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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

doi: 10.1213/ANE.0000000000001516
Critical Care and Resuscitation: Narative Review Article
Continuing Medical Education

Hemorrhage in the setting of severe trauma is a leading cause of death worldwide. The pathophysiology of hemorrhage and coagulopathy in severe trauma is complex and remains poorly understood. Most clinicians currently treating trauma patients acknowledge the presence of a coagulopathy unique to trauma patients—trauma-induced coagulopathy (TIC)—independently associated with increased mortality. The complexity and incomplete understanding of TIC has resulted in significant controversy regarding optimum management. Although the majority of trauma centers utilize fixed-ratio massive transfusion protocols in severe traumatic hemorrhage, a widely accepted “ideal” transfusion ratio of blood to blood products remains elusive. The recent use of viscoelastic hemostatic assays (VHAs) to guide blood product replacement has further provoked debate as to the optimum transfusion strategy. The use of VHA to quantify the functional contributions of individual components of the coagulation system may permit targeted treatment of TIC but remains controversial and is unlikely to demonstrate a mortality benefit in light of the heterogeneity of the trauma population. Thus, VHA-guided algorithms as an alternative to fixed product ratios in trauma are not universally accepted, and a hybrid strategy starting with fixed-ratio transfusion and incorporating VHA data as they become available is favored by some institutions. We review the current evidence for the management of coagulopathy in trauma, the rationale behind the use of targeted and fixed-ratio approaches and explore future directions.

From the *Intensive Care Unit, Gold Coast University Hospital, Southport, Queensland, Australia; Gold Coast University Hospital Critical Care Research Group, Queensland, Australia; Joint Health Command, Australian Defence Force and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia; §Heart Foundation Research Centre, School of Medicine, Griffith University, Gold Coast, Queensland, Australia; Trauma Department, Gold Coast University Hospital, Queensland, Australia; Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany; #Tem International GmbH, Munich, Germany; and **Critical Care Research Group, The Prince Charles Hospital and University of Queensland, Brisbane, Queensland, Australia.

Accepted for publication June 9, 2016.

Funding: The program of trauma research is supported by grants from the Queensland Emergency Medicine Research Foundation and Gold Coast University Hospital Foundation.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Klaus Görlinger, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; and Tem International GmbH, Munich, Germany. Address e-mail to klaus.goerlinger@tem-international.de and klaus@goerlinger.net.

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

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.

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RATIO-BASED MASSIVE TRANSFUSION PROTOCOLS

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.

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TRANSFUSION-ASSOCIATED ADVERSE EVENTS

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.

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CONCERNS REGARDING STANDARD LABORATORY TESTS

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.

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VISCOELASTIC HEMOSTATIC ASSAYS

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.

Table. C

Table. C

Figure 2

Figure 2

Figure 3

Figure 3

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.

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IMPLEMENTATION OF A VHA-TARGETED APPROACH: ONE INSTITUTION’S PROCESS

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

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.

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DEVELOPMENT OF A VHA-GUIDED TREATMENT ALGORITHM

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

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.

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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

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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

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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

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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

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THE CURRENT STATE OF EVIDENCE

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.

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Challenges

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.

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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.

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CONCLUSIONS

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.

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ACKNOWLEDGMENTS

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.

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DISCLOSURES

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.

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