Pathophysiology of Trauma-Induced Coagulopathy

Abstract

Trauma-induced coagulopathy (TIC) is a complex hemostatic disturbance that can develop early after a major injury. There is no universally accepted definition of TIC. However, TIC primarily refers to the inability to achieve sufficient hemostasis in severely injured trauma patients, resulting in diffuse microvascular and life-threatening bleeding. Endogenous TIC is driven by the combination of hypovolemic shock and substantial tissue injury, resulting in endothelial damage, glycocalyx shedding, upregulated fibrinolysis, fibrinogen depletion, altered thrombin generation, and platelet dysfunction. Exogenous factors such as hypothermia, acidosis, hypokalemia, and dilution due to crystalloid and colloid fluid administration can further exacerbate TIC. Established TIC upon emergency room admission is a prognostic indicator and is strongly associated with poor outcomes. It has been shown that patients with TIC are prone to higher bleeding tendencies, increased requirements for allogeneic blood transfusion, higher complication rates such as multi-organ failure, and an almost fourfold increase in mortality. Thus, early recognition and individualized treatment of TIC is a cornerstone of initial trauma care. However, patients who survive the initial insult switch from hypocoagulability to hypercoagulability, also termed “late TIC,” with a high risk of developing thromboembolic complications.

Zusammenfassung

Die trauma-induzierte Koagulopathie (TIC) ist eine komplexe hämostatische Störung, die sich früh nach einer schweren Verletzung entwickeln kann. Bisher gibt es keine allgemein anerkannte Definition von TIC. TIC bezeichnet in erster Linie die Unfähigkeit, schwer verletzter Traumapatienten eine suffiziente Blutstillung zu erreichen, was zu diffusen mikrovaskulären und somit lebensbedrohlichen Blutungen führen kann. Die TIC ist eine „endogene Gerinnungsstörung“ die durch die Kombination aus hypovolämischem Schock und erheblicher Gewebeschädigung verursacht wird. Dadurch kommt es zu substanziellen Endothelschäden, Glykokalyxablösungen, einer hochregulierten Fibrinolyse, Fibrinogenmangel, veränderter Thrombinbildung und einer Plättchenfunktionsstörung. „Exogene Faktoren“ wie Hypothermie, Azidose, Hypokaliämie und Verdünnung aufgrund der Verabreichung von Kristalloiden und Kolloiden können eine TIC weiter verschlimmern. Eine bestehende TIC bei Schockraum-Aufnahme ist ein prognostischer Indikator und eng mit einem schlechten Outcome assoziiert. Es hat sich gezeigt, dass Patienten mit TIC eine höhere Blutungsneigung aufweisen, einen erhöhten Bedarf an allogenen Bluttransfusionen unterliegen, signifikant mehr Komplikationen wie etwa ein Multiorganversagen zeigen und eine fast vierfach höhere Mortalität aufweisen als gerinnungkompetente Traumapatienten. Daher ist die Früherkennung und individuelle Behandlung einer bestehenden TIC essenziell in der initialen Versorgung von schwerverletzten Patienten. Trauma Patienten, die das initiale Trauma überleben, wechseln von einer Hypokoagulabilität in einen hyperkoagulablen Zustand, der auch als „späte TIC“ bezeichnet wird. Damit erhöht sich das Risiko für die Entwicklung thromboembolischer Komplikationen.

Keywords

trauma-induced coagulopathy - endotheliopathy - hyperfibrinolysis - altered thrombin generation - platelet dysfunction

Schlüsselwörter

traumainduzierte Koagulopathie - Endotheliopathie - Hyperfibrinolyse - eingeschränkte Thrombinbildung - Plättchenfunktionsstörung

Publication History

Received: 22 October 2023

Accepted: 22 November 2023

Article published online:
28 February 2024

• References

• 1 Oyeniyi BT, Fox EE, Scerbo M, Tomasek JS, Wade CE, Holcomb JB. Trends in 1029 trauma deaths at a level 1 trauma center: impact of a bleeding control bundle of care. Injury 2017; 48 (01) 5-12
• 2 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 1997; 42 (05) 857-861 , discussion 861–862
• 3 Duque P, Mora L, Levy JH, Schöchl H. Pathophysiological response to trauma-induced coagulopathy: a comprehensive review. Anesth Analg 2020; 130 (03) 654-664
• 4 Floccard B, Rugeri L, Faure A. et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury 2012; 43 (01) 26-32
• 5 MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003; 55 (01) 39-44
• 6 Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54 (06) 1127-1130
• 7 Maegele M, Lefering R, Yucel N. et al; AG Polytrauma of the German Trauma Society (DGU). Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007; 38 (03) 298-304
• 8 Moore EE, Moore HB, Kornblith LZ. et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021; 7 (01) 30
• 9 Rappold JF, Sheppard FR, Carmichael Ii SP. et al. Venous thromboembolism prophylaxis in the trauma intensive care unit: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document. Trauma Surg Acute Care Open 2021; 6 (01) e000643
• 10 Baksaas-Aasen K, Gall LS, Stensballe J. et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med 2021; 47 (01) 49-59
• 11 Frith D, Goslings JC, Gaarder C. et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost 2010; 8 (09) 1919-1925
• 12 Bouzat P, Charbit J, Abback PS. et al; PROCOAG Study Group. Efficacy and safety of early administration of 4-factor prothrombin complex concentrate in patients with trauma at risk of massive transfusion: the PROCOAG randomized clinical trial. JAMA 2023; 329 (16) 1367-1375
• 13 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
• 14 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 (03) 561-567 , discussion 567–568
• 15 Kutcher ME, Redick BJ, McCreery RC. et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 2012; 73 (01) 13-19
• 16 Vulliamy P, Montague SJ, Gillespie S. et al. Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients. Blood Adv 2020; 4 (12) 2623-2630
• 17 Zipperle J, Altenburger K, Ponschab M. et al. Potential role of platelet-leukocyte aggregation in trauma-induced coagulopathy: ex vivo findings. J Trauma Acute Care Surg 2017; 82 (05) 921-926
• 18 Zipperle J, Schmitt FCF, Schöchl H. Point-of-care, goal-directed management of bleeding in trauma patients. Curr Opin Crit Care 2023; 29 (06) 702-712
• 19 Connelly CR, Yonge JD, McCully SP. et al. Assessment of three point-of-care platelet function assays in adult trauma patients. J Surg Res 2017; 212: 260-269
• 20 Schriner JB, George MJ, Cardenas JC. et al. Platelet function in trauma: is current technology in function testing missing the mark in injured patients?. Shock 2022; 58 (01) 1-13
• 21 Chang R, Fox EE, Greene TJ. et al; PROHS Study Group. Abnormalities of laboratory coagulation tests versus clinically evident coagulopathic bleeding: results from the prehospital resuscitation on helicopters study (PROHS). Surgery 2018; 163 (04) 819-826
• 22 Chang R, Kerby JD, Kalkwarf KJ. et al; PROPPR Study Group. Earlier time to hemostasis is associated with decreased mortality and rate of complications: Results from the Pragmatic Randomized Optimal Platelet and Plasma Ratio trial. J Trauma Acute Care Surg 2019; 87 (02) 342-349
• 23 Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60 (6, Suppl): S3-S11
• 24 Johansson PI, Stensballe J, Ostrowski SR. Erratum to: Shock induced endotheliopathy (SHINE) in acute critical illness: a unifying pathophysiologic mechanism. Crit Care 2017; 21 (01) 187
• 25 Cardenas JC, Dong JF, Kozar RA. Injury-induced endotheliopathy: what you need to know. J Trauma Acute Care Surg 2023; 95 (04) 454-463
• 26 Haywood-Watson RJ, Holcomb JB, Gonzalez EA. et al. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS One 2011; 6 (08) e23530
• 27 Hofmann N, Zipperle J, Jafarmadar M. et al. experimental models of endotheliopathy: impact of shock severity. Shock 2018; 49 (05) 564-571
• 28 Rahbar E, Cardenas JC, Baimukanova G. et al. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med 2015; 13: 117
• 29 Xu L, Yu WK, Lin ZL. et al. Chemical sympathectomy attenuates inflammation, glycocalyx shedding and coagulation disorders in rats with acute traumatic coagulopathy. Blood Coagul Fibrinolysis 2015; 26 (02) 152-160
• 30 Ostrowski SR, Henriksen HH, Stensballe J. et al. Sympathoadrenal activation and endotheliopathy are drivers of hypocoagulability and hyperfibrinolysis in trauma: a prospective observational study of 404 severely injured patients. J Trauma Acute Care Surg 2017; 82 (02) 293-301
• 31 Johansson PI, Henriksen HH, Stensballe J. et al. Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients. Ann Surg 2017; 265 (03) 597-603
• 32 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 (01) 60-66
• 33 Zipperle J, Oberladstätter D, Weichselbaum N. et al. Thromboelastometry fails to detect autoheparinization after major trauma and hemorrhagic shock. J Trauma Acute Care Surg 2022; 92 (03) 535-541
• 34 Chapman MP, Moore EE, Ramos CR. et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg 2013; 75 (06) 961-967 , discussion 967
• 35 Cotton BA, Harvin JA, Kostousouv V. et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg 2012; 73 (02) 365-370 , discussion 370
• 36 Ives C, Inaba K, Branco BC. et al. Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg 2012; 215 (04) 496-502
• 37 Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009; 67 (01) 125-131
• 38 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 (05) 812-818
• 39 Cap A, Hunt BJ. The pathogenesis of traumatic coagulopathy. Anaesthesia 2015; 70 (1, Suppl 1): 96-101 , e32–e34
• 40 Schöchl H, Cadamuro J, Seidl S. et al. Hyperfibrinolysis is common in out-of-hospital cardiac arrest: results from a prospective observational thromboelastometry study. Resuscitation 2013; 84 (04) 454-459
• 41 Koami H, Sakamoto Y, Furukawa T, Imahase H, Iwamura T, Inoue S. Utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis. Blood Coagul Fibrinolysis 2016; 27 (04) 450-453
• 42 Schöchl H, Voelckel W, Maegele M, Solomon C. Trauma-associated hyperfibrinolysis. Hamostaseologie 2012; 32 (01) 22-27
• 43 Taylor III JR, Fox EE, Holcomb JB. et al; PROPPR Study Group. The hyperfibrinolytic phenotype is the most lethal and resource intense presentation of fibrinolysis in massive transfusion patients. J Trauma Acute Care Surg 2018; 84 (01) 25-30
• 44 Theusinger OM, Wanner GA, Emmert MY. et al. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg 2011; 113 (05) 1003-1012
• 45 Farrell MS, Moore EE, Thomas AV. et al. “Death diamond” tracing on thromboelastography as a marker of poor survival after trauma. Am Surg 2022; 88 (07) 1689-1693
• 46 Moore EE, Moore HB, Thomas SG. et al. Serial “death diamond” TEGs are a bedside indicator of futile resuscitation during massive transfusion. J Trauma Acute Care Surg 2023; 95 (03) e19-e21
• 47 Raza I, Davenport R, Rourke C. et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013; 11 (02) 307-314
• 48 Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses 2010; 75 (06) 564-567
• 49 Moore HB, Moore EE, Neal MD. et al. Fibrinolysis shutdown in trauma: historical review and clinical implications. Anesth Analg 2019; 129 (03) 762-773
• 50 Shimono K, Ito T, Kamikokuryo C. et al. Damage-associated molecular patterns and fibrinolysis perturbation are associated with lethal outcomes in traumatic injury. Thromb J 2023; 21 (01) 91
• 51 Moore HB, Moore EE, Liras IN. et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg 2016; 222 (04) 347-355
• 52 Moore HB, Moore EE, Huebner BR. et al. Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator. J Trauma Acute Care Surg 2017; 83 (06) 1014-1022
• 53 David JS, Lambert A, Bouzat P. et al. Fibrinolytic shutdown diagnosed with rotational thromboelastometry represents a moderate form of coagulopathy associated with transfusion requirement and mortality: a retrospective analysis. Eur J Anaesthesiol 2020; 37 (03) 170-179
• 54 Liu B, Yang C, Deng Y. et al. Persistent fibrinolysis shutdown is associated with increased mortality in traumatic pancreatic injury. Injury 2023; 54 (05) 1265-1270
• 55 Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg 2017; 224 (04) 575-582
• 56 Gall LS, Vulliamy P, Gillespie S. et al; Targeted Action for Curing Trauma-Induced Coagulopathy (TACTIC) partners. The S100A10 pathway mediates an occult hyperfibrinolytic subtype in trauma patients. Ann Surg 2019; 269 (06) 1184-1191
• 57 Cardenas JC, Wade CE, Cotton BA. et al; PROPPR Study Group. TEG lysis shutdown represents coagulopathy in bleeding trauma patients: analysis of the PROPPR cohort. Shock 2019; 51 (03) 273-283
• 58 Duque P, Calvo A, Lockie C, Schöchl H. Pathophysiology of trauma-induced coagulopathy. Transfus Med Rev 2021; 35 (04) 80-86
• 59 Popescu NI, Lupu C, Lupu F. Disseminated intravascular coagulation and its immune mechanisms. Blood 2022; 139 (13) 1973-1986
• 60 Schöchl H, Solomon C, Schulz A. et al. Thromboelastometry (TEM) findings in disseminated intravascular coagulation in a pig model of endotoxinemia. Mol Med 2011; 17 (3–4): 266-272
• 61 Lowe GD, Rumley A, Mackie IJ. Plasma fibrinogen. Ann Clin Biochem 2004; 41 (Pt 6): 430-440
• 62 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3 (08) 1894-1904
• 63 Dorgalaleh A, Rashidpanah J. Blood coagulation factor XIII and factor XIII deficiency. Blood Rev 2016; 30 (06) 461-475
• 64 Kononova O, Litvinov RI, Blokhin DS. et al. Mechanistic Basis for the Binding of RGD- and AGDV-peptides to the platelet integrin αIIbβ3. Biochemistry 2017; 56 (13) 1932-1942
• 65 Schlimp CJ, Schöchl H. The role of fibrinogen in trauma-induced coagulopathy. Hamostaseologie 2014; 34 (01) 29-39
• 66 Chambers LA, Chow SJ, Shaffer LE. Frequency and characteristics of coagulopathy in trauma patients treated with a low- or high-plasma-content massive transfusion protocol. Am J Clin Pathol 2011; 136 (03) 364-370
• 67 McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: a five-year statewide cohort study. Injury 2017; 48 (05) 1074-1081
• 68 Rourke C, Curry N, Khan S. et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost 2012; 10 (07) 1342-1351
• 69 Lv K, Yuan Q, Fu P. et al. Impact of fibrinogen level on the prognosis of patients with traumatic brain injury: a single-center analysis of 2570 patients. World J Emerg Surg 2020; 15 (01) 54
• 70 Hagemo JS, Stanworth S, Juffermans NP. et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care 2014; 18 (02) R52
• 71 Rossaint R, Afshari A, Bouillon B. et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care 2023; 27: 80
• 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 (05) 1002-1009 , discussion 1009–1010
• 73 Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg 2007; 246 (05) 831-835
• 74 Schlimp CJ, Voelckel W, Inaba K, Maegele M, Ponschab M, Schöchl H. Estimation of plasma fibrinogen levels based on hemoglobin, base excess and Injury Severity Score upon emergency room admission. Crit Care 2013; 17 (04) R137
• 75 Schlimp CJ, Ponschab M, Voelckel W, Treichl B, Maegele M, Schöchl H. Fibrinogen levels in trauma patients during the first seven days after fibrinogen concentrate therapy: a retrospective study. Scand J Trauma Resusc Emerg Med 2016; 24: 29
• 76 Cardenas JC, Rahbar E, Pommerening MJ. et al. Measuring thrombin generation as a tool for predicting hemostatic potential and transfusion requirements following trauma. J Trauma Acute Care Surg 2014; 77 (06) 839-845
• 77 Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion 2009; 49 (12) 2652-2660
• 78 Meng ZH, Wolberg AS, Monroe III DM, 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 2003; 55 (05) 886-891
• 79 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 (06) 1221-1228
• 80 Woolley T, Gwyther R, Parmar K. et al. A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield. Transfusion 2020; 60 (Suppl. 03) S52-S61
• 81 Rizoli SB, Scarpelini S, Callum J. et al. Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma 2011; 71 (5, Suppl 1): S427-S434
• 82 Gangloff C, Mingant F, Theron M. et al. New considerations on pathways involved in acute traumatic coagulopathy: the thrombin generation paradox. World J Emerg Surg 2019; 14: 57
• 83 Coleman JR, Moore EE, Samuels JM. et al. Whole blood thrombin generation in severely injured patients requiring massive transfusion. J Am Coll Surg 2021; 232 (05) 709-716
• 84 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 (03) 475-480 , discussion 480–481
• 85 Holnthoner W, Bonstingl C, Hromada C. et al. Endothelial cell-derived extracellular vesicles size-dependently exert procoagulant activity detected by thromboelastometry. Sci Rep 2017; 7 (01) 3707
• 86 Schöchl H, Maegele M, Grottke O. Is “thrombin burst” now the worst option in trauma?. Shock 2017; 47 (06) 780-781
• 87 Monroe DM, Hoffman M. What does it take to make the perfect clot?. Arterioscler Thromb Vasc Biol 2006; 26 (01) 41-48
• 88 Ed Rainger G, Chimen M, Harrison MJ. et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets 2015; 26 (06) 507-520
• 89 Sirajuddin S, Valdez C, DePalma L. et al. Inhibition of platelet function is common following even minor injury. J Trauma Acute Care Surg 2016; 81 (02) 328-332
• 90 Solomon C, Traintinger S, Ziegler B. et al. Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost 2011; 106 (02) 322-330
• 91 Verni CC, Davila Jr A, Balian S, Sims CA, Diamond SL. Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma. J Trauma Acute Care Surg 2019; 86 (02) 250-259
• 92 Vulliamy P, Kornblith LZ, Kutcher ME, Cohen MJ, Brohi K, Neal MD. Alterations in platelet behavior after major trauma: adaptive or maladaptive?. Platelets 2021; 32 (03) 295-304
• 93 Vulliamy P, Gillespie S, Armstrong PC, Allan HE, Warner TD, Brohi K. Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage. Proc Natl Acad Sci U S A 2019; 116 (35) 17444-17449
• 94 Pommer P, Oberladstätter D, Schlimp CJ. et al. multiplate platelet function testing upon emergency room admission fails to provide useful information in major trauma patients not on platelet inhibitors. J Clin Med 2022; 11 (09) 11
• 95 Stettler GR, Moore EE, Moore HB. et al. Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion. Surgery 2017; 162 (06) 1286-1294
• 96 Cannon JW, Dias JD, Kumar MA. et al. Use of thromboelastography in the evaluation and management of patients with traumatic brain injury: a systematic review and meta-analysis. Crit Care Explor 2021; 3 (09) e0526