Original Article
The Pathophysiology and Management of Acute Traumatic Coagulopathy
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 645-652 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029613516190 cat.sagepub.com
Kaipeng Duan, MD1, Wenkui Yu, MD1, and Ning Li, MD1
Abstract Acute traumatic coagulopathy (ATC) is commonly seen among patients with severe injury and will lead to uncontrolled bleeding diathesis, which is an important contributor to trauma death. During the past 10 years, the understanding of the mechanism causing ATC has changed rapidly. The mechanisms for ATC are complicated. To date, the possible mechanisms include activation of protein C, shedding of endothelial glycocalyx, catecholamine release, platelet dysfunction, primary, and secondary fibrinolysis, with tissue injury and hypoperfusion as the triggers. Classic factors such as dilution, acidosis, and hypothermia can further aggravate the coagulopathy. Inflammation may have a potential effect on the onset and prognosis of ATC. With the aid of diagnostic device, the outcome can be improved through early and customized treatment. Antifibrinolytics such as tranexamic acid has some benefits in patients with bleeding trauma, especially in the early time. This review presents the current understanding of ATC mechanisms and management. Keywords trauma, coagulopathy, mechanism, treatment
Introduction Trauma is still a very common reason for mortality and morbidity.1,2 Trauma-induced hemorrhage accounts for around 40% of all trauma casualties,3 and control of the bleeding is the priority of the management. Systemic inflammatory response syndrome and multiple organ failure are the ensuing complications without timely or proper treatment.4 In the past, traumatic coagulopathy was considered to be the result of acidosis, hypothermia, dilution, and other conditions.5 In the recent years, robust researchers have emerged to study the pathophysiology and treatment of acute traumatic coagulopathy (ATC). Much attention has been thrown into the protein C (PC) activation, shedding of glycocalyx, catecholamine, and inflammation. In a large multicenter retrospective study, ATC was closely related to tissue damage and systemic hypoperfusion and that was corroborated by a rat model.6 Also, some new devices have been introduced for the early diagnosis of ATC,7 which facilitated the management of the coagulopathy and reduced the usage of blood product. In this article, we reviewed the possible mechanisms for the development of ATC as well as the current treatment.
only were excluded. Specific search terms included ‘‘acute traumatic coagulopathy,’’ ‘‘ATC,’’ ‘‘trauma induced coagulopathy,’’ ‘‘TIC,’’ ‘‘hemorrhagic shock coagulation,’’ ‘‘trauma disseminated intravascular coagulation’’ ‘‘mechanism trauma coagulopathy,’’ and ‘‘treatment trauma coagulopathy.’’
The Characteristics and Definition of ATC Acute traumatic coagulopathy was first described by Brohi et al in 2003.8 It is characterized by dysfunction of the coagulation, anticoagulation, and fibrinolysis system, mainly featuring a hypocoagulant state, with a prolonged prothrombin time (PT), active partial thromboplastin time (aPTT), and a relative sparing of platelet and fibrinogen in the very early phase (less than 30 minutes).9 Patients with ATC often result in increased transfusion requirements, incidence of organ dysfunction, critical care unit stay, and mortality.10 In particular, ATC is often presented with a functional reduction in clot strength with a smaller change in clotting times.11 Increased bleeding in the early stage after trauma switch into a hypercoagulable state with a high risk of thrombosis in the following days is the main clinical
Methods A literature search (PubMed) was performed to locate relevant articles and studies pertaining to the mechanism and treatment of ATC. The reference lists of relevant articles were then hand searched for other references. Relevant articles also underwent a ‘‘cited reference search’’ (ISI Web of Science). Studies that were not in English language or published in abstract form
1
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
Corresponding Author: Ning Li, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China. Email: [email protected]
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
646
Clinical and Applied Thrombosis/Hemostasis 21(7)
trajectory.5,12,13 The dynamic process indicates the complex and variable features of the disease. Whether ATC is a new disease or just a disease entity similar or equal to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype is under intense discussion.14,15 Gando et al have proposed the 2 diseases to be the same one due to the similar characteristics, laboratory data, time courses, and prognosis.14 In a prospective study, Yanagida et al have shown that almost all patients with ATC overlapped patients with DIC, and the changes in the measured variables in patients with ATC coincided with those in patients with DIC.16 However, 2 recent studies focusing on the coagulation status after trauma failed to find convincing evidence to support the unification of the 2 concepts.17,18 Despite the higher Injury Severity Score, transfusion requirements, and mortality, none of these patients with ATC met the criteria for overt DIC. According to the general concepts, ATC is hypocoagulable both inside and outside the vessels, whereas DIC is hypercoagulable inside the vessels and hypocoagulable outside the vessels.14 So a clear distinction of the properties of blood between the inside and the outside of vessels may provide some evidence to solve the puzzle. At present, there are no prospectively validated diagnostic criteria for ATC. Previously, PT test (Quick value) 100 109/L in the central nervous system injury.13,65 Several retrospective studies have shown improved results with high platelet–RBC ratio (eg, >1:5 or >1:2),65 but others have found that platelet transfusion may not be essential.11
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
Duan et al
649
The lack of convincing evidence prompts further studies on the platelet administration in patients with ATC.
Fibrinogen Administration Although fibrinogen has shown reduction to some extent in several animal models of ATC or retrospective studies,68,69 it is still controversial whether fibrinogen has declined to the critical level for adequate hemostasis.11,65 One retrospective study of 252 combat-related patients who received MT has shown a better result in high concentrations fibrinogen group (0.2 g per unit of PRBC).70 Restoration of fibrinogen could mitigate coagulation disorder and reduce blood loss in the animal model, but the difference was not significant between the high- and the low-dose groups on blood loss.69 Two observational studies have demonstrated improved outcome or reduced transfusion requirements in the fibrinogen-treated group,71,72 but the evidence is low, considering the criteria of logistic or screening test difference. Most researchers have suggested supplementation of fibrinogen concentrate (3-4 g) or cryoprecipitate (50 mg/kg) to ensure that fibrinogen level was more than 1 g/L65 or increase fibrin-based clot strength clot firmness at 10 minutes (FIBTEM CA10) to 10 to 12 mm.13
Recombinant Activated Factor VII and Tranexamic Acid Recombinant activated factor VII (rFVIIa) is another resort to treat trauma-induced coagulopathy, which was first reported in 1999.60 Incipiently, rFVIIa was approved for the treatment of bleeding in patients with hemophilia A or B. Numerous anecdotal reports have described the efficiency of rFVIIa in the treatment of ATC,60 and an off-label usage can be commonly seen (4% or even higher).73 In a review of 13 trials comprising 1938 patients, Stanworth demonstrated reduced blood requirement in patients receiving rFVIIa (relative risk [RR] ¼ 0.85) with a elevated thromboembolic event (RR ¼1 .25).74 D’Angelo also reported 2 doses of rFVIIa administration for patients with active ongoing hemorrhage with a high dose (100mg/kg, with shock) and low dose (50mg/kg, without shock), both resulting in favorable endings.60 However, recently 2 large RCTs have shown few benefits and modest reduction in blood usage after rFVIIa application,75,76 thus leading us to reconsider the efficiency and risks of the miracle drug. After analyzing data from 35 RCTs containing 4468 patients on the off-label basis, Levi et al found increased arterial thromboembolic events in patients receiving rFVIIa (5.5% vs 3.2%) than placebos, especially high among the elderly patients (>65 or 75 years), although the rates of venous thromboembolic events are comparable.77 Reaching its peak in 2006, the usage of rFVIIa in the US military is dropping in recent years.78 An ‘‘old’’ antifibrinolytic drug, tranexamic acid (TXA), is now highly recommended for the early hemorrhage control after sever trauma. By blocking the lysine-binding sites on plasminogen, TXA can reduce blood transfusion as well as blood loss without obvious complications in patients undergoing elective surgery.79 Similarly, in patients with trauma or at risk of substantial
bleeding, a multicenter trial evaluating 20 211 patients, CRASH-2, has shown reduced bleeding-caused mortality (4.9% vs 5.7%, RR ¼ 0.85) in the TXA group treated with 2 g TXA within 8 hours.80 In the following subgroup analysis,81 the importance of early administration of TXA was emphasized. Treatment within 3 hours, particularly less than 1 hour, can significantly reduced the risk of death due to bleeding (RR ¼ 0.68 within 1 hour, 0.79 for 1-3 hours). Of note, for the late administration (>3 hours) the harm of TXA would outweigh the benefits. In concert with the results of CRASH-2, a big retrospective observational study including 896 soldiers with combat injury, namely, Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study,82 showed lower mortality in the TXA group than in the non-TXA group (17.4% vs 23.9%). The benefit was even greater among patients who need MT. In the CRASH-2 study, however, the correlative laboratory data have not been collected, limiting the insight of the pathophysiology of TXA effect. The exact mechanism underlying the phenomenon is unclear, probably repressing fibrinolysis in the early stage and reducing uncontrolled clot factor consumption, thus lowering transfusion requirements. In fact, the TXA group showed no increase in vascular occlusive events, including pulmonary embolism and deep vein thrombosis, even after attaining a reduction in myocardial infarction (P ¼ .035). The safety maybe was related to the dose and regime, which present the topic for future investigation. Anne Godier has innovatively hypothesized that TXA has an antithrombotic effect, via inhibition of the inflammatory effects of plasmin, on platelet and factor V and VIII.83 Downregulation of inflammatory response may be achieved,84 for a broad spectrum of proinflammatory responses can be induced by plasmin by binding and activating monocytes, neutrophils, platelets, and endothelial cells via a cytokines-releasing or gene transcription way.52 In the traditional view, inflammation induced by trauma or other chronic disease could activate coagulation, reducing blood loss or even increasing the risk of thrombosis. If inflammation of ATC has been compressed, the stimulator for coagulation could be weakened in some degree. So the importance of inflammation in the ATC, especially on TXA administration, is of a new field worthy of deep exploration. However, the potential side effect of TXA, such as thrombosis, should be noted, since the coagulant state could change into hypercoagulation in the late phase, and several cases of postoperative convulsive seizures have been reported after cardiac surgery using TXA, referring to the structural similarity between TXA and g-aminobutyric acid.52 Other antifibrinolytic agents, such as 6-aminocaproic acid, aprotinin and neutrophil elastase inhibitor, may have a positive role in this early situation but need further studies.46
Summary Acute traumatic coagulopathy is an early and complicated hemostatic derangement after trauma and has its unique dynamic course. Trauma injury and systemic hypoperfusion are the 2 possible initial drivers. The underlying mechanisms include
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
650
Clinical and Applied Thrombosis/Hemostasis 21(7)
activation of protein C, shedding of endothelial glycocalyx, catecholamine release, inflammation, platelet dysfunction, primary, and secondary fibrinolysis. Treatments should be based on the condition of patients with trauma. Early identification and treatment are essential for a positive outcome. Further studies are needed for both the mechanism and the treatment of ATC. Authors’ Note KD contributed to the conception and design of the study, literature research, and article drafting. WY and NL contributed to literature research and language assistance. All authors approved the final version that was submitted.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This article was supported by Grant for 12th five-year plan major project (AWS11J03), Grant for 12th five-year plan major project (WS12J001), Jiangsu Province’s Key Medical Talent Program (RC2011128).
References 1. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis from the German trauma registry on 8724 patients. Injury. 2007;38(3):298-304. 2. Krug EG, Sharma GK, Lozano R. The global burden of injuries. Am J Public Health. 2000;90(4):523-526. 3. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38(2):185-193. 4. Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA, Lezotte DC. Early predictors of postinjury multiple organ failure. Arch Surg. 1994;129(1):39-45. 5. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65(4):748-754. 6. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost. 2010;8(9):1919-1925. 7. Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39(12):2652-2658. 8. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127-1130. 9. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26-32. 10. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007; 13(6):680-685. 11. Davenport R. Pathogenesis of acute traumatic coagulopathy. Transfusion. 2013;53 suppl 1:23S-27S. 12. Gando S. Acute coagulopathy of trauma shock and coagulopathy of trauma: a rebuttal. you are now going down the wrong path. J Trauma. 2009;67(2):381-383.
13. Paul TE, J Damian PG, Sandy LW. Widder trauma-related coagulopathy—current concepts. Oncol Hematol Rev. 2012;8(2):123-128. 14. Gando S, Wada H, Kim HK, et al. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/ acute coagulopathy of trauma-shock. J Thromb Haemost. 2012; 10(12):2593-2595. 15. Gando S, Wada H, Thachil J, Scientific, Standardization Committee on DICotISoT, Haemostasis. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of traumashock (COT/ACOTS). J Thromb Haemost. 2013;11(5):826-835. 16. Yanagida Y, Gando S, Sawamura A, et al. Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. Surgery. 2013;154(1):48-57. 17. Johansson PI, Sorensen AM, Perner A, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? an observational study. Crit Care. 2011;15(6):R272. 18. Rizoli S, Nascimento B Jr, Key N, et al. Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma. 2011;71(5 suppl 1):S441-S447. 19. Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009;17:45. 20. 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. 2007; 245(5):812-818. 21. Cohen MJ, Call M, Nelson M, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255(2):379-385. 22. Chesebro BB, Rahn P, Carles M, et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock. 2009;32(6):659-665. 23. Esmon CT, Ding W, Yasuhiro K, et al. The protein C pathway: new insights. Thromb Haemost. 1997;78(1):70-74. 24. Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38(2 suppl):S26-S34. 25. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101(10):3765-3777. 26. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch. 2000;440(5):653-666. 27. Rehm M, Zahler S, Lotsch M, et al. Endothelial glycocalyx as an additional barrier determining extravasation of 6% hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed. Anesthesiology. 2004;100(5):1211-1123. 28. Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJ, Stroes ES. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16(5):507-511. 29. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295. 30. Rehm M, Bruegger D, Christ F, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
Duan et al
31.
32.
33.
34.
35.
36.
37.
38.
39. 40.
41.
42.
43.
44.
45. 46.
47.
651
global and regional ischemia. Circulation. 2007;116(17): 1896-1906. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194-200. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses. 2010;75(6):564-567. von Kanel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol. 2000; 65(6):357-369. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64(5):1211-1217. Martini WZ, Chinkes DL, Sondeen J, Dubick MA. Effects of hemorrhage and lactated Ringer’s resuscitation on coagulation and fibrinogen metabolism in swine. Shock. 2006;26(4): 396-401. Martini WZ, Chinkes DL, Pusateri AE, et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab. 2005;289(5):E930-E934. Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism. 2007;56(2): 214-221. Martini WZ. Fibrinogen metabolic responses to trauma. Scand J Trauma Resusc Emerg Med. 2009;17:2. Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11(2):307-314. Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. 1996;88(6):2093-100. Bajzar L, Jain N, Wang P, Walker JB. Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis. Crit Care Med. 2004;32(5 suppl):S320-S324. Ohlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost. 2005;3(5):976-982. Sawamura A, Hayakawa M, Gando S, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124(5): 608-613. Gando S. Disseminated intravascular coagulation in trauma patients. Semi Throm Hemost. 2001;27(06):585-592. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg. 2011;254(1):10-19. Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis. 2003;16(1-2):17-20.
48. Adelaida L. Ruseva, Dimitrova AA. A new understanding of the coagulation process - the cell-based model. J Biomed Clin Res. 2011;4(1):17-22. 49. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest. 1999;103(6):879-887. 50. Adam F, Verbeuren TJ, Fauchere JL, Guillin MC, Jandrot-Perrus M. Thrombin-induced platelet PAR4 activation: role of glycoprotein Ib and ADP. J Throm Haemost. 2003;1(4):798-804. 51. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. Journal Trauma Acute Care Surg. 2012;73(1):13-19. 52. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet. 2010;376(9734):3-4. 53. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131(4):417-430. 54. Esmon CT. Inflammation and thrombosis. J Thromb Haemost. 2003;1(7):1343-1348. 55. Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR. Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26(5):430-437. 56. Glaros T, Larsen M, Li L. Macrophages and fibroblasts during inflammation, tissue damage and organ injury. Front Biosci (Landmark Ed). 2009;14:3988-3993. 57. Farkash U, Lynn M, Scope A, et al. Does prehospital fluid administration impact core body temperature and coagulation functions in combat casualties? Injury. 2002;33(2):103-110. 58. Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma. 2009;67(1):202-208. 59. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58(5):1002-1009. 60. D’Angelo MR, Dutton RP. Management of trauma-induced coagulopathy: trends and practices. AANA J. 2010;78(1):35-40. 61. Shaz BH, Winkler AM, James AB, Hillyer CD, MacLeod JB. Pathophysiology of early trauma-induced coagulopathy: emerging evidence for hemodilution and coagulation factor depletion. J Trauma. 2011;70(6):1401-1407. 62. Holcomb JB. Damage control resuscitation. J Trauma. 2007;62(6 suppl):S36-S37. 63. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 64. Doran CM, Doran CA, Woolley T, et al. Targeted resuscitation improves coagulation and outcome. J Trauma Acute Care Surg. 2012;72(4):835-843. 65. Davenport R, Khan S. Management of major trauma haemorrhage: treatment priorities and controversies. Br J Haematol. 2011;155(5): 537-548. 66. Stanworth SJ, Hyde CJ, Murphy MF. Evidence for indications of fresh frozen plasma. Transfus Clin Biol. 2007;14(6):551-556. 67. Frith D, Davenport R, Brohi K. Acute traumatic coagulopathy. Curr Opin Anaesthesiol. 2012;25(2):229-234. 68. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
652
69.
70.
71.
72.
73. 74.
75.
76.
Clinical and Applied Thrombosis/Hemostasis 21(7) association with patient outcomes. J Thromb Haemost. 2012; 10(7):1342-1351. Grottke O, Braunschweig T, Henzler D, Coburn M, Tolba R, Rossaint R. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care. 2010;14(2):R62. Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma. 2008;64(2 suppl):S79-S85. Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67(1):125-131. Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14(2):R55. Aledort LM. Off-label use of recombinant activated factor VII– safe or not safe? N Engl J Med. 2010;363(19):1853-1854. Stanworth SJ, Birchall J, Doree CJ, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Datab Syst Rev. 2007;(2):CD005011. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, doubleblind clinical trials. J Trauma. 2005;59(1):8-15. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69(3):489-500.
77. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791-1800. 78. Pidcoke HF, Aden JK, Mora AG, et al. Ten-year analysis of transfusion in operation iraqi freedom and operation enduring freedom: increased plasma and platelet use correlates with improved survival. J Trauma Acute Care Surg. 2012;73(6 suppl 5):S445-S452. 79. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007;(4):CD001886. 80. collaborators C-t. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebocontrolled trial. Lancet. 2010;376(9734):23-32. 81. collaborators C-, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-101, 101 e1-e2. 82. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147(2): 113-119. 83. Godier A, Roberts I, Hunt BJ. Tranexamic acid: less bleeding and less thrombosis? Crit Care. 2012;16(3):135. 84. Jimenez JJ, Iribarren JL, Lorente L, et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care. 2007; 11(6):R117.
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
The Pathophysiology and Management of Acute Traumatic Coagulopathy
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 645-652 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029613516190 cat.sagepub.com
Kaipeng Duan, MD1, Wenkui Yu, MD1, and Ning Li, MD1
Abstract Acute traumatic coagulopathy (ATC) is commonly seen among patients with severe injury and will lead to uncontrolled bleeding diathesis, which is an important contributor to trauma death. During the past 10 years, the understanding of the mechanism causing ATC has changed rapidly. The mechanisms for ATC are complicated. To date, the possible mechanisms include activation of protein C, shedding of endothelial glycocalyx, catecholamine release, platelet dysfunction, primary, and secondary fibrinolysis, with tissue injury and hypoperfusion as the triggers. Classic factors such as dilution, acidosis, and hypothermia can further aggravate the coagulopathy. Inflammation may have a potential effect on the onset and prognosis of ATC. With the aid of diagnostic device, the outcome can be improved through early and customized treatment. Antifibrinolytics such as tranexamic acid has some benefits in patients with bleeding trauma, especially in the early time. This review presents the current understanding of ATC mechanisms and management. Keywords trauma, coagulopathy, mechanism, treatment
Introduction Trauma is still a very common reason for mortality and morbidity.1,2 Trauma-induced hemorrhage accounts for around 40% of all trauma casualties,3 and control of the bleeding is the priority of the management. Systemic inflammatory response syndrome and multiple organ failure are the ensuing complications without timely or proper treatment.4 In the past, traumatic coagulopathy was considered to be the result of acidosis, hypothermia, dilution, and other conditions.5 In the recent years, robust researchers have emerged to study the pathophysiology and treatment of acute traumatic coagulopathy (ATC). Much attention has been thrown into the protein C (PC) activation, shedding of glycocalyx, catecholamine, and inflammation. In a large multicenter retrospective study, ATC was closely related to tissue damage and systemic hypoperfusion and that was corroborated by a rat model.6 Also, some new devices have been introduced for the early diagnosis of ATC,7 which facilitated the management of the coagulopathy and reduced the usage of blood product. In this article, we reviewed the possible mechanisms for the development of ATC as well as the current treatment.
only were excluded. Specific search terms included ‘‘acute traumatic coagulopathy,’’ ‘‘ATC,’’ ‘‘trauma induced coagulopathy,’’ ‘‘TIC,’’ ‘‘hemorrhagic shock coagulation,’’ ‘‘trauma disseminated intravascular coagulation’’ ‘‘mechanism trauma coagulopathy,’’ and ‘‘treatment trauma coagulopathy.’’
The Characteristics and Definition of ATC Acute traumatic coagulopathy was first described by Brohi et al in 2003.8 It is characterized by dysfunction of the coagulation, anticoagulation, and fibrinolysis system, mainly featuring a hypocoagulant state, with a prolonged prothrombin time (PT), active partial thromboplastin time (aPTT), and a relative sparing of platelet and fibrinogen in the very early phase (less than 30 minutes).9 Patients with ATC often result in increased transfusion requirements, incidence of organ dysfunction, critical care unit stay, and mortality.10 In particular, ATC is often presented with a functional reduction in clot strength with a smaller change in clotting times.11 Increased bleeding in the early stage after trauma switch into a hypercoagulable state with a high risk of thrombosis in the following days is the main clinical
Methods A literature search (PubMed) was performed to locate relevant articles and studies pertaining to the mechanism and treatment of ATC. The reference lists of relevant articles were then hand searched for other references. Relevant articles also underwent a ‘‘cited reference search’’ (ISI Web of Science). Studies that were not in English language or published in abstract form
1
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
Corresponding Author: Ning Li, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China. Email: [email protected]
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
646
Clinical and Applied Thrombosis/Hemostasis 21(7)
trajectory.5,12,13 The dynamic process indicates the complex and variable features of the disease. Whether ATC is a new disease or just a disease entity similar or equal to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype is under intense discussion.14,15 Gando et al have proposed the 2 diseases to be the same one due to the similar characteristics, laboratory data, time courses, and prognosis.14 In a prospective study, Yanagida et al have shown that almost all patients with ATC overlapped patients with DIC, and the changes in the measured variables in patients with ATC coincided with those in patients with DIC.16 However, 2 recent studies focusing on the coagulation status after trauma failed to find convincing evidence to support the unification of the 2 concepts.17,18 Despite the higher Injury Severity Score, transfusion requirements, and mortality, none of these patients with ATC met the criteria for overt DIC. According to the general concepts, ATC is hypocoagulable both inside and outside the vessels, whereas DIC is hypercoagulable inside the vessels and hypocoagulable outside the vessels.14 So a clear distinction of the properties of blood between the inside and the outside of vessels may provide some evidence to solve the puzzle. At present, there are no prospectively validated diagnostic criteria for ATC. Previously, PT test (Quick value) 100 109/L in the central nervous system injury.13,65 Several retrospective studies have shown improved results with high platelet–RBC ratio (eg, >1:5 or >1:2),65 but others have found that platelet transfusion may not be essential.11
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
Duan et al
649
The lack of convincing evidence prompts further studies on the platelet administration in patients with ATC.
Fibrinogen Administration Although fibrinogen has shown reduction to some extent in several animal models of ATC or retrospective studies,68,69 it is still controversial whether fibrinogen has declined to the critical level for adequate hemostasis.11,65 One retrospective study of 252 combat-related patients who received MT has shown a better result in high concentrations fibrinogen group (0.2 g per unit of PRBC).70 Restoration of fibrinogen could mitigate coagulation disorder and reduce blood loss in the animal model, but the difference was not significant between the high- and the low-dose groups on blood loss.69 Two observational studies have demonstrated improved outcome or reduced transfusion requirements in the fibrinogen-treated group,71,72 but the evidence is low, considering the criteria of logistic or screening test difference. Most researchers have suggested supplementation of fibrinogen concentrate (3-4 g) or cryoprecipitate (50 mg/kg) to ensure that fibrinogen level was more than 1 g/L65 or increase fibrin-based clot strength clot firmness at 10 minutes (FIBTEM CA10) to 10 to 12 mm.13
Recombinant Activated Factor VII and Tranexamic Acid Recombinant activated factor VII (rFVIIa) is another resort to treat trauma-induced coagulopathy, which was first reported in 1999.60 Incipiently, rFVIIa was approved for the treatment of bleeding in patients with hemophilia A or B. Numerous anecdotal reports have described the efficiency of rFVIIa in the treatment of ATC,60 and an off-label usage can be commonly seen (4% or even higher).73 In a review of 13 trials comprising 1938 patients, Stanworth demonstrated reduced blood requirement in patients receiving rFVIIa (relative risk [RR] ¼ 0.85) with a elevated thromboembolic event (RR ¼1 .25).74 D’Angelo also reported 2 doses of rFVIIa administration for patients with active ongoing hemorrhage with a high dose (100mg/kg, with shock) and low dose (50mg/kg, without shock), both resulting in favorable endings.60 However, recently 2 large RCTs have shown few benefits and modest reduction in blood usage after rFVIIa application,75,76 thus leading us to reconsider the efficiency and risks of the miracle drug. After analyzing data from 35 RCTs containing 4468 patients on the off-label basis, Levi et al found increased arterial thromboembolic events in patients receiving rFVIIa (5.5% vs 3.2%) than placebos, especially high among the elderly patients (>65 or 75 years), although the rates of venous thromboembolic events are comparable.77 Reaching its peak in 2006, the usage of rFVIIa in the US military is dropping in recent years.78 An ‘‘old’’ antifibrinolytic drug, tranexamic acid (TXA), is now highly recommended for the early hemorrhage control after sever trauma. By blocking the lysine-binding sites on plasminogen, TXA can reduce blood transfusion as well as blood loss without obvious complications in patients undergoing elective surgery.79 Similarly, in patients with trauma or at risk of substantial
bleeding, a multicenter trial evaluating 20 211 patients, CRASH-2, has shown reduced bleeding-caused mortality (4.9% vs 5.7%, RR ¼ 0.85) in the TXA group treated with 2 g TXA within 8 hours.80 In the following subgroup analysis,81 the importance of early administration of TXA was emphasized. Treatment within 3 hours, particularly less than 1 hour, can significantly reduced the risk of death due to bleeding (RR ¼ 0.68 within 1 hour, 0.79 for 1-3 hours). Of note, for the late administration (>3 hours) the harm of TXA would outweigh the benefits. In concert with the results of CRASH-2, a big retrospective observational study including 896 soldiers with combat injury, namely, Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study,82 showed lower mortality in the TXA group than in the non-TXA group (17.4% vs 23.9%). The benefit was even greater among patients who need MT. In the CRASH-2 study, however, the correlative laboratory data have not been collected, limiting the insight of the pathophysiology of TXA effect. The exact mechanism underlying the phenomenon is unclear, probably repressing fibrinolysis in the early stage and reducing uncontrolled clot factor consumption, thus lowering transfusion requirements. In fact, the TXA group showed no increase in vascular occlusive events, including pulmonary embolism and deep vein thrombosis, even after attaining a reduction in myocardial infarction (P ¼ .035). The safety maybe was related to the dose and regime, which present the topic for future investigation. Anne Godier has innovatively hypothesized that TXA has an antithrombotic effect, via inhibition of the inflammatory effects of plasmin, on platelet and factor V and VIII.83 Downregulation of inflammatory response may be achieved,84 for a broad spectrum of proinflammatory responses can be induced by plasmin by binding and activating monocytes, neutrophils, platelets, and endothelial cells via a cytokines-releasing or gene transcription way.52 In the traditional view, inflammation induced by trauma or other chronic disease could activate coagulation, reducing blood loss or even increasing the risk of thrombosis. If inflammation of ATC has been compressed, the stimulator for coagulation could be weakened in some degree. So the importance of inflammation in the ATC, especially on TXA administration, is of a new field worthy of deep exploration. However, the potential side effect of TXA, such as thrombosis, should be noted, since the coagulant state could change into hypercoagulation in the late phase, and several cases of postoperative convulsive seizures have been reported after cardiac surgery using TXA, referring to the structural similarity between TXA and g-aminobutyric acid.52 Other antifibrinolytic agents, such as 6-aminocaproic acid, aprotinin and neutrophil elastase inhibitor, may have a positive role in this early situation but need further studies.46
Summary Acute traumatic coagulopathy is an early and complicated hemostatic derangement after trauma and has its unique dynamic course. Trauma injury and systemic hypoperfusion are the 2 possible initial drivers. The underlying mechanisms include
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
650
Clinical and Applied Thrombosis/Hemostasis 21(7)
activation of protein C, shedding of endothelial glycocalyx, catecholamine release, inflammation, platelet dysfunction, primary, and secondary fibrinolysis. Treatments should be based on the condition of patients with trauma. Early identification and treatment are essential for a positive outcome. Further studies are needed for both the mechanism and the treatment of ATC. Authors’ Note KD contributed to the conception and design of the study, literature research, and article drafting. WY and NL contributed to literature research and language assistance. All authors approved the final version that was submitted.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This article was supported by Grant for 12th five-year plan major project (AWS11J03), Grant for 12th five-year plan major project (WS12J001), Jiangsu Province’s Key Medical Talent Program (RC2011128).
References 1. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis from the German trauma registry on 8724 patients. Injury. 2007;38(3):298-304. 2. Krug EG, Sharma GK, Lozano R. The global burden of injuries. Am J Public Health. 2000;90(4):523-526. 3. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38(2):185-193. 4. Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA, Lezotte DC. Early predictors of postinjury multiple organ failure. Arch Surg. 1994;129(1):39-45. 5. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65(4):748-754. 6. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost. 2010;8(9):1919-1925. 7. Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39(12):2652-2658. 8. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127-1130. 9. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26-32. 10. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007; 13(6):680-685. 11. Davenport R. Pathogenesis of acute traumatic coagulopathy. Transfusion. 2013;53 suppl 1:23S-27S. 12. Gando S. Acute coagulopathy of trauma shock and coagulopathy of trauma: a rebuttal. you are now going down the wrong path. J Trauma. 2009;67(2):381-383.
13. Paul TE, J Damian PG, Sandy LW. Widder trauma-related coagulopathy—current concepts. Oncol Hematol Rev. 2012;8(2):123-128. 14. Gando S, Wada H, Kim HK, et al. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/ acute coagulopathy of trauma-shock. J Thromb Haemost. 2012; 10(12):2593-2595. 15. Gando S, Wada H, Thachil J, Scientific, Standardization Committee on DICotISoT, Haemostasis. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of traumashock (COT/ACOTS). J Thromb Haemost. 2013;11(5):826-835. 16. Yanagida Y, Gando S, Sawamura A, et al. Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. Surgery. 2013;154(1):48-57. 17. Johansson PI, Sorensen AM, Perner A, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? an observational study. Crit Care. 2011;15(6):R272. 18. Rizoli S, Nascimento B Jr, Key N, et al. Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma. 2011;71(5 suppl 1):S441-S447. 19. Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009;17:45. 20. 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. 2007; 245(5):812-818. 21. Cohen MJ, Call M, Nelson M, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255(2):379-385. 22. Chesebro BB, Rahn P, Carles M, et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock. 2009;32(6):659-665. 23. Esmon CT, Ding W, Yasuhiro K, et al. The protein C pathway: new insights. Thromb Haemost. 1997;78(1):70-74. 24. Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38(2 suppl):S26-S34. 25. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101(10):3765-3777. 26. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch. 2000;440(5):653-666. 27. Rehm M, Zahler S, Lotsch M, et al. Endothelial glycocalyx as an additional barrier determining extravasation of 6% hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed. Anesthesiology. 2004;100(5):1211-1123. 28. Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJ, Stroes ES. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16(5):507-511. 29. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295. 30. Rehm M, Bruegger D, Christ F, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
Duan et al
31.
32.
33.
34.
35.
36.
37.
38.
39. 40.
41.
42.
43.
44.
45. 46.
47.
651
global and regional ischemia. Circulation. 2007;116(17): 1896-1906. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194-200. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses. 2010;75(6):564-567. von Kanel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol. 2000; 65(6):357-369. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64(5):1211-1217. Martini WZ, Chinkes DL, Sondeen J, Dubick MA. Effects of hemorrhage and lactated Ringer’s resuscitation on coagulation and fibrinogen metabolism in swine. Shock. 2006;26(4): 396-401. Martini WZ, Chinkes DL, Pusateri AE, et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab. 2005;289(5):E930-E934. Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism. 2007;56(2): 214-221. Martini WZ. Fibrinogen metabolic responses to trauma. Scand J Trauma Resusc Emerg Med. 2009;17:2. Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11(2):307-314. Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. 1996;88(6):2093-100. Bajzar L, Jain N, Wang P, Walker JB. Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis. Crit Care Med. 2004;32(5 suppl):S320-S324. Ohlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost. 2005;3(5):976-982. Sawamura A, Hayakawa M, Gando S, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124(5): 608-613. Gando S. Disseminated intravascular coagulation in trauma patients. Semi Throm Hemost. 2001;27(06):585-592. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg. 2011;254(1):10-19. Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis. 2003;16(1-2):17-20.
48. Adelaida L. Ruseva, Dimitrova AA. A new understanding of the coagulation process - the cell-based model. J Biomed Clin Res. 2011;4(1):17-22. 49. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest. 1999;103(6):879-887. 50. Adam F, Verbeuren TJ, Fauchere JL, Guillin MC, Jandrot-Perrus M. Thrombin-induced platelet PAR4 activation: role of glycoprotein Ib and ADP. J Throm Haemost. 2003;1(4):798-804. 51. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. Journal Trauma Acute Care Surg. 2012;73(1):13-19. 52. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet. 2010;376(9734):3-4. 53. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131(4):417-430. 54. Esmon CT. Inflammation and thrombosis. J Thromb Haemost. 2003;1(7):1343-1348. 55. Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR. Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26(5):430-437. 56. Glaros T, Larsen M, Li L. Macrophages and fibroblasts during inflammation, tissue damage and organ injury. Front Biosci (Landmark Ed). 2009;14:3988-3993. 57. Farkash U, Lynn M, Scope A, et al. Does prehospital fluid administration impact core body temperature and coagulation functions in combat casualties? Injury. 2002;33(2):103-110. 58. Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma. 2009;67(1):202-208. 59. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58(5):1002-1009. 60. D’Angelo MR, Dutton RP. Management of trauma-induced coagulopathy: trends and practices. AANA J. 2010;78(1):35-40. 61. Shaz BH, Winkler AM, James AB, Hillyer CD, MacLeod JB. Pathophysiology of early trauma-induced coagulopathy: emerging evidence for hemodilution and coagulation factor depletion. J Trauma. 2011;70(6):1401-1407. 62. Holcomb JB. Damage control resuscitation. J Trauma. 2007;62(6 suppl):S36-S37. 63. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 64. Doran CM, Doran CA, Woolley T, et al. Targeted resuscitation improves coagulation and outcome. J Trauma Acute Care Surg. 2012;72(4):835-843. 65. Davenport R, Khan S. Management of major trauma haemorrhage: treatment priorities and controversies. Br J Haematol. 2011;155(5): 537-548. 66. Stanworth SJ, Hyde CJ, Murphy MF. Evidence for indications of fresh frozen plasma. Transfus Clin Biol. 2007;14(6):551-556. 67. Frith D, Davenport R, Brohi K. Acute traumatic coagulopathy. Curr Opin Anaesthesiol. 2012;25(2):229-234. 68. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
652
69.
70.
71.
72.
73. 74.
75.
76.
Clinical and Applied Thrombosis/Hemostasis 21(7) association with patient outcomes. J Thromb Haemost. 2012; 10(7):1342-1351. Grottke O, Braunschweig T, Henzler D, Coburn M, Tolba R, Rossaint R. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care. 2010;14(2):R62. Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma. 2008;64(2 suppl):S79-S85. Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67(1):125-131. Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14(2):R55. Aledort LM. Off-label use of recombinant activated factor VII– safe or not safe? N Engl J Med. 2010;363(19):1853-1854. Stanworth SJ, Birchall J, Doree CJ, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Datab Syst Rev. 2007;(2):CD005011. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, doubleblind clinical trials. J Trauma. 2005;59(1):8-15. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69(3):489-500.
77. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791-1800. 78. Pidcoke HF, Aden JK, Mora AG, et al. Ten-year analysis of transfusion in operation iraqi freedom and operation enduring freedom: increased plasma and platelet use correlates with improved survival. J Trauma Acute Care Surg. 2012;73(6 suppl 5):S445-S452. 79. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007;(4):CD001886. 80. collaborators C-t. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebocontrolled trial. Lancet. 2010;376(9734):23-32. 81. collaborators C-, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-101, 101 e1-e2. 82. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147(2): 113-119. 83. Godier A, Roberts I, Hunt BJ. Tranexamic acid: less bleeding and less thrombosis? Crit Care. 2012;16(3):135. 84. Jimenez JJ, Iribarren JL, Lorente L, et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care. 2007; 11(6):R117.
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 28, 2015
