Pathophysiology of Trauma-Induced Coagulopathy and Management of Critical Bleeding Requiring Massive Transfusion

Abstract

Trauma-induced coagulopathy is caused by multiple factors, such as anemia, hemodilution, hypothermia, acidosis, shock, and serious trauma itself, which affects patient outcomes due to critical bleeding requiring massive transfusion. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype directly caused by trauma and/or traumatic shock has been considered to be the primary pathophysiology of trauma-induced coagulopathy. The key to controlling DIC is vigorous treatment of the underlying disorder, that is, trauma itself and hemorrhagic shock. Damage control resuscitation, consisting of damage control surgery, permissive hypotension, and hemostatic resuscitation, aims to control severe trauma and critical bleeding, which is equivalent to managing the underlying disorder of DIC. At present, however, evidence-based practices for damage control resuscitation are lacking. A robust prospective outcome study for damage control resuscitation that considers DIC with the fibrinolytic phenotype as the main pathological condition of trauma-induced coagulopathy affecting patient outcome is essential for improving therapeutic strategies.

Keywords

blood products - coagulopathy - critical bleeding - disseminated intravascular coagulation - transfusion - trauma

• References

• 1 Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011; 254 (1) 10-19
• 2 Spahn DR, Bouillon B, Cerny V , et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17 (2) R76
• 3 Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care 2015; 19: 72
• 4 Gando S, Wada H, Kim HK , et al; Scientific and Standardization Committee on DIC of the ISTH. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock. J Thromb Haemost 2012; 10 (12) 2593-2595
• 5 Gando S, Wada H, Thachil J ; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 2013; 11 (5) 826-835
• 6 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
• 7 Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma 1997; 42 (4) 716-720 , discussion 720–722
• 8 Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma 2005; 58 (3) 475-480 , discussion 480–481
• 9 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M ; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (5) 1327-1330
• 10 Sawamura A, Hayakawa M, Gando S , et al. Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma. Thromb Res 2009; 124 (6) 706-710
• 11 Oshiro A, Yanagida Y, Gando S, Henzan N, Takahashi I, Makise H. Hemostasis during the early stages of trauma: comparison with disseminated intravascular coagulation. Crit Care 2014; 18 (2) R61
• 12 Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care 2014; 2 (1) 20
• 13 Levi M. Disseminated intravascular coagulation. Crit Care Med 2007; 35 (9) 2191-2195
• 14 Gando S. Hemostasis and thrombosis in trauma patients. Semin Thromb Hemost 2015; 41 (1) 26-34
• 15 Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg 2012; 99 (Suppl. 01) 12-20
• 16 Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care 2014; 2 (1) 67
• 17 Cohen MJ, Brohi K, Calfee CS , et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care 2009; 13 (6) R174
• 18 Kutcher ME, Xu J, Vilardi RF, Ho C, Esmon CT, Cohen MJ. Extracellular histone release in response to traumatic injury: implications for a compensatory role of activated protein C. J Trauma Acute Care Surg 2012; 73 (6) 1389-1394
• 19 Abrams ST, Zhang N, Manson J , et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med 2013; 187 (2) 160-169
• 20 Zhang Q, Raoof M, Chen Y , et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464 (7285) 104-107
• 21 Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood 2011; 118 (13) 3708-3714
• 22 Semeraro F, Ammollo CT, Morrissey JH , et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118 (7) 1952-1961
• 23 Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 2011; 9 (9) 1795-1803
• 24 Ito T, Kawahara K, Nakamura T , et al. High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost 2007; 5 (1) 109-116
• 25 Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med 1995; 23 (11) 1835-1842
• 26 Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury 2007; 38 (12) 1336-1345
• 27 Esmon CT. Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Best Pract Res Clin Haematol 1999; 12 (3) 343-359
• 28 Armstead VE, Opentanova IL, Minchenko AG, Lefer AM. Tissue factor expression in vital organs during murine traumatic shock: role of transcription factors AP-1 and NF-kappaB. Anesthesiology 1999; 91 (6) 1844-1852
• 29 Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion 2009; 49 (12) 2652-2660
• 30 Chandler WL. Procoagulant activity in trauma patients. Am J Clin Pathol 2010; 134 (1) 90-96
• 31 Ishii H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76 (6) 2178-2181
• 32 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost 1991; 65 (5) 618-623
• 33 Boehme MWJ, Deng Y, Raeth U , et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87 (1) 134-140
• 34 Gando S, Nanzaki S, Morimoto Y, Ishitani T, Kemmotsu O. Tissue factor pathway inhibitor response does not correlate with tissue factor-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome in trauma patients. Crit Care Med 2001; 29 (2) 262-266
• 35 Taylor F, Chang A, Ferrell G , et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood 1991; 78 (2) 357-363
• 36 Engelman DT, Gabram SGA, Allen L, Ens GE, Jacobs LM. Hypercoagulability following multiple trauma. World J Surg 1996; 20 (1) 5-10
• 37 Gando S, Nakanishi Y, Kameue T, Nanzaki S. Soluble thrombomodulin increases in patients with disseminated intravascular coagulation and in those with multiple organ dysfunction syndrome after trauma: role of neutrophil elastase. J Trauma 1995; 39 (4) 660-664
• 38 Gando S, Kameue T, Matsuda N , et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb Haemost 2002; 88 (6) 943-949
• 39 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
• 40 Gando S, Tedo I, Kubota M. Posttrauma coagulation and fibrinolysis. Crit Care Med 1992; 20 (5) 594-600
• 41 Marder VJ, Feinstein DI, Colman RW, Levi M. Consumptive thrombohemorrhagic disorders. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: 1571-1600
• 42 Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med 2005; 15 (8) 302-308
• 43 Stump DC, Taylor Jr FB, Nesheim ME, Giles AR, Dzik WH, Bovill EG. Pathologic fibrinolysis as a cause of clinical bleeding. Semin Thromb Hemost 1990; 16 (3) 260-273
• 44 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320 (18) 1165-1172
• 45 Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270 (8) 975-979
• 46 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 1997; 77 (2) 278-282
• 47 Hayakawa M, Sawamura A, Gando S , et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery 2011; 149 (2) 221-230
• 48 Gando S, Makise H, Tedo I. [Gaisyogo no sosyochiyu insi]. Nippon Geka Gakkai Zasshi 1990; 91 (1) 17-22
• 49 Giles AR, Nesheim ME, Mann KG. Studies of Factors V and VIII:C in an animal model of disseminated intravascular coagulation. J Clin Invest 1984; 74 (6) 2219-2225
• 50 Wyshock EG, Suffredini AF, Parrillo JE, Colman RW. Cofactors V and VIII after endotoxin administration to human volunteers. Thromb Res 1995; 80 (5) 377-389
• 51 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
• 52 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
• 53 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 , discussion 1217
• 54 Hess JR, Brohi K, Dutton RP , et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008; 65 (4) 748-754
• 55 Davenport R. Pathogenesis of acute traumatic coagulopathy. Transfusion 2013; 53 (Suppl. 01) 23S-27S
• 56 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007; 13 (6) 680-685
• 57 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
• 58 Noel P, Cashen S, Patel B. Trauma-induced coagulopathy: from biology to therapy. Semin Hematol 2013; 50 (3) 259-269
• 59 Maegele M, Schöchl H, Cohen MJ. An update on the coagulopathy of trauma. Shock 2014; 41 (Suppl. 01) 21-25
• 60 Valeri CR, Khuri S, Ragno G. Nonsurgical bleeding diathesis in anemic thrombocytopenic patients: role of temperature, red blood cells, platelets, and plasma-clotting proteins. Transfusion 2007; 47 (4, Suppl): 206S-248S
• 61 Escolar G, Garrido M, Mazzara R, Castillo R, Ordinas A. Experimental basis for the use of red cell transfusion in the management of anemic-thrombocytopenic patients. Transfusion 1988; 28 (5) 406-411
• 62 Eugster M, Reinhart WH. The influence of the haematocrit on primary haemostasis in vitro. Thromb Haemost 2005; 94 (6) 1213-1218
• 63 Blajchman MA, Bordin JO, Bardossy L, Heddle NM. The contribution of the haematocrit to thrombocytopenic bleeding in experimental animals. Br J Haematol 1994; 86 (2) 347-350
• 64 Peyrou V, Lormeau JC, Hérault JP, Gaich C, Pfliegger AM, Herbert JM. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost 1999; 81 (3) 400-406
• 65 Santos MT, Valles J, Marcus AJ , et al. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. J Clin Invest 1991; 87 (2) 571-580
• 66 Santos MT, Valles J, Aznar J, Marcus AJ, Broekman MJ, Safier LB. Prothrombotic effects of erythrocytes on platelet reactivity. Reduction by aspirin. Circulation 1997; 95 (1) 63-68
• 67 Valeri CR, Cassidy G, Pivacek LE , et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion 2001; 41 (8) 977-983
• 68 Iwata H, Kaibara M. Activation of factor IX by erythrocyte membranes causes intrinsic coagulation. Blood Coagul Fibrinolysis 2002; 13 (6) 489-496
• 69 Iwata H, Kaibara M, Dohmae N, Takio K, Himeno R, Kawakami S. Purification, identification, and characterization of elastase on erythrocyte membrane as factor IX-activating enzyme. Biochem Biophys Res Commun 2004; 316 (1) 65-70
• 70 Kaibara M, Iwata H, Ujiie H, Himeno R, Kaibara M. Rheological analyses of coagulation of blood from different individuals with special reference to procoagulant activity of erythrocytes. Blood Coagul Fibrinolysis 2005; 16 (5) 355-363
• 71 Quaknine-Orlando B, Samama CM, Riou B , et al. Role of the hematocrit in a rabbit model of arterial thrombosis and bleeding. Anesthesiology 1999; 90 (5) 1454-1461
• 72 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 , discussion 1009–1010
• 73 Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma 2009; 67 (1) 202-208 , discussion 208–209
• 74 Wolberg AS, Meng ZH, Monroe III DM, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 2004; 56 (6) 1221-1228
• 75 Ho AM, Karmakar MK, Dion PW. Are we giving enough coagulation factors during major trauma resuscitation?. Am J Surg 2005; 190 (3) 479-484
• 76 Wada H, Thachil J, Di Nisio M , et al; The Scientific and Standardization Committee on DIC of the ISTH. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761-767
• 77 Shakur H, Roberts I, Bautista R , et al; CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376 (9734) 23-32
• 78 Roberts I, Shakur H, Afolabi A , et al; CRASH-2 collaborators. 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) 1096-1101 , 1101.e1–1101.e2
• 79 Gando S. Disseminated intravascular coagulation. In: Gonzalez E, Moore EB, Moore EE, eds. Trauma-Induced Coagulopathy. New York, NY: Springer; 2015. (in press)
• 80 Duchesne JC, McSwain Jr NE, Cotton BA , et al. Damage control resuscitation: the new face of damage control. J Trauma 2010; 69 (4) 976-990
• 81 Pohlman TH, Walsh M, Aversa J, Hutchison EM, Olsen KP, Lawrence Reed R. Damage control resuscitation. Blood Rev 2015; 29 (4) 251-262
• 82 Jansen JO, Thomas R, Loudon MA, Brooks A. Damage control resuscitation for patients with major trauma. BMJ 2009; 338: b1778
• 83 Jaunoo SS, Harji DP. Damage control surgery. Int J Surg 2009; 7 (2) 110-113
• 84 Bickell WH, Wall Jr MJ, Pepe PE , et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331 (17) 1105-1109
• 85 Kwan I, Bunn F, Roberts I ; WHO Pre-Hospital Trauma Care Steering Committee. Timing and volume of fluid administration for patients with bleeding. Cochrane Database Syst Rev 2003; 3 (3) CD002245
• 86 Berry C, Ley EJ, Bukur M , et al. Redefining hypotension in traumatic brain injury. Injury 2012; 43 (11) 1833-1837
• 87 Pham HP, Shaz BH. Update on massive transfusion. Br J Anaesth 2013; 111 (Suppl. 01) i71-i82
• 88 Waters JH. Role of the massive transfusion protocol in the management of haemorrhagic shock. Br J Anaesth 2014; 113 (Suppl. 02) ii3-ii8
• 89 Dzik WH, Blajchman MA, Fergusson D , et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products—Massive Transfusion Consensus Conference 2011: report of the panel. Crit Care 2011; 15 (6) 242
• 90 Curry N, Stanworth S, Hopewell S, Dorée C, Brohi K, Hyde C. Trauma-induced coagulopathy—a review of the systematic reviews: is there sufficient evidence to guide clinical transfusion practice?. Transfus Med Rev 2011; 25 (3) 217-231.e2
• 91 McQuilten ZK, Crighton G, Engelbrecht S , et al. Transfusion interventions in critical bleeding requiring massive transfusion: a systematic review. Transfus Med Rev 2015; 29 (2) 127-137
• 92 Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med 2012; 20: 15
• 93 Holcomb JB, Minei KM, Scerbo ML , et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg 2012; 256 (3) 476-486
• 94 Khan S, Brohi K, Chana M , et al; International Trauma Research Network (INTRN). Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg 2014; 76 (3) 561-567 , discussion 567–568
• 95 Chitlur M, Sorensen B, Rivard GE , et al. Standardization of thromboelastography: a report from the TEG-ROTEM working group. Haemophilia 2011; 17 (3) 532-537
• 96 Afshari A, Wikkelsø A, Brok J, Møller AM, Wetterslev J. Thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion. [Review] Cochrane Database Syst Rev 2011; 3 (3) CD007871
• 97 Da Luz LT, Nascimento B, Shankarakutty AK, Rizoli S, Adhikari NK. Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care 2014; 18 (5) 518
• 98 Hunt H, Stanworth S, Curry N , et al. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. [Review] Cochrane Database Syst Rev 2015; 2: CD010438
• 99 Borgman MA, Spinella PC, Perkins JG , et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007; 63 (4) 805-813
• 100 Ho AM, Dion PW, Yeung JHH , et al. Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology 2012; 116 (3) 716-728
• 101 Stansbury LG, Dutton RP, Stein DM, Bochicchio GV, Scalea TM, Hess JR. Controversy in trauma resuscitation: do ratios of plasma to red blood cells matter?. Transfus Med Rev 2009; 23 (4) 255-265
• 102 Phan HH, Wisner DH. Should we increase the ratio of plasma/platelets to red blood cells in massive transfusion: what is the evidence?. Vox Sang 2010; 98 (3, Pt 2) 395-402
• 103 Curry N, Hopewell S, Dorée C, Hyde C, Brohi K, Stanworth S. The acute management of trauma hemorrhage: a systematic review of randomized controlled trials. Crit Care 2011; 15 (2) R92
• 104 Hallet J, Lauzier F, Mailloux O , et al. The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit Care Med 2013; 41 (12) 2800-2811
• 105 Murad MH, Stubbs JR, Gandhi MJ , et al. The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion 2010; 50 (6) 1370-1383
• 106 Johansson PI, Oliveri RS, Ostrowski SR. Hemostatic resuscitation with plasma and platelets in trauma. J Emerg Trauma Shock 2012; 5 (2) 120-125
• 107 National Blood Authority. Australia. Patient blood management guidelines: Module 1, Critical bleeding/massive transfusion. 2011 . Available at: http://www.blood.gov.au/pbm-module-1. Accessed May 14, 2015
• 108 Holcomb JB, del Junco DJ, Fox EE , et al; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg 2013; 148 (2) 127-136
• 109 del Junco DJ, Holcomb JB, Fox EE , et al; PROMMTT Study Group. Resuscitate early with plasma and platelets or balance blood products gradually: findings from the PROMMTT study. J Trauma Acute Care Surg 2013; 75 (1) (Suppl. 01) S24-S30
• 110 Holcomb JB, Tilley BC, Baraniuk S , et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015; 313 (5) 471-482
• 111 Cotton BA, Podbielski J, Camp E , et al; Early Whole Blood Investigators. A randomized controlled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions. Ann Surg 2013; 258 (4) 527-532 , discussion 532–533
• 112 Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A. Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study. Semin Thromb Hemost 2015; 41 (1) 35-42
• 113 Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014; 54 (5) 1389-1405 , quiz 1388
• 114 Warmuth M, Mad P, Wild C. Systematic review of the efficacy and safety of fibrinogen concentrate substitution in adults. Acta Anaesthesiol Scand 2012; 56 (5) 539-548
• 115 Wikkelsø A, Lunde J, Johansen M , et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013; 8: CD008864
• 116 Kozek-Langenecker S, Sørensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care 2011; 15 (5) R239
• 117 Meyer MAS, Ostrowski SR, Windeløv NA, Johansson PI. Fibrinogen concentrates for bleeding trauma patients: what is the evidence?. Vox Sang 2011; 101 (3) 185-190
• 118 Aubron C, Reade MC, Fraser JF, Cooper DJ. Efficacy and safety of fibrinogen concentrate in trauma patients—a systematic review. J Crit Care 2014; 29 (3) 471.e11-471.e17
• 119 Grottke O, Rossaint R, Henskens Y, van Oerle R, Ten Cate H, Spronk HMH. Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model. PLoS ONE 2013; 8 (5) e64100
• 120 Ferreira J, DeLosSantos M. The clinical use of prothrombin complex concentrate. J Emerg Med 2013; 44 (6) 1201-1210
• 121 Matsushima K, Benjamin E, Demetriades D. Prothrombin complex concentrate in trauma patients. Am J Surg 2015; 209 (2) 413-417
• 122 Innerhofer P, Westermann I, Tauber H , et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury 2013; 44 (2) 209-216
• 123 Schöchl H, Voelckel W, Maegele M, Kirchmair L, Schlimp CJ. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care 2014; 18 (4) R147
• 124 Grundman C, Plesker R, Kusch M , et al. Prothrombin overload causes thromboembolic complications in prothrombin complex concentrates: in vitro and in vivo evidence. Thromb Haemost 2005; 94 (6) 1338-1339
• 125 Grottke O, Braunschweig T, Spronk HMH , et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011; 118 (7) 1943-1951
• 126 Boffard KD, Riou B, Warren B , et al; NovoSeven Trauma Study Group. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005; 59 (1) 8-15 , discussion 15–18
• 127 Hauser CJ, Boffard K, Dutton R , et al; CONTROL Study Group. 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
• 128 Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. (Review) Cochrane Database Syst Rev 2012; 3: CD005011
• 129 Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way?. Crit Care Med 2012; 40 (9) 2704-2708