1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References


Trauma-induced coagulopathy has a multifactorial aetiology. Coagulopathy is related to blood loss including consumption of clotting factors and platelets and haemodilution. Additionally hyperfibrinolysis, hypothermia, acidosis and metabolic changes affect the coagulation system.


This is a review of pathophysiology and new treatment strategies for trauma-induced coagulopathy.


Paradigms are actively changing and there is still a shortage of data. The aim of any haemostatic therapy is to control bleeding and minimize blood loss and transfusion requirements. Transfusion of allogeneic blood products as well as trauma-induced coagulopathy cause increased morbidity and mortality. Current opinion is based on present studies and results from small case series, combined with findings from experimental studies in animals, in vitro studies and expert opinions, as opposed to large, randomized, placebo-controlled studies. A summary of new and emerging strategies, including medical infusion and blood products, to beneficially manipulate the coagulation system in the critically injured patient is suggested.


Future treatment of trauma-induced coagulopathy may be based on systemic antifibrinolytics, local haemostatics and individualized point-of-care-guided rational use of coagulation factor concentrates such as fibrinogen, prothrombin complex concentrate, recombinant factor VIIa and factor XIII. The authors speculate that timely and rational use of coagulation factor concentrates will be more efficacious and safer than ratio-driven use of transfusion packages of allogeneic blood products. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References

In patients with identical Injury Severity Scores, the mortality rate is virtually doubled with the presence of coagulopathy. The main goal of any haemostatic intervention is to promptly secure haemostasis, minimize blood loss and avoid unnecessary transfusion of allogeneic blood products1.

Currently, no consensus on the definition of massive bleeding or massive transfusion exists. In general, a blood loss of 100 per cent or more of the blood volume within 24 h, 50 per cent or more within 3 h, or 150 ml/min or 1·5 ml per min per kg over 20 min is considered massive bleeding2. Trauma, bleeding and massive transfusion of allogeneic blood products result in dysfunction and severely compromised haemostatic performance. A thorough understanding of the multifactorial aetiology of trauma-induced coagulopathy (TIC) as well as the timely development of the pathophysiology are expected to facilitate diagnosis and treatment. Massive bleeding treatment protocols include packages of allogeneic blood products. However, transfusion of allogeneic blood products is known to increase morbidity and mortality3.

During the past two decades the overall understanding of the haemostatic system has undergone considerable revision. Currently, the formation of a haemostatic plug starts with establishment of a primary haemostatic platelet plug. All the coagulation factors assemble on the surface of the activated platelets. Thrombin generation is initiated by exposure of extravascular tissue factor. The early minute amounts of thrombin stimulate a positive amplification resulting in a propagation phase of thrombin generation. Thrombin cleaves fibrinogen and fibrin polymerizes to a dense network. The fibrin network is stabilized by establishment of covalent bonds facilitated by coagulation factor XIII and by removal of lysin motifs by thrombin activatable fibrinolysis inhibitor4, 5.

The pathophysiological fundamentals have to be considered in the coagulation management of traumatized and bleeding patients. Traditionally, the overall haemostatic performance as well as the need for replacement therapy is assessed using the results of routine coagulation tests such as the platelet count, fibrinogen level, prothrombin time and activated partial thromboplastin time. These laboratory parameters have never been validated for the prediction of haemorrhagic tendency in injured patients. More importantly, the results are rarely available promptly, which further compromises their utility in trauma. Improvement of viscoelastic methods (thrombelastography (TEG®; Haemoscope Division, Hoemonetis, Niles, Illinois, USA)/thrombelastometry (ROTEM®; Tem International, Munich, Germany) has led to increasing clinical use in recent years, and they provide individualized and quick monitoring and management6.

Pathophysiology of trauma-induced coagulopathy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References

TIC needs to be distinctly differentiated from disseminated intravascular coagulation. TIC is specifically associated with the extent and severity of injuries, and correlates with mortality. Despite rapid and effective damage control, surgical bleeding is the main cause of death in injured patients, even in specialized centres. In TIC, as opposed to disseminated intravascular coagulation, there is no generalized intravascular microcoagulation and subsequent consumption; instead, there is a bleeding-related loss of coagulation factors and platelets (loss coagulopathy). The endogenous procoagulant stimulus is diluted by the administration of crystalloids and, particularly, colloids (dilutional coagulopathy). Finally, the release of tissue factor from traumatized tissue causes localized activation of coagulation with accompanying consumption (consumption coagulopathy). The complexity of the haemostatic equilibrium is further challenged by activation of the plasminogen fibrinolytic system, hypothermia, acidosis, anaemia and electrolyte disturbances (Table1). Moreover, in severely injured patients, tissue perfusion deficits may lead to increased concentrations of activated protein C through an increase in thrombomodulin and an inappropriate anticoagulation and shut-down of thrombin generation7–9.

Table 1. Common causes of coagulation disturbances in patients with massive bleeding or massive transfusion
Loss coagulopathy
Dilutional coagulopathy
Consumption coagulopathy
Electrolyte disturbances

Timely development of trauma-induced coagulopathy

Overall, the pathological events are multifactorial and occur almost simultaneously. However, the metabolic changes related to haemorrhagic shock are likely to trigger the initial TIC. Theoretically, before fluid resuscitation, the first coagulation abnormalities are likely to be assigned to excessive hyperfibrinolysis and hyperfibrinogenolysis. On subsequent treatment of hypovolaemic shock with fluid resuscitation, in particular with synthetic hydroxyethyl starch (HES) colloid expanders, patients develop a dilutional coagulopathy10.

Hypothermia and coagulation

Hypothermia is virtually unavoidable in severely injured patients; it reduces haemostatic performance and is linked to an increased tendency to bleed11. The activity of the coagulation proteome is temperature-dependent and below 33–34 °C there will be clinically relevant impairment of plasma coagulation12. Platelet function is also impaired at body temperatures below 34 °C. In addition to increased pooling in the spleen, platelet adhesion and aggregation disturbances occur; platelet aggregation—at least in mild hypothermia—is increased initially13, 14.

It should be remembered that laboratory tests of coagulation, blood-gas analysis and TEG®/ROTEM® are carried out under normal temperature conditions. The values obtained may represent false normal values and must be interpreted with this in mind.

Acidosis and metabolic changes

Iatrogenic factors (citrate overload in the context of massive transfusion and/or large quantities of ‘physiological’ saline) as well as hypovolaemia/shock, ischaemia and reperfusion phenomena are the main causes of acidosis, which in turn leads to impairment of the haemostatic potential15. The combination (‘lethal triad’) of hypothermia, acidosis and disturbed coagulation increases mortality considerably, and the degree of acidosis correlates with the severity of the coagulation disorder and mortality16, 17.

Clinical experience has shown that procoagulant therapy with recombinant factor VIIa has little effect in acidotic patients18. Plasma coagulation, particularly thrombin generation, is impaired even at pH values below 7·3, and also fibrinogen degradation is increased by acidosis19–21.

Dilutional coagulopathy

Volume resuscitation or transfusion of packages of fresh frozen plasma (FFP) and packed red blood cells lead to dilution (Fig.1). There is still insufficient evidence whether colloid solutions have an advantage over crystalloids. Two different meta-analyses have suggested that administration of colloids is associated with increased mortality22, 23. These studies were conducted in North America and the results may not be applicable to European circumstances. In North America the most commonly used colloids are dextrans or high-molecular-weight HES which are no longer used in Central Europe because of their adverse effects on the coagulation system.

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Figure 1. Dilutional effects and cell clotting with different transfusion solutions: a whole blood or blood, diluted by 50 per cent with b Ringer's lactate, c 6 per cent hydroxyethyl starch (HES) 130/0·4 (Voluven®; Fresenius Kabi, Bad Hornburg, Germany) and d gelatin (Gelofusine®; B. Braun, Melsungen, Germany). Six per cent HES disturbed the fibrin meshwork more than Ringer's lactate or gelatin (original magnification × 100)

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Crystalloids compromise the coagulation system mainly through their diluting effect. The principal side-effects of crystalloid solutions are oedema and decreased viscosity, which affect the microcirculation. If large quantities of physiological saline are used, dilutional acidosis with impaired thrombin formation and fibrin polymerization disorder may occur.

Hyperosmolar infusion solutions allow rapid mobilization and displacement of quantities of extravascular fluid from the intracellular space and the interstitium. Some in vitro and in vivo studies have reported an anticoagulant effect or impaired platelet function after the use of hyperosmolar solutions, whereas new animal studies found less impairment of the plasmatic coagulation system compared with HES and gelatin24.

Gelatin products can be used without the dose limitations of starch solutions, but in addition to their diluting effect fibrin polymerization is impaired25.

If HES solutions are used, a dose limit needs to be observed. In addition to accumulation of HES molecules in the reticuloendothelial tissue and induction of pruritus, there have been reports of an increased haemorrhagic tendency26–28. Further, HES causes platelet coating, blockade of the fibrinogen receptor (GPIIb–IIIa), von Willebrand type 1-like syndrome and fibrin polymerization disturbance which might exceed the anticoagulant effect of gelatin and is less readily treated by fibrinogen concentrate than is the case with crystalloids or gelatin28–30. The molecular weights of HES solutions, their degree of substitution and their C2/C6 ratio are the principal determinants of the intravascular half-life and thus the duration of effect on coagulation.


The occurrence of hyperfibrinolysis in injured patients cannot be predicted reliably but appears to be linked to the severity of the trauma and the organ systems affected (craniocerebral trauma, urogenital tract, after mechanical resuscitation). Hyperfibrinolysis is most often seen in patients with haemodynamic instability31. Currently, the best way to detect acute hyperfibrinolysis is thromboelastography or thromboelastometry. In the case of hyperfibrinolysis, haemorrhagic tendency can only be treated with the administration of antifibrinolytics before the administration of fibrinogen8, 10, 32–34.


Ionized Ca2+ serves as a bridge between the negatively charged vitamin-K-dependent coagulation factors, phospholipids and the endothelium. Moreover, calcium protects fibrinogen from denaturation and proteolysis; and influences platelet function. Haemostasis is impaired at values below 0·6–0·7 mmol/l. Critical values can be expected early when administering colloids and after rapid transfusion of large quantities of FFP, particularly in patients with impaired liver function10, 16.

Anaemia and coagulation

Transfusion of allogeneic blood products is associated with increased morbidity and mortality. This partly reflects the severity of the underlying disease or the extent of the injury3, 35, but also highlights the importance of restrictive use of erythrocyte transfusions. Hence, for critically ill patients requiring intensive care treatment, acceptance of low haemoglobin levels may be beneficial36, 37. However, it may be argued that such experience cannot be transferred to patients with severe polytrauma and massive bleeding. Adequate haematocrit is very important not only for tissue oxygenation and perfusion but also for coagulation. In volunteers, a drop of only 15 per cent in haematocrit was associated with a 60 per cent increase in bleeding time38, 39. Anaemia leads to impairment of platelet adhesion/aggregation in vitro and in vivo. Due to the decrease in haematocrit, the number of platelets in the peripheral plasma decreases, and adhesion and activation to endothelial damage/vascular injuries is disturbed. Erythrocytes also release adenosine 5′-diphosphate (ADP) (stimulating thromboxane A2 synthesis), increase thrombin40, 41 and activate coagulation factor IX. If the haematocrit is below 20 per cent, there is likely to be clinically relevant impairment of haemostasis. More severe anaemia aggravates the effect of thrombocytopenia41, 42.

Acquired thrombocytopenia and exhaustion of platelet performance

Guidelines for trauma- or surgery-related blood loss and platelet counts below 50 000/µl recommend administration of platelet concentrates; if the central nervous system is also affected and/or there is additional platelet dysfunction, values of more than 100 000/µl should be aimed for. These recommendations are based largely not on clinical studies but on consensus and expert experience. For patient-specific estimation of substitution requirements ROTEM®/TEG® measurements of clot strength in relation to fibrinogen polymerization can give valuable clues, because good fibrin polymerization can compensate a reduction in the platelets involved in clot strength43.

New rational treatment strategies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References

A point-of-care-driven rationale for transfusion strategies is given in Fig.2 and Table2. Detailed elaboration of each point will be addressed in the following paragraphs.

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Figure 2. Proposal for a point-of-care driven-strategy to manage trauma-induced coagulopathy: RBC, red blood cell concentrate; Hb, haemoglobin; ROTEM®, thromboelastometry system; FibTEM®, fibrin polymerization test; A5 (10), maximum amplitude after 5 (10) min; ExTEM®, extrinsic activated thromboelastometry; CT, clotting time; pcc, prothrombin complex concentrate; BGA, blood gas analysis. The vertical axis gives the time for changing coagulation management in trauma-related massive bleeding. All TEM products from TEM International (Munich, Germany)

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Table 2. Summary of transfusion strategies
Clinical situationClinical implication
AcidosisBuffer therapy only when coagulation therapy is indicated
HypothermiaActive warming, infusion of warmed solutions
(Hyper)fibrinolysisAdministration of 20–25 mg/kg tranexamic acid. Readministration in the case of TEG®/ROTEM® signs of hyperfibrinolysis
AnaemiaTry to maintain a haemoglobin level of more than 8 g/dl
Platelet count50 000–100 000 × 103/µl
Fresh frozen plasma (FFP)Patients with severe trauma and coagulopathy may not recover after treatment with FFP alone; targeted administration of clotting factor concentrates might be favourable
Fibrinogen concentrate50 mg/kg fibrinogen concentrate in the case of fibrinogen above 1·5–2 g/dl and/or FibTEM® maximum clot firmness above 10 mm (A10 above 7 mm)
Prothrombin complex concentrate (PCC)Patients on oral anticoagulant therapy require PCC and vitamin K. In the case of increased bleeding tendency and prolonged clotting time in patients not on oral anticoagulant therapy, PCC (20–30 units per kg bodyweight) can be administered. A prolonged prothrombin time alone is no indication for the use of PCC
Factor XIII (FXIII) concentrateIn cases of ongoing or diffuse bleeding and if clot strength remains too low despite adequate fibrinogen levels, it is likely that FXIII activity is critically reduced. A significant FXIII deficiency can be assumed when FXIII activity is below 60%. In such cases FXIII concentrate (30 units/kg) can be administered
Recombinant factor VIIa (rFVIIa; NovoSeven®)Consider rFVIIa if surgery, interventional radiology, packing, etc. fails and only after appropriate coagulation therapy
Local haemostyptic dressingsLocal haemostyptic dressings (QuickClot®, HemCon®, Combat Gauze, etc.) seem to be more effective than standard gauze dressing and can be used


The efficacy of antifibrinolytics in hyperfibrinolysis has been thoroughly investigated, especially in trauma, cardiac surgery, orthopaedic surgery and liver (transplant) surgery44–51.

Tranexamic acid

Tranexamic acid blocks the lysine binding site of the plasmin molecule irreversibly, thereby blocking the binding of plasminogen to tissue plasminogen activator and to fibrinogen, which is needed for activation. A reduction of approximately 30 per cent in transfusion requirements has been demonstrated with tranexamic acid; although this is a smaller effect than that observed with aprotinin, tranexamic acid has a preferable side-effect profile. A recently published study analysed the effect of tranexamic acid in 20 211 injured patients. The authors came to the conclusion that the administration of tranexamic acid improved survival by approximately 10 per cent in this population52.

Haemostatic wound dressings

Local haemostatic dressings, which are used particularly in crisis areas and war situations as a temporary measure until definitive wound care can be given, have been available for several years. All these products actively facilitate local haemostasis and are considered superior to commonly used standard gauze dressings. Unfortunately, only retrospective data analyses and experimental animal studies are available53, 54.

QuickClot® (Z-Medica, Wallingford, Connecticut, USA) is a ‘molecular sponge’. It is biologically inert, not absorbed and binds water molecules. The removal of water gives rise to local coagulation, with the formation of a stable clot. This product is applied directly on to the wound and kept under manual compression for 5–6 min. A pressure dressing is then applied over the haemostatic product. The dressing should not be removed until definitive surgical care of the wound can be undertaken53.

Combat Gauze (Z-Medica) is a gauze impregnated with kaolin and indicated for temporary external control of traumatic bleeding. In animal trials, this product was superior to other wound dressings. Nevertheless, so far no clinical trials have been performed to prove the efficacy of this bandage. At present, Combat Gauze is recommended by the US military to control life-threatening haemorrhage.

HemCon® (HernCon Medical Technologies, Portlant, Oregun, USA) consists of chitosan, a deacetylated form of chitin, and has a topical haemostatic effect. HemCon® was licensed by the US Food and Drug Administration in 2003 and has been used extensively in Operation Iraqi Freedom. HemCon® is part of the Prehospital Trauma Life Support Military Section, and all of the Special Operations Forces are trained to use it. In a retrospective analysis, HemCon® was used successfully in 68 patients, the bleeding being halted or the haemorrhagic tendency being markedly improved in 97 per cent of patients. In 66 per cent of the patients, conventional pressure and gauze dressings initially failed to stop the bleeding54.

Coagulation factor concentrates

Compared with FFP, coagulation factor concentrates are immediately available, contain a defined concentration of the relevant factors, can be administered without volume overload, and may be considered safe in relation to the transmission of viral diseases and induction of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO).

Fibrinogen concentrate

In severely traumatized and massively bleeding patients, fibrinogen usually reaches critical levels at an early stage. Clinical data from gynaecology55, neurology56 and cardiac surgery57 show that the perioperative and postoperative haemorrhagic tendency is increased when fibrinogen levels are below 150–200 mg/dl. Data on the efficacy of fibrinogen concentrates in acquired fibrinogen deficiency are limited. In vitro studies and experimental investigations58–63, as well as reports from postmarketing surveillance and retrospective data analyses, have shown consistently that fibrinogen can increase clot firmness and improve survival of severely injured massively bleeding patients/soldiers64. Four small prospective clinical studies examined the use of fibrinogen concentrate (ROTEM®-assisted in two studies). In all four studies coagulation was optimized, perioperative bleeding was reduced by 32 per cent and transfusion requirement was significantly reduced65–68.

Prothrombin complex concentrate

Prothrombin complex concentrate has been used for many years for the treatment of congenital coagulation disorders and is recommended for reversing oral anticoagulation. It contains coagulation factors II, VII, IX and X. There are differences between products in the concentrations of these factors and other constituents including heparin, protein C and protein S.

Reduced thrombin formation and an associated need for prothrombin complex concentrate must be expected if the activity of the procoagulants, and prothrombin especially, is less than 30 per cent. This generally only occurs with blood losses greater than 150–200 per cent of the estimated blood volume69. Critical levels can be detected using standard coagulation tests (prothrombin time less than 30 per cent) or TEG®/ROTEM®6. Whether simultaneous administration of antithrombin is justified by the theoretical risk of thromboembolic complications has not yet been investigated. However, the authors are of the opinion that, if prothrombin complex concentrate is administered to a bleeding injured patient, simultaneous administration of antithrombin should not be undertaken as the theoretical risk of thromboembolism is negligible compared with that of acute bleeding.

Factor XIII

The fibrin stabilizing factor XIII is produced mainly in the liver and in megakaryocytes, is activated by thrombin to factor XIIIa and permits stable cross-linking of the fibrin clot while simultaneously protecting against fibrinolysis; it also promotes wound healing. In some clinical studies, an increased tendency to bleed has been observed in surgical patients even at factor XIII activities of below 60 per cent56, 70, 71. There is as yet insufficient evidence to show the extent of blood loss needed to trigger a critical decrease in factor XIII. However, particularly when colloids are used, factor XIII activities below 60 per cent are likely even with blood losses of below 100 per cent of the estimated blood volume.

Recombinant activated factor VIIa (NovoSeven®)

Recombinant activated factor VIIa (rFVIIa; NovoSeven®, Novo Nordisk, Copenhagen, Denmark) exerts its effect through accelerating timely and sufficient development of thrombin at vessel lesion sites. The mechanism of action depends on the presence of tissue factor, activated platelet surface and factor X. It is licensed as a bypassing agent for treatment of patients with haemophilia and inhibitory antibodies. However, throughout the past decade rFVIIa has been used successfully off-label in numerous patients with of trauma- and surgery-related bleeding72–77. Furthermore, patients with intracerebral haematoma following a traumatic craniocerebral injury showed a statistically non-significant trend towards reduced post-traumatic haematoma increase after administration of rFVIIa. To achieve a successful effect from rFVIIa, the product should be administered as early as possible, at a time when the patient's own haemostasis is not yet severely compromised77. Existing hypofibrinogenaemia and thrombocytopenia should as far as possible be corrected before administration, as thrombin formation alone is not enough to produce a stable haemostatic plug. Hypothermia and acidosis decrease the efficacy of rFVIIa and should likewise be optimized if possible; acidosis in particular should be avoided. If the pH is less than 7·2, therefore, buffer therapy should be administered. If hyperfibrinolysis is present or the accompanying clinical circumstances suggest this (for example postpartum bleeding, after weaning from cardiopulmonary bypass pump, or after administration of protamine), the patient should be treated with antifibrinolytics and fibrinogen before rFVIIa is used2, 10.

Allogeneic blood products

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References


According to international recommendations, replacement therapy using platelet concentrates should be administered for trauma- or surgery-related bleeding if the platelet count is below 50 000/µl. In some patients with central nervous system co-involvement, and if drug-related, acquired or congenital platelet dysfunction is present, a target platelet count around 100 000/µl should be achieved78, 79. These instructions are for the most part based on consensus conferences and are not underpinned by clinical data. It is noteworthy that not only the platelet count but also platelet quality is a fundamental prerequisite for functional haemostasis. For assessing an individual's need for replacement therapy, TEG®/ROTEM® measurements of clot firmness in relation to fibrinogen polymerization can provide valuable information, as strong fibrin polymerization can compensate for the decrease in the platelet contribution to clot firmness43.

Pooled platelet concentrate consists of platelets obtained from the buffy coats of whole-blood donations from four to six individual donors. The normal therapeutic dose is one concentrate (60–80 × 109 platelets) per 10 kg bodyweight. The platelet content of single-donor apheresis concentrates (200–400 × 109 platelets in 200–300 ml donor plasma) corresponds to that of approximately six single platelet concentrates. The efficacy of platelet administration should be checked 1 h and 20–24 h after transfusion; the recovery is normally about 60–70 per cent. If the platelet count does not rise sufficiently (more than 20 000–30 000/µl; next day more than 10 000/µl), the possible causes may be immunological (ABO incompatibility, alloimmunization due to leucocyte antigens) or non-immunological (duration of storage, fever, infection, splenomegaly, disseminated intravascular coagulation, etc.).

Platelets are associated with higher rates of complications/side-effects than all other blood products (TRALI, infection, increased mortality, etc.).

Fresh frozen plasma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References

In many hospitals, the administration of FFP remains the standard therapy for the prevention and treatment of plasma coagulation disorders. FFP has been available since the 1940s and was initially used as a volume expander. With the advent of synthetic volume expanders, the indication has shifted toward the prevention of bleeding, treatment of coagulation disorders and influencing pathological coagulation outcomes. However, transfusion of FFP has considerable drawbacks.

It needs to be borne in mind that the main constituents of FFP are water, albumin (40–50 g/l) and other plasma proteins. Nevertheless, albumin has been shown in the past to increase mortality in injured patients with brain injury80. It is obvious that the administration of FFP is unavoidably associated with volume expansion (FFP corresponds to an 8·5 per cent protein solution), and that the concentration of critically decreased factors cannot be increased only by administration of 10–15 ml per kg bodyweight of FFP81, 82. Consequently, large quantities of FFP are needed (more than 30 ml FFP/kg) to achieve a clinically meaningful rise in coagulation factor concentrations in the presence of a deficit and ongoing loss. In a coagulopathic but normovolaemic patient, the resulting volume overload can lead to the clinical situation of TACO, particularly in patients with cardiac failure, renal impairment and liver disorders. Furthermore, a series of retrospective studies showed that the rate of severe infections and respiratory complications was distinctly increased in patients who received FFP83–86. This effect was also proven to be dose-dependent. Watson et al.87 have shown in a prospective cohort analysis that the risk of nosocomial infection, acute respiratory distress syndrome and multiple organ failure was also related to the total amount of transfused FFP. Further, if administered in large quantities, FFP causes citrate overload (coagulopathy, decreased ejection fraction, arrhythmias, increased neuromuscular excitability). Another concern with FFP transfusion is the risk of TRALI, which is now one of the most common fatal side-effects of blood transfusion and can be triggered, amongst other things, by an interaction with donor-specific leucocyte antibodies. Because of the logistics involved, there is also a delay of 35–45 min until requested units of FFP are obtained. This means either that FFP must be ordered early on suspicion and administered ‘prophylactically’—a practice that many specialist societies flatly reject—or that it is actually received and administered too late, particularly when massive bleeding and coagulopathy is present.

With regard to the quantity or the ratio of erythrocyte concentrate/FFP transfused, the literature contains a highly diverse array of recommendations that describe institution-related algorithms but that do not refer to prospectively collected data. Several recent retrospective data analyses indicate that, for FFP therapy, early administration in a ratio of 1 : 1 (erythrocyte concentrate : FFP) appears to be advantageous. However, interpretation of these data might be severely biased. Snyder et al.88 analysed the time delay when red blood cells and FFP were transfused. While red blood cells were transfused within 18 min, it took more than 93 min to transfuse FFP. This means patients did not survive because they received plasma; they received plasma because they survived. A second confounding factor might be that volume resuscitation in severely injured and bleeding patients is quite restrictive even in US Army casualties (personal communication). Maybe the patients who received plasma have had the most benefit from the volume effect but not from coagulation therapy in these retrospective observations. However, FFP is not indicated for volume replacement and there is no discussion that volume replacement is much easier and safer by using a combination of crystalloids and modern colloids like medium-weight HES solutions or gelatin.

Based on current evidence and decades of empirical experience with point-of-care-guided coagulation management algorithms, it is proposed that future treatment of trauma-induced coagulopathy can be based on systemic antifibrinolytics, local haemostatics and individualized point-of-care-guided rational use of coagulation factor concentrates such as fibrinogen, prothrombin complex concentrate, recombinant factor VIIa and factor XIII. The authors speculate that timely and rational use of coagulation factor concentrates will be more efficacious and safer than ratio-driven use of transfusion packages of allogeneic blood products. Massive transfusion protocols are unlikely to be suited to all kinds of bleeding. Nevertheless, prospective randomized controlled trials are necessary to prove this hypothesis.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of trauma-induced coagulopathy
  5. New rational treatment strategies
  6. Allogeneic blood products
  7. Fresh frozen plasma
  8. Disclosure
  9. References
  • 1
    Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54: 11271130.
  • 2
    Martinowitz U, Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost 2005; 3: 640648.
  • 3
    Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54: 898905.
  • 4
    Rojkjaer LP, Rojkjaer R. Clot stabilization for the prevention of bleeding. Hematol Oncol Clin North Am 2007; 21: 2532.
  • 5
    Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann N Y Acad Sci 2001; 936: 291311.
  • 6
    Schochl H, Nienaber U, Hofer G, Voelckel W, Jambor C, Scharbert G et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 14: R55.
  • 7
    Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007; 245: 812818.
  • 8
    Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008; 64: 12111217.
  • 9
    Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma 2007; 63: 12541261.
  • 10
    Fries D, Innerhofer P, Perger P, Gutl M, Heil S, Hofmann N et al. [Coagulation management in trauma-related massive bleeding. Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI).] Anasthesiol Intensivmed Notfallmed Schmerzther 2010; 45: 552561.
  • 11
    Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma 2005; 58: 10021009.
  • 12
    Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism 2007; 56: 214221.
  • 13
    Watts DD, Trask A, Soeken K, Perdue P, Dols S, Kaufmann C. Hypothermic coagulopathy in trauma: effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma 1998; 44: 846854.
  • 14
    Straub A, Breuer M, Wendel HP, Peter K, Dietz K, Ziemer G. Critical temperature ranges of hypothermia-induced platelet activation: possible implications for cooling patients in cardiac surgery. Thromb Haemost 2007; 97: 608616.
  • 15
    Kiraly LN, Differding JA, Enomoto TM, Sawai RS, Muller PJ, Diggs B et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma 2006; 61: 5764.
  • 16
    Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma. J Trauma 2008; 65: 951960.
  • 17
    Dirkmann D, Hanke AA, Gorlinger K, Peters J. Hypothermia and acidosis synergistically impair coagulation in human whole blood. Anesth Analg 2008; 106: 16271632.
  • 18
    Meng ZH, Wolberg AS, Monroe DM III, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma 2003; 55: 886891.
  • 19
    Martini WZ, Dubick MA, Pusateri AE, Park MS, Ryan KL, Holcomb JB. Does bicarbonate correct coagulation function impaired by acidosis in swine? J Trauma 2006; 61: 99106.
  • 20
    Martini WZ, Dubick MA, Wade CE, Holcomb JB. Evaluation of tris-hydroxymethylaminomethane on reversing coagulation abnormalities caused by acidosis in pigs. Crit Care Med 2007; 35: 15681574.
  • 21
    Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg 2007; 246: 831835.
  • 22
    Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med 1999; 27: 200210.
  • 23
    Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ 1998; 316: 961964.
  • 24
    Haas T, Fries D, Holz C, Innerhofer P, Streif W, Klingler A et al. Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution. Anesth Analg 2008; 106: 10781086.
  • 25
    Mardel SN, Saunders FM, Allen H, Menezes G, Edwards CM, Ollerenshaw L et al. Reduced quality of clot formation with gelatin-based plasma substitutes. Br J Anaesth 1998; 80: 204207.
  • 26
    Fries D, Streif W, Haas T, Kuhbacher G. [Dilutional coagulopathy, an underestimated problem?.] Anasthesiol Intensivmed Notfallmed Schmerzther 2004; 39: 745750.
  • 27
    Innerhofer P, Fries D, Margreiter J, Klingler A, Kuhbacher G, Wachter B et al. The effects of perioperatively administered colloids and crystalloids on primary platelet-mediated hemostasis and clot formation. Anesth Analg 2002; 95: 858865.
  • 28
    Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A et al. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg 2007; 105: 905917.
  • 29
    Haas T, Fries D, Velik-Salchner C, Oswald E, Innerhofer P. Fibrinogen in craniosynostosis surgery. Anesth Analg 2008; 106: 725731.
  • 30
    Niemi TT, Kuitunen AH. Artificial colloids impair haemostasis. An in vitro study using thromboelastometry coagulation analysis. Acta Anaesthesiol Scand 2005; 49: 373378.
  • 31
    Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009; 67: 125131.
  • 32
    Adam DJ, Haggart PC, Ludlam CA, Bradbury AW. Coagulopathy and hyperfibrinolysis in ruptured abdominal aortic aneurysm repair. Ann Vasc Surg 2004; 18: 572577.
  • 33
    Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 2008; 100: 792797.
  • 34
    Tauber H, Innerhofer P, Breitkopf R, Westermann I, Beer R, El Attal R et al. Prevalence and impact of abnormal ROTEM(R) assays in severe blunt trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’. Br J Anaesth 2011; 107: 378387.
  • 35
    Dunne JR, Riddle MS, Danko J, Hayden R, Petersen K. Blood transfusion is associated with infection and increased resource utilization in combat casualties. Am Surg 2006; 72: 619625.
  • 36
    Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340: 409417.
  • 37
    McIntyre L, Hebert PC, Wells G, Fergusson D, Marshall J, Yetisir E et al. Is a restrictive transfusion strategy safe for resuscitated and critically ill trauma patients? J Trauma 2004; 57: 563568.
  • 38
    Valeri CR, Cassidy G, Pivacek LE, Ragno G, Lieberthal W, Crowley JP et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion 2001; 41: 977983.
  • 39
    Zupan IP, Sabovic M, Salobir B, Ponikvar JB, Cernelc P, Lavre J et al. The study of anaemia-related haemostasis impairment in haemodialysis patients by in vitro closure time test. Thromb Haemost 2005; 93: 375379.
  • 40
    Peyrou V, Lormeau JC, Herault JP, Gaich C, Pfliegger AM, Herbert JM. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost 1999; 81: 400406.
  • 41
    Gerrard JM, Docherty JC, Israels SJ, Cheang MS, Bishop AJ, Kobrinsky NL et al. A reassessment of the bleeding time: association of age, hematocrit, platelet function, von Willebrand factor, and bleeding time thromboxane B2 with the length of the bleeding time. Clin Invest Med 1989; 12: 165171.
  • 42
    Kaibara M, Iwata H, Ujiie H, Himeno R. Rheological analyses of coagulation of blood from different individuals with special reference to procoagulant activity of erythrocytes. Blood Coagul Fibrinolysis 2005; 16: 355363.
  • 43
    Velik-Salchner C, Haas T, Innerhofer P, Streif W, Nussbaumer W, Klingler A et al. The effect of fibrinogen concentrate on thrombocytopenia. J Thromb Haemost 2007; 5: 10191025.
  • 44
    Ak K, Isbir CS, Tetik S, Atalan N, Tekeli A, Aljodi M et al. Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg 2009; 24: 404410.
  • 45
    Coats T, Roberts I, Shakur H. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev 2004; (4)CD004896.
  • 46
    Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999; 57: 10051032.
  • 47
    Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 23192331.
  • 48
    Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; (4)CD001886.
  • 49
    Henry DA, Moxey AJ, Carless PA, O'Connell D, McClelland B, Henderson KM et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001; (1)CD001886.
  • 50
    Molenaar IQ, Warnaar N, Groen H, Tenvergert EM, Slooff MJ, Porte RJ. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007; 7: 185194.
  • 51
    Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006; 105: 10341046.
  • 52
    Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 2332.
  • 53
    Kheirabadi BS, Scherer MR, Estep JS, Dubick MA, Holcomb JB. Determination of efficacy of new hemostatic dressings in a model of extremity arterial hemorrhage in swine. J Trauma 2009; 67: 450459.
  • 54
    Wedmore I, McManus JG, Pusateri AE, Holcomb JB. A special report on the chitosan-based hemostatic dressing: experience in current combat operations. J Trauma 2006; 60: 655658.
  • 55
    Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007; 5: 266273.
  • 56
    Gerlach R, Tolle F, Raabe A, Zimmermann M, Siegemund A, Seifert V. Increased risk for postoperative hemorrhage after intracranial surgery in patients with decreased factor XIII activity: implications of a prospective study. Stroke 2002; 33: 16181623.
  • 57
    Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, Hellstern P et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005; 93: 11011107.
  • 58
    Fries D, Innerhofer P, Reif C, Streif W, Klingler A, Schobersberger W et al. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro model. Anesth Analg 2006; 102: 347351.
  • 59
    Fries D, Krismer A, Klingler A, Streif W, Klima G, Wenzel V et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95: 172177.
  • 60
    Fenger-Eriksen C, Anker-Moller E, Heslop J, Ingerslev J, Sorensen B. Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005; 94: 324329.
  • 61
    Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sorensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth 2008; 101: 769773.
  • 62
    Fenger-Eriksen C, Moore GW, Rangarajan S, Ingerslev J, Sorensen B. Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders. Transfusion 2010; 50: 25712576.
  • 63
    Fenger-Eriksen C, Tonnesen E, Ingerslev J, Sorensen B. Mechanisms of hydroxyethyl starch-induced dilutional coagulopathy. J Thromb Haemost 2009; 7: 10991105.
  • 64
    Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma 2008; 64(Suppl): S7985.
  • 65
    Fenger-Eriksen C, Jensen TM, Kristensen BS, Jensen KM, Tonnesen E, Ingerslev J et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7: 795802.
  • 66
    Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Flinck A, Skrtic S et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102: 137144.
  • 67
    Rahe-Meyer N, Pichlmaier M, Haverich A, Solomon C, Winterhalter M, Piepenbrock S et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth 2009; 102: 785792.
  • 68
    Rahe-Meyer N, Solomon C, Winterhalter M, Piepenbrock S, Tanaka K, Haverich A et al. Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery. J Thorac Cardiovasc Surg 2009; 138: 694702.
  • 69
    Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81: 360365.
  • 70
    Wettstein P, Haeberli A, Stutz M, Rohner M, Corbetta C, Gabi K et al. Decreased factor XIII availability for thrombin and early loss of clot firmness in patients with unexplained intraoperative bleeding. Anesth Analg 2004; 99: 15641569.
  • 71
    Gerlach R, Raabe A, Zimmermann M, Siegemund A, Seifert V. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures. Surg Neurol 2000; 54: 260264.
  • 72
    Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R et al. 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: 815.
  • 73
    Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 2008; 248: 6168.
  • 74
    Lynn M, Jeroukhimov I, Klein Y, Martinowitz U. Updates in the management of severe coagulopathy in trauma patients. Intensive Care Med 2002; 28(Suppl 2): S241S247.
  • 75
    Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001; 51: 431438.
  • 76
    Narayan RK, Maas AI, Marshall LF, Servadei F, Skolnick BE, Tillinger MN. Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial. Neurosurgery 2008; 62: 776786.
  • 77
    Perkins JG, Schreiber MA, Wade CE, Holcomb JB. Early versus late recombinant factor VIIa in combat trauma patients requiring massive transfusion. J Trauma 2007; 62: 10951099.
  • 78
    Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 2006; 105: 198208.
  • 79
    Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E et al. Management of bleeding following major trauma: an updated European guideline. Crit Care 2010; 14: R52.
  • 80
    Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007; 357: 874884.
  • 81
    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: 6973.
  • 82
    Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006; 46: 12791285.
  • 83
    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: 26672671.
  • 84
    Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore SB et al. Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007; 131: 13081314.
  • 85
    Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH. Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med 2008; 36: 11141118.
  • 86
    Nienaber U, Innerhofer P, Westermann I, Schochl H, Attal R, Breitkopf R et al. The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury 2011; 42: 697701.
  • 87
    Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE et al. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma 2009; 67: 221227.
  • 88
    Snyder CW, Weinberg JA, McGwin G Jr, Melton SM, George RL, Reiff DA et al. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma 2009; 66: 358362.