Secondary Logo

Journal Logo

Cardiovascular Anesthesiology: Review Article

Trauma Bleeding Management

The Concept of Goal-Directed Primary Care

Schöchl, Herbert MD*†; Schlimp, Christoph J. MD

Author Information
doi: 10.1213/ANE.0b013e318270a6f7
  • Free
  • CE Test

Severe trauma often results in uncontrolled, noncompressible diffuse microvascular bleeding, potentially leading to exsanguination;1,2 importantly, approximately 40% of all trauma-related deaths are linked to pronounced coagulopathy.3 Patient management strategies in cases of major bleeding prioritize attenuating the hemorrhage, the resuscitation of intravascular volume, and the early support of coagulation.4 Recent experiences derived initially from military trauma-care providers suggest the administration of a ratio of fresh frozen plasma (FFP), platelet concentrate (PC), and red blood cells (RBCs) close to 1:1:1 reduces mortality in patients with major bleeding.5–9 However, the evidence supporting this approach is not conclusive, and the optimal ratio of FFP:PC:RBCs is still under investigation.10–16

An alternative management strategy for the treatment of trauma-induced coagulopathy (TIC) has been developed after the emergence of viscoelastic point-of-care (POC) coagulation monitoring tools such as rotational thromboelastometry (ROTEM®; Tem International, Munich, Germany) and thrombelastography (TEG®; Haemonetics, Braintree, MA).15,17–19 These tests offer the ability to rapidly assess the initiation processes of clot formation, clot strength, and clot stability.20 The use of these rapid POC assessment techniques can facilitate the aim of an individualized coagulation therapy based on FFP, PC, RBCs, and hemostatic agents. In some European trauma centers, viscoelastic tests are used to guide an approach to hemostatic therapy in which coagulation factor concentrates are prominent.18,21,22 This management strategy is in contrast to the ratio-driven concept, because such testing allows deficits in certain phases of the clotting process to be identified and specifically addressed. It is important to note that both strategies focus on the same therapeutic goals: the aggressive increase in hemostatic capacity via the administration of coagulation factors and platelets, and as a result, facilitating the rapid reversal of shock and endothelial dysfunction while supporting effective coagulation. Ultimately, the aims are a reduction in blood loss and an improvement in survival rates; these 2 treatment approaches are compared in this article. It is important to note that although more precise resuscitation is an appropriate aim for trauma physicians, the debate surrounding both the administration of the optimum ratio of blood products, or a targeted therapy based on rapid coagulation assessment, should not distract from the need to act quickly in cases of TIC; when resuscitation is necessary, “blind” protocol-guided transfusion is appropriate in the absence of diagnostic data.


Standard Laboratory Tests

Routine coagulation tests, such as prothrombin time (PT), prothrombin index, International Normalized Ratio (INR), and/or activated partial thromboplastin time (aPTT) are used in most trauma centers worldwide to assess coagulopathy in trauma and to guide hemostatic therapy.23 The value of these standard coagulation analyses in adequately reporting the complexities of trauma-associated coagulopathy has been challenged.18,23,24 Because whole cells are removed by centrifugation before standard coagulation testing, the contribution to clotting from platelets, erythrocytes, and tissue factor–bearing cells, are not considered.18 Standard tests do not provide any information regarding the strength or stability of clot formation; the important role of fibrinogen in mediating coagulation is also not recognized and the extent of any existing hyperfibrinolysis (a significant confounder of the coagulation process)25–27 is not adequately assessed.28 Moreover, extended lengths of time are required for clinical laboratories to process the results of such tests, with waits of between 78 (range, 62–103 minutes)29 and 88 minutes (range, 29–295 minutes)30 being reported. In short, standard coagulation tests are time consuming and were neither developed nor validated to diagnose the complex nature of TIC.18

A Role for Thromboelastometry and Thromboelastography in Identifying Acute Trauma Patients at Risk of Massive Transfusion?

Alternatives to routine coagulation tests including viscoelastic coagulation monitors such as ROTEM and TEG are proving to be of increasing clinical value to trauma physicians. ROTEM and TEG devices measure the changes in clot formation in whole blood, accounting for the contributions to the clotting process of platelets, and tissue factor–bearing cells; this provides a more comprehensive analysis than conventional testing21,29,31–33 that is, relative to plasma-based coagulation variables, more reflective of the in vivo coagulation status of the patient and, importantly, can be available within minutes.29,34 It should be noted that the contribution to clotting mediated by endothelial cells (which remains largely unknown and underappreciated) is not assessed by either standard laboratory or viscoelastic tests of coagulation. However, whole blood tests do assess the role of any endothelial-derived factors that are present.

Both ROTEM and TEG provide the opportunity to discern between different potential causes of bleeding. A general picture of coagulation status, looking at both the intrinsic and extrinsic activation pathways can be assessed (e.g., impaired, normal, hypercoagulable); furthermore, the fibrin-dependent component of the clot and an assessment of hyperfibrinolysis is also possible. The functional properties of the assays used by ROTEM and TEG have been described in detail,28,35 and an example of ROTEM traces observed during normal and impaired coagulation are shown in Figure 1.18

Figure 1:
An example of ROTEM (EXTEM and FIBTEM) traces observed during normal, impaired, and hyperfibrinolytic coagulation states.18 A, Normal test result. B, Reduced MCF in EXTEM and FIBTEM, normal CT, prolonged CFT. C, Severe coagulopathy: delayed initiation of coagulation (prolonged CT), low CFT, and MCF; no measurable FIBTEM. E, Hyperfibrinolysis: complete breakdown of the clot, very low FIBTEM. CT = coagulation time; CFT = clot formation time; MCF = maximum clot firmness.

How Useful Is the Rapid Assessment of Coagulation Status in Patients with Major Bleeding?

A retrospective analysis of severely injured trauma patients (n = 44) presenting at a level 1 trauma center compared the results of conventional coagulation tests with rapid TEG (r-TEG). The use of r-TEG performed on noncitrated whole blood was an effective real-time measure of thrombostatic function, which could guide transfusion therapy and may result in reduced FFP administration compared with conventional testing.20 The feasibility of using ROTEM to assess the coagulation status of patients requiring massive transfusion accurately was investigated prospectively in deployed military personnel.36 ROTEM was shown to detect significantly more coagulation abnormalities than PT and aPTT, and its use was effective in both monitoring and guiding individualized therapy during massive transfusion.36 It is important to note that further prospective study into the application of POC viscoelastic devices for real-time assessment of coagulation status in severely bleeding patients is required.

Early Identification of Patients At Risk for Massive Transfusion Is Crucial

It is of paramount importance for trauma-care providers to identify those patients at risk for massive transfusion early in the course of initial treatment for 2 reasons; first, it has been shown that a delay in the initiation of coagulation therapy is associated with a poor outcome when patients were massive bleeders.10,12 Second, there is evidence that the use of high plasma:RBC ratios in patient groups who ultimately do not receive massive transfusion may not improve survival and can increase complication rates.37–39

Predictive scores were developed to assess the risk of the individual patient for massive transfusion. Most of these scores are based on both anatomical findings and rapidly available laboratory data, such as hemoglobin and base deficit.40–44 Massive transfusion scores were mostly developed from retrospective data sets, and few were prospectively validated.45,46

How Can Early Coagulation Therapy Be Achieved in Trauma Patients with Major Bleeding?

Ratio-Driven Volume Resuscitation

To both overcome insufficiencies in therapy, and improve the hemostatic capacity of the bleeding patient, the adoption of the “damage-control resuscitation” concept has led to the introduction of massive transfusion protocols (MTPs) in recent years,47–49 with experience from both military and civilian studies leading to a reappraisal of treatment protocols in bleeding trauma victims. This approach proposes the early and aggressive transfusion of FFP and PCs to replace both circulating volume, depleted clotting factors, and platelets.50 Geeraedts et al.51 suggested that the majority of trauma patients who died because of exsanguination within the first 24 hours after admission (82%) received insufficient amounts of FFP and PCs. These data were confirmed by Gonzalez et al.52 who found that trauma patients were coagulopathic on admission to the intensive care unit (ICU) due to inadequate pre-ICU coagulation therapy. INR and aPTT were prolonged at ICU admission (INR, 1.6 ± 0.1; aPTT, 36 ± 2 seconds) and did not fully normalize by the end of day 1 in the ICU.52

High Ratio of FFP:RBC

Hirshberg et al.53 developed a computer model where they showed that to sufficiently correct coagulopathy in major bleeding, FFP treatment has to be started early with a necessary ratio of FFP:RBC of 2:3.

This mathematical model was confirmed by Borgman et al.5 who performed a retrospective review of patients receiving massive transfusion (≥10 units RBCs in 24 hours) at a military trauma center. When patient groups receiving a median plasma:RBCs ratio of 1:8, 1:2.5, and 1:1.4 were compared, the overall mortality rates observed were 65%, 34%, and 19% (P < 0.001), respectively. The increased survival rate was associated with decreased death from hemorrhage,5 findings which were supported by similar results in a retrospective study of civilian patients.7

In addition to any resulting improvements in hemostatic capacity, other potential beneficial effects of plasma transfusion have been suggested. Johansson et al.54 identified that high levels of circulating syndectan–1, a marker of endothelial glycocalyx degradation, was associated with increased mortality. Experimental studies in rats have suggested a potential role for plasma in protecting the endothelial glycocalyx after hemorrhagic shock compared with a crystalloid-based fluid therapy,55 as well as improving endothelial cell function and hemodynamic stability.56

Although many published studies have supported a high FFP:RBC transfusion ratio,5,7–9,57–60 limitations to these observations have been identified,10,12 and a consensus within the literature remains to be established.48,49,61 The evidence currently available is either retrospective or nonrandomized; consequently, results from these studies can only be hypothesis generating.12,15,47,49,62,63

Advantages and Limitations of the Ratio-Driven Concept

Survivor Bias

There are limitations to the ratio-driven concept. A survivor bias can skew the data in observational studies, whereby an artificially high number of patients with a poor prognosis have the potential to be included in the low plasma ratio cohorts, because such patients died before more plasma units could be transfused.12 Moreover, there is the possibility of selection bias also, whereby physicians expended more resources, including plasma transfusions, on those patients most likely to survive. It should also be considered that the decision to cease coagulation therapy in severely injured patients with no chance of survival can often occur after RBC transfusion, but before FFP and other allogeneic administration. As such, reported FFP:RBC ratios will be significantly lower in this subsection of patients. Attempts to mitigate these sources of bias include performing time covariant analysis,64 as well as the exclusion from retrospective data sets of patients who died within 1 to 2 hours. Both methods produce data that show an association of high ratio transfusion with improved survival; however, the sources of bias cannot be completely excluded. A recent analysis of 26 studies relating to blood ratios in trauma concluded that, because of the difficulties presented in trying to exclude survivor bias, the available evidence relating to higher ratios of FFP:RBC are inconclusive, and prospective trials are required.10

Transfusion Volume

The physiological concentrations of plasma proteins present in standard FFP and solvent/detergent plasma necessitate high transfusion volumes to sufficiently increase coagulation factor activity.65 Chowdary et al.66 measured the recovery of coagulation factors after the transfusion of 12.2 mL/kg compared with 33.5 mL/kg, showing that only high-volume plasma transfusion induced increases in the concentrations of factors to or above target levels. Thus, a formula-driven strategy requires immediate access to large volumes of universal donor FFP. Thawing before transfusion is required for FFP, which is time consuming and can potentially delay necessary and immediate coagulation therapy. To overcome this hindrance, some centers instigate the prethawing of FFP in ready-to-administer transfusion packages;47 however, a universal implementation of this strategy beyond busy trauma centers would potentially result in wasted plasma, its overuse, or both.67 Lyophilized plasma, which is available immediately, could address these logistical problems.68,69

Timing of Intervention

It is becoming increasingly evident that effective treatment of TIC requires early intervention to improve the hemostatic capacity of exsanguinating patients. Snyder et al.70 report a mean time of 93 minutes until first FFP transfusion, compared with 18 minutes for RBCs. This lag in FFP administration can distort the true ratio of administered blood products. Because the time between FFP and RBC transfusion can vary so widely, it is difficult to state definitively the true ratio of products transfused. As such, the transfusion of FFP and RBC units within a 30-minute period is proposed for a 1:1 ratio to be considered an accurate reflection of the clinical reality. This limitation has been highlighted by de Biasi et al.71 reporting a significant relationship between the by-hour mortality rate and the observed plasma deficit status within the first 2 hours of volume resuscitation. Furthermore, Riskin et al.72 reviewed data on trauma patients requiring massive transfusion (≥10 units RBCs) before and after the implementation of an MTP. The FFP:RBC ratios were identical in both observation periods (1:1.8 and 1:1.8; P = 0.97), but the mean time to administration of the first FFP decreased from 254 to 169 minutes (P = 0.04). Despite the unchanged ratio of blood products, mortality decreased from 45% to 19% (P = 0.02), suggesting a time-dependent variable and underscoring that the early transfusion intervention might be vital.72 It should be highlighted that the introduction of MTPs that use prethawed plasma products have now been reported, allowing the administration of the first blood product within as little as 3 minutes (range, 0–23 minutes).47 However, in this study, the storage of prethawed FFP in the blood bank was only allowed for up to 72 hours, raising the possibility for the wastage of this valuable resource using this approach. Moreover, preclinical data have indicated that administration of human plasma stored for 5 days resulted in significantly decreased survival compared with freshly thawed plasma in a rat model of acute hemorrhage after hepatic injury (P = 0.03).73

Potential Adverse Events

High-volume transfusions are associated with a risk of complications. In patients without massive bleeding, FFP transfusion is associated with both acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).12,37,65,74,75 A dose-dependent relationship between FFP administration and ARDS has been observed.74 It is important to note that, as previously discussed, massive transfusion that includes FFP has been shown in several studies to improve survival, irrespective of the associated complications. However, in nonmassively transfused patients (<10 U packed RBC within 12 hours of admission) FFP transfusion was associated with large increases in complications, particularly ARDS, with no concomitant improvement in survival.37 The prospective analysis of patients admitted to the ICU at a combat support hospital found an independent relationship between the amount of FFP transfused and the onset of ALI.76 A separate study found the incidence of multiple organ failure in massively transfused trauma patients was associated with early FFP administration.38 As such, the need for carefully chosen transfusion triggers for FFP administration is clear.37,38

Platelet Administration

The role of platelet transfusion in the management of TIC is currently unclear. Improved survival in patients receiving high platelet:RBC ratios have been reported8; however, the reported improvements in survival associated with platelet transfusion are subject to survival and selection biases similar to those seen with FFP,15 and the efficacy of platelet transfusion in a predetermined ratio is not established. The before and after comparison of an MTP published by Dirks et al.47 showed a significant increase in platelet concentrate transfusion with no improvement in survival rate, while similar results were observed by Simmons et al.49 who reported that the introduction of new clinical practice guidelines forcing early platelet transfusion resulted in no survival benefit. As such, there is the potential for wasting valuable and expensive resources risk to patients being exposed to potential complications (e.g., ALI and pathogen transmission) unnecessarily. The authors believe this treatment option should not be routine.

Goal-Directed, POC-Guided Hemostatic Therapy in Trauma

The increased sensitivity and range of testing capabilities provided by modern viscoelastic coagulation monitors (ROTEM and TEG), coupled with the increased awareness of physicians of such techniques means that an alternative modern theragnostic approach toward the early assessment and management of TIC is now a possibility.18,77 A theragnostic management strategy relies on real-time monitoring of coagulation status to guide the targeted supplementation of hemostatic agents. Such a methodology allows for a feedback loop to be established, whereby the treatment is responsive to patient physiology and rapidly addresses the hemostatic needs of the individual.18 This approach is in stark contrast to the formulaic ratio-driven approach.

Improving and Maintaining Clot Quality During TIC

The primary focus of goal-directed coagulation therapy is the maintenance, or restoration, of clot strength. Reductions in clot firmness reported by viscoelastic tests have been shown to be predictive of increases in bleeding rates, requirements for blood product transfusion, and mortality.32,78–81 Further retrospective analysis of the coagulation profiles of severely bleeding trauma patients at admission showed that abnormal clot firmness results measured using ROTEM, as well as hemoglobin levels at or below 10 g/dL, reliably predicted the requirement for massive transfusion.82 An example of a goal-directed POC treatment algorithm used at the authors’ institute (AUVA Trauma Hospital, Salzburg, Austria)18 demonstrates the key coagulation variables that are measured, and the respective treatment approaches, when treating TIC with this approach (Fig. 2).

Figure 2:
ROTEM-guided treatment algorithm: managing trauma-induced coagulopathy and diffuse microvascular bleeding (AUVA Trauma Hospital, Salzburg, Austria).18 The algorithm is the standard operating procedure for ROTEM-guided hemostatic therapy on admission of trauma patients to the emergency room. Hemostatic agents suggested for use in clinics where coagulation factor concentrates are not available. *For patients who are unconscious or known to be taking platelet inhibitor medication, Multiplate tests (adenosine diphosphate [ADP] test, arachidonic acid [ASPI] test, and thrombin receptor activating peptide-6 [TRAP] test) are also performed. §If decreased ATIII is suspected or known, consider coadministration of ATIII. Any major improvement in extrinsicaly activated test plus aprotinin (APTEM) parameters compared with corresponding EXTEM parameters may be interpreted as a sign of hyperfibrinolysis. Only for patients not receiving TXA at an earlier stage of the algorithm. Traumatic brain injury: platelet count 80,000 to100,000/μL. Normal values: EXTEM/APTEM coagulation time (CT): 38 to 79 seconds; EXTEM/APTEM clot amplitude at 10 minutes (CA10): 43 to 65 mm; EXTEM/APTEM maximum lysis (ML) < 15%; FIBTEM CA10: 7 to 23 mm; intrinsically activated test (INTEM) CT: 100 to 240 seconds. CA10 = clot amplitude at 10 minutes; BGA = blood gas analysis; BW = body weight; Ca = calcium; CT = clotting time; FFP = fresh frozen plasma; ISS = injury severity score; MAPTECF = maximum clot firmness; ML = maximum lysis; PCC = prothrombin complex concentrate; TXA = tranexamic acid.


Hyperfibrinolysis is a key consideration in patients with severe shock and major tissue trauma.1,26,83,84 Early primary fibrinolysis was detected in 34% of trauma-related admissions (determined by r-TEG) and was associated with massive transfusion requirements, coagulopathy, and hemorrhage-related death.25 Hyperfibrinolysis was also found to be a predictor of poor survival, being associated with high mortality rates.26 Tranexamic acid (TXA) is a synthetic lysine derivative that inhibits fibrinolysis by blocking the lysine binding sites of plasminogen.85,86 TXA administration reduced the risk of death caused by bleeding in trauma patients significantly compared with placebo (n = 10,060 vs n = 10,067, respectively) during the recent Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage study (4.9% vs 5.7%, respectively; relative risk, 0.85; 95% confidence interval, 0.76–0.96; P = 0.0077).86 As such, the use of TXA should be considered for the treatment of severely bleeding trauma patients. In contrast to the patients included in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage study, a recent study of the military application of TXA in trauma emergency resuscitation analyzed data from cohorts where all patients were operated on and received RBC transfusion.87 The military application of TXA in trauma emergency resuscitation study showed that overall mortality rates were 6.5% lower in the TXA group compared with the non-TXA group (P = 0.03), whereas the difference in mortality rates was even greater in patients receiving massive transfusion (14.4% vs 28.1%, respectively; P = 0.004).87Figure 3 shows an example of severe hyperfibrinolysis.

Figure 3:
An example of severe hyperfibrinolysis. Note the fulminant breakdown of the clot within minutes in the EXTEM test. No clot formation in the FIBTEM test. When adding aprotinin (APTEM) or tranexamic acid (TXA), stable clot formation could be achieved.

Fibrinogen Supplementation

There is increasing evidence that fibrinogen supplementation is helpful in major bleeding and during the management of TIC.88,89 Hippalla et al.90 observed that fibrinogen was the first coagulation factor to reach a critically low concentration in cases of blood loss, whereas a recent study showed fibrinogen deficiency (<100 mg/dL) was the initial abnormality of coagulation in almost all trauma patients who developed coagulopathy.91 The maximum clot strength (measured by ROTEM) is a result of the interaction of activated platelets, fibrin, and aFXIII.35 As such, an improvement of the maximum amplitude of the clot in severe bleeding patients can be achieved by administration of sufficient amounts of fibrinogen.34 Current European guidelines now recommend supplementation of fibrinogen when plasma concentrations are in the critical range 1.5 g/L to 2.0 g/L.92

When considering the ratio of fibrinogen to RBCs administered to military trauma patients receiving massive transfusion, Stinger et al.93 reported that an increased total amount of fibrinogen administered was independently associated with improved survival rates. However, it is important to note that patients included in this study receiving higher ratios of fibrinogen:RBCs also received more PCs, FFP, and cryoprecipitate, making the interpretation of the data difficult, especially given the central role of platelets in maintaining primary and secondary hemostasis.

Fibrinogen supplementation can be undertaken via the transfusion of large volumes of FFP, or the administration of either cryoprecipitate or fibrinogen concentrate. Cryoprecipitate has been used for the treatment of congenital fibrinogen deficiency and for intravascular volume resuscitation in trauma;94 however, it has been withdrawn in many European countries because of significant safety concerns relating to its administration.92 Fibrinogen concentrate can be easily and quickly reconstituted using sterile water or saline for administration without thawing or cross-matching,88 allowing rapid and controlled dosing. Although used primarily in Europe, it should be noted that the administration of fibrinogen concentrate for the treatment of acquired bleeding is off-label in some countries including the United States. Consistent and high doses of fibrinogen can be delivered in small volumes, and in cases of urgent treatment of severe bleeding, delivery of 6 g in 1 to 2 minutes has been reported.95 Clearly, given the physiological concentrations of fibrinogen present in FFP (2.0–2.7 g/L),96,97 an equivalent approach is not feasible because it would involve the transfusion of approximately 2500 mL. It is possible to monitor improvements in clot formation and clot strength using POC testing regimes such as EXTEM, FIBTEM, which provide real-time information about the patient’s coagulation status, and allow for guided dosing and administration. Thus, a theragnostic approach to fibrinogen supplementation is possible.

Improving Initiation of the Coagulation Process

It appears thrombin generation is not an acute problem in the very early stages of TIC. Dunbar and Chandler98 reported on 15 trauma patients with PT >18 seconds or an INR >1.5, suggesting possible TIC. When thrombin generation was measured, it was found to be 3-fold higher compared with controls (P = 0.01). According to the TEG results of trauma patients (n = 65), the majority were hypercoagulable immediately after injury.99 These data are in accordance with findings of Davenport et al.29 who reported that TIC was mainly characterized by a reduction in maximum clot firmness rather than a prolonged ROTEM clotting time.

To increase thrombin generation, prothrombin complex concentrates (PCCs) and activated recombinant factor VII (rFVIIa) have been used as coagulation therapy during trauma-related bleeding.21,100–102 However, randomized controlled studies did not reveal a survival benefit in trauma patients receiving rFVIIa.100,101 Few studies have reported the use of PCC in trauma patients.21,103,104 Although these reports have described a survival benefit associated with PCC administration, prospective trials are lacking. Because of the retrospective nature of the available study data, safety issues surrounding PCC were not adequately assessed. PCCs are potent procoagulants and, as such, the possibility of associated thromboembolic event should be considered92,104,105; it is important to note that there are currently no robust safety data relating to PCC use in TIC. The coadministration of PCCs with antithrombotic factors such as antithrombin III has been suggested as a potential approach to minimize the risk of thromboembolism;18 however, this is yet to be validated by prospective study.

To date, only initial results indicate the potential for goal-directed administration of clotting factor concentrates to reduce the requirement for allogeneic transfusion in the management of severe trauma-related bleeding, and prospective, randomized trials that interrogate this management strategy are necessary.

Advantages and Limitations of a Goal-Directed Approach Using Coagulation Factor Concentrates

The use of clotting factor concentrates for goal-directed coagulation management during trauma-related bleeding is a relatively new concept. Although there are significant potential benefits with this approach,106–108 currently there is no consensus among physicians regarding this treatment strategy.109,110 Care must be taken to consider the potential risks associated with this approach. A goal-directed approach that uses function measures of coagulation for factor concentrate administration may be able to avoid the adverse thrombotic events that have been reported with nonguided use of these agents.

The individualized theragnostic management of TIC holds many theoretical advantages over the ratio-driven approach. The formulaic administration of FFP and RBCs used by the latter of these strategies means that the undertransfusion and overtransfusion of some patients are inevitable. There is a clear need to avoid inappropriate transfusion levels, as too little will not effectively treat TIC whereas too much will increase the risk of ARDS, multiple organ failure, and ALI.38,65,74,75,111


It is clear that TIC management requires the early and aggressive replenishment of coagulation factors. When using high-volume plasma therapy, it is necessary to sufficiently increase hemostatic capacity of the patients, maintain circulating volume, and tissue oxygenation. Based on the available data, it is currently unknown which ratio of FFP:RBC is optimal to achieve this.

An individualized hemostatic treatment strategy based on viscoelastic test results is another promising concept for patients with severe trauma-related bleeding. It is still not clear whether this approach can improve outcomes while not increasing morbidity, nor is it clear what the optimal goal-directed algorithm in severe trauma patients should be. The availability of clotting factor concentrates is key to allow for the targeted supplementation of procoagulants. The administration of fibrinogen concentrate in cases of TIC can address the problems of early and critical fibrinogen depletion; this product holds significant timing and safety advantages over FFP transfusion for fibrinogen supplementation. The need for further prospective study of this technique is both clear and imperative.


Name: Herbert Schöchl, MD.

Contribution: This author helped review and prepare the manuscript.

Attestation: Herbert Schöchl approved the final manuscript.

Conflicts of Interest: Herbert Schöchl has received study grants and honoraria as speaker from CSL Behring (manufacturer of fibrinogen concentrate and PCC) and Tem International (manufacturer of the ROTEM device).

Name: Christoph J. Schlimp, MD.

Contribution: This author helped review and prepare the manuscript.

Attestation: Christoph J. Schlimp approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.


Editorial assistance was provided by John Timney of Fishawack Communications Ltd. during the preparation of this manuscript.


1. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680–5
2. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 2005;9 Suppl 5:S1–9
3. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38:185–93
4. Stainsby D, MacLennan S, Thomas D, Isaac J, Hamilton PJ; British Committee for Standards in Haematology. . Guidelines on the management of massive blood loss. Br J Haematol. 2006;135:634–41
5. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63:805–13
6. Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM, Young PP. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. J Trauma. 2009;66:41–8
7. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris JA Jr, St Jacques P, Young PP. Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma. 2008;64:1177–82
8. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447–58
9. Holcomb JB, Zarzabal LA, Michalek JE, Kozar RA, Spinella PC, Perkins JG, Matijevic N, Dong JF, Pati S, Wade CE, Holcomb JB, Wade CE, Cotton BA, Kozar RA, Brasel KJ, Vercruysse GA, MacLeod JB, Dutton RP, Hess JR, Duchesne JC, McSwain NE, Muskat PC, Johannigamn JA, Cryer HM, Tillou A, Cohen MJ, Pittet JF, Knudson P, DeMoya MA, Schreiber MA, Tieu BH, Brundage SI, Napolitano LM, Brunsvold ME, Sihler KC, Beilman GJ, Peitzman AB, Zenati MS, Sperry JL, Alarcon LH, Croce MA, Minei JP, Steward RM, Cohn SM, Michalek JE, Bulger EM, Nunez TC, Ivatury RR, Meredith JW, Miller PR, Pomper GJ, Marin B; Trauma Outcomes Group. . Increased platelet:RBC ratios are associated with improved survival after massive transfusion. J Trauma. 2011;71:S318–28
10. Ho AM, Dion PW, Yeung JH, Holcomb JB, Critchley LA, Ng CS, Karmakar MK, Cheung CW, Rainer TH. Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology. 2012;116:716–28
11. Stansbury LG, Dutton RP, Stein DM, Bochicchio GV, Scalea TM, Hess JR. Controversy in trauma resuscitation: do ratios of plasma to red blood cells matter? Transfus Med Rev. 2009;23:255–65
12. Murad MH, Stubbs JR, Gandhi MJ, Wang AT, Paul A, Erwin PJ, Montori VM, Roback JD. The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion. 2010;50:1370–83
13. Scalea TM, Bochicchio KM, Lumpkins K, Hess JR, Dutton R, Pyle A, Bochicchio GV. Early aggressive use of fresh frozen plasma does not improve outcome in critically injured trauma patients. Ann Surg. 2008;248:578–84
14. Mitra B, Mori A, Cameron PA, Fitzgerald M, Paul E, Street A. Fresh frozen plasma (FFP) use during massive blood transfusion in trauma resuscitation. Injury. 2010;41:35–9
15. Allen SR, Kashuk JL. Unanswered questions in the use of blood component therapy in trauma. Scand J Trauma Resusc Emerg Med. 2011;19:5
16. Zehtabchi S, Nishijima DK. Impact of transfusion of fresh-frozen plasma and packed red blood cells in a 1:1 ratio on survival of emergency department patients with severe trauma. Acad Emerg Med. 2009;16:371–8
17. Schöchl H, Forster L, Woidke R, Solomon C, Voelckel W. Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate. Anaesthesia. 2010;65:199–203
18. 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
19. 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
20. Kashuk JL, Moore EE, Le T, Lawrence J, Pezold M, Johnson JL, Cothren CC, Biffl WL, Barnett C, Sabel A. Noncitrated whole blood is optimal for evaluation of postinjury coagulopathy with point-of-care rapid thrombelastography. J Surg Res. 2009;156:133–8
21. Schöchl H, Nienaber U, Hofer G, Voelckel W, Jambor C, Scharbert G, Kozek-Langenecker S, Solomon C. 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
22. Grassetto A, De Nardin M, Ganzerla B, Geremia M, Saggioro D, Serafini E, Zampieri S, Toffoli M, Penzo D, Bossi A, Maggiolo C. ROTEM®-guided coagulation factor concentrate therapy in trauma: 2-year experience in Venice, Italy. Crit Care. 2012;16:428
23. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127–30
24. Johansson PI. Coagulation monitoring of the bleeding traumatized patient. Curr Opin Anaesthesiol. 2012;25:235–41
25. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, Biffl WL, Burlew CC, Johnson JL, Sauaia A. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252:434–42
26. 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;67:125–31
27. Theusinger OM, Wanner GA, Emmert MY, Billeter A, Eismon J, Seifert B, Simmen HP, Spahn DR, Baulig W. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg. 2011;113:1003–12
28. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366–75
29. Davenport R, Manson J, De’Ath H, Platton S, Coates A, Allard S, Hart D, Pearse R, Pasi KJ, MacCallum P, Stanworth S, Brohi K. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39:2652–8
30. 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;101:394–401
31. Johansson PI. Goal-directed hemostatic resuscitation for massively bleeding patients: the Copenhagen concept. Transfus Apher Sci. 2010;43:401–5
32. Cotton BA, Faz G, Hatch QM, Radwan ZA, Podbielski J, Wade C, Kozar RA, Holcomb JB. Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma. 2011;71:407–14
33. Kashuk JL, Moore EE, Sawyer M, Le T, Johnson J, Biffl WL, Cothren CC, Barnett C, Stahel P, Sillman CC, Sauaia A, Banerjee A. Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. Ann Surg. 2010;251:604–14
34. Schöchl H, Cotton B, Inaba K, Nienaber U, Fischer H, Voelckel W, Solomon C. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265
35. Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Haematol. 2005;27:81–90
36. Doran CM, Woolley T, Midwinter MJ. Feasibility of using rotational thromboelastometry to assess coagulation status of combat casualties in a deployed setting. J Trauma. 2010;69 Suppl 1:S40–8
37. Inaba K, Branco BC, Rhee P, Blackbourne LH, Holcomb JB, Teixeira PG, Shulman I, Nelson J, Demetriades D. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg. 2010;210:957–65
38. Johnson JL, Moore EE, Kashuk JL, Banerjee A, Cothren CC, Biffl WL, Sauaia A. Effect of blood products transfusion on the development of postinjury multiple organ failure. Arch Surg. 2010;145:973–7
39. Sambasivan CN, Kunio NR, Nair PV, Zink KA, Michalek JE, Holcomb JB, Schreiber MA, Wade CE, Brasel KJ, Vercruysse G, MacLeod J, Dutton RP, Hess JR, Duchesne JC, McSwain NE, Muskat P, Johannigamn J, Cryer HM, Tillou A, Cohen MJ, Pittet JF, Knudson P, De Moya MA, Tieu B, Brundage S, Napolitano LM, Brunsvold M, Sihler KC, Beilman G, Peitzman AB, Zenait MS, Sperry J, Alarcon L, Croce MA, Minei JP, Kozar R, Gonzalez EA, Stewart RM, Cohn SM, Bulger EM, Cotton BA, Nunez TC, Ivatury R, Meredith JW, Miller P, Pomper GJ, Marin B; Trauma Outcomes Group. . High ratios of plasma and platelets to packed red blood cells do not affect mortality in nonmassively transfused patients. J Trauma. 2011;71:S329–36
40. Nunez TC, Voskresensky IV, Dossett LA, Shinall R, Dutton WD, Cotton BA. Early prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)? J Trauma. 2009;66:346–52
41. Rainer TH, Ho AM, Yeung JH, Cheung NK, Wong RS, Tang N, Ng SK, Wong GK, Lai PB, Graham CA. Early risk stratification of patients with major trauma requiring massive blood transfusion. Resuscitation. 2011;82:724–9
42. Yücel N, Lefering R, Maegele M, Vorweg M, Tjardes T, Ruchholtz S, Neugebauer EA, Wappler F, Bouillon B, Rixen D; Polytrauma Study Group of the German Trauma Society. . Trauma Associated Severe Hemorrhage (TASH)-Score: probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma. J Trauma. 2006;60:1228–36
43. McLaughlin DF, Niles SE, Salinas J, Perkins JG, Cox ED, Wade CE, Holcomb JB. A predictive model for massive transfusion in combat casualty patients. J Trauma. 2008;64:S57–63
44. Maegele M, Brockamp T, Nienaber U, Probst C, Schoechl H, Görlinger K, Spinella P. Predictive Models and Algorithms for the Need of Transfusion Including Massive Transfusion in Severely Injured Patients. Transfus Med Hemother. 2012;39:85–97
45. Cotton BA, Dossett LA, Haut ER, Shafi S, Nunez TC, Au BK, Zaydfudim V, Johnston M, Arbogast P, Young PP. Multicenter validation of a simplified score to predict massive transfusion in trauma. J Trauma. 2010;69 Suppl 1:S33–9
46. Maegele M, Lefering R, Wafaisade A, Theodorou P, Wutzler S, Fischer P, Bouillon B, Paffrath T; Trauma Registry of Deutsche Gesellschaft für Unfallchirurgie (TR-DGU). . Revalidation and update of the TASH-Score: a scoring system to predict the probability for massive transfusion as a surrogate for life-threatening haemorrhage after severe injury. Vox Sang. 2011;100:231–8
47. 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
48. 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;50:1545–51
49. 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:S75–80
50. Holcomb JB. Damage control resuscitation. J Trauma. 2007;62:S36–7
51. Geeraedts LM Jr, Demiral H, Schaap NP, Kamphuisen PW, Pompe JC, Frölke JP. ‘Blind’ transfusion of blood products in exsanguinating trauma patients. Resuscitation. 2007;73:382–8
52. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, Cocanour CS, Balldin BC, McKinley BA. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007;62:112–9
53. Hirshberg A, Dugas M, Banez EI, Scott BG, Wall MJ Jr, Mattox KL. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a computer simulation. J Trauma. 2003;54:454–63
54. 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;254:194–200
55. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, Ko TC, Paredes A. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112:1289–95
56. Pati S, Matijevic N, Doursout MF, Ko T, Cao Y, Deng X, Kozar RA, Hartwell E, Conyers J, Holcomb JB. Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw. J Trauma. 2010;69 Suppl 1:S55–63
57. Maegele M, Lefering R, Paffrath T, Tjardes T, Simanski C, Bouillon B; Working Group on Polytrauma of the German Society of Trauma Surgery (DGU). . Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox Sang. 2008;95:112–9
58. Sperry JL, Ochoa JB, Gunn SR, Alarcon LH, Minei JP, Cuschieri J, Rosengart MR, Maier RV, Billiar TR, Peitzman AB, Moore EE; Inflammation the Host Response to Injury Investigators. . An FFP:PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion. J Trauma. 2008;65:986–93
59. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg. 2009;197:565–70
60. Peiniger S, Nienaber U, Lefering R, Braun M, Wafaisade A, Wutzler S, Borgmann M, Spinella PC, Maegele M; Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. . Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care. 2011;15:R68
61. Davenport R, Curry N, Manson J, De’Ath H, Coates A, Rourke C, Pearse R, Stanworth S, Brohi K. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70:90–5
62. Kashuk JL, Moore EE, Johnson JL, Haenel J, Wilson M, Moore JB, Cothren CC, Biffl WL, Banerjee A, Sauaia A. Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma. 2008;65:261–70
63. Stanworth SJ, Morris TP, Gaarder C, Goslings JC, Maegele M, Cohen MJ, König TC, Davenport RA, Pittet JF, Johansson PI, Allard S, Johnson T, Brohi K. Reappraising the concept of massive transfusion in trauma. Crit Care. 2010;14:R239
64. Lustenberger T, Frischknecht A, Brüesch M, Keel MJ. Blood component ratios in massively transfused, blunt trauma patients–a time-dependent covariate analysis. J Trauma. 2011;71:1144–50
65. Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, Cuschieri J, Maier RV, Billiar TR, Peitzman AB; 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;67:221–7
66. Chowdary P, Chowdhury P, Saayman AG, Paulus U, Findlay GP, Collins PW. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol. 2004;125:69–73
67. Nascimento B, Callum J, Rubenfeld G, Neto JB, Lin Y, Rizoli S. Clinical review: Fresh frozen plasma in massive bleedings - more questions than answers. Crit Care. 2010;14:202
68. Daban JL, Clapson P, Ausset S, Deshayes AV, Sailliol A. Freeze dried plasma: a French army specialty. Crit Care. 2010;14:412
69. Shuja F, Shults C, Duggan M, Tabbara M, Butt MU, Fischer TH, Schreiber MA, Tieu B, Holcomb JB, Sondeen JL, Demoya M, Velmahos GC, Alam HB. Development and testing of freeze-dried plasma for the treatment of trauma-associated coagulopathy. J Trauma. 2008;65:975–85
70. Snyder CW, Weinberg JA, McGwin G Jr, Melton SM, George RL, Reiff DA, Cross JM, Hubbard-Brown J, Rue LW 3rd, Kerby JD. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma. 2009;66:358–62
71. de Biasi AR, Stansbury LG, Dutton RP, Stein DM, Scalea TM, Hess JR. Blood product use in trauma resuscitation: plasma deficit versus plasma ratio as predictors of mortality in trauma (CME). Transfusion. 2011;51:1925–32
72. Riskin DJ, Tsai TC, Riskin L, Hernandez-Boussard T, Purtill M, Maggio PM, Spain DA, Brundage SI. Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg. 2009;209:198–205
73. Letourneau PA, McManus M, Sowards K, Wang W, Wang YW, Matijevic N, Pati S, Wade CE, Holcomb JB. Aged plasma transfusion increases mortality in a rat model of uncontrolled hemorrhage. J Trauma. 2011;71:1115–9
74. Chaiwat O, Lang JD, Vavilala MS, Wang J, MacKenzie EJ, Jurkovich GJ, Rivara FP. Early packed red blood cell transfusion and acute respiratory distress syndrome after trauma. Anesthesiology. 2009;110:351–60
75. Dara SI, Rana R, Afessa B, Moore SB, Gajic O. Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy. Crit Care Med. 2005;33:2667–71
76. Edens JW, Chung KK, Pamplin JC, Allan PF, Jones JA, King BT, Cancio LC, Renz EM, Wolf SE, Wade CE, Holcomb JB, Blackbourne LH. Predictors of early acute lung injury at a combat support hospital: a prospective observational study. J Trauma. 2010;69 Suppl 1:S81–6
77. Woolley T, Midwinter M, Spencer P, Watts S, Doran C, Kirkman E. Utility of interim ROTEM(®) values of clot strength, A5 and A10, in predicting final assessment of coagulation status in severely injured battle patients. 2012 Apr 7. [Epub ahead of print]
78. Nystrup KB, Windeløv NA, Thomsen AB, Johansson PI. Reduced clot strength upon admission, evaluated by thrombelastography (TEG), in trauma patients is independently associated with increased 30-day mortality. Scand J Trauma Resusc Emerg Med. 2011;19:52
79. Pezold M, Moore EE, Wohlauer M, Sauaia A, Gonzalez E, Banerjee A, Silliman CC. Viscoelastic clot strength predicts coagulation-related mortality within 15 minutes. Surgery. 2012;151:48–54
80. Schöchl H, Solomon C, Traintinger S, Nienaber U, Tacacs-Tolnai A, Windhofer C, Bahrami S, Voelckel W. Thromboelastometric (ROTEM) findings in patients suffering from isolated severe traumatic brain injury. J Neurotrauma. 2011;28:2033–41
81. Plotkin AJ, Wade CE, Jenkins DH, Smith KA, Noe JC, Park MS, Perkins JG, Holcomb JB. A reduction in clot formation rate and strength assessed by thrombelastography is indicative of transfusion requirements in patients with penetrating injuries. J Trauma. 2008;64:S64–8
82. Leemann H, Lustenberger T, Talving P, Kobayashi L, Bukur M, Brenni M, Brüesch M, Spahn DR, Keel MJ. The role of rotation thromboelastometry in early prediction of massive transfusion. J Trauma. 2010;69:1403–8
83. Schöchl H, Voelckel W, Maegele M, Solomon C. Trauma-associated hyperfibrinolysis. Hamostaseologie. 2012;32:22–7
84. Cotton BH, Harvin JA, Kostousouv V, Minei KM, Radwan ZA, Schöchl H, Wade CE, Holcomb JB, Matijevic, N .. Hyperfibrinolysis on admission is an uncommon but highly lethal event associated with shock and pre-hospital fluid administration. J Trauma Acute Care Surg. 2012;73:365–70
85. Okamoto S, Hijikata-Okunomiya A, Wanaka K, Okada Y, Okamoto U. Enzyme-controlling medicines: introduction. Semin Thromb Hemost. 1997;23:493–501
86. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S; CRASH-2 trial collaborators. . 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;376:23–32
87. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147:113–9
88. Fenger-Eriksen C, Ingerslev J, Sørensen B. Fibrinogen concentrate–a potential universal hemostatic agent. Expert Opin Biol Ther. 2009;9:1325–33
89. Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and hemostasis: a primary hemostatic target for the management of acquired bleeding. Anesth Analg. 2012;114:261–74
90. Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg. 1995;81:360–5
91. 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;136:364–70
92. 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
93. Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, Hess JR, Dubick MA, Simon CD, Beekley AC, Wolf SE, Wade CE, Holcomb JB. 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:S79–85
94. Rourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, Stanworth S, Brohi K. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342–51
95. Solomon C, Pichlmaier U, Schoechl H, Hagl C, Raymondos K, Scheinichen D, Koppert W, Rahe-Meyer N. Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery. Br J Anaesth. 2010;104:555–62
96. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, Williamson LM; British Committee for Standards in Haematology, Blood Transfusion Task Force. . Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126:11–28
97. Theusinger OM, Baulig W, Seifert B, Emmert MY, Spahn DR, Asmis LM. Relative concentrations of haemostatic factors and cytokines in solvent/detergent-treated and fresh-frozen plasma. Br J Anaesth. 2011;106:505–11
98. Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:2652–60
99. Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma. 2005;58:475–80
100. Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R, Axelsen M, Kluger Y; NovoSeven Trauma Study Group. . Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005;59:8–15
101. Hauser CJ, Boffard K, Dutton R, Bernard GR, Croce MA, Holcomb JB, Leppaniemi A, Parr M, Vincent JL, Tortella BJ, Dimsits J, Bouillon B; CONTROL Study Group. . Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69:489–500
102. Schick KS, Fertmann JM, Jauch KW, Hoffmann JN. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care. 2009;13:R191
103. Schöchl H, Nienaber U, Maegele M, Hochleitner G, Primavesi F, Steitz B, Arndt C, Hanke A, Voelckel W, Solomon C. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15:R83
104. Joseph B, Amini A, Friese RS, Houdek M, Hays D, Kulvatunyou N, Wynne J, O’Keeffe T, Latifi R, Rhee P. Factor IX complex for the correction of traumatic coagulopathy. J Trauma Acute Care Surg. 2012;72:828–34
105. Warren O, Simon B. Massive, fatal, intracardiac thrombosis associated with prothrombin complex concentrate. Ann Emerg Med. 2009;53:758–61
106. Rahe-Meyer N, Sørensen B. Fibrinogen concentrate for management of bleeding. J Thromb Haemost. 2011;9:1–5
107. Tanaka KA, Szlam F. Treatment of massive bleeding with prothrombin complex concentrate: argument for. J Thromb Haemost. 2010;8:2589–91
108. 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;39:104–13
109. Ozier Y, Hunt BJ. Against: Fibrinogen concentrate for management of bleeding: against indiscriminate use. J Thromb Haemost. 2011;9:6–8
110. Godier A, Susen S, Samama CM. Treatment of massive bleeding with prothrombin complex concentrate: argument against. J Thromb Haemost. 2010;8:2592–5
111. Holness L, Knippen MA, Simmons L, Lachenbruch PA. Fatalities caused by TRALI. Transfus Med Rev. 2004;18:184–8
© 2014 International Anesthesia Research Society