UTD Coagulopathy

Coagulopathy associated with trauma Page 1 of 24
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Coagulopathy associated with trauma
Authors Section Editors Deputy Editor

Mitchell Cohen, MD, FACS Heidi L Frankel, MD, FACS Kathryn A Collins, MD, PhD, FACS
Matthew E Kutcher, MD Lawrence LK Leung, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2013. | This topic last updated: Dec 10, 2012.
INTRODUCTION — Trauma remains a leading cause of death and disability in adults in spite of advances in resuscitation, surgical
management, and critical care [1]. Between 25 to 35 percent of injured civilian trauma patients develop a biochemically evident coagulopathy
upon arrival in the emergency department, in spite of improved efficiency of trauma systems, military and civilian, in reducing the time interval
between acute injury and treatment [2-4]. Coagulopathy may be the result of physiologic derangements such as acidosis, hypothermia, or
hemodilution related to fluid or blood administration; however, an acute coagulopathy can also occur in severely injured patients independent
of, or in addition to, these factors [2,3]. Several terms are used in the literature to refer to this condition, including acute traumatic
coagulopathy (ATC), early coagulopathy of trauma (ECT), trauma-induced coagulopathy, and the acute coagulopathy of trauma-shock
(ACoTS) [2,3,5,6].
The etiology, diagnosis and treatment of coagulopathy associated with trauma will be reviewed here. The general principles of shock
management in the trauma patient and the treatment of excessive anticoagulation related to medical treatment are discussed elsewhere.
(See "Correcting excess anticoagulation after warfarin" and "Initial evaluation and management of shock in adult trauma".)
IMPACT — Coagulopathy in trauma patients, and specifically acute traumatic coagulopathy (ATC), is associated with higher transfusion
requirements, longer intensive care unit and hospital stays, more days requiring mechanical ventilation, and a greater incidence of multiorgan
dysfunction. Compared with patients who do not have coagulopathy, those with coagulopathy have a threefold to fourfold greater mortality,
and are up to eight times more likely to die within the first 24 hours following injury [2-4,7,8].
Injury to brain tissue may predispose to acute traumatic coagulopathy and about one-third of patients with traumatic brain injury (TBI) have a
coagulopathy.
ETIOLOGY — The etiology of coagulopathy in the injured patient is multifactorial with overlapping contributions depending upon the injury
and nature of resuscitation. Normal coagulation is a balance between hemostatic and fibrinolytic processes which permit control of bleeding
following mild injury while preventing inappropriate intravascular thrombosis. (See "Overview of hemostasis".)
Etiologies that upset this balance include the classic elements of the ‘vicious triad’ which includes acidosis related to tissue injury and shock,
hypothermia from exposure and fluid administration, and hemodilution due to fluid or component blood product administration. Systemic
consumption of clotting factors manifesting as disseminated intravascular coagulation (DIC) may occur early after injury due to inadequate
clotting factor repletion in the face of ongoing consumption, or later in the hospital course triggered by secondary insults (eg, sepsis).
Frequently complicating these etiologies but mechanistically different, acute traumatic coagulopathy (ATC) is a biochemical response to
injury and shock leading to hyperfibrinolysis and hypocoagulability.
Acidosis — Inadequate tissue perfusion in patients with hypovolemic shock due to bleeding leads to metabolic (lactic) acidosis, which can
be exacerbated by excessive chloride and component blood administration. (See "Shock in adults: Types, presentation, and diagnostic
approach", section on 'Hypovolemic shock'.)
Acidosis causes demonstrable clotting dysfunction in experimental models at pH<7.2 by interfering with the assembly of coagulation factor
complexes involving calcium and negatively-charged phospholipids [9-12]. As an example, the activity of the
factor Xa/Va/phospholipid/prothrombin (“prothrombinase”) complex is reduced by 50, 70, and 90 percent at a pH of 7.2, 7.0, and 6.8,
respectively. However, correction of acidosis alone does not always correct the associated coagulopathy, indicating that tissue injury causes
coagulopathy via additional mechanisms [13,14].
Hypothermia — Hypothermia in injured patients is graded into mild (36 to 34ºC), moderate (34 to 32ºC), and severe (<32ºC) [15]. Nearly two-
thirds of trauma patients have a temperature below 36ºC on presentation; 9 percent of trauma patients have a temperature at or below 33ºC
[11,16-19].
Hypothermia following injury is due to cold exposure at the time of injury, during transport, and during the trauma examination compounded
by the administration of cold intravenous fluids. Patients who require surgery are at a greater risk for hypothermia due to further physical
exposure in the operating room, additional fluid administration, and the effects of general anesthesia. Injured patients with hypothermia
generally have worse outcomes compared with non-injured patients with hypothermia; however, hypothermia alone is a weak independent
predictor of mortality [15,20]. Acidosis and hypothermia are synergistic with increased mortality when both are present, compared with one or
the other [21].
The effect of hypothermia on clotting includes platelet dysfunction and impaired enzymatic function. Overall thrombin generation in activated
in vitro clotting systems is generally preserved at a temperature of 33ºC; however, impairment of tissue factor activity, platelet aggregation,
and platelet adhesion are evident at temperatures between 33 to 37ºC [11,16]. It is important to note that no effects on standard coagulation
tests are seen in hypothermia-induced coagulopathy without special sample handling due to the standard practice of pre-warming blood
samples to 37ºC prior to analysis, which corrects the defect.
Specific measures to correct hypothermia include controlling physical exposure, the administration of warmed fluids, and passive rewarming
with blankets and forced-air devices. Rapid identification and control of bleeding is vital to preserve normal temperature. Continuous
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temperature monitoring is essential to ensure that mild hypothermia does not worsen. In the case of moderate or severe hypothermia and
coagulopathy, central rewarming may be needed.
Resuscitation-associated (dilutional) coagulopathy — Resuscitation-associated coagulopathy (RAC) refers to alterations of the

coagulation system induced by large volumes of fluid or unbalanced component blood administration during the management of shock [22].
Trauma resuscitation historically focused on the treatment of hypotension and acidosis with aggressive crystalloid resuscitation followed by
packed red blood cells (PRBC). At that time, treatment of coagulopathy was initiated only in response to abnormal standard coagulation
tests. Similarly, platelet transfusion was generally not performed until laboratory evidence of thrombocytopenia was present.
Computer modeling [23], in vitro experiments [24], and clinical studies in healthy volunteers have found that large volume resuscitation with
crystalloid, colloid, and packed red blood cells leads to dilution of plasma clotting proteins [25]. A retrospective study of 8724 injured patients
found a positive correlation between prehospital fluid resuscitation volume and coagulopathy [4]. Coagulopathy was present on admission in
more than 50 percent of patients who received >3L of intravenous fluid prior to arrival, but coagulopathy was also present in 10 percent of
patients administered <500 mL and in 32 patients who had received no prehospital fluids, which appears to reflect the frequently overlapping
contribution of acute traumatic coagulopathy (ATC). (See 'Acute traumatic coagulopathy' below.)
Another factor contributing to resuscitation associated coagulopathy is the effect of storage time on packed red blood cells which undergo
progressive functional and structural changes over time. The ‘storage lesion’ includes decreased pH, chelation of calcium, low 2,3
diphosphoglycerate levels, and decreased clotting factor concentration. Transfusion of older blood can further impair microvascular
perfusion, and has inflammatory and immunomodulatory effects [26-28]. (See "Red blood cell transfusion in adults: Storage, specialized
modifications, and infusion parameters", section on 'Effect of storage conditions on transfusion outcome'.)
The median duration of storage of a unit of red blood cells in the United States is about 15 days, which is relatively old, with even older units
frequently allocated to high-use facilities such as trauma centers [29]. Thus, the storage lesion is particularly relevant for massively
transfused trauma patients. Several studies suggest that an older storage age of transfused PRBCs may be linked to higher morbidity and
mortality [30,31] but this remains an area of controversy and current investigation [32].
Disseminated intravascular coagulation — Disseminated intravascular coagulation (DIC) is a systemic process producing consumptive
coagulopathy in concert with diffuse microvascular thrombosis (table 1). In trauma patients, tissue-injury-induced exposure of tissue factor
and activation of the extrinsic coagulation cascade leads to thrombin generation proportional to injury severity. In addition, systemic
embolism of tissue-specific thromboplastins from sites of injury (including bone marrow lipid material, amniotic fluid, and brain phospholipids)
may predispose patients to DIC [33]. (See "Pathogenesis and etiology of disseminated intravascular coagulation".)
Acute traumatic coagulopathy — Acute traumatic coagulopathy (ATC) is an impairment of hemostasis and activation of fibrinolysis that
occurs early after injury and is biochemically evident prior to, and independent of, the development of significant acidosis, hypothermia, or
hemodilution. The risk of ATC increases with hypotension, higher injury severity scores, worsening base deficit, and head injury [3,7,8]. Once
established, ATC is often compounded by other etiologies. (See 'Acidosis' above and 'Hypothermia' above and 'Resuscitation-associated
(dilutional) coagulopathy' above.)
Patients with ATC frequently meet criteria for DIC and some authors have argued that acute traumatic coagulopathy (ATC) may represent an
early, partially-compensated stage of DIC [22,34,35]. However, the concept of DIC as a final common pathway for several different
phenomena is insufficient to explain the hematologic abnormalities post-injury [7,36,37]. Coagulopathy in the absence of thrombocytopenia
and hypofibrinogenemia, as seen in ATC, argues against consumption as a necessary underlying mechanism [13] Although D-dimer levels
are frequently elevated and fibrinogen levels depleted in acutely injured patients, indicating intravascular fibrin deposition and active
fibrinolysis [38], functional thrombin generation (assayed by the presence of prothrombin fragments and thrombin-antithrombin complexes)
remains intact [7,39-41]. Furthermore, ATC occurs only when tissue injury is combined with systemic hypoperfusion. Thus, it is most likely
that ATC is mechanistically distinct from DIC but that these frequently overlap. Exploring this distinction is an area of ongoing research.
(See 'Disseminated intravascular coagulation' above and 'Diagnosis' below.)
Mechanism — Initial observations in hypoperfused trauma patients found a correlation between acute traumatic coagulopathy (ATC) and
elevated levels of activated protein C (aPC), reduced levels of non-activated protein C, and elevated soluble thrombomodulin [7]. Activation
of the thrombomodulin-protein C system is a principle pathway mediating ATC, a mechanism that is distinct from clotting factor consumption
or dysfunction [7,42].
Under normal circumstances, tissue injury leads to thrombin generation, fibrin deposition, and clot formation via the extrinsic pathway (figure
1). The enzymatic pathways making up the coagulation cascade are discussed in detail elsewhere. (See "Overview of hemostasis".)
Initiation of the clotting process is localized to the site of tissue injury. Systemic coagulation due to the escape of thrombin from the injury site
is inhibited by circulating antithrombin III, or by the binding of thrombin to constitutively-expressed thrombomodulin on nearby undamaged
endothelial cells [43].
Protein C, a systemic anticoagulant, is proteolytically converted from an inactive zymogen to activated protein C (aPC) by the complex of
thrombin with thrombomodulin. Activated protein C is a serine protease that proteolytically inactivates factors Va and VIIIa and depletes
plasminogen inhibitors (figure 2 and table 2) [42,44]. In this manner, aPC can serve a protective function by inhibiting thrombosis during
periods of decreased flow.
Sustained hypoperfusion is associated with increased circulating soluble thrombomodulin levels, which can increase the availability of
thrombomodulin-bound thrombin [7]. Thus, thrombin can be diverted from a predominantly procoagulant role to a pathologic, anticoagulant
role via excess activation of protein C [7]. Although the precise biochemical mechanisms are still under investigation, the importance of
protein C in this process has been confirmed. Inhibition of protein C by an antibody-mediated mechanism in an animal model has been
shown to prevent the development of ATC in response to trauma and hemorrhagic shock [42].
With widespread protein C activation, thrombin generation is inhibited, impairing clot formation, and fibrinolysis is enhanced causing
degradation of existing clot. Consumption of endogenous plasminogen activator inhibitor-1 (PAI-1) by ATC-mediated aPC destabilizes the
fibrinolytic balance, leading to uninhibited tissue plasminogen activator (tPA)-mediated conversion of plasminogen to plasmin [45]. Diversion
of thrombin to protein C activation may also reduce activation of thrombin-activatable fibrinolysis inhibitor (TAFI), further enhancing fibrinolytic
activity [46]. These mechanisms lead to the hyperfibrinolytic state seen in trauma patients with ATC, which is reflected in increased levels of
tissue plasminogen activator (tPA), decreased plasminogen activator inhibitor (PAI-1), and increased D-dimer [7].
Activated protein C also has antiinflammatory and cytoprotective effects. Profound activation and consumption of protein C can deplete
protein C stores, potentially leading to infectious and later thrombotic sequelae. These effects are mediated via binding of aPC to a protease-
activated receptor-1 (PAR-1) and endothelial protein C receptor (EPCR) that are likely independent of the role of aPC as an anticoagulant
[47]. The importance of these mechanisms is suggested by separate murine models in trauma and sepsis. In these experiments, selective
antibody-mediated inhibition of the anticoagulant function of aPC reduced the rate of coagulopathy, but not mortality, while inhibition of
anticoagulant and cytoprotective functions increased mortality after a challenge with trauma/hemorrhagic shock [42], or injection of
lipopolysaccharide (LPS) [48].
These animal model results are supported by a recent study of 203 critically-injured trauma patients, for whom early coagulopathy was linked
to high levels of activated protein C, and later, protein C depletion as early as six hours after injury [49]. Patients who demonstrated protein C
depletion had a significantly increased risk of acute lung injury, ventilator-associated pneumonia, multiorgan failure, and death. A smaller
prospective study that also identified protein C depletion in trauma patients found elevated markers of endothelial injury and coagulopathy,
and noted a threefold higher risk of mortality [50].
Cytoprotective functions of aPC may also play a role in pulmonary capillary endothelial barrier function as suggested by in vitro studies
[51,52], and in human studies that found that persistently low protein C levels in critically-injured, mechanically-ventilated trauma patients are
associated with increased rates of pneumonia [53]. Ongoing studies are evaluating the interactions of the protein C system, innate [54,55]
and cellular immunity [56,57], and endothelial activation and barrier permeability [52,58-60].
The recently identified importance of ATC-associated depletion of protein C stores after traumatic injury suggests a potential mechanism for
later hypercoagulability and risk of thromboembolic complications after trauma [49,61,62]. Although this phenomenon has not been studied in
the trauma population, a prothrombotic state associated with protein C depletion has been reported in septic patients [44]. In one
observational study, injured patients with coagulopathy on admission had a significantly higher risk of thromboembolic complications, but a
link to protein C depletion was not specifically investigated [63]. However, the potential link between protein C depletion and late
hypercoagulability after trauma requires further investigation. Despite initial trials demonstrating the efficacy of recombinant aPC
supplementation in sepsis, the recent PROWESS-SHOCK trial failed to show a survival benefit in severe sepsis, and the drug was voluntarily
withdrawn from the market [64,65]; as such, there is no role for protein C replacement in trauma.
DIAGNOSIS — Severely injured trauma patients are routinely screened with standard laboratory evaluation, including complete blood count,
serum electrolytes, arterial blood gas analysis, and standard coagulation tests. These laboratory studies provide an assessment of acidosis
and hemodilution, indicate the severity of shock (as measured by base deficit and/or lactate), guide specific component blood product
administration, and serve as a baseline for the assessment of ongoing hemorrhage. (See "Initial evaluation and management of shock in
adult trauma", section on 'Evaluation and management'.)
Readily obtainable coagulation tests (prothrombin time, international normalized ratio, and activated partial thromboplastin time) are the
current standard for establishing a definitive diagnosis of coagulopathy. Fibrinogen and D-dimer levels are also available in most clinical
laboratories, and should be drawn in patients with evidence of hemorrhage or shock since these are surrogate markers of clotting factor
consumption and hyperfibrinolysis. (See "Clinical use of coagulation tests".)
Although these assays are commonly relied upon to evaluate bleeding risk in trauma patients, these tests were originally designed to screen
for heritable coagulopathies such as hemophilia, and subsequently used to monitor anticoagulant therapy [66]. The normal ranges are
derived from the general population and correlate poorly with bleeding risk in elective general and vascular surgical operations [67].
Additionally, the results from standard laboratory analysis can take up to 30 minutes and may not accurately reflect the patient’s evolving
coagulation status; the delay in the availability of results may make them irrelevant in the face of exsanguinating hemorrhage. As a result,
there has been a trend toward the use of point-of-care laboratory testing (thromboelastography) and clinical scoring systems to guide
management of the severely injured patient. (See 'Thromboelastography' below.)
Patients with prolonged clotting times due to known bleeding diatheses or pharmacological anticoagulation are not traditionally defined as
having ATC, although ATC physiology may exacerbate any preexisting coagulation disorders. (See "Approach to the adult patient with a
bleeding diathesis" and "Correcting excess anticoagulation after warfarin".)
Standard coagulation tests — Clinical studies have used several diagnostic criteria to identify clinically relevant coagulopathy following
injury. These include prothrombin time (PT)>18 seconds [39], international normalized ratio (INR)>1.5 [68], activated partial thromboplastin
time (PTT)>60 seconds [39], or any of these values at a threshold of 1.5 times the laboratory reference value [69]. The prevalence of
prolonged PT is higher, but prolongation of the PTT is more specific.
In a trauma registry study involving 20,103 patients, the PT and PTT were prolonged in 28 and 8 percent of patients, respectively [3].
The adjusted odds ratios for mortality were 1.35 for PT and 4.26 for PTT prolongation.
A five-center international retrospective study of 3646 trauma patients identified patients with significantly greater transfusion
requirements and increased mortality using a more liberal cutoff >1.2 of prothrombin time ratio (an inter-center standardized version of
the INR) [70]. This lower INR value may be a more appropriate cutoff for patients with more severe injury (injury severity scale [ISS]
>15) and shock.
Decreased platelet count (100,000/µL) and decreased platelet function also contribute to coagulopathy and poor outcome following trauma
[71]. Little information about platelet function is evident from the platelet count alone. In one study, serial functional analyses demonstrated
increased platelet activation and function in survivors following traumatic injury, while non-survivors had significant dysfunction [72].
Instrumentation available to assess platelet function includes the platelet function analyzer (PFA-100), and the electrical impedance whole
blood aggregometer (Multiplate®) [73,74]. However, these devices have not been clinically evaluated in trauma and resuscitation.
(See "Platelet function testing".)
It is unknown whether ATC might exist in patients with normal-range values of PT/INR and PTT. A careful study of markers of coagulopathy
and inflammation in 80 trauma patients identified that increasing injury severity correlated with elevated markers of endothelial cell and
glycocalyx damage, protein C activation, and clotting factor consumption even when INR and PTT values were in the normal range,
suggesting that the biochemical derangement of ATC lies on a continuum dependent upon injury and shock severity [41]. Similarly, there
have been anecdotal reports of injured patients with clinically relevant hyperfibrinolysis identified using thromboelastography, but without
prolonged PT or PTT. Thus, patients who present with the combination of significant injury (ISS>15) and a base deficit (<-6) should be
closely monitored and aggressively treated for clinical coagulopathy even in the face of normal standard coagulation tests, pending further
clinical studies.
Because ATC can occur in patients who have normal platelet and fibrinogen levels, specific platelet or fibrinogen levels are not included in
current diagnostic criteria; however, when abnormalities are present, thrombocytopenia and hypofibrinogenemia certainly contribute to
clinical hemorrhage and should be corrected [2,3,7]. (See 'Treatment' below.)
Thromboelastography — Thromboelastography assesses the viscoelastic properties of clot formation in fresh or citrated whole blood in real-
time. The test synthesizes information obtained from multiple coagulation tests (PT, PTT, thrombin time, fibrinogen level, and platelet count)
into a single read out (figure 3) providing information regarding clot initiation, clot strength, and fibrinolysis simultaneously. Until recently, the
bulk of its clinical use has been as a point-of-care adjunct during cardiopulmonary bypass [75] and liver transplantation [76]. As a functional
test of clot formation and lysis, it is conceptually well-suited to monitor the progress or resolution of coagulopathy after injury.
Thromboelastography parameters have been validated against standard laboratory tests [77,78], thrombin-antithrombin complex levels for
TEG® [79], and euglobin clot lysis times for RoTEM® [80]. Specific elements of the clotting cascade can be interrogated by performing tests
in the presence of specific clotting activators or inhibitors (table 3). (See "Platelet function testing", section on 'Thromboelastography'.)
Representative tracings compared with normal are given for each of the following abnormalities:
Primary fibrinolysis – (figure 4A-B)

Secondary hyperfibrinolysis – (figure 4A, 4C)
Thrombocytopenia – (figure 4A, 4D)
Clotting factor consumption – (figure 4A, 4E)
Hypercoagulability – (figure 4A, 4F)
Multiple studies have used thromboelastography to diagnose immediate hypocoagulability and later hypercoagulability following moderate
injury despite normal-range standard coagulation tests [81,82]. Studies involving trauma patients have correlated thromboelastography
parameters with increased mortality [83-86]. In one of these studies, the mortality rate for a group of patients who demonstrated
hyperfibrinolysis was significantly greater (77 versus 41 percent) compared with the group that did not demonstrate hyperfibrinolysis [85]. Cut-
off values for RoTEM®-based parameters correlate with standard laboratory transfusion cut-off values [87]. The use of thromboelastography
in trauma as a guide to transfusion is discussed below. (See 'Thromboelastography-based transfusion' below.)
Factor levels — Although coagulation factors are not commonly assessed in injured patients, coagulation factor depletion due to
hemodilution and unbalanced component blood transfusion exacerbates coagulopathy associated with trauma. Fibrinogen (factor I) is the
first factor to become depleted [88]. Of the commonly numbered coagulation factors, V and VIII are the most labile and may become
selectively depleted during trauma resuscitation, particularly in the setting of low plasma to red blood cell unit transfusion ratios.
Clinical scoring systems — Rapid clinical assessment of the trauma patient provides information that helps predict the potential for
coagulopathy and empiric need for massive transfusion based upon the mechanism and severity of injuries, hemodynamic status of the
patient, and evidence of active hemorrhage (eg, positive focused assessment with sonography for trauma [FAST], or brisk bleeding from a
chest tube) [89-91].
Several clinical scoring systems have been evaluated for this purpose, but are not widely used. These include the Trauma-Associated
Severe Hemorrhage (TASH) score [91], McLaughlin score [92], and Assessment of Blood Consumption (ABC) score [89]. A retrospective
review compared these clinical scores in 596 patients. Significantly higher TASH (13 versus 6), McLaughlin (3.4 versus 2.4) and ABC (2
versus 1) scores were seen in patients who required massive transfusion compared with patients who did not, but no significant predictive
differences were identified between these scores [89]. None of these scoring systems include coagulation parameter measurements,
highlighting the fact that massive hemorrhage is generally due to active bleeding requiring surgical or interventional control, not as a result of
coagulopathy.
The utility of any clinical scoring system requires the demonstration that mortality is reduced as a result of a high score triggering a
transfusion protocol, and that earlier activation of these protocols is associated with a further decrease in mortality. There are no prospective
trials that demonstrate such a survival benefit; however, significant reductions in overall blood product use and hospital costs have been
reported [93,94].
Given that many massive transfusion protocols call for the early use of plasma and increased transfusion ratios (1:1:1), a sensitive scoring
system may allow the early identification of patients at risk for ATC and more precise transfusion triggers, but these scoring systems have not
been designed or validated as diagnostic tests for coagulopathy.
TREATMENT — A diagnosis of acute traumatic coagulopathy (ATC) predicts significantly higher transfusion requirements in the first 24
hours of hospitalization. In one study, patients with ATC on admission received an average of 10 units of blood, compared with the 2
received by those with normal clotting studies [7]. The need for blood transfusion and number of units transfused is a predictor of systemic
inflammation, acute respiratory distress, and mortality following traumatic injury [95-97].
Although red blood cell transfusion improves perfusion and oxygen carrying capacity, there is an increasing awareness that traditional
transfusion protocols produce or exacerbate resuscitation-associated coagulopathy. Resuscitation protocols continue to vary widely between
trauma centers and ratios of plasma:PRBC range from 1:1 to 1:10 [23,98-100]. With low plasma ratios, treatment of coagulopathy becomes
delayed, and ultimately a greater volume of blood is required. The recognition of this problem has led to a widespread re-evaluation of
transfusion protocols, particularly in patients who demonstrate acute traumatic coagulopathy.
Although no prospective, randomized trials are yet available to provide a definitive approach to transfusion for the trauma population, patients
with acute traumatic coagulopathy are at risk for massive transfusion and they appear to benefit from a resuscitation protocol using fresh
frozen plasma, packed red blood cells, and platelets (1:1:1 ratios) given early and aggressively, while limiting crystalloid [101,102]. However,
the value of this approach is controversial, and benefits remain to be proven in randomized trials. Not all investigators feel there is a clear
survival benefit to 1:1:1 resuscitation [68,103,104]. The retrospective nature of these studies introduces selection and survival biases, with
patients who have died early in the resuscitation effort often excluded [105]. Patients may have had longer survival not because they
received more plasma, but rather received more plasma because they survived long enough to do so [106]. The initial management of the
severely injured patient is discussed in detail elsewhere. (See "Initial evaluation and management of shock in adult trauma".)
Thromboelastography-based transfusion — Transfusion protocols based upon thromboelastography parameters including clotting time,
clot formation time, amplitude, and clot lysis index (table 4) have been suggested for standard and rotational thromboelastography based
upon single center experiences [83,87,90,107-109].
Although thromboelastography-guided transfusion triggers are preliminary, the authors feel that thromboelastography is a promising
technology. As institutional experience and clinical guidelines accrue, the rapid turnaround and multifaceted information provided by point-of-
care thromboelastography will likely provide improved criteria for transfusion in acutely injured patients. Thrombelastography-
guided “thrombostatic” resuscitation protocols will likely emerge as the new standard, but only single-center studies are currently available
[109,110].
An example protocol from Denver Health Medical Center, providing normal ranges and transfusion cutoffs, is given in the table (table 5)
[110,111]. Examples of the utility of thromboelastography in trauma are given below:
The Denver group found that TEG® “G” values and thrombin generation parameters obtained six hours after arrival were significantly
associated with survival, while the INR was not [112].
A retrospective evaluation of TEG® used in 44 combat patients found that maximal amplitude (MA) correlated more strongly with 24-
hour transfusion requirements than standard laboratory values [113].
In another retrospective study of 832 patients requiring massive transfusion (21 percent trauma patients), patients whose transfusion
was guided by TEG® parameters received more plasma and platelets, and had significantly better 30-day survival (32 versus 20
percent) compared with retrospective controls transfused using standard laboratory measurements [114].
Pharmaceutical hemostatic agents — In addition to repletion of coagulation factors by transfusion, several pharmaceutical hemostatic
agents are available for the treatment of severe coagulopathy in the injured patient including recombinant factor VIIa, prothrombin complex
concentrate, antifibrinolytic agents (tranexamic acid, aminocaproic acid, aprotinin) and desmopressin.
Recombinant factor VIIa – Recombinant factor VIIa was initially developed and approved for the treatment of hemophilia and
congenital factor deficiencies [115]. The recognition of injury-exposed tissue factor binding to activated factor VII as the principle
trigger of clot formation after trauma led to interest in using recombinant factor VIIa for the management of acute traumatic
coagulopathy. Recombinant human factor VIIa is an adjunctive treatment for coagulopathy associated with trauma but should be
reserved for salvage therapy. When used, it is important to correct acidosis, hypothermia, thrombocytopenia, and hypofibrinogenemia
prior to its use. The dosing of recombinant factor VIIa in trauma patients is discussed in detail elsewhere. (See "Therapeutic uses of
recombinant coagulation factor VIIa in non-hemophiliacs", section on 'Managing post-traumatic hemorrhage'.)
Prothrombin complex concentrate – Prothrombin complex concentrate (PCC) is a factor concentrate enriched for factors II, VII, IX, and
X originally developed for hemorrhagic complications of hemophilia B [115]. The clinical use of PCC has been well studied in the
reversal of warfarin anticoagulation, since PCC is preferentially rich in the vitamin K-dependent clotting factors [116]. Some centers
have used PCC to correct coagulopathy after trauma and preliminary studies in animal models of hemorrhagic shock are promising,
but PCC has not been thoroughly evaluated in trauma patients [117]. (See "Plasma derivatives and recombinant DNA-produced
coagulation factors", section on 'Prothrombin complex concentrates'.)
Antifibrinolytic therapy – An interest in antifibrinolytic therapy has been renewed because of the presence of enhanced fibrinolysis
following severe trauma, [7,118-122]. Antifibrinolytic therapy may be appropriate for patients with ongoing hemorrhagic shock who
have an elevated D-dimer and depleted fibrinogen.
In the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial, an absolute mortality reduction of
1.5 percent was identified in patients receiving empiric tranexamic acid compared with placebo [119]. The coagulation status
(standard parameters or thromboelastography) of the patients enrolled was not specified. Enrollment criteria included adult trauma
patients within eight hours of injury with significant hemorrhage (systolic blood pressure <90 mmHg or heart rate >110 beats per
min, or both), or those who were considered to be at risk of significant hemorrhage.
The subsequent Military Application of Tranexamic acid in Trauma Emergency Resuscitation (MATTERs) study evaluated
outcomes in 896 patients who were treated with tranexamic acid or not [123]. For the first half of the study, patients received
tranexamic acid at the discretion of the treating surgeon, and thereafter, the drug was administered as part of a major hemorrhage
protocol or clinical practice guideline to patients requiring emergency blood products or patients with evidence of hyperfibrinolysis.
Unadjusted mortality rates were significantly reduced for treated (17 versus 24 percent) versus nontreated casualties. In a
subgroup of patients requiring massive transfusion, greater reductions in mortality were seen for those who were treated (28
versus 14 percent).
Further studies of tranexamic acid in patients with demonstrable ATC are needed to identify appropriate treatment criteria [119].
Other antifibrinolytic agents include aminocaproic acid and aprotinin, but these have not been evaluated in patients with traumatic
coagulopathy [120]. (See "Initial evaluation and management of shock in adult trauma", section on 'Antifibrinolytic agents'.)
Desmopressin – Desmopressin was developed for the treatment of inherited bleeding diatheses [124], and to counteract uremic
bleeding [125]. There is insufficient clinical evidence to support the use of desmopressin in the trauma population except in those
patients with preexisting bleeding diatheses [126]. Preliminary animal studies show that desmopressin administration improves but
does not completely correct hypothermia or acidosis-induced platelet dysfunction, but clinical validation of these experimental data
needs to be performed [127,128]. (See "Platelet dysfunction in uremia", section on 'Desmopressin (dDAVP)'.)
Monitoring — Reliance upon standard serial laboratory measurements is not compatible with the timely correction of coagulopathy [129].
Thromboelastography provides more comprehensive information in real-time and readily identifies hyperfibrinolysis [84]. Serial
thromboelastography, when available, should be used to monitor the patient’s coagulation status, and to guide transfusion and the correction
of coagulopathy. (See 'Thromboelastography' above and 'Thromboelastography-based transfusion' above.)
Where thromboelastography is not available, serial PT/INR, PTT, hemoglobin/hematocrit, platelet count, and fibrinogen levels should be
obtained on arrival and following transfusion to verify an appropriate response to blood products and/or pharmaceutical hemostatic agents,
before and after operative interventions, and as dictated by the patient’s clinical course.
Serial measurements of arterial blood gas for pH and base deficit are indicated for monitoring the resolution of acidosis and tissue
hypoperfusion in response to resuscitation. During the course of operative intervention and ongoing shock resuscitation, central temperature
monitoring (eg, via Foley catheter or esophageal temperature probe) should be performed until normothermia is reestablished.
In the massively resuscitated patient, the early institution of intermittent intraabdominal pressure transducer is also appropriate to monitor for
the development of abdominal compartment syndrome and the need for abdominal decompression. (See "Abdominal compartment
syndrome", section on 'Measurement of intraabdominal pressure'.)
SUMMARY AND RECOMMENDATIONS
Coagulopathy is associated with greater transfusion requirements, longer intensive care unit and hospital stays, more days of
mechanical ventilation, and a greater incidence of multiorgan failure and mortality. The identification and early correction of
coagulopathy is important to decrease fluid and transfusion requirements, decrease complications and improve survival. (See 'Impact'
above.)
The etiology of coagulopathy in the injured patient is multifactorial with overlapping contributions from acidosis related to tissue injury
and shock, hypothermia related to exposure and fluid administration, hemodilution due to fluid or component blood product
administration. In severely injured patients, an additional biochemical process that remains incompletely characterized underlies ‘acute
traumatic coagulopathy’. Consumption of clotting factors manifesting as disseminated intravascular coagulation (DIC) may contribute
upon presentation or later in the hospital course. (See 'Etiology' above.)
Acute traumatic coagulopathy (ATC) is an impairment of hemostasis and activation of fibrinolysis that occurs in response to severe
injury and is biochemically evident prior to, and independent of, the development of significant acidosis, hypothermia, or hemodilution.
Acute traumatic coagulopathy is mediated primarily by activation of the thrombomodulin-protein C system. (See 'Acute traumatic
coagulopathy' above.)
Standard coagulation tests including prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time
(PTT), fibrinogen level, and platelet count are part of the initial laboratory evaluation of trauma patients. In patients without pre-existing
coagulation defects, a prolonged prothrombin time (PT) and/or activated partial thromboplastin time (PTT) greater than 1.5 times
normal on admission defines the presence of acute traumatic coagulopathy. Clinically relevant ATC can occur in patients who have
normal platelet and fibrinogen levels. (See 'Diagnosis' above.)
Thromboelastography is emerging as an important tool for identifying patients with acute traumatic coagulopathy and for real-time
monitoring of ongoing resuscitation efforts in injured patients. Thromboelastography measures the viscoelastic properties of clot
formation providing information on clot initiation, clot strength, and fibrinolysis. Additional clinical evaluation is ongoing in an effort to
establish guidelines for more widespread use. (See 'Thromboelastography' above.)
For patients diagnosed with acute traumatic coagulopathy, we suggest plasma-based resuscitation, targeting ratios of packed red
blood cells, fresh frozen plasma, and platelets approaching 1:1:1 over protocols with lower ratios (Grade 2C). Injured patients with
acute traumatic coagulopathy are more likely to require massive transfusion and benefit from early matched transfusion. We prefer to
use thromboelastography to guide transfusion and monitor patients rather than treatment and follow-up guided by standard
coagulation tests. (See 'Treatment' above and "Initial evaluation and management of shock in adult trauma", section on 'Transfusion of
blood products'.)
Pharmaceutical hemostatic agents available as adjuncts for the treatment of severe coagulopathy in the injured patient include
recombinant factor VIIa, prothrombin complex concentrate, antifibrinolytic agents (tranexamic acid, aminocaproic acid, aprotinin) and
desmopressin. (See 'Pharmaceutical hemostatic agents' above and "Initial evaluation and management of shock in adult trauma",
section on 'Developing treatments for hemorrhage'.)
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Topic 15147 Version 6.0
GRAPHICS
Coagulation parameters in acute and chronic disseminated intravascular coagulation
Parameter Acute (decompensated) DIC Chronic (compensated) DIC

Platelet count Reduced Variable
Prothrombin time Prolonged Normal
Activated partial thromboplastin time Prolonged Normal
Thrombin time Prolonged Normal
Plasma fibrinogen Reduced Normal-elevated
Plasma factor V Reduced Normal
Plasma factor VIII Reduced Normal
Fibrin degradation products Elevated Elevated
D-dimer Elevated Elevated
Coagulation cascade initiated by tissue factor release at the site

of tissue injury
Factors in squares are inactive forms, whereas factors in circles are active
enzymes.
PT: prothrombin; Th: thrombin.
Adapted from: Ferguson JJ, et al. Eur Heart J 1998; 19(Suppl D):D6.
Regulation of fibrinolysis by plasminogen activator

inhibitor-1 (PAI-1), α2-antiplasmin, and thrombin-
activatable fibrinolysis inhibitor (TAFI)
PAI-1 inhibits plasmin formation by inhibiting tissue-type plasminogen

activator (t-PA). α2-antiplasmin inhibits the activity of plasmin, thereby
inhibiting fibrinolysis. TAFI circulates in plasma as a zymogen. It is
activated by thrombin when thrombin is bound on endothelial
thrombomodulin, and therefore represents a link between blood
coagulation and fibrinolysis. During fibrinolysis, plasmin cleaves intact
fibrin at lysine residues, initially yielding large, insoluble fibrin
fragments with lysine residues at their carboxyl termini. Plasminogen
binds avidly to C-terminal lysine residues within the partially degraded
fibrin clot and assumes a conformation that is susceptible to activation
by t-PA, thereby promoting plasmin formation, continued fibrinolysis
("rapid lysis by plasmin"), and generation of smaller, soluble fibrin
fragments that are dispersed by flowing blood. Activated TAFI (TAFIa) is
a carboxypeptidase that removes lysine residues from the carboxy (C)
termini of partially degraded fibrin fragments. By removing C-terminal
lysine residues from large fibrin fragments in the partially degraded
clot, TAFI inhibits recruitment of plasminogen to the clot, thereby
slowing fibrinolysis ("slow lysis by plasmin").
Diagram supplied by William P Fay, MD.
Components of the plasma fibrinolytic system
Molecular weight (d) Activity

Plasminogen 88,000 (single chain) Proenzyme form of fibrinolytic enzyme
Plasmin 88,000 (two chain) Active fibrinolytic enzyme
TPA 70,000 (one/two chain) Enzyme present in tissues that coverts plasminogen to plasmin
UPA 54,000 (two chain) Plasminogen activator (different from tPA)
α2PI 70,000 (single chain) Specific fast-acting inhibitor in plasma
PAI-1 40,000 (single chain) Fast-acting inhibitor of tPA (and UPA) secreted by endothelial cells)
d: Daltons; TPA: tissue plasminogen activator; UPA: urokinase-like plasminogen activator; α2PI: alpha-2 plasmin inhibitor; PAI-1:
plasminogen activator inhibitor-1.
TEG tracing interpretation
TEG: thromboelastograph
%: percent.
Image of the TEG® Thromboelastograph ® Hemostasis Analyzer Parameters LY30 Clot Breakdown is used
by permission of Haemonetics Corporation.
Image of the TEG® Thromboelastograph ® Hemostasis Analyzer Tracing is used by permission of
Haemonetics Corporation.
TEG® and Thromboelastograph ® are registers trademarks of Haemonetics Corporation in the US, other
countries, or both.
Various types of thromboelastograms
Native TEG Measures clot formation in the absence of a specific activator in either untreated whole blood or in
citrated whole blood after recalcification.
Rapid-TEG Tissue factor is used as the activator inducing clot formation via the extrinsic pathway. Compared with
(rTEG) native TEG, rTEG gives a readout of clot characteristics within about 10 minutes. The corresponding
RoTEM® test is the EXTEM.
Kaolin-TEG Phospholipid and kaolin are used to induce activation via the intrinsic pathway. The corresponding
RoTEM® test is the INTEM, which uses phospholipid and ellagic acid as activators.
Heparinase Simultaneous measurements can be performed comparing heparinase-treated blood with untreated blood
treatment to identify the effects of endogenous heparan sulfates, exogenous heparin and heparinoids. The
corresponding RoTEM® assay is the HEPTEM.
Platelet Platelet mapping assesses platelet function via the cyclooxygenase and ADP/P2 signaling pathways. The
mapping decrement in MA can be measured in the presence of platelet antagonists such as acetylsalicylic acid,
dipyridamole, and clopidogrel and compared with the untreated MA.
Fibrin function The RoTEM® FIBTEM test activates the extrinsic pathway in the presence of cytochalasin D, which is a
testing cytoskeletal inhibitor of platelet activity. This test qualitatively assesses fibrinogen levels since the clot
formation in this test is attributable to fibrin polymerization alone.
TEG: thromboelastogram; ADP/P2: adenosine diphosphate/P2 receptor; MA: maximal amplitude.
Normal thromboelastography and parameters
Normal citrated rapid TEG tracing with normal ACT, R time, K time, alpha angle, MA, G,
and LY30.
R (reaction time): time from sample placement or activation until the tracing amplitude reaches 2 mm;
K (clot formation time): time elapsed between the R-time and the point where the tracing amplitude
reaches 20 mm; alpha angle: angle between the middle line of the tracing and a tangential line to the
developing "body" of the tracing; MA (maximal amplitude): the maximal amplitude reached after clot
initiation; G: a calculated measure of total clot strength based on amplitude; LY30: the amount of clot
lysis detected 30 minutes after the maximal amplitute (MA) is reached; SP (split point): time from
sample placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.
Primary hyperfibrinolysis as assessed by thromboelastography
Citrated rapid thromboelastography study (rapid-TEG) showing primary

hyperfibrinolysis. The red tracing indicates a normal study.
This study has a normal ACT, normal R time, normal K time, and normal alpha angle;
low MA and G, reflecting significant fibrinolysis prior to achieving maximal clot
strength; high LY30 reflecting hyperfibrinolysis.
resistance.
Secondary hyperfibrinolysis
Citrated rapid-TEG showing secondary hyperfibrinolysis. The red tracing indicates a

normal study.
This study shows a normal ACT, R time, K time, and alpha angle; high LY30 reflecting
hyperfibrinolysis; normal MA and G, reflecting onset of fibrinolysis after achieving
maximal clot strength.
resistance.
Thrombocytopenia
Citrated rapid-TEG reflecting thrombocytopenia.The red line is a normal tracing.

This study shows a normal ACT, R time, K time, and LY30; low alpha angle, MA, and G,
reflecting platelet hypocoagulability.
resistance.
Clotting factor consumption and hypofibrinogenemia
Citrated rapid-TEG reflecting clotting factor consumption and hypofibrinogenemia. The

red line indicates a normal study.
This study shows a prolonged ACT, R time, and K time, reflecting enzymatic
hypocoagulability; markedly low alpha angle, MA, and G, reflecting platelet
hypocoagulability and poor fibrin deposition; normal LY30.
resistance.
Hypercoagulability
Citrated rapid-TEG reflecting hypercoagulability. The red tracing indicates a normal

study.
This study shows a shortened to normal ACT, R time, and K time, reflecting enzymatic
hypercoagulability; high alpha angle, MA, and G, reflecting platelet hypercoagulability
and/or excessive fibrin deposition; normal LY30. To distinguish the relative contribution
of platelet hypercoagulability and excessive fibrin deposition, one would need to
perform TEG platelet mapping or RoTEM® fibrin function testing.
resistance.
Thromboelastography definitions
Clot
Parameter Measurement TEG® ROTEM® Enzymatic
Abnormalities
phase abbreviation abbreviation stage
Clot Clotting time Time from start of Reaction time Clot time (CT) Early Prolonged by
initiation sample to 2 mm (R) activation of clotting factor
clot amplitude clotting deficiencies,
cascade anticoagulants, and
resulting in hypofibrinogenemia.
initial Shortened in
thrombin hypercoagulable
burst states.
Clot Clot formation Time from 2 mm Clot formation Clot formation Clot Prolonged by
kinetics time to 20 mm clot time (K) time (CFT) potentiation clotting factor
amplitude by activation deficiencies,
of platelets hypofibrinogenemia,
and thrombocytopenia,
thrombin- and platelet
mediated dysfunction.
cleavage of
Angle Angle of tangent Alpha angle Alpha angle soluble Abnormally low in
line from 2 mm to fibrinogen clotting factor
20 mm clot deficiencies,
formation hypofibrinogenemia,
thrombocytopenia,
and platelet
dysfunction.
Clot Maximal clot Amplitude Maximal Maximal clot Maximal clot Abnormally low in
strength strength measured at peak amplitude (MA) firmness (MCF) strength hypofibrinogenemia,
clot strength achieved via thromboyctopenia,
GP IIb/IIIa- or platelet
mediated dysfunction.
platelet-fibrin
Clot Calculated from G Maximal clot interactions Abnormally high in
viscoelasticity maximal elasticity (MCE) platelet
amplitude hypercoagulability.
Clot Clot lysis Percentage of loss Lysis at 30 min Lysis index at 30 Activation of Abnormally high in
lysis of amplitude at (LY30), min (LI30), fibrinolytic enzymatic or
fixed time after estimated maximal lysis system mechanical
maximal percentage of (ML) hyperfibrinolysis.
amplitude lysis (EPL)
Thromboelastography-guided transfusion parameters
r-TEG parameter Normal range Transfusion trigger

TEG-ACT 78-110 seconds >120 seconds (FFP)
Alpha angle 66°-82° <66° (cryoprecipitate)
K value 30-120 seconds >120 seconds (cryoprecipitate)
MA (maximum amplitude) 54-72 mm <54 mm (platelets)
G value 5.3-12.4 dynes/second <5.3 dynes/second*
LY-30 (lysis at 30 min) 0-8 percent >8 percent•
Values in the table are for non-citrated whole blood samples.

r-TEG: rapid thromboelastography; ACT: activated clotting time; FFP: fresh frozen plasma.
* Reevaluate all parameters per massive transfusion algorithm-decision tree.
• Consider antifibrinolytic.
Reproduced with permission from: Stahel PF, Moore EE, Schreier SL, et al. Transfusion strategies in postinjury coagulopathy. Curr Opin
Anaesthesiol 2009; 22:289. Copyright © 2009 Lippincott Williams & Wilkins.

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Coagulopathy associated with trauma Page 1 of 24

Official reprint from UpToDate®

Coagulopathy associated with trauma

Authors Section Editors Deputy Editor

Resuscitation-associated (dilutional) coagulopathy — Resuscitation-associated coagulopathy (RAC) refers to alterations of the

Primary fibrinolysis – (figure 4A-B)

of coagulopathy. (See 'Thromboelastography' above and 'Thromboelastography-based transfusion' above.)

SUMMARY AND RECOMMENDATIONS

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Topic 15147 Version 6.0

Coagulation parameters in acute and chronic disseminated intravascular coagulation

Parameter Acute (decompensated) DIC Chronic (compensated) DIC

Prothrombin time Prolonged Normal

Activated partial thromboplastin time Prolonged Normal

Thrombin time Prolonged Normal

Plasma fibrinogen Reduced Normal-elevated

Plasma factor V Reduced Normal

Plasma factor VIII Reduced Normal

Fibrin degradation products Elevated Elevated

D-dimer Elevated Elevated

Coagulation cascade initiated by tissue factor release at the site

Regulation of fibrinolysis by plasminogen activator

PAI-1 inhibits plasmin formation by inhibiting tissue-type plasminogen

Components of the plasma fibrinolytic system

Molecular weight (d) Activity

Plasmin 88,000 (two chain) Active fibrinolytic enzyme

UPA 54,000 (two chain) Plasminogen activator (different from tPA)

α2PI 70,000 (single chain) Specific fast-acting inhibitor in plasma

TEG tracing interpretation

Various types of thromboelastograms

TEG: thromboelastogram; ADP/P2: adenosine diphosphate/P2 receptor; MA: maximal amplitude.

Normal thromboelastography and parameters

Primary hyperfibrinolysis as assessed by thromboelastography

Citrated rapid thromboelastography study (rapid-TEG) showing primary

Citrated rapid-TEG showing secondary hyperfibrinolysis. The red tracing indicates a

Citrated rapid-TEG reflecting thrombocytopenia.The red line is a normal tracing.

Clotting factor consumption and hypofibrinogenemia

Citrated rapid-TEG reflecting clotting factor consumption and hypofibrinogenemia. The

Citrated rapid-TEG reflecting hypercoagulability. The red tracing indicates a normal

Thromboelastography-guided transfusion parameters

r-TEG parameter Normal range Transfusion trigger

Alpha angle 66°-82° <66° (cryoprecipitate)

K value 30-120 seconds >120 seconds (cryoprecipitate)

MA (maximum amplitude) 54-72 mm <54 mm (platelets)

G value 5.3-12.4 dynes/second <5.3 dynes/second*

LY-30 (lysis at 30 min) 0-8 percent >8 percent•

Values in the table are for non-citrated whole blood samples.

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