Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2015

01-12-2015 | Review

Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock

Authors: Satoshi Gando, Yasuhiro Otomo

Published in: Critical Care | Issue 1/2015

Login to get access

Abstract

Knowing the pathophysiology of trauma-induced coagulopathy is important for the management of severely injured trauma patients. The aims of this review are to provide a summary of the recent advances in our understanding of thrombosis and hemostasis following trauma and to discuss the pathogenesis of disseminated intravascular coagulation (DIC) at an early stage of trauma. Local hemostasis and thrombosis respectively act to induce physiological wound healing of injuries and innate immune responses to damaged-self following trauma. However, if overwhelmed by systemic inflammation caused by extensive tissue damage and tissue hypoperfusion, both of these processes foster systemic DIC associated with pathological fibrin(ogen)olysis. This is called DIC with the fibrinolytic phenotype, which is characterized by the activation of coagulation, consumption coagulopathy, insufficient control of coagulation, and increased fibrin(ogen)olysis. Irrespective of microvascular thrombosis, the condition shows systemic thrombin generation as well as its activation in the circulation and extensive damage to the microvasculature endothelium. DIC with the fibrinolytic phenotype gives rise to oozing-type non-surgical bleeding and greatly affects the prognosis of trauma patients. The coexistences of hypothermia, acidosis, and dilution aggravate DIC and lead to so-called trauma-induced coagulopathy.
He that would know what shall be must consider what has been.
The Analects of Confucius.
Literature
1.
Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haesmost. 1980;43:28–33.
2.
Marder VJ, Feinstein DI, Colman RW, Levi M. Consumptive thrombohemorrhagic disorders. In Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th edition. Edited by Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ. Philadelphia: Lippincott Williams & Wilkins; 2006;1571–1600.
3.
Engelmann B, Massberg S. Thrombosis and intravascular effector of innate immunity. Nat Rev Immunol. 2013;13:34–45.PubMed
4.
Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65:748–54.PubMed
5.
Maegele M, Schöchl H, Cohen MJ. An up-date on the coagulopathy of trauma. Shock. 2014;41:21–5.PubMed
6.
Gando S, Sawamura S, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation. Ann Surg. 2011;254:10–9.PubMed
7.
Gando S, Wada H, Kim HK, Kurosawa S, Nielsen JD, Thachil J, et al. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock. J Thromb Haemost. 2012;10:2593–5.PubMed
8.
Gando S, Wada H, Thachil J. 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;11:826–35.PubMed
9.
Kutcher ME, Ferguson AR, Cohen MJ. A principle component analysis of coagulation after trauma. J Trauma Acute Care Surg. 2013;74:1223–30.PubMedPubMedCentral
10.
Castellheim A, Brekke OL, Espevik T, Harboe M, Mollnes TE. Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol. 2009;69:479–91.PubMed
11.
Esmon CT. Inflammation and thrombosis. J Thromb Haemost. 2003;1:1343–8.PubMed
12.
13.
Rivers RP, Hathaway WE, Weston W. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol. 1975;30:311–6.PubMed
14.
Müller I, Klocke A, Alex M, Kotzsch M, Luther T, Morgenstern E, et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J. 2003;17:476–8.PubMed
15.
McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CCM, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330:362–6.PubMed
16.
Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. PNAS. 2010;107:15880–5.PubMedPubMedCentral
17.
Fuchs TA, Bhandari AA, Wanger DD. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118:3708–14.PubMedPubMedCentral
18.
Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118:1952–61.PubMedPubMedCentral
19.
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;9:1795–803.PubMed
20.
von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelet cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209:819–35.
21.
Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime? TRENDS Immunol. 2007;28:184–92.PubMed
22.
Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. PNAS. 2007;104:6388–93.PubMedPubMedCentral
23.
Rapaport SI, Rao VM. Initiation and regulation of tissue factor-dependent blood coagulation. Arterioscler Thromb. 1992;12:1111–21.PubMed
24.
Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887–96.PubMed
25.
26.
Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost. 1991;65:618–23.PubMed
27.
Levi M. Disseminated intravascular coagulation. Crit Care Med. 2007;35:2191–5.PubMed
28.
Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–65.PubMed
29.
Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg. 2012;99:12–20.PubMed
30.
Cohen MJ, Brohi K, Calfee CS, Rhan P, Chesebro BB, Christiaans SC, 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:R174.PubMedPubMedCentral
31.
Kutcher ME, Xu J, Vilardi RF, Ho C, Esmon CT, Cohen MJ. Extracellular histone release in response to traumatic injury: implications for compensatory role of activated protein C. J Trauma Acute Care Surg. 2012;73:1389–94.PubMed
32.
Abrams ST, Zhang N, Manson J, Liu T, Dart C, Baluwa F, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Crit Care Med. 2013;187:160–9.
33.
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–8.PubMedPubMedCentral
34.
Ito T, Kawahara K, Nakamura T, Yamada S, Nakamura T, Abeyama K, et al. High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost. 2007;5:109–16.PubMed
35.
Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction. Crit Care Med. 1995;23:1835–42.PubMed
36.
Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187:2626–31.PubMed
37.
Esmon CT. Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Clin Haematol. 1999;12:343–59.
38.
Boehme MWJ, Deng Y, Raeth U, Bierhaus A, Ziegler R, Stremmel W, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology. 1996;87:134–40.PubMedPubMedCentral
39.
Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–30.PubMed
40.
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124:608–13.PubMed
41.
Bakhtiari K, Meijers JCM, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med. 2004;32:2416–21.PubMed
42.
Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med. 2008;6:145–50.
43.
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, 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;124:706–10.PubMed
44.
Oshiro A, Yanagida Y, Gando S, Henzan N, Takahashi I, Makise H. Hemostasis during the early stage of trauma: comparison with disseminated intravascular coagulation. Crit Care. 2014;18:R61.PubMedPubMedCentral
45.
Gando S, Nanzaki S, Morimoto Y, Ishitani T, Kemmotsu O. Tissue factor pathway inhibitor does not correlate with tissue-factor induced disseminated intravascular coagulation and multiple organ dysfunction syndrome in trauma patients. Crit Care Med. 2001;29:262–6.PubMed
46.
Petersen LC, Valentin S, Hedner U. Regulation of the extrinsic pathway system in health and disease: the role of factor VIIa and tissue factor pathway inhibitor. Thromb Res. 1995;79:1–47.PubMed
47.
Hayakawa M, Sawamura A, Gando S, Kubota N, Uegaki S, Shimojima H, 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;149:221–30.PubMed
48.
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;39:660–4.PubMed
49.
Ogawa S, Shreeniwas R, Butura C, Brett J, Stern DM. Modulation of endothelial function by hypoxia: perturbation of barrier and anticoagulant function, and induction of a novel factor X activator. Adv Exp Med Biol. 1990;281:303–12.PubMed
50.
Ogawa S, Gerlach H, Esposito C, Pasagian-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties. J Clin Invest. 1990;85:1090–8.PubMedPubMedCentral
51.
Öhlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost. 2005;3:976–82.PubMed
52.
Taylor FB, Chang A, Ferrell G, Mather T, Catlett R, Blick K, et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood. 1991;78:357–63.PubMed
53.
Engelman DT, Gabram SGA, Allen L, Ens GE, Jacobs LM. Hypercoagulability following multiple trauma. World J Surg. 1996;20:5–10.PubMed
54.
Liaw PCY, Ferrell G, Esmon CT. A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. J Thromb Haemost. 2003;1:662–70.PubMed
55.
Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255:379–85.PubMed
56.
Butenas S, van’t Veer C, Mann KG. ‘Normal’ thrombin generation. Blood. 1999;94:2169–78.PubMed
57.
Grottke O, Braunschweig T, Spronk HMH, Esch S, Rieg AD, van Oerle R, et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–51.PubMed
58.
Miller RS, Weatherford DA, Stein D, Crane MM, Stein M. Antithrombin III and trauma patients: factors that determine low levels. J Trauma. 1994;37:442–5.PubMed
59.
Liener UC, Brückner UB, Strecker W, Steinback G, Kinzl L, Gebhard F. Trauma severity-dependent changes in ATIII activity. Shock. 2001;15:344–7.PubMed
60.
Owings JT, Bagley M, Gosselin R, Romac D, Disbrow E. Effect of critical injury on plasma antithrombin activity: low antithrombin levels are associated with thromboembolic complications. J Trauma. 1996;41:396–406.PubMed
61.
Gando S, Tedo I, Kubota M. Posttrauma coagulation and fibrinolysis. Crit Care Med. 1992;20:594–600.PubMed
62.
Yanagida Y, Gando S, Hayakawa M, Sawamura A, Uegaki S, Kubota N, et al. Normal prothrombinase activity, increased systemic thrombin generation, 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;154:48–57.PubMed
63.
Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:2652–60.PubMed
64.
Chandler WL. Procoagulant activity in trauma patients. Am J Clin Pathol. 2010;134:90–6.PubMed
65.
Taylor FB. Responses of anticoagulant pathways in disseminated intravascular coagulation. Semin Thromb Haemost. 2001;27:619–31.
66.
Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost. 1998;79:1111–5.PubMed
67.
Ogura H, Kawasaki T, Tanaka H, Koh T, Tanaka R, Ozeki Y, et al. Activated platelets enhance microparticle formation and platelet-leucocyte interaction in severe trauma and sepsis. J Trauma. 2001;50:801–9.PubMed
68.
Nakashima M, Uematsu T, Umemura K, Maruyama I, Tsuruta K. A novel recombinant human soluble thrombomodulin, ART-123, activates the protein C pathway in healthy male volunteers. J Clin Pharmacol. 1998;38:540–4.PubMed
69.
Mohri M, Sata M, Gomi K, Maruyama Y, Osame M, Maruyama I. Abnormalities in the protein C anticoagulant pathway detected by a novel assay using human thrombomodulin. Lupus. 1997;6:590–6.PubMed
70.
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;74:2219–25.PubMedPubMedCentral
71.
Wyshock EG, Sufferendini AF, Parrillo JE, Colman RE. Cofactors V and VIII after endotoxin administration to human volunteers. Thromb Res. 1995;80:377–89.PubMed
72.
Hiippala S. Replacement of massive blood loss. Vox Sang. 1998;74:399–407.PubMed
73.
Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trend Cardivasc Med. 2005;15:302–8.
74.
Terraube V, O'Donnell JS, Jenkins PV. Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance. Haemophilia. 2010;16:3–13.PubMed
75.
Clarke BJ, Sridhara S, Woskowska Z, Blajchman MA. Consumption of plasma factor VII in a rabbit model of non-overt disseminated intravascular coagulation. Thromb Res. 2003;108:329–34.
76.
Gando I, Makise H, Tedo I. Variation in wound healing factors in trauma patients. Jp J Surg. 1990;91:17–22.
77.
McKay DG. Trauma and disseminated intravascular coagulation. J Trauma. 1969;9:646–60.PubMed
78.
Flute PT. Coagulation and fibrinolysis after injury. J Clin Pathol. 1970;23:102–9.
79.
80.
Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11:307–14.PubMed
81.
Stump DC, Taylor FBJ, Nesheim ME, Giles AR, Dzik WH, Bovill EG. Pathologic fibrinolysis as a cause of clinical bleeding. Semin Thromb Hemost. 1990;16:260–73.PubMed
82.
Levi M, ten Cate H, van der Poll T, van Daventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975–9.PubMed
83.
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 Hemost. 1997;77:278–82.
84.
Hayakawa M, Gando S, Ieko M, Honma Y, Homma T, Yanagida Y, et al. Massive amount of tissue factor induce fibrinogenolysis without tissue hypoperfusion in rats. Shock. 2013;39:514–9.PubMed
85.
Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 2010;38:S35–42.PubMed
86.
Bergentz SE, Leandoer L. Disseminated intravascular coagulation in shock. Ann Chir Gynecol Fenn. 1971;60:175–9.
87.
Turpini R, Stefanini M. The nature and mechanism of the hemostatic breakdown in the course of experimental hemorrhagic shock. J Clin Invest. 1959;38:53–65.PubMedPubMedCentral
88.
Borgström S, Gelin LE, Zederfeldt B. The formation of vein thrombi following tissue injury. An experimental study in rabbits. Act Chir Scand 1959;Suppl 247:1–36.
89.
Allardyce B, Hamit HF, Matsumoto T, Moseley RV. Pulmonary vascular changes in hypovolemic shock: radiography of the pulmonary microcirculation and the possible role of platelet embolism in increasing vascular resistance. J Trauma. 1999;9:403–11.
90.
Lungqvist U, Bergentz SE, Lewis DH. The distribution of platelets, fibrin and erythrocytes in various organs following experimental trauma. Eur Surg Res. 1971;3:293–300.
91.
Leandoer L, Bergentz SE. Haemorrhagic shock in the dog. The formation of thromboemboli during antifibrinolytic therapy. Eur Surg Res. 1970;2:341–7.PubMed
92.
Avikainen V, Eklund B. Disseminated intravascular coagulation after inhibition of fibrinolysis with tranexamic acid (AMCA) and proteinase inhibitor trasylol in experimental traumatic and haemorrhagic shock. Ann Chir Gynecol Fenn. 1974;63:226–34.
93.
Hardaway RM. The significance of coagulative and thrombotic changes after haemorrhage and injury. J Clin Pathol (R Coll Pathol). 1970;4:110–20.
94.
Nuytinck HK, Offermans XJ, Kubat K, Goris JA. Whole-body inflammation in trauma patients. An autopsy study. Arch Surg. 1988;123:1519–24.PubMed
95.
Rizoli S, Nascimento B, Key N, Tien HC, Muraca S, Pinto R, et al. Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma. 2011;71:S441–7.PubMed
96.
Parr MJ, Bouillon B, Brohi K, Dutton RP, Hauser CJ, Hess JR, et al. Traumatic coagulopathy: where are the good experimental models? J Trauma. 2008;65:766–71.PubMed
97.
Frith D, Cohen MJ, Brohi K. Animal models of trauma-induced coagulopathy. Thromb Res. 2012;129:551–6.PubMed
98.
Gentile LF, Nacionales DC, Cuenca AG, Armbruster MA, Ungaro RF, Abouhamze AS, et al. Identification and description of a novel murine model for polytrauma and shock. Crit Care Med. 2013;41:1075–85.PubMedPubMedCentral
99.
Tanabe K, Yoshitake J. A study on coagulation and fibrinolytic dynamics in experimental traumatic shock. Masui (Jp J Anesthesiol). 1981;30:826–31.
100.
Kugimiya H. A pathophysiological and biochemical study on the experimental traumatic shock in rats. A relationship between coagulation/fibrinolytic system and DIC. Masui (Jp J Anesthesiol) 1982;31:75–84.
101.
Armstead VE, Opetanova IL, Minchenko AG, Lefer AM. Tissue factor expression in vital organs during murine traumatic shock. Anesthesiology. 1999;91:1844–52.PubMed
Metadata
Title
Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock
Authors
Satoshi Gando
Yasuhiro Otomo
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-0735-x

Other articles of this Issue 1/2015

Critical Care 1/2015 Go to the issue

Research

Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood

Research

Monitoring of serum lactate level during cardiopulmonary resuscitation in adult in-hospital cardiac arrest

Research

Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests

Commentary

Dehydroepiandrosterone sulphate: diabolical hormone or epiphenomenon in aneurysmal subarachnoid hemorrhage?

Research

Reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock

Research

Outcomes associated with bacteremia in the setting of methicillin-resistant Staphylococcus aureus pneumonia: a retrospective cohort study