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Critical Care and Resuscitation

Targeted Coagulation Management in Severe Trauma: The Controversies and the Evidence

Winearls, James BSc, MBBS, MRCP, FCICM*†; Reade, Michael MBBS, MPH, DPhil, FANZCA, FCICM; Miles, Helen MBBS*; Bulmer, Andrew BAppSc, PhD†§; Campbell, Don MBBS, FACEM; Görlinger, Klaus MD¶#; Fraser, John F. MD, MBChB, PhD, MRCP, FRCA, FCICM**

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doi: 10.1213/ANE.0000000000001516
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Trauma is the leading cause of death worldwide in individuals aged 18 to 39 years, and, despite advances in trauma management, a significant proportion of these deaths are because of hemorrhage.1–3 Associated with severe trauma is a unique, complex, and multifactorial coagulopathy, the mechanisms of which are not fully determined.4–6

In addition to a lack of clarity regarding the pathophysiology of trauma-associated coagulopathy, no consensus exists regarding the nomenclature used to describe the process.7 Various terms have been suggested—acute traumatic coagulopathy, acute coagulopathy of trauma, acute coagulopathy of trauma shock, trauma-induced coagulopathy (TIC), and early TIC.4,8,9 These terms are often used interchangeably, adding to the confusion. In this article, we will use the term TIC.

Several mechanisms have been proposed to explain the development of TIC. TIC is characterized by reduced clot strength related to hypofibrinogenemia/dysfibrinogenemia, platelet dysfunction, hyperfibrinolysis, and endothelial dysfunction.10 TIC is subsequently compounded by acidosis, hypothermia, hemodilution, and factor consumption associated with severe hemorrhage and large volume fluid resuscitation (Figure 1).11

Figure 1.
Figure 1.:
Pathophysiology of trauma-induced coagulopathy (TIC) and its detection by thromboelastometry. A5EX indicates amplitude 5 minutes after coagulation time (CT) in EXTEM; A5FIB, amplitude 5 minutes after CT in FIBTEM; ADP, adenosine diphosphate; AUC, area under the curve in impedance aggregometry (ROTEM platelet); CTEX, coagulation time in EXTEM; CTHEP, coagulation time in HEPTEM; CTIN, coagulation time in INTEM; ML, maximum lysis (within 1 hour run time); PAI-1, plasminogen activator inhibitor-1; Thrombin gen., thrombin generation; TRAP, thrombin receptor–activating peptide.

Central to the proposed mechanisms is the effect of direct tissue injury, shock, and hypoperfusion on the endothelium, which causes systemic anticoagulation and hyperfibrinolysis.12 The role of tissue injury is supported by the observation that the degree of coagulopathy is proportional to injury severity and is present before large volume fluid or blood product transfusion.13,14 In the presence of tissue hypoperfusion and hypoxia, thrombomodulin (TM) expression is increased. TM binds thrombin (also generated in response to tissue trauma), and the resulting TM–thrombin complex activates the protein C (PC) pathway. Activated PC (aPC) inactivates factor Va and VIIIa, producing a hypocoagulable state. In addition, aPC inactivates plasminogen activator inhibitor-1 (PAI-1), causing fibrinolysis.12,15 Hyperfibrinolysis is further enhanced by the release of tissue plasminogen activator. A 2016 study suggests that the increased levels of tissue plasminogen activator that complex with PAI-1 play a larger role in hyperfibrinolysis than aPC-driven PAI-1 inactivation.16

The neurohormonal axis and the endothelial glycocalyx may also contribute to TIC. In response to tissue injury and shock, a catecholamine surge results, which triggers an up-regulation of the endothelial cells and a shedding of the endothelial glycocalyx.17 Shedding of the glycocalyx is thought to cause thrombin generation, PC activation, and subsequent hyperfibrinolysis.18 In addition, endogenous heparinization from endothelial glycocalyx disruption has been reported.19 Although evidence from human studies is limited, some have argued that a potential benefit of plasma is due to its ability to restore the endothelial glycocalyx rather than to replace coagulation factors.18 A protective effect on the endothelium and the glycocalyx has also been shown for 4-factor prothrombin complex concentrate (PCC), too, but not for albumin.20

The role of platelets and fibrinogen in maintaining effective hemostasis is widely accepted.21 However, the mechanisms by which platelet and fibrinogen dysfunction occur in severe trauma are not well understood. In the early stages of trauma, the number of platelets is preserved at levels unlikely to worsen coagulation. However, evidence from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) and Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) studies suggest that early platelet transfusion in severe trauma is associated with improved hemostasis.22,23 Thus, it is possible that platelet dysfunction induced by severe trauma may contribute to TIC. Recent research has also demonstrated that platelet dysfunction as measured by decreased aggregation is associated with worse outcomes after trauma.24–26 Moore et al27 have proposed that platelet dysfunction may play an additional role in hyperfibrinolysis. However, the mechanisms by which platelet dysfunction occurs during trauma remain largely unclear. Similarly hypofibrinogenemia/dysfibrinogenemia correlates with worse outcomes in severely injured trauma patients, although the pathophysiologic mechanisms are not understood.28–30

Regardless of the exact mechanisms, patients with TIC have significantly increased transfusion requirements and mortality.31,32 As our understanding of the complex nature of traumatic coagulopathy evolves, our treatment is also likely to do so.


Many trauma centers utilize massive transfusion protocols (MTPs), where a predefined fixed ratio of blood and blood products (fresh frozen plasma and platelets) are given to prevent and “treat” TIC.33 MTPs were originally implemented in response to evidence that inadequate replacement of coagulation factors is associated with poor outcomes in massive transfusion.34 Initial MTPs were based on military experience.35 Subsequent civilian studies have supported this approach and have increased the use of MTPs in severe trauma and in patients with nontraumatic critical bleeding.36 Although it is clear that an MTP can improve survival, the optimal ratio of packed red blood cells to other blood components remains controversial.37,38

Based on military data, MTP ratios have increasingly trended toward 1:1:1 (plasma:platelets:packed red blood cell [PRBC]).35 The PROMMTT observational study found that higher ratios of plasma and platelets were associated with improved survival,22 possibly because of earlier replacement of consumed clotting factors mitigating the effect of TIC.39 Recent animal studies have suggested that the beneficial effects of plasma as part of an MTP are more related to restoration of the endothelial glycocalyx rather than factor replacement.18 In addition, little evidence supports plasma administration in patients requiring <10 units PRBCs, and several studies have found that, in patients receiving PRBC:fresh frozen plasma ratios >1:1, survival is unchanged despite an increase in transfusion-related adverse events and the amount of plasma transfused.40–43 The inherent limitations of retrospective studies, and the survival bias associated with many study designs,44 led to the PROPPR trial, published in 2015. This 680-patient multicenter trial randomly assigned trauma patients predicted to require >10 U PRBC to receive either a 1:1:1 or a 1:1:2 ratio and found no difference in either 24-hour or 30-day mortality. However, more patients in the 1:1:1 group achieved hemostasis, and fewer died of exsanguination.23 Although this study found no overall benefit, mortality in the 1:1:2 group was lower than expected, and several thousand patients would have been required to reach statistical significance. Performance targets in this trial were unusually stringent, with an expected delivery of blood products within 10 minutes of the request. Most centers met this requirement by having thawed universal donor (AB) plasma continuously available.45 This strategy may be difficult in smaller, lower-volume trauma units. Furthermore, the safety aspects of AB universal donor plasma are unclear.46–48 In contrast to the PROPPR study, Nascimento et al49 and Tapia et al50 reported significant increases in plasma wastage and a decreased survival rate associated with implementation of fixed high ratio MTP.

Although the 12 centers in the PROPPR trial successfully implemented a high fixed-ratio MTP, a recent study from Stanworth et al51 found widespread variations in blood product delivery in UK trauma centers, with very few patients receiving an “optimal” product ratio, a median time of 68 minutes to delivery of plasma and >2 hours for delivery of cryoprecipitate and platelets. These observations suggest that PROPPR level performance may not be possible in all centers.


Although widely used by trauma centers, high volume ratio–based transfusion of allogenic blood products can result in transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), transfusion-related immunomodulation, nosocomial infection, sepsis, and multiple organ failure.52,53 TACO and TRALI are the leading causes of transfusion-related death in the United States and the United Kingdom.54 Although the PROPPR trial found no safety differences between groups,23 a 2015 review by Clifford et al55,56 noted that TRALI increases with the volume of blood products transfused, is more common than previously reported, and has not fallen in incidence despite the introduction of mitigating strategies.57 These transfusion-related adverse events suggest that the routine use of fixed-ratio MTPs be reexamined.

In light of the complexity of TIC, a fixed-ratio MTP may be too simplistic for all trauma patients. Traumatic coagulopathy is multifactorial, the pattern of injury is varied, and the underlying physiology of each patient is unique. In principle, a targeted way to measure and treat the coagulopathy on an individual patient basis should allow clinicians to better address TIC.


A targeted approach to blood product transfusion has historically been hindered by the lack of accurate laboratory tests to diagnose and guide therapy. The diagnosis of TIC was originally made using prothrombin time (PT) and activated partial thromboplastin time. These tests were developed to assess single-factor deficiencies and anticoagulant effects, are performed on platelet poor plasma, and are poor predictors of bleeding in trauma.58 In addition, results may take up to 60 minutes to obtain,58,59 limiting their value in managing coagulation in the severely bleeding patient. Although point-of-care rapid PT (rPT) devices have been tried, their utility and accuracy remain controversial. In a prospective observational study, Davenport et al60 reported that standard laboratory PT results were available at a median of 78 minutes, and point-of-care rPT results were available more quickly but were inaccurate when compared with laboratory testing.


An emerging approach to diagnosing and treating TIC utilizes viscoelastic hemostatic assays (VHAs) to rapidly identify coagulation defects and allow targeted intervention to correct coagulopathy faster with fewer side effects.61,62 VHAs have a higher sensitivity for the detection of traumatic coagulopathy and provide results more rapidly than standard laboratory testing (SLT).30,60,63,64 Holcomb et al65 studied almost 2000 patients, found thromboelastography (TEG) to be superior to SLT across several parameters, and concluded that “SLT can be replaced with r-TEG.” In addition to identifying those patients with TIC more rapidly, it is possible that VHA may identify patients who are not coagulopathic and thus prevent unnecessary blood product transfusion. Preventing overuse is also relevant because many severely injured patients may in fact be hypercoagulable at presentation.27 Goodman et al66 suggested that point-of-care rPT may provide a practical alternative for rapid coagulopathy assessment in trauma patients at institutions that lack VHA capability. VHAs have been incorporated into a number of trauma management guidelines and are used at several trauma centers in place of fixed-ratio MTP.67–72 An increasing number of major trauma centers utilize a hybrid approach that combines early fixed-ratio transfusion with subsequent VHA-targeted therapy as surgical control of hemorrhage is gained.73–76

The concept of thromboelastometry/thromboelastography is not new and was first described by Hartert77 in the 1950s. Two devices are commercially and widely available for performing VHA: TEG (Haemonetics, Braintree, MA) and ROTEM (TEM International GmbH, Munich, Germany). In our institution, the ROTEM delta is utilized. The key characteristics of both viscoelastic devices are presented in Table, and several excellent reviews address the differences.78,79,92,99,100 A description of the ROTEM/TEG devices and assays is provided in Figures 2 and 3.

Characteristics and Performance of TEG and ROTEM
Figure 2.
Figure 2.:
Rotational thromboelastometry. A5 indicates amplitude 5 minutes after coagulation time; CFR, clot formation rate; CFT, clot formation time; CT, coagulation time; MCF, maximum clot firmness; ML, maximum lysis during run time.
Figure 3.
Figure 3.:
ROTEM and TEG parameters. A5 indicates amplitude 5 minutes after coagulation time; A10, amplitude 10 minutes after coagulation time; CFT, clot formation time; CT, coagulation time; MA, maximum amplitude; MCF, maximum clot firmness; ML, maximum lysis during run time; ROTEM, thromboelastometry; TEG, thrombelastography.

In contrast to SLT, VHAs allow for assessment of cellular and plasmatic component interactions. VHA measures clot formation up to and including fibrinolysis in contrast to PT and activated partial thromboplastin time that stop at the beginning of fibrin formation when only 5% of total thrombin has been generated. Unlike SLTs, VHAs provide information on time to clot formation, clot strength, and clot lysis, allowing different components of the coagulation cascade to be assessed.101,102

Platelet function is not directly interrogated by the standard VHA, and these tests are insensitive to the effects of antiplatelet agents. This diagnostic gap can be closed by combining VHA with whole blood impedance aggregometry (Multiplate, Roche Diagnostics, Mannheim, Germany, or ROTEM platelet, TEM International GmbH) to assess platelet function.24–26,95,96 Although platelet dysfunction is clearly associated with mortality in severe trauma, the pathophysiologic mechanisms remain unclear, and the role of platelet function assessment in trauma is evolving.24–26 Current evidence is insufficient to support the use of aggregometric measures of platelet dysfunction to guide therapeutic intervention.

Currently, VHA is more expensive than SLT testing. However, many articles report a reduction in transfusion costs with VHA-targeted therapy, thus potentially offsetting the increased cost of testing.103–105 A health economic assessment forms part of the before-and-after study underway at our institution in Queensland, Australia. A full panel of tests (EXTEM, FIBTEM, and INTEM) at our institution costs approximately AUD$44.


The use of VHA to monitor and guide transfusion therapy in trauma is now endorsed by several international transfusion guidelines from Europe and North America.67,106 To illustrate this approach, we describe the routine use of ROTEM in the management of trauma patients as part of a prospective before-and-after study.

We identified specific attributes needed to enable improvement on current MTP and to facilitate clinician buy-in:

  • Short turnaround time by using early variables of clot firmness (amplitude 5 minutes after coagulation time [A5] and amplitude 10 minutes after coagulation time [A10])87,88
  • Robustness with minimal interoperator variation in results82
  • Clinically relevant30,64,67,106,107
  • Easy to use, interpret, teach, and train
  • Supported by laboratory staff

We implemented a bedside model of care run by clinicians and supported by a hematology laboratory scientist. VHA devices were located in the intensive care unit (ICU) and operating room with results streamed live to key clinical areas.

As part of our protocol, every trauma patient triggering criteria for trauma call activation underwent ROTEM analysis as part of their initial blood test panel on admission. Subsequent testing is performed postintervention, as clinically indicated and on admission to the ICU. The triggers for MTP activation and the damage control approach to the management of severe trauma are unchanged.

The responsibility of coordinating blood and blood product transfusion has been designated to the ICU member of the trauma team. The reasoning for this is 2-fold:

  1. Designating this role to a predetermined individual removes the confusion that can be created in a complex multidisciplinary team environment.108,109
  2. The ICU will often be responsible for the ongoing care after initial resuscitation and intervention.
Figure 4.
Figure 4.:
Sequential ROTEM in multiple trauma. A, A 38-year-old man sustained multitrauma secondary to an unwitnessed motorbike accident. Prehospital resuscitation included intubation and ventilation, left-sided thoracotomy, pelvic sling application, 3 units packed red blood cells (PRBCs), and 1 g TXA. On arrival in emergency department (ED) 90 minutes after injury, the patient was hemodynamically unstable with a temperature of 33.1°C, pH 6.9, and a lactate of 9 mmol/L. Damage control surgery was performed and blood product administration guided by our ROTEM treatment algorithm. B, Transfusion requirements first 10 hours: 16 U PRBCs, 60 U of cryoprecipitate (fibrinogen concentrate not available at this time), 2 platelets, 1 unit of fresh frozen plasma (FFP; this single unit of FFP was administered inadvertently and not as per protocol), 3 L of Hartman and 1.5 L of 4% albumen. C, Injuries included bilateral rib fractures 1 to 10 with hematopneumothoraces, splenic rupture, serosal tears to the descending colon, left kidney laceration with associated retroperitoneal hematoma, complex open book pelvic fracture, and multiple long-bone fractures (ISS 59). D, Definitive orthopedic management of his complex pelvic and multiple long-bone fractures was performed on day 6. The patient was extubated on day 12 without suffering any of the potentially expected complications of severe trauma or massive transfusion. A5 indicates amplitude 5 minutes after coagulation time; A10, amplitude 10 minutes after coagulation time; CFT, clot formation time; CT, coagulation time; ICU, intensive care unit; MCF, maximum clot firmness.

Competency must be demonstrated before unsupervised VHA use, and most staff involved in the care of the trauma patient (emergency physicians, anesthetists, anesthetic nurses, surgeons, trauma nurses, intensivists, and ICU nurses) has been trained in device operation and result interpretation. We aimed for wide diffusion across the hospital to remove the perceived mystique surrounding viscoelastic testing, unlike the majority of centers where use of the device is tightly controlled by either the hospital laboratory or the specific clinical units. Our approach is illustrated in Figure 4.


Successful and appropriate use of any viscoelastic device only occurs with an associated treatment algorithm. Our algorithm used at Gold Coast University Hospital, Queensland, is designed to be simple to teach, understand, and use (Figure 5).

Figure 5.
Figure 5.:
Gold Coast University Hospital (GCUH) ROTEM trauma algorithm. A5 indicates amplitude 5 minutes after coagulation time; A10, amplitude 10 minutes after coagulation time; CFT, clot formation time; CT, coagulation time; FFP, fresh frozen plasma; MCF, maximum clot firmness; PCC, prothrombin complex concentrate; ROTEM, thromboelastometry; TXA, tranexamic acid.

To optimize the ability to correct coagulopathy, A5 is used.87,88,107 A5 results correlate very well with maximum clot firmness in a number of clinical settings.88 In our algorithm, tests are run and interpreted in a stepwise manner.

Step 1: EXTEM and FIBTEM for Assessment of Fibrinolysis

Definition of lysis parameters is different between TEG and ROTEM. Although in TEG, lysis 30 (LY30) is defined as the decrease in clot firmness in percentage of maximum amplitude (MA) 30 minutes after MA, in ROTEM, lysis index 30 (LI30) is defined as the residual clot firmness in percentage of maximum clot firmness 30 minutes after coagulation time (CT). Accordingly, LY30 and LI30 describe the degree of fibrinolysis at different time points during measurement. Because it usually takes 20 to 30 minutes to reach MA in TEG, LY30 is detected after about 50 to 60 minutes run time. In contrast, CT is reached in ROTEM EXTEM after 1 to 2 minutes, and therefore, LI30 is already determined after about 31 minutes run time. Accordingly, LY30 in TEG chronologically corresponds more to lysis index 60 in ROTEM. Historically, hyperfibrinolysis was defined as LY30 > 7.5% in TEG or maximum lysis >15% within 60 minutes run time in ROTEM.90,91

Hyperfibrinolysis after severe trauma is rare, but it is associated with poor outcomes.101 Even “low-grade fibrinolysis” (LY30 > 3%) is associated with increased bleeding, increased transfusion requirements, and higher mortality in trauma.110,111 However, fibrinolysis shutdown (LY30 < 1%) is also associated with increased mortality in trauma, and the benefit of prophylactic tranexamic acid (TXA) administration is still under debate.112–116 Some ROTEM centers are using the difference between early ROTEM parameters (CT, A5, A10, and A15) in the EXTEM and APTEM test (addition of aprotinin or TXA) for early detection of fibrinolysis.104 However, this test combination cannot detect small increments in profibrinolytic activation reliably, and our algorithm is no longer using the APTEM test to aid in the early diagnosis of hyperfibrinolysis. Notably, EXTEM A5 and A10 (amplitude in clot firmness 10 minutes after CT) can be used for early risk assessment of fibrinolysis.89 Functional fibrinogen contribution to clot strength in both ROTEM (FIBTEM) and TEG assays (FF) are even more sensitive to fibrinolysis than the corresponding EXTEM and kaolin TEG assays.117,118 This sensitivity suggests that fibrinogen assays should be utilized early in the management of traumatic coagulopathy to guide antifibrinolytic therapy.

Because of a lack of knowledge, using VHA to guide TXA therapy in trauma is difficult. Both hyperfibrinolysis and fibrinolysis shut down are pathologic and associated with poor outcome. Between these extremes, however, is a physiologic level of fibrinolysis that may confer a survival benefit.111 Some recently published studies have suggested that TXA therapy in severe trauma may be associated with increased mortality regardless of time of administration.112,113 In view of the relative insensitivity of VHA, the conflicting evidence and the wide spectrum of fibrinolysis early in trauma, the use of TXA should be guided best by the clinical scenario and not solely based on the results of VHA.115,116,119 In our institution, TXA is routinely used early in severe trauma. If early ROTEM parameters suggest high risk of hyperfibrinolysis (FIBTEM CT > 600 seconds and EXTEM A5 < 35 mm), we would verify that TXA had been given.89 We would also recommend that, if fibrinolysis is detected on subsequent testing (maximum lysis > 5% within 60 minutes), then further TXA should be administered.110 The Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (PATCH) study, a large multicenter randomized trial investigating the use of prehospital TXA in severe trauma, is currently underway in Australia.120

Step 2: FIBTEM (A5/A10) to Assess Need for Fibrinogen Replacement

Increasing evidence supports the importance of fibrinogen in TIC.29,121 Fibrinogen is the first factor to drop below reference values during bleeding and reaches critically low levels in trauma earlier than any other coagulation factors.122

Hypofibrinogenemia after severe trauma is also associated with an increased risk of massive transfusion and mortality.28,107 Thus, early fibrinogen replacement in TIC may be efficacious in correction of coagulopathy, assist in hemorrhage control, and decrease transfusion requirements.28,123,124 Two military studies suggest that maintaining higher fibrinogen levels is associated with improved survival.125,126 However, these studies are retrospective and may be confounded by injury severity. The CRYOSTAT (ISRCTN55509212) randomized controlled trial (RCT), recently published by Curry et al,127 demonstrated that the administration of cryoprecipitate within 90 minutes after admission is technically feasible in trauma patients.

Fibrinogen can be replaced in 3 ways: by fibrinogen concentrate (FC), cryoprecipitate, or plasma. Each contains different amounts of fibrinogen: 20, 8–16, and about 2 g/L, respectively, and thus, different volumes are required.128 In fixed-ratio MTP, the transfusion of cryoprecipitate usually occurs later in the treatment protocol, and even high plasma/red blood cell ratios (1:1:1) may actually dilute fibrinogen concentrations. Rourke et al28 found that standard protocol-driven transfusion ratios were ineffective in maintaining fibrinogen levels, and the addition of cryoprecipitate was required. A 2015 article by Khan et al129 showed that high-dose plasma transfusion alone does not correct TIC and that coagulation parameters only improve with combined plasma, cryoprecipitate, and platelet transfusion. Because of the large volumes of plasma required for fibrinogen replacement, our algorithm focuses on the early use of cryoprecipitate and FC. In our algorithm, FC is used as a first line in severe bleeding with a FIBTEM A5 ≤ 8 mm, where the time delay to obtaining cryoprecipitate (approximately 30 minutes) could be detrimental. This practice is supported by the CRYOSTAT study, where the median time to cryoprecipitate administration was 60 minutes.127 In addition, in a recent article investigating transfusion practices in traumatic hemorrhage, the median time to delivery of cryoprecipitate was >2 hours and almost 50% of patients did not receive cryoprecipitate as part of their initial resuscitation.51

When compared with cryoprecipitate, FC has several theoretical advantages including a reduction in transfused volume, lack of variability in fibrinogen concentration, no requirement for ABO compatibility matching, viral inactivation, durable storage at room temperature, and easy reconstitution and administration. However, robust clinical trials have not found a survival or cost-effectiveness benefit.121,130,131 FC is safe in terms of thromboembolic complications,132 and in Australia, the cost is similar to an equivalent dose of cryoprecipitate.

Fibrinogen dosing is controversial with widespread variability in recommendations from different professional bodies.133 Tanaka et al134 describe in detail the rationale behind cryoprecipitate and FC dosing. Our algorithm relies on a simple weight-based approach that approximately equates to more complex dosing strategies.128,135 Recent European guidelines for massive hemorrhage in severe trauma recommend FC 3 to 4 g or cryoprecipitate 50 mg/kg to restore fibrinogen levels.67

Step 3: EXTEM (A5/A10) to Assess Need for Platelet Transfusion

If the FIBTEM (A5/A10) is within normal range, then low EXTEM amplitude is treated with platelets. Platelets serve as a matrix for a coagulation factors, and their transfusion is usually mandated in most MTPs.41,136 However, evidence that platelet transfusion in a fixed and high ratio confers any survival benefit is controversial.40,137 The pathophysiologic mechanisms underlying platelet dysfunction in severe trauma and its contribution to the development of TIC remain poorly understood. Although platelet dysfunction (as quantified by platelet aggregometry devices) is associated with increased mortality, insufficient evidence supports their use in the routine management of traumatic hemorrhage. In view of the potential downstream immunomodulatory and thromboembolic risks associated with platelet transfusions, we feel that their use is better guided by tests of clot quality rather than an absolute number or in a predefined ratio manner.138

Step 4: EXTEM (CT) to Assess the Need for Coagulation Factor Replacement

In case of normal FIBTEM and EXTEM clot firmness (A5/A10), prolonged EXTEM CT indicates impaired thrombin generation and the potential need for plasma or PCC.134,139 Thrombin is a key component of the coagulation system, but its generation is not substantially affected in the early stages of trauma, and in most patients with severe trauma, thrombin generation is increased.12,140 We worry that if most patients have increased thrombin generation, then early and aggressive therapy with plasma or PCC may be detrimental. To compound the issue, the diagnosis of impaired thrombin generation is difficult with both SLT and VHA.140 Accordingly, our algorithm focuses on thrombin generation and factor replacement only after adequate fibrinogen and/or platelet replacement. Frequently, a prolonged EXTEM CT can be corrected with adequate fibrinogen replacement alone.141 A recently published study from the AUVA (Allgemeine Unfallversicherungsanstalt) Trauma Center supports our approach, demonstrating that prolonged EXTEM clotting time can be significantly reduced by the administration of FC alone.142 An EXTEM CT of >90 seconds is used because it represents the point where the activity of coagulation factors is at least <30% of normal.143

Whether to use plasma or PCC to augment thrombin generation is also controversial. Many retrospective and animal model studies report favorable results with the use of PCC, but we remain mindful of the risks of thromboembolic complications.69,144–146 The administration of a potent procoagulant drug (PCC) to a group of patients at high risk of subsequent thrombosis must be very carefully considered, because recent animal studies have demonstrated increased thrombosis rates at high PCC doses (50 U/kg).139,146,147 Thus, PCC and VHA use in severe trauma are extremely controversial, with little consensus among experts.62 The use of a well-defined EXTEM CT value and low doses of PCC and plasma only after appropriate fibrinogen and platelet replacement with normal FIBTEM and EXTEM clot firmness (A5/A10) may hopefully mitigate these risks.90,148


Bleeding and subsequent massive transfusion are associated with adverse outcomes after trauma and other clinical settings. Historically, the management of coagulopathic bleeding has involved an empirical “shotgun” approach, where all products are given to “cover all bases.” Although it is clear that product replacement is an essential component of damage control resuscitation and MTP, a consensus approach remains elusive. It is imperative to ensure that the appropriate product is given at the appropriate time in the appropriate quantity, because each coagulation abnormality requires a different intervention.

To more precisely target specific coagulation abnormalities, many European protocols have moved away from fixed-ratio MTP and toward the use of VHA-guided algorithms involving factor concentrates.69 This approach enables rapid correction of specific deficiencies without large volume transfusion and may reduce complications associated with plasma transfusion.69,124,144 Although considerable theoretical benefit is possible, little high-quality evidence to date supports this approach. Despite an explosion in the literature over the past 10 years regarding traumatic coagulopathy and transfusion strategies, little level 1 evidence exists, and many studies contain significant methodologic and statistical flaws.49,50,72,149

However, outside the trauma setting, there is a growing evidence base that the use of VHA-targeted algorithms with predominant use of factor concentrates can improve patient outcomes.103,150–153 Unfortunately, the heterogeneous nature of traumatic injury and underlying patient physiology and the complex nature of TIC make investigation difficult. In 2 recent articles, Khan et al129,154 commented that “significant opportunities exist to tailor management and improve outcomes for bleeding trauma patients.”

Widespread debate and controversy exist regarding the optimum management strategy for the severely injured, bleeding trauma patient. Two main camps exist: those that favor a predetermined fixed-ratio approach and those that endorse a targeted approach using primarily factor concentrates. However, there is insufficient evidence to support either approach with any certainty.155,156 In addition to opinion,62,70,134,157,158 many retrospective and cohort studies report improved outcomes with a targeted approach, but the findings are often not robust.159

One approach to combining the 2 camps is to pursue a hybrid strategy, starting with a fixed-ratio transfusion strategy to treat massive hemorrhage when the exact nature of TIC is not known. Subsequently, as more data and clinical information become available, a VHA-targeted approach is used.73–76 This approach potentially marries the best of both worlds, allowing the rapid delivery of blood products in massive hemorrhage and subsequently tailoring product replacement to what is actually required. It can be argued that utilizing rapidly available results from VHA negates the requirement for a fixed-ratio approach but robust systematic institution-wide implementation is needed to rapidly perform VHA. However, as the PROPPR trial noted, fixed-ratio MTP also requires considerable expertise. Over the past decade, implementation of MTPs has clearly improved survival in traumatic hemorrhage.23,37,38 However, MTP performance among trauma centers varies considerably, as does its success.51,160

Improved survival may only be attributable, in part, to the rapid delivery of blood component therapy. The successful implementation of a damage control resuscitation team likely plays a primary role, providing access to a highly skilled team (trauma surgeons, anesthetists, critical care physicians, etc) dedicated to doing the one thing that will save the patient’s life—surgical control of hemorrhage. The effect of such teamwork on survival is indirectly supported by reduced control mortality in the PROPPR trial.23 MTPs are a key part of the improved survival in severe trauma, but as responsible clinicians, we should not rest on our laurels.

A recently published systematic review identified 55 nonrandomized and observational studies (including >12,000 patients) related to viscoelastic testing in trauma and concluded “there is a rapidly growing observational evidence base on the use of viscoelastic testing in trauma but adequately powered and methodologically sound studies are required to prove positive effects on patient outcomes.”92 Two single-center RCTs comparing efficacy and safety of a VHA-guided protocol to a fixed ratio–driven approach are currently running in Innsbruck, Austria (Reversal of Trauma Induced Coagulopathy; RETIC Trial, NCT01545635), and Sao Paulo, Brazil (Strategy of Transfusion in Trauma Patients; STATA Trial, NCT02416817). Although these studies are a big step forward, a well-designed, large multicenter trial is still needed. The ongoing iTACTIC study (Implementing Treatment Algorithms for the Correction of Trauma Induced Coagulopathy; NCT02593877) may also answer some questions regarding management of trauma coagulopathy, but it differs slightly from the RETIC and STATA trials. This multicenter, individual patient RCT will randomly assign severely bleeding trauma patients to either MTP (ratio of 1:1:1) with subsequent VHA-guided product replacement or MTP (ratio of 1:1:1) with subsequent SLT-guided product replacement and is expected to conclude in January 2018.


Compounding the variability in traumatic mechanism and patient physiology is considerable practice variability, which can make performing studies on TIC even more challenging. A recently published study from the TACTIC (Targeted Action for Curing Trauma Induced Coagulopathy) group revealed widespread variability in the management of bleeding trauma patients among 6 European level 1 trauma centers.160 In some Western European centers, a VHA-targeted approach is currently standard of care, and studies comparing a targeted approach with standard fixed-ratio MTP would not be considered ethical.155 In the United States, a fixed high ratio approach is standard of care in most large volume trauma centers, and a move to a targeted approach would be equally controversial. In addition, the varying volume of severe trauma in these centers may make a multicenter trial logistically challenging.156 Controversies also exist regarding exactly what question is to be answered with the current studies. Despite these challenges, definitive and coordinated studies in severely injured trauma patients are needed before viscoelastic testing is widely adopted into practice.

Potential Alternatives to Individual Patient Randomized Controlled Trials

A pragmatic alternative to individual patient RCT in severely bleeding trauma patients has just been published.72 This study compared a TEG-guided MTP versus a SLT-guided MTP. Randomization was achieved by alternating the 2 treatment interventions on a weekly basis until enrollment was completed. The study showed improved survival in the TEG-guided MTP with reduced use of plasma and platelet transfusions. Although only a single-center study, it provides further evidence that the targeted approach to severe traumatic hemorrhage is feasible, and performing such studies is logistically possible.

We propose another alternative to the individual patient randomized trial—a large multicenter stepped wedge study design. In this approach, a baseline period of fixed-ratio care is followed by “crossing over” care clusters in a random order to the treatment (VHA-guided) group with blood and blood product use and noninferiority in mortality as coprimary end points. The inherent logistical problems associated with an individual patient RCT in this area makes such a design an attractive option.161 This random crossover strategy could also avoid the challenges of simultaneously managing patients in the same institution with different treatment protocols. Regardless of study design, because of the heterogeneous nature of trauma patients, a large number of patients will be required to attain sufficient study power to show a mortality difference. However, we feel that a finding of reduced blood product usage would support a change in practice to a VHA-guided approach. Ultimately, such a study will only be possible through the collaborative input from established research groups, with support from industry and governmental sources.


Definitive evidence to support the use of VHA-guided algorithms as an alternative to fixed-ratio MTP in trauma is lacking at this time. However, viscoelastic testing will continue to play a role in the management of the severely bleeding trauma patient. We believe that now is the time to perform a well-designed study before widespread diffusion of VHA testing into routine clinical practice makes performing a study nearly impossible. The 2013/2016 European Trauma Treatment Guidelines has already upgraded its recommendations to use viscoelastic testing in severely injured trauma patients from 2C to 1C, with a plea to implement goal-directed individualized treatment algorithms.67 The recently published American Society of Anesthesiologists Practice Guidelines for Perioperative Blood Management also advocate the use of transfusion algorithms based on thromboelastometric/graphic testing.106 Statements such as “all hospitals should have individualized and goal-directed coagulation algorithm: don’t wait – act now!” have also appeared in the literature.162

On the one hand, PROPPR demonstrates that high-quality pragmatic studies in severe trauma can be performed, but a 1:1:1 transfusion ratio produces similar outcomes to a 1:1:2 ratio.23 On the other hand, Gonzalez et al72 showed improved survival and less plasma and platelet transfusion in a VHA-guided MTP compared with a SLT-guided MTP. Now it is time for a large international multicenter trial to put this debate to rest.


We acknowledge Associate Professor Brent Richards for logistical support, Tony Ghent for technical assistance and logistical support, and Elizabeth Rahilly in her role as a trauma research nurse.


Name: James Winearls, BSc, MBBS, MRCP, FCICM.

Contribution: This author helped conceive the manuscript, perform the literature review, write the first draft, and edit subsequent drafts.

Conflicts of Interest: James Winearls declares no conflicts of interest.

Name: Michael Reade, MBBS, MPH, DPhil, FANZCA, FCICM.

Contribution: This author helped review the manuscript and modify drafts.

Conflicts of Interest: Michael Reade declares no conflicts of interest.

Name: Helen Miles, MBBS.

Contribution: This author helped review the literature, prepare the first draft, and review and modify further drafts.

Conflicts of Interest: Helen Miles declares no conflicts of interest.

Name: Andrew Bulmer, BAppSc, PhD.

Contribution: This author helped review the manuscript and modify drafts.

Conflicts of Interest: Andrew Bulmer declares no conflicts of interest.

Name: Don Campbell, MBBS, FACEM.

Contribution: This author helped review the manuscript and modify drafts.

Conflicts of Interest: Don Campbell declares no conflicts of interest.

Name: Klaus Görlinger, MD.

Contribution: This author helped review the manuscript, modify drafts, and expert technical guidance.

Conflicts of Interest: Klaus Görlinger works as the Medical Director of Tem International GmbH, Munich, Germany, since July 2012.

Name: John F. Fraser, MD, MBChB, PhD, MRCP, FRCA, FCICM.

Contribution: This author helped conceive the manuscript and review and modify drafts.

Conflicts of Interest: John F. Fraser declares no conflicts of interest.

This manuscript was handled by:Avery Tung, MD, FCCM.


1. Cothren CC, Moore EE, Hedegaard HB, Meng K. Epidemiology of urban trauma deaths: a comprehensive reassessment 10 years later. World J Surg. 2007;31:15071511.
2. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 2005;9(suppl 5):S1S9.
3. Tien HC, Spencer F, Tremblay LN, Rizoli SB, Brenneman FD. Preventable deaths from hemorrhage at a level I Canadian trauma center. J Trauma. 2007;62:142146.
4. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680685.
5. Simmons JW, Pittet JF, Pierce B. Trauma-induced coagulopathy. Curr Anesthesiol Rep. 2014;4:189199.
6. Christiaans SC, Duhachek-Stapelman AL, Russell RT, Lisco SJ, Kerby JD, Pittet JF. Coagulopathy after severe pediatric trauma. Shock. 2014;41:476490.
7. Dobson GP, Letson HL, Sharma R, Sheppard FR, Cap AP. Mechanisms of early trauma-induced coagulopathy: the clot thickens or not? J Trauma Acute Care Surg. 2015;79:301309.
8. Gonzalez E, Moore EE, Moore HB, Chapman MP, Silliman CC, Banerjee A. Trauma-induced coagulopathy: an institution’s 35 year perspective on practice and research. Scand J Surg. 2014;103:89103.
9. Gando S, Wada H, Thachil J; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11:826835.
10. Davenport RA, Brohi K. Cause of trauma-induced coagulopathy. Curr Opin Anaesthesiol. 2016;29:212219.
11. Cap A, Hunt BJ. The pathogenesis of traumatic coagulopathy. Anaesthesia. 2015;70(suppl 1):96101, e32e34.
12. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64:12111217.
13. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg. 2007;245:812818.
14. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43:2632.
15. Cohen MJ, Call M, Nelson M, et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255:379385.
16. Chapman MP, Moore EE, Moore HB, et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg. 2016;80:1625.
17. 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.
18. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112:12891295.
19. 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.
20. Pati S, Potter DR, Baimukanova G, Farrel DH, Holcomb JB, Schreiber MA. Modulating the endotheliopathy of trauma: factor concentrate versus fresh frozen plasma. J Trauma Acute Care Surg. 2016;80:576585.
21. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958965.
22. Holcomb JB, del Junco DJ, Fox EE, et al.; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148:127136.
23. Holcomb JB, Tilley BC, Baraniuk S, et al.; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471482.
24. Solomon C, Traintinger S, Ziegler B, et al. Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost. 2011;106:322330.
25. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73:1319.
26. Chapman MP, Moore EE, Moore HB, et al. Early TRAP pathway platelet inhibition predicts coagulopathic hemorrhage in trauma. Shock. 2015;43(6 suppl 1):33.
27. Moore HB, Moore EE, Chapman MP, et al. Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients. J Thromb Haemost. 2015;13:18781887.
28. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:13421351.
29. Hagemo JS, Stanworth S, Juffermans NP, et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care. 2014;18:R52.
30. Hagemo JS, Christiaans SC, Stanworth SJ, et al. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care. 2015;19:97.
31. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:11271130.
32. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55:3944.
33. Holcomb JB. Optimal use of blood products in severely injured trauma patients. Hematology Am Soc Hematol Educ Program. 2010;2010:465469.
34. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007;62:112119.
35. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63:805813.
36. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447458.
37. Snyder CW, Weinberg JA, McGwin G Jr, et al. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma. 2009;66:358364.
38. Schuster KM, Davis KA, Lui FY, Maerz LL, Kaplan LJ. The status of massive transfusion protocols in United States trauma centers: massive transfusion or massive confusion? Transfusion. 2010;50:1545155.1.
39. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62:307310.
40. Dirks J, Jørgensen H, Jensen CH, Ostrowski SR, Johansson PI. Blood product ratio in acute traumatic coagulopathy—effect on mortality in a Scandinavian level 1 trauma centre. Scand J Trauma Resusc Emerg Med. 2010;18:65.
41. Simmons JW, White CE, Eastridge BJ, Mace JE, Wade CE, Blackbourne LH. Impact of policy change on US Army combat transfusion practices. J Trauma. 2010;69(suppl 1):S75S80.
42. Davenport R, Curry N, Manson J, et al. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70:9096.
43. Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg. 2010;210:957965.
44. Ho AM, Dion PW, Yeung JH, et al. Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology. 2012;116:716728.
45. Novak DJ, Bai Y, Cooke RK, et al.; PROPPR Study Group. Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. Transfusion. 2015;55:13311339.
46. Shanwell A, Andersson TM, Rostgaard K, et al. Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma. Vox Sang. 2009;96:316323.
47. Inaba K, Branco BC, Rhee P, et al. Impact of ABO-identical vs ABO-compatible nonidentical plasma transfusion in trauma patients. Arch Surg. 2010;145:899906.
48. Balvers K, Saleh S, Zeerleder SS, et al. Are there any alternatives for transfusion of AB plasma as universal donor in an emergency release setting? Transfusion. 2016;56:14691474.
49. Nascimento B, Callum J, Tien H, et al. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ. 2013;185:E583E589.
50. Tapia NM, Chang A, Norman M, et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74:378386.
51. Stanworth SJ, Davenport R, Curry N, et al. Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice. Br J Surg. 2016;103:357365.
52. Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH. Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med. 2008;36:11141118.
53. Watson GA, Sperry JL, Rosengart MR, et al.; Inflammation and Host Response to Injury Investigators. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma. 2009;67:221230.
54. Bolton-Maggs PH, Cohen H. Serious hazards of transfusion (SHOT) haemovigilance and progress is improving transfusion safety. Br J Haematol. 2013;163:303314.
55. Clifford L, Jia Q, Subramanian A, et al. Characterizing the epidemiology of postoperative transfusion-related acute lung injury. Anesthesiology. 2015;122:1220.
56. Clifford L, Jia Q, Yadav H, et al. Characterizing the epidemiology of perioperative transfusion-associated circulatory overload. Anesthesiology. 2015;122:2128.
57. Simmons JW, Pittet JF. Revealing the real risks of perioperative transfusion: rise of the machines! Anesthesiology. 2015;122:12.
58. Haas T, Fries D, Tanaka KA, Asmis L, Curry NS, Schöchl H. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence? Br J Anaesth. 2015;114:217224.
59. Toulon P, Ozier Y, Ankri A, Fléron MH, Leroux G, Samama CM. Point-of-care versus central laboratory coagulation testing during haemorrhagic surgery. A multicenter study. Thromb Haemost. 2009;101:394401.
60. Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39:26522658.
61. Johansson PI, Stensballe J. Effect of haemostatic control resuscitation on mortality in massively bleeding patients: a before and after study. Vox Sang. 2009;96:111118.
62. Inaba K, Rizoli S, Veigas PV, et al.; Viscoelastic Testing in Trauma Consensus Panel. 2014 Consensus conference on viscoelastic test-based transfusion guidelines for early trauma resuscitation: report of the panel. J Trauma Acute Care Surg. 2015;78:12201229.
63. Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009;17:45.
64. Tauber H, Innerhofer P, Breitkopf R, et al. Prevalence and impact of abnormal ROTEM® assays in severe blunt trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’. Br J Anaesth. 2011;107:378387.
65. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256:476486.
66. Goodman MD, Makley AT, Hanseman DJ, Pritts TA, Robinson BR. All the bang without the bucks: defining essential point-of-care testing for traumatic coagulopathy. J Trauma Acute Care Surg. 2015;79:117124.
67. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.
68. Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med. 2012;20:15.
69. Schöchl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14:R55.
70. Schöchl H, Schlimp CJ. Trauma bleeding management: the concept of goal-directed primary care. Anesth Analg. 2014;119:10641073.
71. Tobin JM, Tanaka KA, Smith CE. Factor concentrates in trauma. Curr Opin Anaesthesiol. 2015;28:217226.
72. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg. 2016;263:10511059.
73. Johansson PI, Sørensen AM, Larsen CF, et al. Low hemorrhage-related mortality in trauma patients in a level I trauma center employing transfusion packages and early thromboelastography-directed hemostatic resuscitation with plasma and platelets. Transfusion. 2013;53:30883099.
74. Johansson PI, Stensballe J, Oliveri R, Wade CE, Ostrowski SR, Holcomb JB. How I treat patients with massive hemorrhage. Blood. 2014;124:30523058.
75. Stensballe J, Ostrowski SR, Johansson PI. Viscoelastic guidance of resuscitation. Curr Opin Anaesthesiol. 2014;27:212218.
76. Stephens CT, Gumbert S, Holcomb JB. Trauma-associated bleeding: management of massive transfusion. Curr Opin Anaesthesiol. 2016;29:250255.
77. Hartert H. [Thrombelastography, a method for physical analysis of blood coagulation]. Z Gesamte Exp Med. 1951;117:189203.
78. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol. 2014;89:228232.
79. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:13661375.
80. Keene DD, Nordmann GR, Woolley T. Rotational thromboelastometry-guided trauma resuscitation. Curr Opin Crit Care. 2013;19:605612.
81. Espinosa A, Seghatchian J. What is happening? The evolving role of the blood bank in the management of the bleeding patient: the impact of TEG as an early diagnostic predictor for bleeding. Transfus Apher Sci. 2014;51:105110.
82. Anderson L, Quasim I, Steven M, et al. Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thromboelastometry. J Cardiothorac Vasc Anesth 2014;28:15501557.
83. Gronchi F, Perret A, Ferrari E, et al. Validation of rotational thromboelastometry during cardiopulmonary bypass: a prospective, observational in-vivo study. Eur J Anaesthesiol. 2014;31:6875.
84. Ortmann E, Rubino A, Altemimi B, Collier T, Besser MW, Klein AA. Validation of viscoelastic coagulation tests during cardiopulmonary bypass. J Thromb Haemost. 2015;13:12071206.
85. Dunham CM, Rabel C, Hileman BM, et al. TEG® and RapidTEG® are unreliable for detecting warfarin-coagulopathy: a prospective cohort study. Thromb J 2014;12:4.
    86. Schmidt DE, Holmström M, Majeed A, Näslin D, Wallén H, Ågren A. Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls. Thromb Res. 2015;135:10071011.
    87. Meyer AS, Meyer MA, Sørensen AM, et al. Thrombelastography and rotational thromboelastometry early amplitudes in 182 trauma patients with clinical suspicion of severe injury. J Trauma Acute Care Surg. 2014;76:682690.
    88. Görlinger K, Dirkmann D, Solomon C, Hanke AA. Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. Br J Anaesth. 2013;110:222230.
    89. Dirkmann D, Görlinger K, Peters J. Assessment of early thromboelastometric variables from extrinsically activated assays with and without aprotinin for rapid detection of fibrinolysis. Anesth Analg. 2014;119:533542.
    90. Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma. 2009;67:125131.
    91. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73:365370.
    92. Da Luz LT, Nascimento B, Shankarakutty AK, Rizoli S, Adhikari NK. Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care. 2014;18:518.
    93. Larsen OH, Fenger-Eriksen C, Christiansen K, Ingerslev J, Sørensen B. Diagnostic performance and therapeutic consequence of thromboelastometry activated by kaolin versus a panel of specific reagents. Anesthesiology. 2011;115:294302.
    94. Solomon C, Sørensen B, Hochleitner G, Kashuk J, Ranucci M, Schöchl H. Comparison of whole blood fibrin-based clot tests in thrombelastography and thromboelastometry. Anesth Analg. 2012;114:721730.
    95. Paniccia R, Priora R, Liotta AA, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag. 2015;11:133148.
    96. Petricevic M, Konosic S, Biocina B, et al. Bleeding risk assessment in patients undergoing elective cardiac surgery using ROTEM(®) platelet and Multiplate(®) impedance aggregometry. Anaesthesia. 2016;71:636647.
    97. Karon BS, Tolan NV, Koch CD, et al. Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. Clin Chem. 2014;60:15241531.
    98. Hans GA, Besser MW. The place of viscoelastic testing in clinical practice. Br J Haematol. 2016;173:3748.
    99. Görlinger K, Dirkmann D, Hanke AA. Gonzalez E, Moore HB, Moore EE. Rotational Thromboelastometry (ROTEM®). Trauma Induced Coagulopathy. 20161st ed. New York: Springer.
    100. Sankarankutty A, Nascimento B, Teodoro da Luz L, Rizoli S. TEG® and ROTEM® in trauma: similar test but different results? World J Emerg Surg. 2012;7(suppl 1):S3.
    101. Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci. 2008;38:1523.
    102. Tanaka KA, Bolliger D, Vadlamudi R, Nimmo A. Rotational thromboelastometry (ROTEM)-based coagulation management in cardiac surgery and major trauma. J Cardiothorac Vasc Anesth. 2012;26:10831093.
    103. Weber CF, Görlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531547.
    104. Nardi G, Agostini V, Rondinelli B, et al. Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs. Crit Care. 2015;19:83.
    105. Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2015;19:1228, vvi.
    106. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the american society of anesthesiologists task force on perioperative blood management. Anesthesiology. 2015;122:241275.
    107. Schöchl H, Cotton B, Inaba K, et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265.
    108. Tiel Groenestege-Kreb D, van Maarseveen O, Leenen L. Trauma team. Br J Anaesth. 2014;113:258265.
    109. Vallier HA, Moore TA, Como JJ, et al. Teamwork in Trauma: system adjustment to a protocol for the management of multiply injured patients. J Orthop Trauma. 2015;29:e446e450.
    110. Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75:961967.
    111. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77:811817.
    112. Harvin JA, Peirce CA, Mims MM, et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78:905911.
    113. Valle EJ, Allen CJ, Van Haren RM, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76:13731378.
    114. Moore EE, Moore HB, Gonzalez E, et al. Postinjury fibrinolysis shutdown: rationale for selective tranexamic acid. J Trauma Acute Care Surg. 2015;78:S65S69.
    115. Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A, Silliman CC. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion. 2016;56(suppl 2):S110S114.
    116. Roberts I. Fibrinolytic shutdown: fascinating theory but randomized controlled trial data are needed. Transfusion. 2016;56(suppl 2):S115S118.
    117. Harr JN, Moore EE, Chin TL, et al. Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early. Eur J Trauma Emerg Surg. 2015;41:4956.
    118. Abuelkasem E, Lu S, Tanaka K, Planinsic R, Sakai T. Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation. Br J Anaesth. 2016;116:507512.
    119. 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.
    120. Gruen RL, Jacobs IG, Reade MC; PATCH-Trauma Study. Trauma and tranexamic acid. Med J Aust. 2013;199:310311.
    121. Aubron C, Reade MC, Fraser JF, Cooper DJ. Efficacy and safety of fibrinogen concentrate in trauma patients—a systematic review. J Crit Care. 2014;29:471.e11471.e17.
    122. Chambers LA, Chow SJ, Shaffer LE. Frequency and characteristics of coagulopathy in trauma patients treated with a low- or high-plasma-content massive transfusion protocol. Am J Clin Pathol. 2011;136:364370.
    123. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008;101:769773.
    124. Innerhofer P, Westermann I, Tauber H, et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury. 2013;44:209216.
    125. Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma. 2008;64:S79S85.
    126. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg. 2013;148:218225.
    127. Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115:7683.
    128. Collins PW, Solomon C, Sutor K, et al. Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Br J Anaesth. 2014;113:585595.
    129. Khan S, Davenport R, Raza I, et al. Damage control resuscitation using blood component therapy in standard doses has a limited effect on coagulopathy during trauma hemorrhage. Intensive Care Med. 2015;41:239247.
    130. Faraday N. Fibrinogen concentrate and allogeneic blood transfusion in high-risk surgery. Anesthesiology. 2013;118:79.
    131. Theodoulou A, Berryman J, Nathwani A, Scully M. Comparison of cryoprecipitate with fibrinogen concentrate for acquired hypofibrinogenaemia. Transfus Apher Sci. 2012;46:159162.
    132. Solomon C, Gröner A, Ye J, Pendrak I. Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. Thromb Haemost. 2015;113:759771.
    133. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth. 2014;113:922934.
    134. Tanaka KA, Bader SO, Görlinger K. Novel approaches in management of perioperative coagulopathy. Curr Opin Anaesthesiol. 2014;27:7280.
    135. Görlinger K, Fries D, Dirkmann D, Weber CF, Hanke AA, Schöchl H. Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy. Transfus Med Hemother. 2012;39:104113.
    136. Pidcoke HF, Aden JK, Mora AG, et al. Ten-year analysis of transfusion in Operation Iraqi Freedom and Operation Enduring Freedom: increased plasma and platelet use correlates with improved survival. J Trauma Acute Care Surg. 2012;73:S445S452.
    137. Hallet J, Lauzier F, Mailloux O, et al. The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit Care Med. 2013;41:28002811.
    138. Greene LA, Chen S, Seery C, Imahiyerobo AM, Bussel JB. Beyond the platelet count: immature platelet fraction and thromboelastometry correlate with bleeding in patients with immune thrombocytopenia. Br J Haematol. 2014;166:592600.
    139. Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology. 2015;122:923931.
    140. Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:26522660.
    141. Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meyer N, Menicanti L, Frigiola A; Surgical Clinical Outcome REsearch (SCORE) Group. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc. 2015;4:e002066.
    142. Ponschab M, Voelckel W, Pavelka M, Schlimp CJ, Schöchl H. Effect of coagulation factor concentrate administration on ROTEM® parameters in major trauma. Scand J Trauma Resusc Emerg Med. 2015;23:84.
    143. Weiss G, Lison S, Spannagl M, Heindl B. Expressiveness of global coagulation parameters in dilutional coagulopathy. Br J Anaesth. 2010;105:429436.
    144. Schöchl H, Nienaber U, Maegele M, et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15:R83.
    145. Hanke AA, Joch C, Görlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth. 2013;110:764772.
    146. Grottke O, Braunschweig T, Spronk HM, et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:19431951.
    147. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates—evaluation of safety and thrombogenicity. Crit Care. 2011;15:201.
    148. Kirchner C, Dirkmann D, Treckmann JW, et al. Coagulation management with factor concentrates in liver transplantation: a single-center experience. Transfusion. 2014;54:27602768.
    149. Poole D. Coagulopathy and transfusion strategies in trauma. Overwhelmed by literature, supported by weak evidence. Blood Transfus. 2016;14:37.
    150. Karkouti K, McCluskey SA, Callum J, et al. Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis. Anesthesiology. 2015;122:560570.
    151. Rahe-Meyer N, Solomon C, Hanke A, et al. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology. 2013;118:4050.
    152. Görlinger K, Dirkmann D, Hanke AA, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology. 2011;115:11791191.
    153. Pearse BL, Smith I, Faulke D, et al. Protocol guided bleeding management improves cardiac surgery patient outcomes. Vox Sang. 2015;109:267279.
    154. Khan S, Brohi K, Chana M, et al.; International Trauma Research Network (INTRN). Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg. 2014;76:561568.
    155. Schöchl H, Voelckel W, Schlimp CJ. Management of traumatic haemorrhage—the European perspective. Anaesthesia. 2015;70(suppl 1):102107, e35e37.
    156. Dutton RP. Management of traumatic haemorrhage—the US perspective. Anaesthesia. 2015;70(suppl 1):108111, e38.
    157. Theusinger OM, Stein P, Spahn DR. Transfusion strategy in multiple trauma patients. Curr Opin Crit Care. 2014;20:646655.
    158. Maegele M, Zinser M, Schlimp C, Schöchl H, Fries D. Injectable hemostatic adjuncts in trauma: fibrinogen and the FIinTIC study. J Trauma Acute Care Surg. 2015;78:S76S82.
    159. Haas T, Görlinger K, Grassetto A, et al. Thromboelastometry for guiding bleeding management of the critically ill patient: a systematic review of the literature. Minerva Anestesiol. 2014;80:13201335.
    160. Schäfer N, Driessen A, Fröhlich M, Stürmer EK, Maegele M; TACTIC Partners. Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres. Scand J Trauma Resusc Emerg Med. 2015;23:74.
    161. Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review. BMC Med Res Methodol. 2006;6:54.
    162. Spahn DR. TEG®- or ROTEM®-based individualized goal-directed coagulation algorithms: don’t wait—act now! Crit Care. 2014;18:637.
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