Professional Documents
Culture Documents
URRENT
C
OPINION
Purpose of review
Transfusion paradigms and protocols have evolved at a rapid pace in the last few years to ameliorate the
adverse effects of trauma-induced coagulopathy (TIC). This has occurred despite fragmented and
inadequate knowledge of the underlying pathophysiology that they are supposed to treat. This review will
collate and assimilate the most recent data about TIC in order to present our state-of-the-art understanding
of this condition.
Recent findings
TIC was conventionally construed simply as depletion, dysfunction or dilution of procoagulant factors.
However, contemporary understanding recognizes it as an imbalance of the dynamic equilibrium between
procoagulant factors, anticoagulant factors, platelets, endothelium and fibrinolysis. The endogenous
component of TIC (acute traumatic coagulopathy) is not merely a consumptive coagulopathy, but is
characterized by isolated factor V inhibition, dysfibrinogenaemia, systemic anticoagulation, impaired
platelet function and hyperfibrinolysis. Acute traumatic coagulopathy then becomes exacerbated by
hypothermia, acidosis and resuscitation with hypocoagulable fluids.
Summary
Further improvement in the outcome from trauma-haemorrhage is possible with more refined and tailored
haemostatic resuscitation. Achieving this will depend upon a better understanding of the haemostatic
defects that develop after injury.
Keywords
coagulopathy, fibrinolysis, protein C, transfusion, trauma
INTRODUCTION
Trauma-induced coagulopathy (TIC) has long been
known to coexist with severe haemorrhage. However, our understanding of the mechanisms and
clinical importance of coagulopathy changed significantly after the identification of an endogenous
acute traumatic coagulopathy (ATC) nearly a decade ago [1,2]. Presence of this haemostatic impairment early after injury is an independent predictor
for increased organ injury, infection and death [3 ].
Although not yet proven in a human study, these
outcomes are probably mediated in part by
increased blood loss and greater exposure to transfusion products. Better prevention and treatment of
ATC should theoretically deliver improved outcomes for our trauma patients.
Other mediators of haemostatic impairment
such as hypothermia, acidosis and haemodilution
exacerbate the early ATC and contribute collectively
to TIC. Transfusion paradigms and protocols have
evolved at a rapid pace in the last few years to
&&
www.co-criticalcare.com
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Trauma
KEY POINTS
PROCOAGULANT IMPAIRMENT
MECHANISMS OF TRAUMA-INDUCED
COAGULOPATHY
TIC was conventionally construed simply as depletion, dysfunction or dilution of procoagulant factors.
However, contemporary understanding recognizes it
as an imbalance of the dynamic equilibrium between
632
www.co-criticalcare.com
&&
&&
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
SYSTEMIC ANTICOAGULATION
We have previously proposed that systemic anticoagulation via activation of protein C may be a
functional mediator of ATC [15]. Data from our
murine model of trauma and haemorrhaghic shock
support this hypothesis [16]. Depletion of protein C
at the injury scene and on admission to hospital has
been associated with prolongations of both the
prothrombin time (PT) and aPTT [8 ]. Interestingly,
this also correlated with a specific reduction of
circulating factor V activity, a target substrate of
aPC. Johansson et al. [13] were the first group to
record an increase in aPC concentrations after
injury. However, only 12 patients in this study were
coagulopathic and it did not differentiate between
those with and without ATC.
Resolution of the relationship between aPC and
ATC has been improved by a prospective observational study of 203 major trauma patients performed
at San Francisco General Hospital [3 ]. Patients with
a combination of tissue hypoperfusion and severe
traumatic injury showed a strong activation of the
protein C pathway with significant increase in
circulating aPC and reciprocal reduction in residual
protein C. This was associated with a coagulopathy
characterized by inactivation of the coagulation
factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen
activator and high D-dimers. There is now a significant body of evidence developing to demonstrate
that protein C is activated in ATC and, as a functional anticoagulant, can be expected to influence
the haemostatic competence of victims of severe
trauma. What remains unclear is the magnitude
of this anticoagulant effect in vivo and its dominance
relative to other known and unknown mediators
of coagulopathy.
&&
&&
room and observed hyperfibrinolysis in 23, an incidence of 6.8%. In 14 cases, hyperfibrinolysis was
considered fulminant with a complete breakdown
of the clot observed within 60 min. A reduction of
clot firmness between 16 and 35% was observed in
another nine patients. The mortality rate in patients
with fulminant hyperfibrinolysis was 85.7%,
compared with 11.1% in low-grade fibrinolysis.
Patients with hyperfibrinolyis had higher ISS, lower
Glasgow Coma Score (GCS), lower systolic blood
pressure and higher lactates than patients without
hyperfibrinolysis.
In a study of 118 patients meeting criteria for the
highest tier of trauma team activation, Ives et al. [18]
diagnosed hyperfibrinolysis in 13 (11%) using a TEG
definition of at least 15% estimated percentage lysis.
Nine of these patients died (81.8) and in a stepwise
logistic regression model, consisting of 12 significant univariate variables, hyperfibrinolysis and
massive transfusion (>10 PRBC in 24 h) were the
only significant predictors of early (24 h) mortality
(predicting 53 and 69% of deaths, respectively).
Compared with patients without hyperfibrinolysis,
patients with hyperfibrinolysis had a greater need
for massive transfusion [76.9 vs. 8.7%; adjusted odds
ratio 19.1; 95% confidence interval (CI) 3.6
101.3; P < 0.001] and had a greater early mortality
(69.2 vs. 1.9%; adjusted odds ratio 55.8; 95% CI
7.2432.3; P < 0.001) and in-hospital mortality
(92.3 vs. 9.5%; adjusted odds ratio 55.5; 95% CI
4.8649.7; P 0.001).
Although we have an international randomized
controlled trial to direct the use of tranexamic acid
in trauma, the inclusion criteria for this study were
broad and quite possibly included a large number for
whom it delivered no haemostatic benefit [19]. Over
half of the study cohort did not receive any blood
transfusion and for those who did, the study drug
had minimal impact upon the volume they
received. There is scope for refinement in the selection criteria of recipients of this therapeutic. At
present, TEG appears to have poor sensitivity for
detecting subtle fibrinolysis that might still contribute to ATC and be modified by antifibrinolytics.
Better assessment tools are needed to direct tailored
management of fibrinolysis after trauma.
PLATELET DYSFUNCTION
HYPERFIBRINOLYSIS
Fibrinolysis is also clearly a functional component
of ATC. Some recent prospective clinical studies
have better defined the incidence and clinical
importance of this entity. Tauber et al. [17 ] performed RoTEM analysis on 334 major trauma
patients (ISS >15) upon admission to the emergency
&
&
www.co-criticalcare.com
633
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Trauma
&
ENDOTHELIAL ACTIVATION
Vascular endothelium is an active participant in the
pathophysiology of ATC. Large capillary beds host
thrombomodulin and endothelial protein C receptors anchored through their luminal surface that
capture thrombin and accelerate protein C activation 1000-fold [25]. In addition to inactivating
coagulation factors Va and VIIIa, aPC also consumes
plasminogen activator inhibitor-1 (PAI-1), the
major antagonist of tissue-type plasminogen activator inhibitor-1 (t-PA). Consequently, traumatic
haemorrhage with tissue hypoperfusion leads to
overwhelming release of t-PA from vascular endothelial cells and subsequent hyperfibrinolysis [26].
However, aPC is potentially not the only endothelial
anticoagulant system influencing ATC. By measuring the difference between KaolinTEG and HeparinaseTEG in samples taken from 77 trauma patients on
ED arrival, a recent study found that four of these
patients (5.2%) had evidence of a high degree of
autoheparinization, which appeared mechanistically linked to endothelial glycocalyx degradation
[27 ]. This group had higher ISS [median IQR, 31
&&
634
www.co-criticalcare.com
&
&
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
&&
&
CONCLUSION
ATC is an endogenous impairment of all components
of haemostasis that develops rapidly in response to
tissue injury and haemorrhagic shock. Rather than
being merely a consumptive coagulopathy, ATC is
characterized by isolated factor V inhibition, dysfibrinogenaemia, systemic anticoagulation, impaired
platelet function and hyperfibrinolysis. It is exacerbated by hypothermia, acidosis and resuscitation
with hypocoagulable fluids, which contribute collectively to establish TIC. Further improvement in
the outcome from trauma-haemorrhage is possible
with more refined and tailored haemostatic resuscitation. Achieving this will depend upon a better
www.co-criticalcare.com
635
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Trauma
18. Ives C, Inaba K, Branco BC, et al. Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg 2012 [Epub ahead of
print].
19. Shakur H, Roberts I, Bautista R, et al. 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; 376:2332.
20. Brown LM, Call MS, Margaret Knudson M, et al. A normal platelet count
&
may not be enough: the impact of admission platelet count on mortality
and transfusion in severely injured trauma patients. J Trauma 2011; 71
(2 Suppl 3):S337S342.
Interesting study showing that poor outcomes are dose-dependently associated with
reductions in admission platelet count, despite often remaining within the normal
range. It suggests that we may need a lower transfusion threshold for platelets.
21. Borgman MA, Spinella PC, Holcomb JB, et al. The effect of FFP:RBC ratio on
morbidity and mortality in trauma patients based on transfusion prediction
score. Vox Sang 2011; 101:4454.
22. Holcomb JB, Zarzabal LA, Michalek JE, et al. Increased platelet:RBC ratios are
&
associated with improved survival after massive transfusion. J Trauma 2011;
71 (2 Suppl 3):S318S328.
This is a good example of the new retrospective reports suggesting that more and
earlier platelet transfusions could improve outcome after injury.
23. Solomon C, Traintinger S, Ziegler B, et al. Platelet function following trauma. A
&
Multiple Electrode Aggregometry study. Thromb Haemost 2011; 106:322
330.
A small but interesting study demonstrating subtle platelet dysfunction after injury.
Much more data are needed in this area.
24. Wohlauer MV, Moore EE, Thomas S, et al. Early platelet dysfunction: an
unrecognized role in the acute coagulopathy of trauma. J Am Coll Surg 2012;
214:739746.
25. Esmon C. The protein C pathway. Chest 2003; 124 (3 Suppl):26S32S.
26. Brohi K, Cohen M, Ganter M, et al. Acute traumatic coagulopathy: initiated by
hypoperfusion modulated through the protein C pathway? Ann Surg 2007;
245:812818.
27. 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; 73:6066.
Part of a suite of novel studies examining endothelial responses during trauma and
haemorrhagic shock. It suggests that other anticoagulant pathways may be
functionally relevant in ATC in addition to aPC.
28. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating
&
adrenaline levels at admission predict increased mortality after trauma.
J Trauma Acute Care Surg 2012; 72:428436.
Highly novel study of possible neurohormonal influences on coagulation after injury.
636
www.co-criticalcare.com
29. 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; 254:194200.
This study is the first to closely examine endothelial perturbations during trauma
and haemorrhagic shock.
30. Johansson PI, Srensen AM, Perner A, et al. High sCD40L levels early after
&
trauma are associated with enhanced shock, sympathoadrenal activation,
tissue and endothelial damage, coagulopathy and mortality. J Thromb
Haemost 2012; 10:207216.
A small study examining the feasibility of using the ISTH scoring system for trauma
patients.
31. Hess J, Brohi K, Dutton R, et al. The coagulopathy of trauma: a review of
mechanisms. J Trauma 2008; 65:748754.
32. Wafaisade A, Wutzler S, Lefering R, et al. Drivers of acute coagulopathy after
severe trauma: a multivariate analysis of 1987 patients. Emerg Med J 2010;
27:934939.
33. Humann B, Lefering R, Taeger G, et al.; Sven Lendemans and the DGU
Trauma Registry. Influence of prehospital fluid resuscitation on patients with
multiple injuries in hemorrhagic shock in patients from the DGU trauma
registry. J Emerg Trauma Shock 2011; 4:465471.
34. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly
addressing the early coagulopathy of trauma. J Trauma 2007; 62:307
310.
35. Frith D, Goslings J, Gaarder C, et al. Definition and drivers of acute traumatic
coagulopathy: clinical and experimental investigations. J Thromb Haemost
2010; 8:19191925.
36. Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damageinduced inflammation. Br J Surg 2012; 99 (Suppl 1):1220.
37. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated
intravascular coagulation: lessons from the classical literature. Ann Surg
2011; 254:1019.
38. Rizoli S, Nascimento B, Key N, et al. Disseminated intravascular coagulo&&
pathy in the first 24 h after trauma: the association between ISTH score
and anatomopathologic evidence. J Trauma 2011; 71 (5 Suppl 1):S441
S447.
A prospective study evaluating the possible involvement of DIC in the pathophysiology of ATC.
39. 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; 149:221230.
A good study examining the response of fibrinolytic components of haemostasis to
injury.
&
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.