Trauma-Induced Coagulopathy: From Biology to Therapy

Trauma-Induced Coagulopathy: From Biology to Therapy Pierre Noel,a Steven Cashen, and Bhavesh Patelb Trauma is a leading cause of death and disability. Hemorrhage is the major mechanism responsible for death during the first 24 hours following trauma. One quarter of severely injured patients present in the emergency room with acute coagulopathy of trauma and shock (ACOT). The drivers of ACOT are tissue hypoperfusion, inflammation, and activation of the neurohumoral system. ACOT is a result of protein C activation with cleavage of activated factor VIII and V and inhibition of plasminogen activator inhibitor-1 (PAI-1). The resuscitation-associated coagulopathy (RAC) is secondary to a combination of acidosis, hypothermia and dilution from intravenous blood and fluid therapy. RAC may further aggravate acidosis and hypoxia resulting in a vicious cycle. This review focuses on the biology of the trauma-associated coagulopathy, and reviews current therapeutic strategies. Semin Hematol 50:259–269. C 2013 Elsevier Inc. All rights reserved.

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rauma is the leading cause of death and disability between the ages of 5 and 44, accounting for over 5 million deaths or 12% of total global disease burden per year. Uncontrolled hemorrhage and coagulopathy are responsible for more than 50% of all trauma-related deaths within the first 48 hours of admission.1 In the United States, approximately 156,000 people die of injury per year, and 93,000 of those deaths involve physical trauma, mainly secondary to road traffic accidents. Half of this subset sustain non-salvageable injuries at the point of injury and die immediately or before reaching the hospital (non-preventable deaths).2 Of those who do reach the hospital alive but later die during the hospital stay (possible preventable deaths), 80% succumb within 24 hours.3 Since one quarter of these severely injured patients present to the emergency room with compromised hemodynamics and acute coagulopathy of trauma (ACOT),4,5 uncontrolled hemorrhage and its downstream effects define the primary mechanism responsible for the demise of trauma patients during the immediate post-injury period. ACOT is associated with higher transfusion requirements in the polytrauma patient, a greater incidence of multiple organ dysfunction syndrome (MODS), longer stays in the hospital and intensive care unit (ICU), and a fourfold increase in mortality.4,5 The drivers of ACOT appear to be tissue hypoperfusion,6 inflammation,7 and a

Division of Hematology, Mayo College of Medicine, Phoenix, AZ. Department of Critical Care, Mayo College of Medicine, Phoenix, AZ. Conflicts of interest: Address correspondence to Pierre Noel, MD, Division of Hematology, Mayo College of Medicine, 5777 E Mayo Blvd, Phoenix, AZ 85054. E-mail: [email protected] 0037-1963/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2013.06.009 b

Seminars in Hematology, Vol 50, No 3, July 2013, pp 259–269

activation of the neurohumoral system,8,9 resulting in release of and rise in the circulating level of catecholamines. Tissue trauma, hypoperfusion,6 sympathoadrenal activation,8,9 and inflammation7 induce systemic endothelial activation and damage, leading to early coagulopathy and endothelial hyperpermeability. Ongoing acidosis in the face of hypotension and hypoxia may further drive sympathoadrenal activation, aggravating the acidosis and hypoxia and resulting in a deleterious “vicious cycle.” In this context, ACOT develops out of the initial (acute) traumatic insult and may be seen as a precursor state along a spectrum that leads to resuscitation-associated coagulopathy (RAC), which is induced later in the post-traumatic period secondary to worsening acidosis, hypothermia, and hemodilution after administration of intravenous fluids or blood component therapy (Figure 1). Activation of protein C is a pivotal component of ACOT (Figure 2). Hypoperfusion is believed to result in increased expression of thrombomodulin on the surface of endothelial cells. Activated PC (APC) cleaves peptide bonds in activated procoagulant factor VIII (FVIIIa) and V (FVa) and promotes fibrinolysis through the inhibition of plasminogen activator inhibitor-1 (PAI-1).10 In addition, endothelial activation and injury leads to release of tissue plasminogen activator (tPA) from Weibel-Palade bodies,11 heparinization from glycocalyx shedding,8,12,13 and increased vascular permeability, which, in part, may result from the downstream effects of glycocalyx degradation14,15 and angiopoietin-2 (Ang-2) release.16

PATHOPHYSIOLOGY Endothelial Injury ACOT is mechanistically linked to disruption of the vascular endothelium and its glycocalyx. The vascular 259

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P. Noel, S. Cashen, and B. Patel Coagulopathy of Trauma

• • • •

Early Events

Late Events

Acute Coagulopathy of Trauma

Resuscitation Associated Coagulopathy

• • •

Decrease of Factors V A and V111 A Hyperfibrinolysis Autoheparinization Increased Endothelial Permeability

Hypothermia Acidosis Hemodilution

Figure 1. Coagulopathy of trauma.

(tPA, Ang-2).11 The endothelial glycocalyx contains 1 L of noncirculating plasma that contains significant amounts of heparin-like substances14,15 that when degraded lead to autoheparinization.12,21 Ostrowski et al13 reported on a prospective observational study, including 77 trauma patients admitted to a level 1 trauma center and demonstrated that 5.2% displayed evidence of high-degree autoheparinization. Johansson et al8 reported on 75 trauma patients participating in a prospective cohort study of trauma patients admitted to a level 1 trauma center from 2003 to 2005. Results indicate that increasing injury severity in patients with high syndecan-1 is associated with progressive protein C depletion, increasing sTM, hyperfibrinolysis, and prolonged activated partial thromboplastin time (aPTT). These results suggest that endothelial glycocalyx degradation may be linked to ACOT.6

endothelium is composed of a single layer of cells that lines every vessel in the body and covers a total surface area of 4,000–7,000 m2.17 The endothelial glycocalix lies on top of the endothelium, comprising a 0.2- to 1-μm thick negatively charged anti-adhesive and anticoagulant carbohydrate-rich surface layer that protects the endothelium and maintains vascular barrier function.18,19 Tissue trauma, hypoperfusion,6,20 sympathoadrenal activation,8,9 and inflammation7 induce systemic endothelial activation and damage, leading to early coagulopathy and endothelial hyperpermeability. Endothelial injury and damage leads to the release of molecules in circulation indicating endothelial glycocalyx degradation (syndecan1),8,21 endothelial cell damage (soluble thrombomodulin [sTM,6 vascular endothelial growth factor [VEGF],22 soluble vascular endothelial growth factor receptor 1 [sVEGFR1]23), and Weibel-Palade body degranulation

Acute Coagulopathy of Trauma

• • • •

Tissue Trauma Hypoperfusion Inflammation Sympathoadrenal activation

Endothelial Activation

Increased Thrombomodulin Expression

Decrease Factor V111 A

Decrease Factor VA

Degranulation of Weibel-Palade Bodies

Glycocalyx Shedding

Decrease PAI-1

TPA Release

Release of Heparin

Hyperfibrinolysis

Hyperfibrinolysis

Figure 2. Acute coagulopathy of trauma.

Increased Endothelial Permeability

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Trauma-induced coagulopathy

High levels of Ang-2, syndecan-1, and sTM predict poor outcome in trauma patients.6,8,22,24 Ang-2 is expressed almost exclusively in endothelial cells and is released from Weibel-Palade bodies; upon endothelial activation, its release leads to destabilization of the endothelium and increased vascular permeability, and triggers an inflammatory response. Haywood-Watson et al24 reported data from a prospective observational study24 involving 35 trauma patients in hemorrhagic shock admitted to a level 1 trauma center. The data demonstrate increased levels of syndecan-1 after injury, followed by a post-resuscitation drop. Changes in endothelial cell permeability correlated with syndecan-1 shedding. Endothelial cell permeability was improved by thawed fresh frozen plasma (FFP). Pati et al25 demonstrated that thawed FFP inhibited endothelial cell permeability in vitro by 10.2-fold. Electron microscopy studies in rats subjected to hemorrhagic shock demonstrated that the protective effects of plasma might be due in part to its ability to restore the endothelium glycocalyx and preserve syndecan-1.26 Disruption of the endothelial cell adherens junctions27,28 plays an important role in microvascular hyperpermeability following hemorrhagic shock. The transmembrane adhesion protein vascular endothelial (VE)-cadherin connects adjacent endothelial cells through calcium-dependent homophobic binding of its extracellular domain. The intracellular domain of VE-cadherin interacts with the actin cytoskeleton through a family of catenins; this interaction is considered an important regulator of junctional strength and paracellular permeability.29 Posttranscriptional gene silencing of β-catenin leads to vascular hyperpermeability in vivo. The enhancement of β-catenin gene expression at the adherens junction or exogenous introduction of β-catenin protein shows protection against vascular hyperpermeability.30,31 Johansson and Ostrowski32 hypothesized that the induction of endogenous anticoagulation reflects an evolutionary adaptation that counterbalances the hypoperfusion and cathecholamine-induced endothelial activation and damage. The rise in cathecholamines after trauma may favor a switch from hypercoagulopathy to hypocoagulability in the circulating blood to keep the progressively more procoagulant microvasculature open. The traumaassociated increase in permeability secondary to glycocalyx degradation and Ang-2 release may, from an evolutionary perspective, generate a survival advantage by shifting fluids from the intra- to the extravascular compartment, thereby reducing blood loss through lowering of blood pressure.32

Thrombomodulin Protein C is a vitamin K–dependent plasma glycoprotein that circulates in plasma as an inactive zymogen, which is activated on the surface of endothelial cells by thrombin bound to the transmembrane glycoprotein thrombomodulin (TM).33–35 APC has a half-life of approximately 20 minutes and is inhibited by α1-antitrypsin and

α2-macroglobulin.35,36 Endothelial cell protein C receptor (EPCR) binds protein C to the endothelial cell surface and enhances the rate of protein C activation by the thrombin–thrombomodulin complex by 5- to 20-fold.37–39 TM is uniformly distributed on all endothelial cells, which results in relatively low TM concentrations in large vessels.40 EPCR is highly expressed on the endothelium of large vessels and is present at trace levels in most capillary beds. The concentration of EPCR in large vessels counterbalances the low TM density and ensures efficacious protein C activation.40 APC can dissociate from EPCR and bind to its cofactor protein S, where it can exert its anticoagulant functions, or it may remain bound to EPCR and display cell-signaling cytoprotective activities.39 Protein C controls the activation of procoagulant protein factor X (FX) and factor II (prothrombin), both of which promote fibrin formation. APC has three distinct functions: (1) it cleaves peptide bonds in activated procoagulant factors VIII (FVIIIa) and V (FVa) that serve as cofactors in the activation of FX and FII, respectively; (2) it promotes fibrinolysis though the inhibition of PAI-1; and (3) it reduces inflammation by decreasing leukocyte nuclear factor-κB activation.35 Protein S is a vitamin K–dependent protein cofactor, which increases the activity of APC. Both protein S and FV are required for the regulation of the tenase (inactivation of FVIIIa), whereas protein S suffices in the regulation of the prothrombinase (inactivation of factor Va).35,41,42 Plasma concentrations of FVIII are almost two orders of magnitude lower than that of FV as a consequence during activation of coagulation, tenase complexes (tntrinsic: FIXa–FVIIIa; extrinsic: FVIIa–Ca2þ) are scarce in comparison to the prothrombinase complexes (FXa–FVa). This explains why protein S and FV are required for the regulation of the tenase (inactivation of FVIIIa), whereas protein S suffices in the regulation of the prothrombinase complexes (inactivation of FVa).35,41,42

Coagulation Factor Deficiency Coagulation abnormalities occur rapidly following trauma. In a cohort of 45 trauma patients, 56% had coagulation abnormalities within 25 minutes from injury.43 Rizoli et al44 reported on 110 adult trauma patients with Injury Severity Scores (ISS) 415. Twenty percent of these patients were found to have critical factor deficiencies (coagulation activity levels o30% of normal). Factor V was deficient in all the 22 cases, whereas only five patients had a critical deficiency of any of the other factors. International normalized ratio (INR), activated prothrombin time (PT), and, thromboelastography (TEG) were abnormal in 32%, 36%, and 35%, respectively, of patients with critically low coagulation factor levels. Patients with critical coagulation factor levels had more severe injuries, were more acidotic, and required more transfusions. The

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critical deficit of factor V is likely mediated by the activation of protein C and the proteolytic cleavage of factor V. FVIII is also cleaved by APC; its activity was increased in 72% of adult trauma patients, likely explained by the acute-phase reactant properties of FVIII.45 Rourke et al46 reported on a prospective cohort study of 517 trauma patients in which declining levels of fibrinogen below 1.5, 1.0, and 0.8 g/L were found in 14%, 5%, and 3% of patients, respectively. Low fibrinogen was found to be a predictor of mortality at both 24 hours and 28 days (P o.001).

Hyperfibrinolysis Hyperfibrinolyis in trauma results from PAI-1 inhibition secondary to protein C activation and release of t-PA from Weibel-Palade bodies secondary to endothelial activation. Hyperfibrinolysis diagnosed by TEG is found in 7%–20% of adult trauma patients and is associated with an increased mortality rate.47–51 There is variability in the literature regarding the criteria used to define hyperfibrinolysis by TEG or ROTEM (rotational TEG; TEM International Gmbh, Munich, Germany). The sensitivity of TEG and ROTEM in detecting low levels of hyperfibrinolysis is unclear. Kutcher et al47 reported on 115 critically injured patients at arrival in a level 1 trauma center. Twenty percent already had hyperfibrinolyis, defined as a maximal clot lysis 410% on TEG, reversible by aprotinin treatment. Hyperfibrinolysis was associated with multi-organ failure and increased mortality. Hypothermia (temperature ≤ 36.01C), acidosis (pH ≤7.2), coagulopathy (INR ≥1.3 or aPTT ≥30), and a platelet count ≤200,000/mL identified hyperfibrinolysis with 100% sensitivity and 55.4% specificity. Holcomb et al,48 using TEG in trauma patients admitted to a level 1 trauma center, identified 7% patients with a percentage clot lysis at minutes (LY30) above 3% at admission (LY30 43%, or the percent amplitude reduction at 30 minutes after maximum amplitude of the tracing, is associated with a doubling of mortality). In a prospective cohort study of 334 severe blunt trauma patients (ISS score ≥15 or Glasgow Coma Score [GCS] ≤14), Tauber et al49 reported a 6.9% incidence of hyperfibrinolysis diagnosed by ROTEM. Fulminant hyperfibrinolysis was defined as complete dissolution of the clot within 60 minutes. Moderate hyperfibrinolysis was defined as reduction of clot firmness of 16%–35%. The overall mortality rates of patients with moderate and fulminant hyperfibrinolysis were 11.1% and 85.7%, respectively. Ives et al51 reported hyperfibrinolysis in 11% of trauma patients. Hyperfibrinolysis was defined as ≥15% lysis on TEG. Patients with hyperfibrinolysis had both an increased early mortality (69.2% v 1.9%; P o.001) and greater in-hospital mortality (92.3% v 9.5%; P ¼ .001) when compared to patients without evidence of hyperfibrinolysis.

P. Noel, S. Cashen, and B. Patel

Diffuse Intravascular Coagulation It is difficult to clearly distinguish between the ACOT and diffuse intravascular coagulation (DIC). Rizoli et al52 evaluated 423 trauma patients for DIC using the International Society for Thrombosis and Hemostasis (ISTH) scoring system. Overt DIC was diagnosed in 11% of patients in the 24 hours following injury. Patients with overt DIC had a higher mortality and required more transfusions. One hundred sixteen patients underwent surgery within 24 hours of trauma, and all 40 excised organs as well as 27 autopsy reports were reviewed by two pathologists. No anatomopathologic evidence of DIC was evident in the first 24 hours following injury.

Platelet Dysfunction The phenomenon of “exhausted platelets” in trauma may be secondary to attenuation of platelet stimulation to adenosine diphosphate (ADP) agonism. Prospective platelet function studies within 30 minutes of injury were performed using TEG-based platelet mapping in 51 trauma patients.53 The median ADP inhibition of platelet function was 86.1% in trauma patients and 4.2% in healthy volunteers. After trauma, the impairment of platelet function in response to arachidonic acid was 44.9% compared to 0.5% in volunteers. Kutcher et al54 reported platelet hypofunction to at least one agonist in 45.5% of trauma patients at admission. Thrombin receptor-activated peptide, arachidonic acid, and collagen responsiveness were found to be independent predictors of in-hospital mortality (P o.05).

RESUSCITATION-ASSOCIATED COAGULOPATHY Traditionally, ACOT has been considered synonymous with the “lethal triad” of coagulopathy, hypothermia, and acidosis, all of which contribute to increased mortality.55,56 If this is the case, RAC in the face of hypothermia, acidosis, coagulopathy, and hemodilution57 could be considered the “lethal quartet,” emphasizing the insult of further dilution of dwindling coagulation factors that occurs during overzealous fluid resuscitation.

Hypothermia Hypothermia is closely linked to the severity of injury and can be caused by convection and radiation heat loss, reduced heat production related to decreased oxygen consumption, exposure of body cavities, and infusion of cold resuscitation fluids. Hypothermia is classified as mild (o361C), moderate (32–361C), and severe (o321C). A 5-year retrospective review of 751 US military personnel injured in Operation Iraqi Freedom/Operation Enduring Freedom who received ≥10 U of red blood cells in the 24 hours following their injuries showed an incidence of 21.5% mild, 1.3% moderate, and 0% severe hypothermia.58

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Trauma-induced coagulopathy Luna et al59 described in trauma patients with an ISS 425 that mortality increased from 10% to 100% when body temperature declined from 35 to o321C. There is a 10% reduction in coagulation factor activity for each 11C drop in temperature.60 Hypothermia o331C reduces factor activities below 33%.61 Hypothermia primarily inhibits the initiation phase of thrombin generation and fibrinogen synthesis, with no effect on fibrinogen degradation.62 In vitro and ex vivo experiments have shown a 5%–10% reduction in thrombin production for each degree drop below 361C.63

Acidosis Acidosis in trauma can be related to hypoperfusion, resuscitation with chloride-containing fluids, and blood stored in citrate phosphate dextrose adenine solution. Clotting factor activity is impaired by acidosis, to the extent that a decrease in pH from 7.4–7.0 reduces the activity of factor VIIa by more than 90%, FVIIa/tissue factor complex by 55%, and FXa/FVa complex by 70%, and impairs the thrombin generation rate.64 Acidosis increases fibrinogen breakdown by 1.8-fold but has no impact on fibrinogen synthesis.65 Acidosis impacts the interaction of coagulation factors with the negatively charged phospholipids on the surface of activated platelets.66

Hemodilution In vitro and in vivo studies on healthy volunteers have found that 1 L of crystalloid had no effect on blood coagulation and 40%–60% hemodilution was required to induce a coagulopathy.67,68 There is an increasing incidence of coagulopathy with increasing amounts of intravenous fluids administered. Maegele et al69 reported an incidence of coagulopathy of 440% in patients receiving more than 2 L of fluid, 450% in patients receiving 43 L of fluid, and 470% in patients receiving 44 L of fluid. Fibrinogen levels o100 mg/dL can occur as a result of dilution and results from blood losses of 150% of circulating volume.70,71 The fibrinogen deficit can occur before clotting-factor depletion, which requires 200% of blood volume loss.71

LABORATORY DIAGNOSIS Routinely used in vitro coagulation tests, such as the PT and the aPTT, performed at 371C at a normal pH, do not accurately reflect the in vivo coagulopathy in bleeding trauma patients. In addition to the PT and aPTT, many centers monitor the platelet count and fibrinogen levels. Unfortunately, these in vitro tests do not provide a physiologically representative picture of the in vivo coagulation process. None of these assays can evaluate the rate of clot propagation versus clot lysis or overall clot strength.72 The sensitivity and predictive value of the PT

and aPTT in hemorrhagic shock are questionable. PT and aPTT are responsive to thrombin generated as a function of procoagulants but much less to thrombin inhibited by anticoagulants such as protein C. PT and aPTT provide information on factor deficiency but not whether this deficiency is counterbalanced by a parallel deficiency of anticoagulants.73 The PT/INR appears to be more sensitive than the aPTT in patients with traumatic coagulopathy.74 A PT ratio 41.2 is associated with worse outcomes and higher transfusion requirements.75 Plasmabased assays take an average of 65 minutes to yield results,76 far too long for actively bleeding patients. Newer viscoelastic tests such as TEG and ROTEM are rapid (5–10 minutes) and provide information about coagulation factors, fibrinogen, platelets, red blood cells, and fibrinolysis. Viscoelastic testing provides a guide to transfusion resuscitation.77 Holcomb et al78 evaluated rapidTEG (r-TEG) in 1,974 major trauma patients and found that r-TEG results correlated with conventional coagulation tests (PT/INR, aPTT, fibrinogen, platelets). They also revealed that the activated clotting time (time in seconds between initiation of the test and the initial fibrin formation) predicted red blood cell transfusions. Furthermore, the alpha-angle (the slope of the tracing that represents the rate of clot formation) predicted massive red cell blood cell transfusions better than PT/aPTT or INR (P o.001), and was also superior to a fibrinogen level for predicting the need for plasma transfusion. The maximal amplitude (MA), which represents platelet contribution to clot strength, was superior to platelet count for predicting platelet transfusions (P o.001), while the Ly-30 (the rate of amplitude reduction 30 minutes after the MA is reached) consistently documented fibrinolysis.

DAMAGE CONTROL RESUSCITATION Damage control resuscitation (DCR) focuses on the prevention of coagulopathy through permissive hypotension, limiting crystalloids and delivering higher ratios of plasma and platelets.79 Definitive hemorrhage control typically requires surgery or interventional radiological control. Damage control surgery focuses on control of bleeding and contamination to allow resuscitation in a critical care setting. Advances in resuscitation with rapid control of bleeding, permissive hypotension, and management of coagulopathy are making definitive surgery during the first operation possible for many patients.79–82 In patients undergoing damage control laparotomy, implementation of DCR reduced crystalloid and blood product administration and was associated with an improvement in 30-day survival.79

Permissive Hypotension The goal of permissive hypotension is to minimize dilutional coagulopathy secondary to the administration of crystalloids and reduce the risk of clot displacement, by

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maintaining a lower systolic blood pressure.80 Bickel et al83 reported a reduction of 10% in mortality in patients with penetrating torso trauma who had permissive hypotension until surgery. Hypotensive resuscitation is indicated for non-compressible penetrating injuries, there is no clear evidence supporting its use in blunt trauma, head injuries, or burns. Morrison et al84 reported on the results of the first 90 patients registered in a randomized trial comparing hypotensive resuscitation with a target mean arterial pressure (MAP) of 50 mm Hg with standard fluid resuscitation with a target mean arterial pressure of 65 mm Hg. Maintaining a target MAP of 50 mm Hg was associated with a decrease in blood product utilization, decreased incidence of coagulopathy, and lowered risk of postoperative death when compared with the higher MAP group. In a retrospective analysis of 307 penetrating torso injuries, patients who underwent restrictive fluid resuscitation had better overall outcomes.85

Hypertonic Saline and Hydroxyethyl Starch Hypertonic saline and hydroxyethyl starch (HES) have been used in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion with a smaller volume of fluids than normal saline or lactated ringers. Dilutional coagulopathy and abdominal compartment syndrome are complications associated with massive crystalloid resuscitation in the trauma setting. The volume of resuscitative fluid is critical in pre-hospital care and combat settings. A multicenter, randomized trial evaluating the impact of initial resuscitation fluid administered by out-ofhospital providers showed no significant difference in mortality at 28 days in patients receiving 7.5% saline per 6% dextran 70, 7.5% saline, or 0.9% saline.86 The first randomized, double-blind, controlled trial (FIRST trial) comparing hydroxyethyl starch (HES) with a molecular weight of 130 kd and a molecular substitution ratio of 0.4 (130 kd/0.4) with saline showed similar outcomes in terms of renal function, organ recovery, and mortality.87 In a prospective study comparing HES 130 kd/0.4 with normal saline performed in 7,000 patients admitted to the ICU for diverse conditions, there was no difference in 90-day mortality between the two arms, but there was a 21% relative increase in the number of patients treated with HES 130 kd/0.4 requiring renal replacement therapy.88 In patients with severe sepsis, HES was associated with increased mortality and acute kidney injury, resulting in the need for renal replacement therapy.89

Transfusion Strategies Definitions of massive transfusion are not evidence based and vary from 410 U of packed red blood cells (PRBCs) per 24 hours, to 100% blood loss in 24 hours, and blood loss exceeding 150 mL/h.72 Patients receiving

P. Noel, S. Cashen, and B. Patel

6–9 U of PRBCs have nearly 2.5 times the mortality of patients receiving 0–5 U.90 One of the central tenets of DCR is the early use of FFP with the aim of obtaining a FFP:PRBC transfusion ratio of 1:1. In 2007 and 2008, Borgman et al91 and Spinella et al92 retrospectively reviewed the impact of high ratios of FFP to PRBCs on the mortality of injured military personnel in Iraq. Borgman et al91 reported a 46% improvement in overall mortality by using a 1:1 FFP:PRBC ratio. Spinella et al92 reported that each unit of FFP transfused was independently associated with survival and each unit of RBCs transfused was independently associated with decreased survival. Based on these data, the United States Army Surgeon General distributed a policy recommending adoption of 1:1 FFP:PRBC ratio for all military patients with significant trauma at risk for requiring massive transfusions.93 In both studies, the FFP required thawing prior to administration, introducing a survivorship bias. Survivorship bias is an important confounding factor, since some patients will have more survivable injuries, and therefore receive more FFP.93 Scalea et al94 and Dirks et al95 found no survival advantage in using a FFP:PRBC in a 1:1 ratio. Their patients had a lower incidence of penetrating trauma and blast injuries than described in Borgman’s91 and Spinella’s92 series. Ho et al96 identified 26 studies comparing high and low FFP:PRBC ratios for bleeding trauma patients. Fifteen of 26 were classified as survivor biasunlikely. Ten of these 15 studies showed an association between higher FFP:PRBC ratio and improved survival, whereas five did not. The PROMMTT study (Prospective, Observational, Multicenter, Major Trauma Transfusion Study)97 reported that increased ratios of FFP:PRBCs were independently associated with decreased 6-hour mortality, during which 81% of the hemorrhagic deaths occurred. In the first 6 hours, patients with ratios less than 1:2 were three to four times more likely to die than patients with ratios 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from non-hemorrhagic causes prevailed. The current evidence for increased ratios of transfused platelet:PRBCs is retrospective. In a multicenter, retrospective study, Holcomb et al98 reported improved survival at 24 hours and 30 days in patients transfused using platelet:PRBC ratios of 1:1. Multi-organ failure mortality was increased, but overall 30-day survival was improved. Results of a multicenter, retrospective study by Spinella et al99 suggest that high platelet:PRBC ratios mostly benefit patients with brain injury. The PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial compares a 1:1:1 ratio with a 1:1:2 ratio of FFP:platelets:PRBC in patients who are predicted to require massive transfusions. Outcomes from this trial will help guide the use of platelets in trauma patients.100 There are no prospective studies evaluating the role of fibrinogen concentrates in trauma. In a retrospective analysis of 252 massive transfusion recipients treated in a

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Trauma-induced coagulopathy United States combat support hospital, Stinger et al101 correlated the amount of fibrinogen in blood products with outcome. The incidence of death from hemorrhage was higher in the low fibrinogen (o0.2 g of fibrinogen/ PRBC unit) (85%), compared to the high fibrinogen (≥0.2 g of fibrinogen/PRBC unit) (44%) (P o.001). A retrospective study published by Schochl et al102 comparing 80 patients treated with fibrinogen concentrate and prothrombin complex concentrate (PCC) with 601 patients from the German trauma registry managed with FFP, demonstrated that the fibrinogen-PCC group avoided PRBC transfusion 29% of the time, compared to 3% in the German plasma cohort. The mortality rate was comparable. Cryoprecipitate, which contains fibrinogen, von Willebrand factor, FVIII, FXIII, and fibronectin, has not been prospectively studied in trauma, its use warrants further prospective studies in the trauma setting. The military, in forward deployed medical units, continues using fresh whole blood (FWB). Spinella et al103 retrospectively reviewed the outcomes of 100 patients who received FWB and compared them to patients receiving component therapy alone. Patients who received FWB had improved 24-hour and 30-day survival rates. One of the advantages of FWB is the absence of storage lesion104; the disadvantages include increased infection transmission risks. The risks and benefits of transfusions have to be cautiously balanced.80 Multi-organ failure, infection and increased length of stay have been linked with massive transfusion of older red blood cells,104 and high FFP: PRBC ratios are associated with increased relative risks of sepsis, single organ failure and acute respiratory distress syndrome.105

Tranexamic Acid Tranexamic acid (TXA) 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 required for activation.106 The CRASH-2 trial107 randomized 20,211 trauma patients with, or at risk of, significant bleeding to receive TXA or placebo. TXA was administered as a 1 g bolus over 10 minutes, followed by infusion of 1 g over 8 hours. Treatment within 1 hour decreased the risk of death due to bleeding from 7.7% to 5.5% (P o.0001). Treatment given between 1 and 3 hours reduced the risk of death due to bleeding from 6.1% to 4.8% (P ¼ .03). Treatment given after 3 hours increased the risk of death due to bleeding from 3.1% to 4.4% (P ¼ .004). The beneficial effect of TXA on all cause mortality or deaths from bleeding was not affected by baseline risk of death.107 There were fewer thrombotic events with TXA with no evidence of heterogeneity by baseline risk.108 A military study conducted in Afghanistan109 showed lower unadjusted mortality in patients treated with TXA than the

control group (17.4% v 23.9%; P ¼ .03), despite being more severely injured. The benefit was greatest in the group of patients who received more than 10 U of PRBCs. The US Food and Drug Administration (FDA) considers the use of TXA in the management of traumatic bleeding off-label.

Factor XIII Upon activation by thrombin, FXIIIa acts on fibrin to form Υ-glutamuyl-ε-lysil amide links between fibrin molecules to form an insoluble clot. FXIII appears to inhibit r-TPA-evoked hyperfibrinolysis.110 The effects of exogenous FXIII appear to be dependent on the presence of functional platelets.110 The role of FXIII in the management of traumatic coagulopathy remains to be determined. The US FDA considers the use of FXIII in the management of traumatic bleeding off-label.

Recombinant Factor VIIa Recombinant FVIIa when complexed with tissue factor can activate coagulation factor X to FXa, as well as FIX to FIXa. Hypofibrinogenemia and thrombocytopenia need to be corrected prior to using FVIIa in order to ensure adequate fibrin clot formation. Hypothermia and acidosis decrease the efficacy of FVIIa and should be corrected if possible.106 In a retrospective study of 124 military patients, Spinella et al111 reported a decrease in 24-hour and 30-day mortality associated with the use of FVIIa. The widespread use of FVIIa in trauma resuscitation decreased following the publication of two large randomized controlled trials, which failed to show decrease in mortality and only showed a modest reduction in blood usage.112,113 A review of 12 therapeutic trials114 showed a nonsignificant decrease in mortality and a nonsignificant increase in thromboembolic events but no difference in control of bleeding or red blood cell transfusion. A metaanalysis conducted in patients with blunt or penetrating brain injury treated with FVIIa, showed that off-label FVIIa use was associated with a higher rate of arterial thrombotic complications, especially in the elderly.115 The US FDA considers the use of FVIIa in the management of traumatic bleeding off-label.

Prothrombin Complex Concentrates PCCs provide a source of vitamin K–dependent factors. PCCs currently available in the United States contain three vitamin K–dependent factors (factors II, IX, and X). The US FDA is in the process of approving a four-factor PCC (factors II, VII, IX, X). The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents.116 A retrospective review of 51 trauma patients treated with PCC, 58% of which were on

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warfarin prior to admission, demonstrated a 7% incidence of thrombotic complications and 36% mortality.117 The advantages of PCC over plasma include decreased volume, lack of concern for ABO type, and lower risk of viral transmission along with the ability of transfusing without thawing. The US FDA considers the use of PCCs in the management of traumatic bleeding off-label. Prospective trials comparing PCC use with plasma are required to better understand its place in the management of traumatic bleeding.

CONCLUSIONS Tissue hypoperfusion, inflammation, and activation of the neurohumoral system play pivotal roles in the coagulopathy of trauma. Hypocoagulability, hyperfibrinolysis, and increased endothelial permeability characterize ACOT. Acidosis, hypothermia, and hemodilution contribute to further exacerbation of entrenched coagulopathy. Major advances in trauma resuscitation have occurred in the last decade. Randomized, prospective trials are needed to better define transfusion strategies and the use of hemostatic adjuncts. The next 10 years will hopefully provide answers on the role of freeze-dried plasma, frozen platelets, fibrinogen concentrates, cryoprecipitate, and FXIII in the management of the coagulopathy of trauma.

REFERENCES 1. Peden M, McGee K, Sharma G. The injury chart book: a graphical overview of the global burden of injuries. Geneva: World Health Organization; 2002 2. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessement. J Trauma. 1995;38: 185-93. 3. Hess JR. Blood and coagulation support in trauma care. Hematology Am Soc Hematol Educ Program:187-91. 4. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127-30. 5. MacLeod JB, Lynn M, Mckenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55:39-44. 6. Brohi K, Cohen MJ, Ganter MT, Mathay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy:initiated by hypoperfusion:modulated through the protein C pathway? Ann Surg. 2007;245:812-8. 7. Ganter MT, Brohi K, Cohen MJ, et al. Role of the alternative pathway in the early complement activation. Shock. 2007;28:29-34. 8. Johansson PL, 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. 9. Johansson PL, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating adrenaline levels at admission predict increased mortality after trauma. J Trauma. 2012;72: 428-36.

P. Noel, S. Cashen, and B. Patel

10. Anastasiou G, Gialeraki A, Merkouri E, Politou M, Travlou A. Thrombomodulin as a regulator of the anticoagulant pathway:implication in the development of thrombosis. Blood Coagul Fibrinolysis. 2012;23:1-10. 11. Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med. 2005;15:302-8. 12. Senzolo M, Coppell, Cholongitas E, et al. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis. 2007;18: 227-36. 13. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73:60-6. 14. Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010; 87:300-10. 15. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx:composition, functions, and visualization. Pflugers Arch. 2007;454: 345-59. 16. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006; 27:552-8. 17. Aird WC. Endothelium as an organ system. Crit Care Med. 2004;32:S271-9. 18. Pries AR, Secomb TW, Gaehtgens P. The endothelium surface layer. Pfugers Arch. 2000;440:653-66. 19. Nieuedorp M, Meuwese MC, Vink H, et al. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16: 507-11. 20. Ten VS, Pinsky Dj. Endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction. Curr Opin Crit Care. 2002;8:242-50. 21. Rehm M, Bruegger D, Christ F, Conzen P, et al. Shedding of the glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116:1896-906. 22. Ganter MT, Cohe MJ, Borji K, et al. Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg. 2008;247: 320-6. 23. Ostrowski SR, Sorensen AM, Windelov NA, et al. High levels of soluble VEGF receptor 1 early after trauma are associated with schock, sympothoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study. Scand J Trauma Resusc Emerg Med. 2012;20:27:1-8. 24. Haywood-Watson R, Pati S, Kozar R, et al. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS One. 2011;6:e23530. 25. Pati S, Matijevic N, Doursout MF, et al. 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. 26. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112:1289-95.

Trauma-induced coagulopathy

27. Kumar P, Shen Q, Pivetti CD, et al. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med. 2009;11:e19. 28. Childs EW, Tharakan B, Byrge N, et al. Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock. Am J Physiol Heart Circ Physiol. 2008;294:H2285-95. 29. Dejana E, Bazzoni G, Lampugnani MG. Vascular endothelial (VE)-cadherin: only an intercellular glue? Exp Cell Res. 1999;252:13-9. 30. Hinck L, Nathke IS, Papkoff J, Nelson WJ. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol. 1994;125:1327-40. 31. Savant DA, Tharakan B, Hunter FA, Smythe WR, Childs EW. Role of β-catenin in regulating microvascular endothelial cell hyperpermeability. J Trauma. 2011;70: 481-8. 32. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses. 2010;75:564-7. 33. Espana F, Medina P, Navarro S, et al. The multifounctional protein C system. Curr Med Chem Cardiovasc Hematol Agents. 2005;3:119-31. 34. Rezaie AR. Regulation of the protein C anticoagulant and anti-inflammatory pathways. Curr Med Chem. 2010; 17:2059-69. 35. Anastasiou G, Gialeraki A, Merkouri W, Politou M, Travlou A. Thrombomodulin as a regulator of the anticoagulant pathway:implication in the development of thrombosis. Blood Coagul Fibrinolysis. 2011;23:1-10. 36. Disse J, Petersen HH, Larsen KS, et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem. 2011;286:5756-67. 37. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A. 1996;93:10212-6. 38. Navarro S, Bonet E, Estelles A, et al. The endothelial cell protein S receptor: Its role in thrombosis. Thromb Res. 2011;128:410-6. 39. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem. 1989;264:4743-6. 40. Laszik Z, Mitro A, Taylor FB, et al. Human protein C receptor is present primarily on endothelium of large vessels: implications for the control of the protein C pathway. Circulation. 1997;96:3633-40. 41. Esmon CT. The protein C pathway. Chest. 2003;124: 26S-32S. 42. Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway. Novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol. 2005;25:1311-20. 43. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43:26-32. 44. Rizoli SB, Scarpelini S, Callum J, et al. Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma. 2011;71(5 Suppl 1):S427-34.

267

45. Jansen JO, Scarpelini S, Pinto R, et al. Hypoperfusion in severely injured trauma patients is associated with reduced coagulation factor activity. J Trauma. 2011;71(5 Suppl 1): S435-40. 46. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342-51. 47. Kutcher ME, Cripps MW, McCreery RC, et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma. 2012;73:87-93. 48. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thromboelastography can replace conventional coagulation tests in the ermergency department. Ann Surg. 2012;256:476-86. 49. Tauber H, Innerhofer P, Breitkopf R, et al. Prevalence and impact of abnormal Rotem assays in severe blunt trauma: results of the “Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study. Br J Anaesth. 2011; 107:378-87. 50. Theusinger OM, Wanner GA, Emmert MY, et al. Hyperfibrinolysis diagnosed by Rotational Thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg. 2011;113: 1003-12. 51. Ives C, Inaba K, Branco BC, et al. Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg. 2012;215:496-502. 52. Rizoli S, Nascimento B, Key N, et al. Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma. 2011;71:S441-7. 53. Wohlauer MV, Moore EE, Thomas S, et al. Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. J Am Coll Surg. 2012;214:739-46. 54. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. J Trauma. 2012;73:13-9. 55. 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;65:951-60. 56. Dirkmann D, Hanke AA, Gorlinger K, Peters J. Hypothermia and acidosis synergistically impair coagulation in human whole blood. Anesth Analg. 2008;106:1627-32. 57. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65: 748-54. 58. Simmons JW, White CE, Ritchie JS, et al. Mechanism of injury affects acute coagulopathy of trauma in combat casualties. J Trauma. 2011;71:S74-7. 59. Luna GK, Maier RV, Pavlin EG, et al. Incidence and effect of hypothermia in seriously injured patients. J Trauma. 1987;27:1014-8. 60. Watts DD, Trask A, Soeken K, et al. Hypothermic coagulopathy in trauma:effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma. 1998;44:846-54. 61. Wolberg AS, Meng ZH, Monroe DM III, Hoffman M. A systemic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56:1221-8.

268

62. Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma. 2009;67:202-9. 63. Waibel BH, Schlitzkus LL, Newell MA, et al. Impact of hypothermia (below 36 degree C) in the rural trauma patient. J Am Coll Surg. 2009;209:580-8. 64. 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;55:886-9. 65. Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg. 2007;246:831-5. 66. Hess JR, Lawson JH. The coagulopathy of trauma versus disseminated intravascular coagulation. J Trauma. 2006;60 (Suppl 6):S12-9. 67. Brazil EV, Coats TJ. Sonoclot coagulation analysis of invitro haemodilution with resuscitation solutions. J R Soc Med. 2000;93:507-10. 68. Coats TJ, Brazil E, Heron M, MacCallum PK. Impairment of coagulation by commonly used resuscitation fluids in human volunteers. Br Med J. 2006;23:846-9. 69. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury. 2007;38:298-304. 70. Fries D, Martini WZ. Role of fibrinogen in traumainduced coagulopathy. Br J Anaesth. 2010;105:116-21. 71. Howard BM, Daley AT, Cohen MJ. Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions. Semin Thromb Hemost. 2012;38:250-8. 72. Davenport R, Khan S. Management of major trauma hemorrhage:treatment priorities and controversies. Br J Haematol. 2011;155:537-48. 73. Tripodi A, Chantarangkul V, Manucci PM. Acquired coagulation disorders:revisited using global coagulation/ anticoagulation testing. Br J Haematol. 2009;147:77-82. 74. Yuan S, Ferrell C, Chandler WL. Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res. 2007;120:29-37. 75. Frith D, Goslings JC, Gaarder C, et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost. 2010;8:1919-25. 76. Victor J, Zimmermann H, Can Exadaktylos AK. Rapid TEG accelerate the search for coagulopathies in the patient with multiple injuries? J Trauma. 2009;66:1253-7. 77. Curry N, Davis PW. What’s new in resuscitation strategies for the patient with multiple trauma? Injury. 2012;43:1021-8. 78. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thromboelastography can replace conventional coagulation tests in the emergency department. Ann Surg. 2012;256:476-86. 79. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a reduction in resuscitative volumes and improved survival in 390 damage control laparotomy patients. Ann Surg. 2011;254:598-605. 80. Curry N, Davis PW. What’s new in resuscitation strategies for the patient with multiple trauma? Injury Int J Care Injured. 2012;43:1021-8. 81. Gruen RL, Brohi K, Schreiber M, et al. Haemorrhage control in severely injured patients. Lancet. 2012;380:1099-108.

P. Noel, S. Cashen, and B. Patel

82. Jaunoo SS, Harji DP. Damage control surgery. Int J Surg. 2009;7:110-3. 83. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso trauma. N Engl J Med. 1994;331: 1105-9. 84. Morrison CA, Carrick MM, Norman MA, et al. Hypotensive resuscitation strategy reduces transfusion requiremnts and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma. 2011;70:652-63. 85. Duke MD, Guidry C, Guice J, et al. Restrictive fluid resuscitation in combination with damage control resuscitation: time for adaptation. J Trauma. 2012;73: 674-8. 86. Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg. 2011;253:431-41. 87. James MF, Mitchell WL, Joubert IA, et al. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth. 2011;107:693-702. 88. Myburgh JA, Finfer S, Bellomo R, et al. Hydoxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901-11. 89. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124-34. 90. Stanworth SJ, Morris TP, Gaarder C, et al. Reappraising the concept of massive transfusion in trauma. Crit Care. 2010;R239. 91. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects the mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63:805-13. 92. Spinella PC, Perkins JG, Gratwohl KW, et al. Effect of plasma and red cell transfusions on survival in patients with combat related traumatic injuries. J Trauma. 2008;64: S69-78. 93. Callum JL, Rizoli S. Plasma transfusion for patients with severe hemorrhage: what is the evidence. Transfusion. 2012;52:30S-7S. 94. Scalea TM, Bochicchio KM, Lumpkins K, et al. Early aggressive use of fresh frozen plasma does not improve outcome in critically injures trauma patients. Ann Surg. 2008;248:578-84. 95. Dirks J, Jorgensen H, Jensen CH, et al. Blood product ratio in acute traumatic coagulopathy-effect on mortality in a Scandinavian level 1 trauma center. Scand J Trauma Resusc. 2010;18:65. 96. Ho AM, Dion PW, Yeung JH, et al. Prevalence of survivor bias in observational studies on fresh frozen plasma: erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology. 2012;116:716-28. 97. Holcomb JB, del Junco DJ, Fox EE, et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study. Arch Surg. 2012, Oct 15:1-10. http:// dx.doi.org/10.1001/2013.jamasurg.387. [Epub ahead of print].

269

Trauma-induced coagulopathy

98. Holcomb JB, Zarzabal LA, Michalek JE, et al. Increased platelet:RBC ratios are associated with improved survival after massive transfusion. J Trauma. 2011;71:S318-28. 99. Spinella PC, Wade CE, Blackbourne LH, et al. The association of blood component use ratios with the survival of massively transfused trauma patients with and without brain injury. J Trauma. 2011;71:S343-52. 100. Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR). Clinical Trails.gov Identifier: NCT01545232. (http://www.clinicaltrials.gov/ct2/show/NCT01545232? term=PROPPR&rank=1) 101. Spinella PC, Perkins JG, Grathwohl KW, et al. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66:S69-76. 102. Lelubre C, Piagnerelli M, Vincent J-L. Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: myth or reality? Transfusion. 2009;49:1384-94. 103. Zehtabchi S, Nishijima DK. Impact of transfusion of freshfrozen 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. 104. Sorensen B, Fries D. Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg. 2012;99:40-50. 105. The CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised trial. Lancet. 2011;377:1096-101. 106. Roberts I, Perel P, Prieto-Merino D, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomized controlled trial. BMJ. 2012;345:e5839. 107. 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. 108. Dirkmann D, Gorlinger K, Gisbertz C, Dusse F, Peters J. Factor XIII and tranexamic acid but not recombinant

109.

110.

111.

112.

113.

114.

115.

116.

117.

factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood. Anesth Analg. 2012;114:1182-8. Spinella PV, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma. 2008;64:286-93. Boffard KD, Riou B, Warren B, et al. Recombiant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebocontrolled, double-blind clinical trials. J Trauma. 2005; 59:8-15. Hauser CJ, Boffard K, Dutton R, et al. Result 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. Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Use of recombinant factor VIIa or the prevention and treatment of bleeding in patients without hemophilia: a systematic review and meta-analysis. CMAJ. 2011;183:E9-19. Zaaroor M, Soustiel JF, Brenner B, et al. Administration off label of recombinant factor-VIIa (rFVIIa) to patients with blunt or penetrating brain injury without coagulopathy. Acta Neurochir. 2008;150:663-8. Sorensen B, Spahn DR, Innerhofer P, et al. Clinical review: prothombin complex concentrates-evaluation of safety and thrombogenicity. Crit Care. 2011;15:201. Bellal J, Amini A, Friese RS, et al. Factor IX complex for the correction of traumatic coagulopathy. J Trauma. 2012;72:828-34. Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma. 2008;64:S79-85. Schochl H, Nienaber U, Maegele M, et al. Transfusion in trauma: thromboelastography-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15:R83.