PCC) and no FFP. Although mortality was similar, patients receiving FFP received more packed RBCs and had an increased frequency of multiorgan failure (118). Recently, a solvent/detergent–treated plasma has been licensed in the United States; this product has been shown to dramatically reduce the risk of adverse advents associated with single-donor FFP, including reduced TRALI (119). The application of solvent/detergent plasma needs to be explored to determine if its use is safer but equally efficacious compared with the use of regular FFP in pediatric trauma patients who are both coagulopathic and hypovolemic.
Advantages of coagulation factor concentrates include immediate availability for administration, lack of excessive volume expansion, standardization of factor concentration and dose, and lack of elevated risk of TRALI (120). In addition, coagulation factor concentrates have a minimal risk of pathogen transmission because they undergo viral inactivation steps. However, it should be pointed out that plasma may have protective properties that are unrelated to its procoagulant activity but are related to the restoration of the endothelial glycocalyx layer that is damaged by hypoperfusion and hypoxia (121).
In summary, pediatric data on successful management of TIC are limited, and practices are largely extrapolated from the adult trauma experience. Few studies have directly looked at hemostatic interventions in children. It is clear that TIC accompanying pediatric trauma is an area where future prospective randomized trials are needed to define ideal treatment strategies necessary to improve outcomes in this unique patient population.
Coagulation abnormalities after pediatric trauma are more common than previously thought and are associated with increased morbidity and mortality. Essential prerequisites needed to investigate coagulation abnormalities after trauma in the pediatric population are the accurate interpretation of coagulation tests, along with a thorough understanding of the normal postnatal development of the human coagulation system. The laboratory-assisted diagnostic approach to several hemostatic disturbances in the newborn and the child is challenging because collection procedures and coagulation assays must be adapted for very small amounts of blood, and the reference intervals for many assays may differ broadly from those for adults. Measurements of viscoelastic properties of whole blood provides a rapid evaluation of clot dynamics in whole blood and are of greater value than coagulation screens in diagnosing and managing TIC. A number of interventions have been undertaken in trauma patients to minimize TIC and hemorrhage, including balanced MTPs, factor concentrate administration, and antifibrinolytic therapy. Despite these interventions, hemorrhage remains the second largest cause of death in adult trauma patients and is responsible for one half of the deaths occurring in the first 24 h (122). The widespread application of adult traumatic coagulopathy management principles to pediatric traumatic coagulopathy management should not be done blindly, and caution needs to be applied in the care of these patients. The mechanisms behind the development of ATC in the pediatric population need to be elucidated, and well-designed prospective clinical trials studying the efficacy of early detection and management in TIC after pediatric trauma are urgently needed.
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Trauma; coagulopathy; children; mechanisms; stratification; treatment
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