Sie sind auf Seite 1von 8

|

Received: 26 August 2019    Accepted: 25 November 2019

DOI: 10.1111/jth.14690

R E C O M M E N D AT I O N S A N D G U I D E L I N E S

Defining trauma-induced coagulopathy with respect to future


implications for patient management: Communication from the
SSC of the ISTH

Hunter B. Moore1 | Satoshi Gando2,3  | Toshiaki Iba4 | Paul Y. Kim5,6  |


7 8,9 10
Calvin H. Yeh  | Karim Brohi  | Beverley J. Hunt  | Jerrold H. Levy11  |
12 13,14,15 16,17 18
Dominik F. Draxler  | Simon Stanworth  | Klaus Görlinger  | Matthew D. Neal  |
19 20,21
Martin A. Schreiber  | Christopher D. Barrett  | Robert L. Medcalf12  |
Ernest E. Moore22 | Nicola J. Mutch23  | Jecko Thachil24 | Tetsumei Urano25 |
Scott Thomas26 | Ecaterina Scărlătescu27 | Mark Walsh26,28,29 |
for the Subcommittees on Fibrinolysis, Disseminated Intravascular Coagulation, and
Perioperative and Critical Care Thrombosis and Hemostasis
1
Department of Surgery, University of Colorado, Denver, CO, USA
2
Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine,
Sapporo, Japan
3
Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
4
Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
5
Department of Medicine, McMaster University, Hamilton, ON, Canada
6
Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
7
Department of Medicine, Division of Emergency Medicine, University of Toronto, Toronto, ON,, Canada
8
Queen Mary University of London, London, UK
9
Centre for Trauma Sciences, London, UK
10
Guy's and St Thomas' NHS Trust, King's College, London, UK
11
Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USA
12
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria,, Australia
13
Transfusion Medicine, NHS Blood and Transplant, Oxford, UK
14
Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
15
Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre,, University of Oxford,, Oxford,, UK
16
Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, Essen, Germany
17
TEM Innovations GmbH, Munich, Germany
18
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
19
Department of Surgery, Oregon Health & Science University, Portland, OR, USA
20
Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
21
Division of Acute Care Surgery and Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
22
Ernest E. Moore Shock Trauma Center at Denver Health, University of Colorado, Denver, CO, USA
23
Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen,
Aberdeen, UK
24
Department of Haematology, Manchester Royal Infirmary, Manchester, UK
25
Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
26
Beacon Medical Group Trauma and Surgical Research Services, South Bend, IN, USA

Manuscript handled by: Marcel Levi

Final decision: Marcel Levi, 25 November 2019

|
740     © 2020 International Society on Thrombosis and wileyonlinelibrary.com/journal/jth J Thromb Haemost. 2020;18:740–747.
Haemostasis
MOORE et al. |
      741

27
Department of Anaesthesia and Intensive Care, Fundeni Clinical Institute, Bucharest, Romania
28
Departments of Emergency and Internal Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, USA
29
Indiana University School of Medicine, South Bend Campus, South Bend, IN, USA

Correspondence: Paul Y. Kim, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, Ontario, L8L 2X2 Canada.
Email: paul.kim@taari.ca

1 |  I NTRO D U C TI O N development of clinical and point-of-care diagnostic strategies for


rapidly and pre-emptively identifying the patient with TIC in order
Trauma-induced coagulopathy (TIC) is a clinical scenario spanning to optimize transfusion and resuscitation.
the spectrum of hypocoagulability to hypercoagulability causing a
wide range of complications including uncontrolled bleeding and
thrombotic disease. TIC is driven by tissue injury,1 where shock and 2 | CU R R E NT U N D E R S TA N D I N G O F TH E
hypoperfusion act synergistically to worsen and provoke TIC. 2
M EC H A N I S M S O F TR AU M A- I N D U C E D
Defining the clinical syndrome of TIC has been hampered by the COAG U LO PATH Y ( TI C)
wide variations in patient presentation. Severely injured patients
manifest diverse phenotypes of TIC spanning hypo- and hyperco- The CRASH-2 trial demonstrated reduced mortality if tranexamic
agulability and may rapidly progress between phenotypes. The pre- acid (TXA) is administered within 3  hours of the onset of trauma
sentation is chiefly thought to be a result of the variability of the in patients at risk of bleeding, providing proof-of-concept for the
magnitude and timing of the interaction between tissue injury and acute management of coagulopathy in trauma. 27 The key coagula-
shock as well as resuscitation practices. Variations in experimental tion system abnormalities have been attributed to (a) systemic en-
measurements such as timing of patient presentation, prior therapy, dotheliopathy from tissue damage, ischemia, and resuscitation, and
and timing to blood sampling complicate the definition of TIC.3-5 (b) the ensuing systemic inflammatory response to this injury, which
As a result of the difficulty in defining clinical TIC, the underlying is thought to trigger (c) platelet activation and dysfunction, (d) dys-
biochemical mechanisms of TIC are unclear. Factors contributing to regulated coagulation factor generation including thrombin and ac-
a hypocoaguable state include impaired thrombin generation, im- tivated protein C, and (e) altered fibrinolysis through the release of
paired platelet function, deficient or defective fibrinogen, increased tissue-type plasminogen activator (t-PA) and/or its inhibitor, plasmi-
fibrinolysis, and endothelial dysfunction, while those contributing to nogen activator inhibitor-1 (PAI-1).
hypercoagulability include excessive thrombin generation, endothe- Trauma-induced coagulopathy is driven by two distinct and syn-
lial injury, platelet hyperactivity and exhaustion, hyperfibrinogene- ergistic insults: hypovolemic shock due to blood loss and extensive
mia, and impaired fibrinolysis.6-16 tissue disruption (Figure 1).28 The variables that modify the TIC phe-
In recent years, multiple definitions of the hemostatic distur- notype and course include (a) trauma: injury extent and severity,
bances in trauma have been published.17-20 The unstandardized no- tissue type injured (head, 29 orthopaedic30), degree of hemorrhagic
menclature and definitions (ATC, acute traumatic coagulopathy; TIC, shock, mechanism of injury (blunt, penetrating/hemorrhagic31,32),
trauma-induced coagulopathy; ACoTS, acute coagulopathy of trau- and time from injury;3,7,20,33-36 (b) patient factors: age, sex, medical
ma-shock; CoT, coagulopathy of trauma; DIC, disseminated intra- comorbidities (cardiovascular disease), concomitant anticoagulant
vascular coagulation; endotheliopathy of trauma and hemorrhagic use, presence of other toxins including alcohol, heritable differences
21 5,6
blood failure; SHINE, shock-induced endotheliopathy ) used to in baseline coagulation; and (c) resuscitation strategies: types of fluids
describe these derangements in trauma has led to a considerable used, the impact of blood components, adjuncts such as TXA, and
degree of confusion within the field. 22-25 timing of surgical intervention.20,33,36 The combination of these three
This communication, from the International Society on variables distinguishes TIC from the other acute coagulopathies (ie,
Thrombosis and Haemostasis (ISTH) Scientific and Standardization open cardiovascular surgery, liver transplantation, postpartum hem-
Committee (SSC) on fibrinolysis, DIC, and perioperative and criti- orrhage, sepsis, malignancy, and autoimmune- and toxin-mediated
cal care thrombosis and hemostasis, builds on a previous consider- coagulopathy).37-39 The timing, treatments, and complex interplay of
ation26 and (a) provides an overview of the current leading theories variables lead to the various TIC phenotypes. Ongoing dysregulation
of the mechanism of TIC, (b) compares and contrasts the major over- of coagulation may eventually lead to a final common pathway of ful-
lapping lessons from coagulopathies related to other critical illnesses minant coagulation failure and the clinical presentation of DIC.
such as sepsis-induced coagulopathy (SIC), (c) addresses the critical Impaired clot formation is driven by both hypoxia and tissue in-
knowledge gaps in our understanding of the pathophysiology of jury (Figure 2). 28 Proposed mechanisms include the activation of pro-
TIC, and (d) defines a new categorization scheme for patient groups tein C with subsequent deactivation of factor (F) V and FVIII, and the
to better stratify the likely coagulopathic phenotypes and patho- release of heparan sulfate and syndecan-1 from the endothelial gly-
physiology based on the patient’s arrival characteristics. Together, cocalyx.6,40 Systemic hyperfibrinolysis is stimulated by hypoxia with
addressing these knowledge gaps may provide a roadmap for the endothelial release of t-PA, and thrombin generated by activation of
|
742       MOORE et al.

Traumatic event

• Genetics Hypoxia Tissue injury

Tissue factor
• Co-Morbidity
Microparticles
Epinephrine
Medication Complement

PMN Elastase
Histones/DNA
Endothelial dysfunction
Polyphosphates
Myosin
HMGB1

RBC Meizothrombin Activated protein C


Heparan sulfate

t-PA
Factor consumption
Va VIIIa

• Acidosis
Fib Platelet dysfunction
AT

• Hypothermia

• Dilution

Clot formation

F I G U R E 1   Mechanisms of impaired clot formation in trauma-induced coagulopathy. Impaired clot formation is driven by both hypoxia
and tissue injury. Proposed mechanisms include the generation of activated protein C with subsequent deactivation of factors Va and VIIIa,
and the release of heparan sulfate from the endothelial glycocalyx. Adapted from Moore et al. 28

coagulation that also stimulates t-PA release. Fibrinolysis can be in- that are tightly coupled with the coagulation system.49 Damage-
hibited via the byproducts of tissue injury and activation of platelets associated molecular pattern proteins (DAMPs) released during
28
releasing antifibrinolytic agents such as PAI-1. tissue injury50,51 and ischemia/reperfusion52-54 elicit time-depen-
Coagulopathic patients can harbor hypofibrinogenemia early dent changes in coagulation and fibrinolysis that may have common
after injury, which can be a marker of TIC, and is dose-dependently pathways; namely, immediate thrombin generation, t-PA availability,
related to shock, injury severity, and mortality.22 Depletion is asso- and later suppression of fibrinolysis by PAI-1. 55,56 The behavior of
ciated with poor outcomes, an effect which can be reversed with DAMPs in TIC may have similar and related responses after sterile
supplementation.41 Low fibrinogen concentrations correlate with injury to pathogen-associated molecular proteins following infec-
increased transfusions, ventilator days, and increased early and late tion, a response thought to regulate the severity and progression in
mortality.42 Fibrinogen supplementation improves clot initiation and sepsis and SIC. 57,58
43,44 45
stability, and may decrease mortality in this group. A large ob-
servational study in combat-injured patients in Afghanistan suggested
that supplementation with cryoprecipitate may have independent sur- 3 | CO M PA R I S O N S A N D LE S S O N S
vival benefit.46 Current European guidelines suggest the early empiric LE A R N E D FRO M S E P S I S - I N D U C E D
administration of higher concentrations of fibrinogen,47 although the COAG U LO PATH Y
benefits are currently being assessed in a number of clinical trials.48
Acute severe injury and haemorrhagic shock cause a com- As with other coagulopathies, SIC fundamentally differs from
plex response of the innate immune and inflammatory systems TIC in its pathophysiology, particularly in the early stage of the
MOORE et al. |
      743

Traumatic event

Yes No

Hypoxia Tissue injury

Endothelial dysfunction

DAMPS

Metabolites • Histones/DNA
Plasminogen • Myosin
• Succinate
t-PA • Polyphophates
• Taurocholic Acid
• HMGB1
• α Enolase
Complement • Actin
• α Globin
• Acylcarnitines
Plasmin
Platelet activation

Platelet dysfunction
Receptors
• PAI-1
• PAR-1
ADP • TAFI

• AA Clot degradation • α2-antiplasmin
• Collagen • α2-macroglobulin
• α1-antirypsin

F I G U R E 2   Factors regulating fibrinolysis in trauma-induced coagulopathy. Systemic hyperfibrinolysis is stimulated by hypoxia with
endothelial release of t-PA that activates plasminogen. On the other hand, fibrinolysis is inhibited via the by-products of tissue injury and
activation of platelets releasing antifibrinolytic agents. Adapted from Moore et al. 28

diseases. Common pathways are activated in both SIC and TIC, Sepsis Trauma
and as the dysregulated inflammatory and coagulo-fibrinolytic
responses progress, they may converge on a final pathway of DIC
(Figure 3).
The systemic infections that most commonly trigger SIC are SIC TIC
with Staphylococcus aureus, Streptococcus pneumonia, Escherichia
coli, klebsiella species, and Pseudomonas aeruginosa.59-61 The clini-
cal presentation is that of DIC and is thought to originate from loss DIC
of localization of clotting factor activation starting in the microvas- Thrombotic phenotype
Fibrinolytic phenotype
culature. Patients present with either thrombotic or bleeding phe-
notypes, and the SIC timeline is unclear as the triggering event to F I G U R E 3   The overlap of sepsis-induced coagulopathy and
coagulopathy is likely distributed over a long phase of infection. The trauma-induced coagulopathy. Adapted from Iba et al.37
infectious trigger causes upregulation of multiple inflammatory bio-
markers, leading to widespread fibrin deposition and microvascular coagulopathies. This is of importance because refining the diagno-
thrombosis. Fibrinolytic shutdown appears to be a common occur- sis of SIC allows for early individual treatment based on clinical and
rence and similar to late trauma.62 TXA is not recommended in these laboratory presentation.37-39,63 Recent clarification of the distinction
patients as their recovery is dependent on fibrinolysis to lyse sys- between what has classically been called DIC and other forms of ac-
tematic thrombi. quired coagulopathy in the early stages have been noted to advance
Recent refinement of the diagnosis of SIC has suggested a unique treatment for those coagulopathies with individualized diagnostic
pathophysiologic mechanism for sepsis when compared to other and therapeutic options.64
|
744       MOORE et al.

4 |  PRO P OS E D S TR ATI FI C ATI O N O F 4.3 | Enhanced versus inhibited fibrinolysis


TI C C LI N I C A L PR E S E NTATI O N FO R
I N V E S TI G ATI O N In primary coagulopathy, trauma and traumatic shock give rise to
systemic and persistent thrombin generation7,14,18,24,50,56,69 asso-
The clinical presentation of coagulopathy in TIC can shift between ciated with platelet dysfunction15,16 from the early to late phases
two ends of the hemostatic spectrum depending on the time of trauma. Fibrinolytic systems bring about dynamic two-phase
course,8,9 injuries, and prior treatments, where one clinical pheno- changes: increased fibrinolysis due to shock-induced t-PA release
type may be more dominant. This heterogeneous presentation and at an early stage,50,70 and the inhibition of fibrinolysis due to per-
treatment, complicated by complex and dynamic underlying patho- sistent expression of PAI-1 at a later stage of trauma.51,71,72 These
physiology, is the likely source of the incomplete definitions in the imbalances are predictors of mortality in observational studies, and
clinical presentation and course of the patient with TIC. We propose importantly, those patients with physiologic levels of fibrinolysis
a clinical stratification to severely injured patients in order to better on admission have been shown to have the lowest mortality.8-11
study and define the underlying mechanisms of the clinical pheno- However, depending on the mechanism of injury, and the type and
types of TIC. speed of resuscitative measures imparted, the evolution from hy-
Currently there is no broadly accepted standard laboratory perfibrinolytic-type to hypofibrinolytic-type can occur in minutes to
method to identify and prognosticate TIC. In the setting of severe hours.10 Increased fibrinolysis accelerates bleeding, thus leading to
injury and shock, elevated international normalized ratio (INR) has uncontrolled hemorrhage.
been the most robust predictor of mortality, length of intensive care
unit stay, and 30-day survival. 22,65,66 These patients with elevated
INR were more than four times more likely to die, a finding consis- 4.4 | Resuscitation responders versus non-
tent between military and civilian trauma registries. TIC has also responders
been found in patients without severe traumatic injuries, although
coagulopathy is associated with high injury severity score. Patients Hemostatic changes in trauma are also modified by resuscitation
with a base deficit less than or equal to − 6 may also be monitored leading to ischemia-reperfusion events, which can further derange
for underlying coagulopathy or occult shock. 35 Viscoelastic assays coagulation. Early TIC is influenced by the degree of resuscitation,
such as thromboelastography and rotational thromboelastom- which is a necessity in most cases. Also, therapeutic measures in-
etry are emerging point-of-care tools for providing a global view cluding surgical interventions and hemostatic resuscitation as a part
of hemostasis.67 The clinical cutoffs of these tests are still under of damage control resuscitation postinjury can modify the late coag-
investigation.68 ulopathy. Sustained systemic inflammatory response syndrome as-
sociated with the activation of tissue factor-dependent coagulation
pathways and inhibition of fibrinolysis contributes to organ dysfunc-
4.1 | Primary versus secondary tion in the late phase of trauma.9,10,51,73 However, when resuscitative
measures and the availability/accessibility of allogeneic blood prod-
Trauma-induced coagulopathy is a primary endogenous coagulopa- ucts may be limited (eg, less-resourced nations or remote locations),
thy that is at least partly caused by dysregulated innate immune in- the TIC spectrum may present a completely different picture, which
flammatory host responses to trauma and traumatic shock, leading often leads to early mortality.
to organ dysfunction and a poor outcome.7 Anemia, dilution, hypo-
thermia, and acidosis exogenously induce secondary coagulopathy,
which can modify primary coagulopathy.35 5 | A D D R E S S I N G K N OW LE D G E G A P S I N
TH E FU T U R E

4.2 | Early versus late Identifying the molecular mechanisms that drive TIC, including the
location of where coagulation occurs (ie, intra- versus extravascu-
In civilian12 and military13 settings, uncontrolled hemorrhage is lar space segregated by the endothelial layer) is crucial for under-
the leading cause of preventable death following traumatic injury. standing the consequent pathophysiology of coagulopathy. 24,26 In
Civilian studies reveal that more than 95% of deaths from hemor- addition, this segregation by the endothelial barrier inherently pro-
rhage occur within the first 24 hours of the onset of trauma, with a vides control of both anticoagulant (eg, antithrombin and negatively
median time of approximately 3 hours.12 The first hours of resuscita- charged glycocalyx, activated protein C) and fibrinolytic (eg, PAI-1,
tion are critical and require prompt identification and management α2-antiplasmin) phenotype. Understanding of the hemostatic effects
to control local and systemic hemostasis. Patients in the “late” phase of the damaged/activated endothelium in TIC that consequently
may have ongoing coagulopathy requiring a biochemically driven leads to pathologic coagulopathy is needed to better understand TIC
resuscitation strategy following surgical hemostasis. and improve its treatment strategies.
MOORE et al. |
      745

In addition, an agreed-upon definition of TIC will subsequently AU T H O R C O N T R I B U T I O N S


allow for clarification and identification of the knowledge gaps HBM, SG, TI, PYK, CHY, MDN, RLM, EEM, NJM, and MW wrote
that exist. These gaps include identifying: (a) factors that regulate the manuscript and participated in the consensus discussion. EEM,
progression of TIC to DIC, (b) the differences between primary HBM, SG, and TI generated the figures and PYK edited the figures.
pathogenic mechanisms driving SIC versus TIC, (c) the significance KB, BJH, JHL, DFD, SS, KG, MAS, CDB, JT, TU, ST, and ES contrib-
of dysregulated fibrinolysis and anticoagulation in TIC, (d) the dis- uted by participating in the consensus discussion and editing of the
tinguishing characteristics of early and late phenotypes in TIC, (e) manuscript.
the role of platelet dysfunction in SIC and TIC, and (f) the diagnostic
criteria of SIC and TIC. ORCID
Satoshi Gando  https://orcid.org/0000-0002-3525-0750
Paul Y. Kim  https://orcid.org/0000-0002-0504-3064
6 |  S U M M A RY Karim Brohi  https://orcid.org/0000-0003-0643-8866
Beverley J. Hunt  https://orcid.org/0000-0002-4709-0774
Trauma-induced coagulopathy is a clinical disease process that Jerrold H. Levy  https://orcid.org/0000-0003-3766-4962
encapsulates multiple defects to major systems in hemostasis in Christopher D. Barrett  https://orcid.org/0000-0001-9720-8155
the acutely severely injured patient. Patients at various stages can Nicola J. Mutch  https://orcid.org/0000-0002-7452-0813
present on a spectrum between bleeding and thromboembolism,
with untreated TIC leading eventually to a picture of fulminant T WITTER
DIC. Heterogeneity in patient injury factors complicate the defi- Paul Y. Kim  @kimpy79
nition of the clinical presentation of TIC, study of the underlying Karim Brohi  @karimbrohi
pathophysiology of TIC, and the devising of optimal strategies for Beverley J. Hunt  @bhwords
treating the primary defects in TIC. To decrease the heterogene- Jerrold H. Levy  @JerroldLevy
ity, this communication proposes that the study of trauma patients Robert L. Medcalf  @MedcalfRobert
suffering from TIC be assessed on the following factors: (a) pri- Nicola J. Mutch  @nikmutch
mary or secondary coagulopathy based on the pathophysiology,
(b) early or late coagulopathy based on the timing, (c) increased REFERENCES
or inhibited fibrinolysis phenotypes based on the dynamics of 1. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of
fibrinolysis, and (d) resuscitated or non-resuscitated state based trauma: mechanism, identification and effect. Curr Opin Crit Care.
2007;13(6):680-685.
on the rescue measures provided. If adopted, these steps could
2. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a
dramatically improve patient care in the acute stages of trauma review of mechanisms. J Trauma. 2008;65(4):748-754.
and facilitate examination of the underlying pathophysiological 3. Kornblith LZ, Moore HB, Cohen MJ. Trauma-induced coagulopathy:
mechanisms. the past, present, and future. J Thromb Haemost. 2019;17(6):852-862.
4. Cohen MJ, Christie SA. New understandings of post injury coagula-
tion and resuscitation. Int J Surg. 2016;33(Pt B):242-245.
C O N FL I C T O F I N T E R E S T 5. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: bal-
SG is a consultant for Asahikasei Pharma America and has received ancing progressive catecholamine induced endothelial activa-
honorarium from Asahikasei Pharma Japan. EEM is a co-founder tion and damage by fluid phase anticoagulation. Med Hypotheses.
2010;75(6):564-567.
of ThromboTherapeutics; holds equity in Haemonetics; and has
6. Johansson PI, Stensballe J, Ostrowski SR. Shock induced endotheli-
received research funding from Haemonetics, Instrumentation opathy (SHINE) in acute critical illness - a unifying pathophysiologic
Laboratory, and Stago. MDN holds equity as a board member mechanism. Crit Care. 2017;21(1):25.
at Haima Therapeutics; received honoraria from CSL Behring 7. Gando S, Hayakawa M. Pathophysiology of trauma-induced coag-
and Janssen Pharmaceuticals; received research funding from ulopathy and management of critical bleeding requiring massive
transfusion. Semin Thromb Hemost. 2016;42(2):155-165.
Haemonetics, Instrumentation Laboraties, Noveome, and Accriva
8. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis physio-
Diagnostics. HBM is a co-founder of ThromboTherapuetics and logic fibrinolysis, and fibrinolysis shutdown: the spectrum of post-
receives research support from Instrument Laboratories. ES has injury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma
received honoraria from Danube University of Krems, Weill- Acute Care Surg. 2014;77(6):811-817; discussion 817.
9. Meizoso JP, Karcutskie CA, Ray JJ, et al. Persistent fibrinolysis
Cornell Medicine, University Hospital Zurich Foundation, CSL
shutdown is associated with increased mortality in severely injured
Behring, and EurAsia Heart Foundation. MAS is a consultant for trauma patients. J Am Coll Surg. 2017;224(4):575-582.
Haemonetics, Arsenal Medical, and Velico Medical. JHL is on the 10. Leeper CM, Neal MD, McKenna CJ, Gaines BA. Trending fibrino-
advisory board for CSL Behring, Instrumentation Laboratories, lytic dysregulation: fibrinolysis shutdown in the days after injury
is associated with poor outcome in severely injured children. Ann
Janssen, Octapharma, Leading Biosciences, and Merck. MW holds
Surg. 2017;266(3):508-515.
research grants from Haemonetics and has received honoraria 11. Gall LS, Brohi K, Davenport RA. Diagnosis and treatment of hy-
from Portola Inc. All other authors have no conflict of interest to perfibrinolysis in trauma (A European Perspective). Semin Thromb.
report. Hemost. 2017;43(2):224-234.
|
746       MOORE et al.

12. Tisherman SA, Schmicker RH, Brasel KJ, et al. Detailed description 33. White NJ. Mechanisms of trauma-induced coagulopathy. Hematol
of all deaths in both the shock and traumatic brain injury hypertonic Am Soc Hematol Educ Progr. 2013;2013:660-663.
saline trials of the Resuscitation Outcomes Consortium. Ann Surg. 3 4. Cohen MJ, Christie SA. Coagulopathy of trauma. Crit Care Clin.
2015;261(3):586-590. 2017;33(1):101-118.
13. Eastridge BJ, Mabry RL, Seguin P, et al. Death on the battlefield 35. Simmons JW, Powell MF. Acute traumatic coagulopathy: pathophys-
(2001–2011): implications for the future of combat casualty care. J iology and resuscitation. Br J Anaesth. 2016;117(suppl 3):iii31-iii43.
Trauma Acute Care Surg. 2012;73(6 Suppl 5):S431-S437. 36. Davenport RA, Brohi K. Cause of trauma-induced coagulopathy.
14. Davenport RA, Guerreiro M, Frith D, et al. Activated protein C Curr Opin Anaesthesiol. 2016;29(2):212-219.
drives the hyperfibrinolysis of acute traumatic coagulopathy. 37. Iba T, Levy JH, Thachil J, Wada H, Levi M. The progression from
Anesthesiology. 2017;126(1):115-127. coagulopathy to disseminated intravascular coagulation in repre-
15. Wohlauer MV, Moore EE, Thomas S, et al. Early platelet dysfunc- sentative underlying diseases. Thromb. Res. 2019;179:11-14.
tion: an unrecognized role in the acute coagulopathy of trauma. J 38. Iba T, Levy JH, Raj A, Warkentin TE. Advance in the management of
Am Coll Surg. 2012;214(5):739-746. sepsis-induced coagulopathy and disseminated intravascular coag-
16. Vogel S, Bodenstein R, Chen Q, et al. Platelet-derived HMGB1 is a crit- ulation. J Clin Med. 2019;8(5):E728.
ical mediator of thrombosis. J Clin Invest. 2015;125(12):4638-4654. 39. Iba T, Levy JH, Wada H, et al. Differential diagnoses for sepsis-in-
17. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J duced disseminated intravascular coagulation: communication from
Trauma. 2003;54(6):1127-1130. the SSC of the ISTH. J Thromb Haemost. 2019;17(2):415-419.
18. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and dissem- 4 0. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high
inated intravascular coagulation: lessons from the classical litera- admission syndecan-1 level, a marker of endothelial glycocalyx
ture. Ann Surg. 2011;254(1):10-19. degradation, is associated with inflammation, protein C depletion,
19. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces fibrinolysis, and increased mortality in trauma patients. Ann Surg.
endogenous heparinization in patients with severe injury and early 2011;254(2):194-200.
traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. 41. Grottke O, Mallaiah S, Karkouti K, Saner F, Haas T. Fibrinogen sup-
20. Chang R, Cardenas JC, Wade CE, Holcomb JB. Advances in plementation and its indications. Semin Thromb Hemost 2020;46(1):
the understanding of trauma-induced coagulopathy. Blood. 38-49.
2016;128(8):1043-1049. 42. Curry N, Foley C, Wong H, et al. Early fibrinogen concentrate ther-
21. White NJ, Ward KR, Pati S, Strandenes G, Cap AP. Hemorrhagic apy for major haemorrhage in trauma (E-FIT 1): results from a UK
blood failure: oxygen debt, coagulopathy, and endothelial damage. multi-centre, randomised, double blind, placebo-controlled pilot
J Trauma Acute Care Surg. 2017;82(6S Suppl 1):S41-S49. trial. Crit Care. 2018;22(1):164.
22. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute 43. Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and fibrin in hemostasis
traumatic coagulopathy: clinical and experimental investigations. J and thrombosis. Arterioscler Thromb Vasc Biol. 2017;37(3):e13-e21.
Thromb Haemost. 2010;8(9):1919-1925. 4 4. Shenkman B, Einav Y, Livnat T, Budnik I, Martinowitz U. In vitro
23. Johansson PI, Sorensen AM, Perner A, et al. Disseminated intravas- evaluation of clot quality and stability in a model of severe throm-
cular coagulation or acute coagulopathy of trauma shock early after bocytopenia: effect of fibrinogen, factor XIII and thrombin-activat-
trauma? An observational study. Crit Care. 2011;15(6):R272. able fibrinolysis inhibitor. Blood Transfus. 2014;12(1):78-84.
24. Gando S, Wada H, Thachil J. Differentiating disseminated intravas- 45. McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ.
cular coagulation (DIC) with the fibrinolytic phenotype from coag- Fibrinogen is an independent predictor of mortality in major
ulopathy of trauma and acute coagulopathy of trauma-shock (COT/ trauma patients: a five-year statewide cohort study. Injury.
ACOTS). J Thromb Haemost. 2013;11(5):826-835. 2017;48(5):1074-1081.
25. Maegele M. The coagulopathy of trauma. Eur J Trauma Emerg Surg. 46. Morrison JJ, Ross JD, Dubose JJ, et al. Association of cryopre-
2014;40(2):113-126. cipitate and tranexamic acid with improved survival following
26. Gando S, Wada H, Kim HK, et al. Comparison of dissemi- wartime injury: findings from the MATTERs II Study. JAMA Surg.
nated intravascular coagulation in trauma with coagulopathy of 2013;148(3):218-225.
trauma/acute coagulopathy of trauma-shock. J Thromb Haemost. 47. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on
2012;10(12):2593-2595. management of major bleeding and coagulopathy following trauma:
27. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on fourth edition. Crit Care. 2016;20:100.
death, vascular occlusive events, and blood transfusion in trauma 48. Winearls J, Wullschleger M, Wake E, et al. Fibrinogen Early In
patients with significant haemorrhage (CRASH-2): a randomised, Severe Trauma studY (FEISTY): study protocol for a randomised
placebo-controlled trial. Lancet. 2010;376(9734):23-32. controlled trial. Trials. 2017;18(1):241.
28. Moore EE, Moore HB, Chapman MP, Gonzalez E, Sauaia A. Goal- 49. Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb
directed hemostatic resuscitation for trauma induced coagulopa- Haemost. 2011;9(Suppl 1):182-188.
thy: maintaining homeostasis. J Trauma Acute Care Surg. 2018;84(6S 50. Gando S, Tedo I, Kubota M. Posttrauma coagulation and fibrinoly-
Suppl 1):S35-S40. sis. Crit Care Med. 1992;20(5):594-600.
29. Zhang J, Zhang F, Dong J-F. Coagulopathy induced by traumatic 51. Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator
brain injury: systemic manifestation of a localized injury. Blood. inhibitor-1 in posttrauma disseminated intravascular coagulation:
2018;131(18):2001-2006. relationship to multiple organ dysfunction syndrome. Crit Care Med.
3 0. Stutz CM, O’Rear LD, O’Neill KR, et al. Coagulopathies in ortho- 1995;23(11):1835-1842.
paedics: links to inflammation and the potential of individualizing 52. Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin forma-
treatment strategies. J Orthop Trauma. 2013;27(4):236-241. tion with consecutive impairment of fibrinolysis in patients with
31. Kanehata K, Ogura T. Abstract 231: difference of the trauma-in- out-of-hospital cardiac arrest. Thromb Haemost. 1997;77(2):278-282.
duced coagulopathy between penetrating and blunt trauma. 53. Adrie C, Laurent I, Monchi M, et al. Postresuscitation disease
Circulation. 2018;138(Suppl_2):A231-A231. after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care.
32. Hayakawa M. Pathophysiology of trauma-induced coagulopathy: 2004;10(3):208-212.
disseminated intravascular coagulation with the fibrinolytic pheno- 54. Adrie C, Monchi M, Laurent I, et al. Coagulopathy after suc-
type. J Intensive Care. 2017;5(1):14. cessful cardiopulmonary resuscitation following cardiac arrest:
MOORE et al. |
      747

implication of the protein C anticoagulant pathway. J Am Coll 6 6. Peltan ID, Vande Vusse LK, Maier RV, Watkins TR. An inter-
Cardiol. 2005;46(1):21-28. national normalized ratio-based definition of acute traumatic
55. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochon- coagulopathy is associated with mortality, venous thromboem-
drial DAMPs cause inflammatory responses to injury. Nature. bolism, and multiple organ failure after injury. Crit Care Med.
2010;464(7285):104-107. 2015;43(7):1429-1438.
56. Abrams ST, Zhang N, Manson J, et al. Circulating histones are me- 67. Gonzalez E, Moore EE, Moore HB. Management of trauma-in-
diators of trauma-associated lung injury. Am J Respir Crit Care Med. duced coagulopathy with thrombelastography. Crit Care Clin.
2013;187(2):160-169. 2017;33(1):119-134.
57. Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhi- 68. Veigas PV, Callum J, Rizoli S, Nascimento B, da Luz LT. A systematic
bition of plasminogen activation after administration of intravenous review on the rotational thrombelastometry (ROTEM(R)) values for
endotoxin to normal subjects. N Engl J Med. 1989;320(18):1165-1172. the diagnosis of coagulopathy, prediction and guidance of blood
58. Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis transfusion and prediction of mortality in trauma patients. Scand J
of disseminated intravascular coagulation in sepsis. JAMA. Trauma Resusc Emerg Med. 2016;24(1):114.
1993;270(8):975-979. 69. Tauber H, Innerhofer P, Breitkopf R, et al. Prevalence and impact of
59. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J abnormal ROTEM(R) assays in severe blunt trauma: results of the
Med. 2013;369(9):840-851. “Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-
60. Savage RD, Fowler RA, Rishu AH, et al. Pathogens and antimicro- TRE-TIC) study.” Br J Anaesth. 2011;107(3):378-387.
bial susceptibility profiles in critically ill patients with bloodstream 70. Chapman MP, Moore EE, Moore HB, et al. Overwhelming tPA
infections: a descriptive study. C open. 2016;4(4):E569-E577. release, not PAI-1 degradation, is responsible for hyperfibrinoly-
61. Textoris J, Wiramus S, Martin C, Leone M. Antibiotic therapy in pa- sis in severely injured trauma patients. J Trauma Acute Care Surg.
tients with septic shock. Eur J Anaesthesiol. 2011;28(5):318-324. 2016;80(1):15-16.
62. Schmitt FCF, Manolov V, Morgenstern J, et al. Acute fibrinolysis 71. Moore HB, Moore EE, Lawson PJ, et al. Fibrinolysis shutdown phe-
shutdown occurs early in septic shock and is associated with in- notype masks changes in rodent coagulation in tissue injury versus
creased morbidity and mortality: results of an observational pilot hemorrhagic shock. Surgery. 2015;158(2):386-392.
study. Ann Intensive Care. 2019;9(1):19. 72. Macko AR, Moore HB, Cap AP, et al. Tissue injury suppresses fi-
63. Levi M, Hunt BJ. A critical appraisal of point-of-care coagulation testing brinolysis after hemorrhagic shock in nonhuman primates (Rhesus
in critically ill patients. J Thromb Haemost. 2015;13(11):1960-1967. macaque). J Trauma Acute Care Surg. 2017;82(4):750-757.
6 4. Thachil J. The elusive diagnosis of disseminated intravascular co- 73. Partrick DA, Moore FA, Moore EE, et al. The inflammatory pro-
agulation: does a diagnosis of DIC exist anymore? Semin Thromb file of interleukin-6, interleukin-8, and soluble intercellular ad-
Hemost. 2019;45(1):100-107. hesion molecule-1 in postinjury multiple organ failure. Am J Surg.
65. Kashuk JL, Moore EE, Johnson JL, et al. Postinjury life threatening 1996;172(5):425-431.
coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the
answer? J Trauma. 2008;65(2):261.

Das könnte Ihnen auch gefallen