Beruflich Dokumente
Kultur Dokumente
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
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740 © 2020 International Society on Thrombosis and wileyonlinelibrary.com/journal/jth J Thromb Haemost. 2020;18:740–747.
Haemostasis
MOORE et al. |
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Department of Anaesthesia and Intensive Care, Fundeni Clinical Institute, Bucharest, Romania
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Departments of Emergency and Internal Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, USA
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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
Traumatic event
Tissue factor
• Co-Morbidity
Microparticles
Epinephrine
Medication Complement
•
PMN Elastase
Histones/DNA
Endothelial dysfunction
Polyphosphates
Myosin
HMGB1
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. |
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Traumatic event
Yes No
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
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744 MOORE et al.
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. |
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