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 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, 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.
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.
1. Avarello JT, Cantor RM: Pediatric major trauma: an approach to evaluation and management. Emerg Med Clin North Am 25 (3): 803–836, 2007.
2. Mace SE, Gerardi MJ, Dietrich AM, Knazik SR, Mulligan-Smith D, Sweeney RL, Warden CR: Injury prevention and control in children. Ann Emerg Med 38 (4): 405–414, 2001.
3. Whittaker B, Christiaans SC, Altice JL, Chen MK, Bartolucci AA, Morgan CJ, Kerby JD, Pittet JF: Early coagulopathy is an independent predictor of mortality in children after severe trauma. Shock 39 (5): 421–426, 2013.
4. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF: Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 245 (5): 812–818, 2007.
5. Brohi K, Singh J, Heron M, Coats T: Acute traumatic coagulopathy. J Trauma 54 (6): 1127–1130, 2003.
6. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M: Early coagulopathy predicts mortality in trauma. J Trauma 55 (1): 39–44, 2003.
7. Rixen D, Raum M, Bouillon B, Schlosser LE, Neugebauer E, Arbeitsgemeinschaft Polytrauma der Deutschen Gesellschaft fur U: [Predicting the outcome in severe injuries: an analysis of 2069 patients from the trauma register of the German Society of Traumatology (DGU)]. Unfallchirurg 104 (3): 230–239, 2001.
8. Patregnani JT, Borgman MA, Maegele M, Wade CE, Blackbourne LH, Spinella PC: Coagulopathy and shock on admission is associated with mortality for children with traumatic injuries at combat support hospitals. Pediatr Crit Care Med 13 (3): 273–277, 2012.
9. Hendrickson JE, Shaz BH, Pereira G, Atkins E, Johnson KK, Bao G, Easley KA, Josephson CD: Coagulopathy is prevalent and associated with adverse outcomes in transfused pediatric trauma patients. J Pediatrics 160 (2): 204–209 e203, 2012.
10. Davenport R: Pathogenesis of acute traumatic coagulopathy. Transfusion 53 (Suppl 1): 23S–27S, 2013.
11. Miner ME, Kaufman HH, Graham SH, Haar FH, Gildenberg PL: Disseminated intravascular coagulation fibrinolytic syndrome following head injury in children: frequency and prognostic implications. J Pediatrics 100 (5): 687–691, 1982.
12. Spinella PC, Holcomb JB: Resuscitation and transfusion principles for traumatic hemorrhagic shock. Blood Rev 23 (6): 231–240, 2009.
13. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 63 (4): 805–813, 2007.
14. Maegele M, Lefering R, Paffrath T, Tjardes T, Simanski C, Bouillon B, Working Group on Polytrauma of the German Society of Trauma S: Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft fur Unfallchirurgie. Vox Sang 95 (2): 112–119, 2008.
15. Peiniger S, Nienaber U, Lefering R, Braun M, Wafaisade A, Wutzler S, Borgmann M, Spinella PC, Maegele M, Trauma Registry of the Deutsche Gesellschaft fur Unfallchirurgie: Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care 15 (1): R68, 2011.
16. Langlois JA, Rutland-Brown W, Thomas KE: The incidence of traumatic brain injury among children in the United States: differences by race. J Head Trauma Rehabil 20 (3): 229–238, 2005.
17. Kipfmueller F, Wyen H, Borgman MA, Spinella PC, Wirth S, Maegele M: [Epidemiology, risk stratification and outcome of severe pediatric trauma]. Klinische Padiatrie 225 (1): 34–40, 2013.
18. Vavilala MS, Dunbar PJ, Rivara FP, Lam AM: Coagulopathy predicts poor outcome following head injury in children less than 16 years of age. J Neurosurg Anesthesiol 13 (1): 13–18, 2001.
19. Chiaretti A, Piastra M, Pulitano S, Pietrini D, De Rosa G, Barbaro R, Di Rocco C: Prognostic factors and outcome of children with severe head injury: an 8-year experience. Childs Nerv Syst 18 (3-4): 129–136, 2002.
20. Talving P, Lustenberger T, Lam L, Inaba K, Mohseni S, Plurad D, Green DJ, Demetriades D: Coagulopathy after isolated severe traumatic brain injury in children. J Trauma 71 (5): 1205–1210, 2011.
21. Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI: Coagulation disorders after traumatic brain injury. Acta Neurochirurgica 150 (2): 165–175, 2008.
22. Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 12 (1): 95–104, 1990.
23. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P: Development of the human coagulation system in the healthy premature infant. Blood 72 (5): 1651–1657, 1988.
24. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P: Development of the human coagulation system in the full-term infant. Blood 70 (1): 165–172, 1987.
25. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 80 (8): 1998–2005, 1992.
26. Flanders MM, Crist RA, Roberts WL, Rodgers GM: Pediatric reference intervals for seven common coagulation assays. Clin Chem 51 (9): 1738–1742, 2005.
27. Flanders MM, Phansalkar AR, Crist RA, Roberts WL, Rodgers GM: Pediatric reference intervals for uncommon bleeding and thrombotic disorders. J Pediatrics 149 (2): 275–277, 2006.
28. Fritsch P, Cvirn G, Cimenti C, Baier K, Gallistl S, Koestenberger M, Roschitz B, Leschnik B, Muntean W: Thrombin generation in factor VIII-depleted neonatal plasma: nearly normal because of physiologically low antithrombin and tissue factor pathway inhibitor. J Thromb Haemost 4 (5): 1071–1077, 2006.
29. Parmar N, Albisetti M, Berry LR, Chan AK: The fibrinolytic system in newborns and children. Clin Lab 52 (3-4): 115–124, 2006.
30. Hinchliffe RF, Bellamy GJ, Bell F, Finn A, Vora AJ, Lennard L: Reference intervals for red cell variables and platelet counts in infants at 2, 5 and 13 months of age: a cohort study. J Clin Pathol 66 (11): 962–966, 2013.
31. Sitaru AG, Holzhauer S, Speer CP, Singer D, Obergfell A, Walter U, Grossmann R: Neonatal platelets from cord blood and peripheral blood. Platelets 16 (3-4): 203–210, 2005.
32. Corby DG, O’Barr TP: Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine. Dev Pharmacol Ther 2 (4): 215–225, 1981.
33. Gelman B, Setty BN, Chen D, Amin-Hanjani S, Stuart MJ: Impaired mobilization of intracellular calcium in neonatal platelets. Pediatr Res 39 (4 Pt 1): 692–696, 1996.
34. Israels SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A: Deficient thromboxane synthesis and response in platelets from premature infants. Pediatr Res 41 (2): 218–223, 1997.
35. Israels SJ, Cheang T, McMillan-Ward EM, Cheang M: Evaluation of primary hemostasis in neonates with a new in vitro
platelet function analyzer. J Pediatrics 138 (1): 116–119, 2001.
36. Andrew M, Mitchell L, Vegh P, Ofosu F: Thrombin regulation in children differs from adults in the absence and presence of heparin. Thromb Haemost 72 (6): 836–842, 1994.
37. Sosothikul D, Seksarn P, Lusher JM: Pediatric reference values for molecular markers in hemostasis. J Pediatr Hematol Oncol 29 (1): 19–22, 2007.
38. Maegele M, Spinella PC, Schochl H: The acute coagulopathy of trauma: mechanisms and tools for risk stratification. Shock 38 (5): 450–458, 2012.
39. Mann KG, Butenas S, Brummel K: The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 23 (1): 17–25, 2003.
40. Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C, David JS: Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 100 (6): 792–797, 2008.
41. Johansson PI, Stensballe J: Effect of haemostatic control resuscitation on mortality in massively bleeding patients: a before and after study. Vox Sang 96 (2): 111–118, 2009.
42. Davenport R, Manson J, De’Ath H, Platton S, Coates A, Allard S, Hart D, Pearse R, Pasi KJ, MacCallum P, et al.: Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 39 (12): 2652–2658, 2011.
43. Krzanicki D, Sugavanam A, Mallett S: Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transplant 19 (8): 852–861, 2013.
44. Ganter MT, Hofer CK: Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 106 (5): 1366–1375, 2008.
45. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, Nelson MF, Cohen MJ: Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 73 (1): 13–19, 2012.
46. McCrath DJ, Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E: Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 100 (6): 1576–1583, 2005.
47. Kashuk JL, Moore EE, Sabel A, Barnett C, Haenel J, Le T, Pezold M, Lawrence J, Biffl WL, Cothren CC, et al.: Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 146 (4): 764–772, 2009.
48. Johansson PI, Stensballe J, Vindelov N, Perner A, Espersen K: Hypocoagulability, as evaluated by thrombelastography, at admission to the ICU is associated with increased 30-day mortality. Blood Coagul Fibrinolysis 21 (2): 168–174, 2010.
49. Leemann H, Lustenberger T, Talving P, Kobayashi L, Bukur M, Brenni M, Bruesch M, Spahn DR, Keel MJ: The role of rotation thromboelastometry in early prediction of massive transfusion. J Trauma 69 (6): 1403–1408, 2010.
50. Cotton BA, Faz G, Hatch QM, Radwan ZA, Podbielski J, Wade C, Kozar RA, Holcomb JB: Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma 71 (2): 407–414, 2011.
51. Schochl H, Cotton B, Inaba K, Nienaber U, Fischer H, Voelckel W, Solomon C: FIBTEM provides early prediction of massive transfusion in trauma. Crit Care 15 (6): R265, 2011.
52. Windelov NA, Welling KL, Ostrowski SR, Johansson PI: The prognostic value of thrombelastography in identifying neurosurgical patients with worse prognosis. Blood Coagul Fibrinolysis 22 (5): 416–419, 2011.
53. Cotton BA, Minei KM, Radwan ZA, Matijevic N, Pivalizza E, Podbielski J, Wade CE, Kozar RA, Holcomb JB: Admission rapid thrombelastography predicts development of pulmonary embolism in trauma patients. J Trauma Acute Care Surg 72 (6): 1470–1475, 2012.
54. Kunio NR, Differding JA, Watson KM, Stucke RS, Schreiber MA: Thrombelastography-identified coagulopathy is associated with increased morbidity and mortality after traumatic brain injury. Am J Surg 203 (5): 584–588, 2012.
55. Pezold M, Moore EE, Wohlauer M, Sauaia A, Gonzalez E, Banerjee A, Silliman CC: Viscoelastic clot strength predicts coagulation-related mortality within 15 minutes. Surgery 151 (1): 48–54, 2012.
56. Haas T, Spielmann N, Mauch J, Madjdpour C, Speer O, Schmugge M, Weiss M: Comparison of thromboelastometry (ROTEM(R)) with standard plasmatic coagulation testing in paediatric surgery. Br J Anaesth 108 (1): 36–41, 2012.
57. Haas T, Spielmann N, Mauch J, Speer O, Schmugge M, Weiss M: Reproducibility of thrombelastometry (ROTEM(R)): point-of-care versus hospital laboratory performance. Scand J Clin Lab Invest 72 (4): 313–317, 2012.
58. Vogel AM, Radwan ZA, Cox CS Jr, Cotton BA: Admission rapid thrombelastography delivers real-time actionable data in pediatric trauma. J Pediatr Surg 48 (6): 1371–1376, 2013.
59. Woolley T, Midwinter M, Spencer P, Watts S, Doran C, Kirkman E: Utility of interim ROTEM((R)) values of clot strength, A5 and A10, in predicting final assessment of coagulation status in severely injured battle patients. Injury 44 (5): 593–599, 2013.
60. Ives C, Inaba K, Branco BC, Okoye O, Schochl H, Talving P, Lam L, Shulman I, Nelson J, Demetriades D: Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg 215 (4): 496–502, 2012.
61. Oswald E, Stalzer B, Heitz E, Weiss M, Schmugge M, Strasak A, Innerhofer P, Haas T: Thromboelastometry (ROTEM) in children: age-related reference ranges and correlations with standard coagulation tests. Br J Anaesth 105 (6): 827–835, 2010.
62. Chan KL, Summerhayes RG, Ignjatovic V, Horton SB, Monagle PT: Reference values for kaolin-activated thromboelastography in healthy children. Anesth Analg 105 (6): 1610–1613, 2007.
63. Miller BE, Bailey JM, Mancuso TJ, Weinstein MS, Holbrook GW, Silvey EM, Tosone SR, Levy JH: Functional maturity of the coagulation system in children: an evaluation using thrombelastography. Anesth Analg 84 (4): 745–748, 1997.
64. Halimeh S, Angelis G, Sander A, Edelbusch C, Rott H, Thedieck S, Mesters R, Schlegel N, Nowak-Gottl U: Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents. Klinische Padiatrie 222 (3): 158–163, 2010.
65. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B: Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 42 (5): 857–861, 1997.
66. Monroe DM: Modeling the action of factor VIIa in dilutional coagulopathy. Thromb Res 122 (Suppl 1): S7–S10, 2008.
67. Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, Simanski C, Neugebauer E, Bouillon B, Society AGPotGT: Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 38 (3): 298–304, 2007.
68. Mann KG, Brummel-Ziedins K, Orfeo T, Butenas S: Models of blood coagulation. Blood Cells Mol Dis 36 (2): 108–117, 2006.
69. Kermode JC, Zheng Q, Milner EP: Marked temperature dependence of the platelet calcium signal induced by human von Willebrand factor. Blood 94 (1): 199–207, 1999.
70. Jurkovich GJ, Greiser WB, Luterman A, Curreri PW: Hypothermia in trauma victims: an ominous predictor of survival. J Trauma 27 (9): 1019–1024, 1987.
71. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M: The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma 55 (5): 886–891, 2003.
72. Schochl H, Frietsch T, Pavelka M, Jambor C: Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 67 (1): 125–131, 2009.
73. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, Biffl WL, Burlew CC, Johnson JL, Sauaia A: Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg 252 (3): 434–442, 2010.
74. Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, Pittet JF: Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 255 (2): 379–385, 2012.
75. Chesebro BB, Rahn P, Carles M, Esmon CT, Xu J, Brohi K, Frith D, Pittet JF, Cohen MJ: Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 32 (6): 659–665, 2009.
76. Maegele M, Schochl H, Cohen MJ: An up-date on the coagulopathy of trauma. Shock 41 (Suppl 1): 21–25, 2014.
77. Ostrowski SR, Johansson PI: Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg 73 (1): 60–66, 2012.
78. Duchesne JC, Holcomb JB: Damage control resuscitation: addressing trauma-induced coagulopathy. Br J Hosp Med (Lond) 70 (1): 22–25, 2009.
79. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sorensen B: Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth 101 (6): 769–773, 2008.
80. Ziegler B, Schimke C, Marchet P, Stogermuller B, Schochl H, Solomon C: Severe Pediatric Blunt Trauma–Successful ROTEM-Guided Hemostatic Therapy With Fibrinogen Concentrate and No Administration of Fresh Frozen Plasma or Platelets. Clin Appl Thromb Hemost 19 (4): 453–459, 2013.
81. Schochl H, Nienaber U, Hofer G, Voelckel W, Jambor C, Scharbert G, Kozek-Langenecker S, Solomon C: Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care (Lond) 14 (2): R55, 2010.
82. Kozek-Langenecker S, Sorensen B, Hess JR, Spahn DR: Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care (Lond) 15 (5): R239, 2011.
83. Alten JA, Benner K, Green K, Toole B, Tofil NM, Winkler MK: Pediatric off-label use of recombinant factor VIIa. Pediatrics 123 (3): 1066–1072, 2009.
84. Morenski JD, Tobias JD, Jimenez DF: Recombinant activated factor VII for cerebral injury-induced coagulopathy in pediatric patients. Report of three cases and review of the literature. J Neurosurg 98 (3): 611–616, 2003.
85. Schulman S, Bech Jensen M, Varon D, Keller N, Gitel S, Horoszowski H, Heim M, Martinowitz U: Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 75 (3): 432–436, 1996.
86. Knudson MM, Cohen MJ, Reidy R, Jaeger S, Bacchetti P, Jin C, Wade CE, Holcomb JB: Trauma, transfusions, and use of recombinant factor VIIa: a multicenter case registry report of 380 patients from the Western Trauma Association. J Am Coll Surg 212 (1): 87–95, 2011.
87. Colomina MJ, Diez Lobo A, Garutti I, Gomez-Luque A, Llau JV, Pita E: Perioperative use of prothrombin complex concentrates. Minerva Anestesiologica 78 (3): 358–368, 2012.
88. Fuentes-Garcia D, Hernandez-Palazon J, Sansano-Sanchez T, Acosta-Villegas F: Prothrombin complex concentrate in the treatment of multitransfusion dilutional coagulopathy in a paediatric patient. Br J Anaesth 106 (6): 912–913, 2011.
89. Patanwala AE, Acquisto NM, Erstad BL: Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 45 (7-8): 990–999, 2011.
90. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM, Warfarin Reversal Consensus G: Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Austr 181 (9): 492–497, 2004.
91. Schochl H, Schlimp C, Maegele M: Tranexamic acid, fibrinogen concentrate and prothrombin complex concentrate: data to support prehospital use? Shock 41 (Suppl 1): 44–46, 2014.
92. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, Hunt BJ, Komadina R, Nardi G, Neugebauer E, et al.: Management of bleeding following major trauma: an updated European guideline. Crit Care (Lond) 14 (2): R52, 2010.
93. Pusateri AE, Weiskopf RB, Bebarta V, Butler F, Cestero RF, Chaudry IH, Deal V, Dorlac WC, Gerhardt RT, Given MB, et al.: Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock 39 (2): 121–126, 2013.
94. Tzortzopoulou A, Cepeda MS, Schumann R, Carr DB: Antifibrinolytic agents for reducing blood loss in scoliosis surgery in children. Cochrane Database Syst Rev (3): CD006883, 2008.
95. Giordano R, Palma G, Poli V, Palumbo S, Russolillo V, Cioffi S, Mucerino M, Mannacio VA, Vosa C: Tranexamic acid therapy in pediatric cardiac surgery: a single-center study. Ann Thorac Surg 94 (4): 1302–1306, 2012.
97. Reade MC, Pitt V, Gruen RL: Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock 40 (2): 160–161, 2013.
98. Perkins JG, Cap AP, Spinella PC, Blackbourne LH, Grathwohl KW, Repine TB, Ketchum L, Waterman P, Lee RE, Beekley AC, et al.: An evaluation of the impact of apheresis platelets used in the setting of massively transfused trauma patients. J Trauma 66 (Suppl 4): S77–S84, 2009.
99. Holcomb JB, Wade CE, Trauma Outcomes G, Brasel KJ, Vercruysse G, MacLeod J, Dutton RP, Hess JR, Duchesne JC, McSwain NE, et al.: Defining present blood component transfusion practices in trauma patients: papers from the Trauma Outcomes Group. J Trauma 71 (2 Suppl 3): S315–S317, 2011.
100. Snyder CW, Weinberg JA, McGwin G Jr, Melton SM, George RL, Reiff DA, Cross JM, Hubbard-Brown J, Rue LW 3rd, Kerby JD: The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma 66 (2): 358–362, 2009.
101. Halmin M, Bostrom F, Brattstrom O, Lundahl J, Wikman A, Ostlund A, Edgren G: Effect of plasma-to-RBC ratios in trauma patients: a cohort study with time-dependent data. Crit Care Med 41 (8): 1905–1914, 2013.
102. Ho AM, Dion PW, Yeung JH, Joynt GM, Lee A, Ng CS, Chang A, So FL, Cheung CW: Simulation of survivorship bias in observational studies on plasma to red blood cell ratios in massive transfusion for trauma. Br J Surg 99 (Suppl 1): 132–139, 2012.
103. Magnotti LJ, Zarzaur BL, Fischer PE, Williams FR, Myers AL, Bradburn EH, Fabian TC, Croce MA: Improved survival after hemostatic resuscitation: does the emperor have no clothes? J Trauma 70: 97–102, 2011.
104. Scalea TM, Bochicchio KM, Lumpkins K, Hess JR, Dutton R, Pyle A, Bochicchio GV: Early aggressive use of fresh frozen plasma does not improve outcome in critically injured trauma patients. Ann Surg 248 (4): 578–584, 2008.
105. Sankarankutty A, Nascimento B, Teodoro da Luz L, Rizoli S: TEG(R) and ROTEM(R) in trauma: similar test but different results? World J Emerg Surg 7 (Suppl 1): S3, 2012.
106. Hallet J, Lauzier F, Mailloux O, Trottier V, Archamblault P, Zarychanski R, Turgeon AF: The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit Care Med 41 (12): 2800–2811, 2013.
107. Lustenberger T, Frischknecht A, Bruesch M, Keel MJ: Blood component ratios in massively transfused, blunt trauma patients—a time-dependent covariate analysis. J Trauma 71 (5): 1144–1150, 2011.
108. Wade CE, del Junco DJ, Fox EE, Cotton BA, Cohen MJ, Muskat P, Schreiber MA, Rahbar MH, Sauer RM, Brasel KJ, et al.: Do-not-resuscitate orders in trauma patients may bias mortality-based effect estimates: an evaluation using the PROMMTT study. J Trauma Acute Care Surg 75 (1 Suppl 1): S89–S96, 2013.
109. The University of Texas Health Science Center, Houston. Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2013 Oct 4]. Available from: http://clinicaltrials.gov/show/NCT01545232
NLM Identifier: NCT01545232. Accessed October 4, 2013.
110. Hendrickson JE, Shaz BH, Pereira G, Parker PM, Jessup P, Atwell F, Polstra B, Atkins E, Johnson KK, Bao G, et al.: Implementation of a pediatric trauma massive transfusion protocol: one institution’s experience. Transfusion 52 (6): 1228–1236, 2012.
111. Dehmer JJ, Adamson WT: Massive transfusion and blood product use in the pediatric trauma patient. Semin Pediatr Surg 19 (4): 286–291, 2010.
112. Barcelona SL, Thompson AA, Cote CJ: Intraoperative pediatric blood transfusion therapy: a review of common issues. Part II: transfusion therapy, special considerations, and reduction of allogenic blood transfusions. Paediatr Anaesth 15 (10): 814–830, 2005.
113. Chidester SJ, Williams N, Wang W, Groner JI: A pediatric massive transfusion protocol. J Trauma Acute Care Surg 73 (5): 1273–1277, 2012.
114. Nosanov L, Inaba K, Okoye O, Resnick S, Upperman J, Shulman I, Rhee P, Demetriades D: The impact of blood product ratios in massively transfused pediatric trauma patients. Am J Surg 206 (5): 655–660, 2013.
115. Levi M, Toh CH, Thachil J, Watson HG: Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 145 (1): 24–33, 2009.
116. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, Williamson LM, British Committee for Standards in Haematology BTTF: Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 126 (1): 11–28, 2004.
117. Karam O, Lacroix J, Robitaille N, Rimensberger PC, Tucci M: Association between plasma transfusions and clinical outcome in critically ill children: a prospective observational study. Vox Sang 104 (4): 342–349, 2013.
118. Nienaber U, Innerhofer P, Westermann I, Schochl H, Attal R, Breitkopf R, Maegele M: The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury 42 (7): 697–701, 2011.
119. Ozier Y, Muller JY, Mertes PM, Renaudier P, Aguilon P, Canivet N, Fabrigli P, Rebibo D, Tazerout M, Trophilme C, et al.: Transfusion-related acute lung injury: reports to the French Hemovigilance Network 2007 through 2008. Transfusion 51 (10): 2102–2110, 2011.
120. Fries D: The early use of fibrinogen, prothrombin complex concentrate, and recombinant-activated factor VIIa in massive bleeding. Transfusion 53 (Suppl 1): 91S–95S, 2013.
121. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, Ko TC, Paredes A: Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg 112 (6): 1289–1295, 2011.
122. Kauvar DS, Lefering R, Wade CE: Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 60 (Suppl 6): S3–S11, 2006.
123. Hymel KP, Abshire TC, Luckey DW, Jenny C: Coagulopathy in pediatric abusive head trauma. Pediatrics 99 (3): 371–375, 1997.
124. Chiaretti A, Pezzotti P, Mestrovic J, Piastra M, Polidori G, Storti S, Velardi F, Di Rocco C: The influence of hemocoagulative disorders on the outcome of children with head injury. Pediatr Neurosurg 34 (3): 131–137, 2001.
125. Holmes JF, Goodwin HC, Land C, Kuppermann N: Coagulation testing in pediatric blunt trauma patients. Pediatr Emerg Care 17 (5): 324–328, 2001.
126. Keller MS, Fendya DG, Weber TR: Glasgow Coma Scale predicts coagulopathy in pediatric trauma patients. Semin Pediatr Surg 10 (1): 12–16, 2001.
127. Hollingworth W, Vavilala MS, Jarvik JG, Chaudhry S, Johnston BD, Layman S, Tontisirin N, Muangman SL, Wang MC: The use of repeated head computed tomography in pediatric blunt head trauma: factors predicting new and worsening brain injury. Pediatr Crit Care Med 8 (4): 348–356, 2007.
128. Marton E, Mazzucco M, Nascimben E, Martinuzzi A, Longatti P: Severe head injury in early infancy: analysis of causes and possible predictive factors for outcome. Childs Nerv Syst 23 (8): 873–880, 2007.
129. Affonseca CA, Carvalho LF, Guerra SD, Ferreira AR, Goulart EM: Coagulation disorder in children and adolescents with moderate to severe traumatic brain injury. J Pediatr (Rio J) 83 (3): 274–282, 2007.
130. Melo JR, Di Rocco F, Lemos-Junior LP, Roujeau T, Thelot B, Sainte-Rose C, Meyer P, Zerah M: Defenestration in children younger than 6 years old: mortality predictors in severe head trauma. Childs Nerv Syst 25 (9): 1077–1083, 2009.
131. Swanson CA, Burns JC, Peterson BM: Low plasma D-dimer concentration predicts the absence of traumatic brain injury in children. J Trauma 68 (5): 1072–1077, 2010.
132. Nylund CM, Borgman MA, Holcomb JB, Jenkins D, Spinella PC: Thromboelastography to direct the administration of recombinant activated factor VII in a child with traumatic injury requiring massive transfusion. Pediatr Crit Care Med 10 (2): e22–e26, 2009.
133. Diab YA, Wong EC, Luban NL: Massive transfusion in children and neonates. Br J Haematol 161 (1): 15–26, 2013.
134. Laroche M, Kutcher ME, Huang MC, Cohen MJ, Manley GT: Coagulopathy after traumatic brain injury. Neurosurgery 70 (6): 1334–1345, 2012.
135. Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, Mackway-Jones K, Parr MJ, Rizoli SB, Yukioka T, et al.: The coagulopathy of trauma: a review of mechanisms. J Trauma 65 (4): 748–754, 2008.
136. Bowen DJ: Haemophilia A and haemophilia B: molecular insights. Mol Pathol 55 (2): 127–144, 2002.