Ganter, M. T.

Spahn, D. R.

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EDITORIALTowards early individual goal-directed coagulationmanagement in trauma patientsD. R. Spahn* and M. T. GanterInstitute of Anaesthesiology, University Hospital Zurich, CH-8091 Zurich, Switzerland* Corresponding author. E-mail: donat.spahn@usz.chMajor trauma is associated with significant blood loss due toboth the severity of injuries and trauma-related coagulopa-thy. Acute coagulopathy in trauma patients is frequent andhas been associated with a worse clinical outcome.1 2 Inthis issue of the British Journal of Anaesthesia, Fries andMartini3 review the mechanisms of trauma-related coagulo-pathy and the central role of fibrinogen in its treatment. Thisis a very timely issue since the understanding of thecoagulopathy of trauma and shock has indeed increasedtremendously in recent years. In addition, fibrinogen isincreasingly viewed as the coagulation factor that is thefirst to become critically low in cases of major haemorrhage.1Acute traumatic coagulopathy has traditionally beenexplained as an acquired disorder in the coagulationsystem which occurs through loss or impaired function ofcoagulation proteases and platelets. However, severetrauma leads to massive haemorrhage with activation andsubsequent exhaustion of the coagulation system. Dilutionfrom fluid resuscitation results in an additional relativedeficiency of coagulation factors and platelets. Finally, phys-ical factors such as acidaemia and hypothermia further com-promise coagulation proteases and platelet function,worsening the evolving coagulopathy.Recent studies have shown that nearly 25% of traumapatients present with a clinically significant coagulopathyupon arrival in the emergency department which affectstheir overall outcome.4 Interestingly, this early coagulopathyoccurred before any significant consumption or fluid admin-istration and in the absence of a relevant acidaemia orhypothermia. Therefore, it has been postulated that theearly coagulopathy after trauma be physiologically andmechanically distinct. This acute coagulopathy of trauma,which has also been called endogenous acute coagulopathy5or acute coagulopathy of trauma and shock,6 is driven by acombination of tissue trauma and shock with systemic hypo-perfusion. Thus, the anticoagulant thrombomodulin protein Cpathway is overtly activated, resulting in reduced pro-coagulatory potential and increased fibrinolytic activity.7 8Once protein C is activated through a thrombin–thrombomodulin-dependent reaction, activated protein C(aPC) exerts its profound anticoagulant effects by irreversiblyinactivating factors Va and VIIIa. In addition to its direct inhi-bition of fibrin formation, aPC causes resolution of formedclots by stopping the inhibition of fibrinolysis by direct inhi-bition of plasminogen activator inhibitor 1.9 10After major trauma, surgeons and anaesthetists are facedwith a dual problem of physical damage, including vascularinjury, with ‘surgical’ haemorrhage and a component of co-agulopathy with ‘coagulopathic’ bleeding (and any combi-nation thereof). The first requires surgical control, and thesecond requires treatment with pro-coagulatory substancessuch as labile/allogeneic blood products, coagulation factorconcentrate, and, potentially, anti-fibrinolytics. In this situ-ation, the physician must first immediately analyse the situ-ation to establish whether coagulopathy is present andsubsequently decide what should be used for treatment,given the hazards, unknowns, and costs of allogeneic bloodproducts, factor concentrates, and anti-fibrinolytics.A first option to boost blood coagulation aftermajor traumais to administer a ‘massive transfusion package’ with a fixedVolume 105, Number 2, August 2010British Journal of Anaesthesia 105 (2): 103–5 (2010)doi:10.1093/bja/aeq166& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournal.orgratio of fresh frozen plasma (FFP) to red blood cell (RBC), somewith a high ratio and some even include platelets.11 Theapparent success of such algorithms in improving survival ofUS Army combat victims has been described.1 12 However,there are also studies, in which a high FFP:RBC regimen hasshown no benefit with regards to survival.13 14 There is animportant study showing that the introduction of ‘massivetransfusion packages’ resulted in a significant reduction inmortality without a change in the FFP:RBC ratio given in thefirst 24 h.15 Interestingly, in this study, FFP (169 vs 254 min)and platelets (241 vs 418 min) were administered muchearlier after the introduction of ‘massive transfusionpackages’.15 There are several important aspects to considerwhen interpreting results of studies showing a benefit of ahigh FFP:RBC ratio in trauma patients. The data are retrospec-tive and primarily refer to young, previously healthy malepatients with penetrating injuries. In addition, the FFP:RBCratio usually is calculated for the first 24 h of treatment. There-fore, theremay be a significant selection bias in that cliniciansmay have allocated most resources, including FFP, to thosepatients most likely to survive.16 There may also be a survivorbias in that those with the worst injury and bleeding died tooearly to receive a large amount of FFP.16 17 In addition, FFPtransfusion is associated with adverse effects such asincreased incidence of nosocomial infections,18 multipleorgan failure,17 lung injury,16 17 and possibly mortality.16 19Therefore, although the use of FFP is suggested in massivebleeding, the recently published AABB guidelines12 and theupdated European guideline on the management of bleedingaftermajor trauma1 do not recommend transfusion of plasmaat a FFP:RBC ratio of 1:3 or more.A second treatment option aimed at early, individualoptimization of blood coagulation after major trauma is toassess each trauma patient’s coagulation status on admissionin the emergency room and throughout the surgery withpoint-of-care viscoelastic coagulation monitoring (thrombe-lastography, TEGw, Haemonetics Corp., formerly Haemoscopeor rotational thromboelastometry, ROTEMw, tem innovationsGmbH, formerly Pentapharm).20 21 These bed-side devicesallow analysis of the entire blood coagulation within 10–15min22 including the detection of (hyper)fibrinolysis.7 8 Withthis information, coagulation can be readily and individuallyoptimized, for example, with anti-fibrinolytics and bloodcoagulation factor concentrates and later, if necessary withlabile blood products. With such an algorithm, the use ofRBC, FFP, and platelets can be significantly reduced23 andsurvival of trauma patients may be significantly improved.24In this study, the observedmortality was 24.4%whichwas sig-nificantly lower than the expected mortality based on thetrauma injury severity score (TRISS) of 33.7%.24Fibrinogen may be the key element of blood coagulationand is the first element to get critically low.1 Fibrin polymer-ization can be compromised by colloids which are frequentlyused in the initial resuscitation of trauma victims. Interest-ingly, this form of blood coagulation compromise can bereversed by the administration of fibrinogen.25 Therefore,aiming at functional fibrinogen levels as assessed bythromboelastometry23 24 appears reasonable. This is alsoproposed in the updated European guidelines on the man-agement of bleeding after major trauma.1 If thrombelasto-metric monitoring is not available, serum fibrinogen levelsof 1.5–2.0 g litre21 should be targeted.1 However, cliniciansshould be aware that in the presence of artificial colloidssuch as hydroxyethyl starch, gelatin, or dextran, themost often used fibrinogen measurement method, theClauss method, significantly overestimates fibrinogen con-centration.26 27An additional benefit of bed-side coagulation monitoringis speed. If the coagulation status measured on arrival inthe emergency department, the main coagulation problemis known within 15 min. The trauma patient can thenimmediately and specifically be treated according to an insti-tutional transfusion algorithm. Importantly, guidelinesaimed at optimizing the individual’s coagulation status alsoavoid excessive pro-coagulatory potential with associatedthrombotic complications. The time advantage of bed-sidecoagulation monitoring compares very favourably with theimproved times of FFP administration described in thestudy of the introduction of a massive transfusion package.15The review by Fries and Martini3 explaining the mechan-isms of coagulopathy of trauma and shock and the centralrole of fibrinogen is an important contribution towards abetter understanding of this complex situation and a bettertreatment of trauma patients. Their recommendation toview fibrinogen as a central element of blood coagulationis in agreement with the updated European guideline onthe management of bleeding after major trauma.1 The firstgoal is that all hospitals treating trauma patients have aninstitutional algorithm for the management of a traumapatient with major bleeding. The ultimate goal is to establishalgorithms allowing early individual goal-directed coagu-lation management in trauma patients. To introduce suchconcepts into general medicine, they need to be rigorouslytested in large prospective randomized trials.Conflict of interestD.R.S.’s department has received grant support from theUniversity of Zurich, the Research Award Center for ZurichIntegrative Human Physiology, the Swiss National ScienceFoundation, the European Society of Anaesthesiology (ESA),the Swiss Society of Anesthesiology and Reanimation(SGAR), the Swiss Foundation for Anesthesia Research,the Swiss Life Foundation Switzerland, BundesprogrammChancengleichheit, Switzerland, Stiftung fu¨r Staublungen-forschung, Switzerland, B. Braun, Switzerland, CSL Behring,Switzerland, Vifor SA, Switzerland, and UBS, Switzerland.D.R.S. is the chairman of the ABC Faculty and a member ofthe ABC Trauma Faculty, both of which are managed byThomson Physicians World GmbH, Mannheim, Germany,and sponsored by an unrestricted educational grant fromNovo Nordisk A/S, Bagsva¨rd, Denmark. In the past 5 yr,D.R.S. has received honoraria or travel support for consultingor lecturing from the following companies: Abbott AG,BJA Editorial104Switzerland; AstraZeneca AG, Switzerland; Bayer (Schweiz)AG, Switzerland; B. Braun Melsungen AG, Germany; Boehrin-ger Ingelheim (Schweiz) GmbH, Switzerland; CSL BehringGmbH, Germany and Switzerland; Curacyte AG, Germany;Ethicon Biosurgery, USA; Fresenius SE, Germany; GalenicaAG, Switzerland; GlaxoSmithKline GmbH & Co. KG, Germany;Janssen-Cilag AG, Switzerland; Novo Nordisk A/S, Denmark;Octapharma AG, Switzerland; Organon AG, Switzerland;Oxygen Biotherapeutics, USA; Pentapharm GmbH, Germany;Roche Pharma (Schweiz) AG, Switzerland; and Schering-Plough International, Inc., USA. In the past 5 yr, M.T.G. hasreceived honoraria or travel support for consulting orlecturing from the following companies: CSL Behring GmbH,Germany; GlaxoSmithKline GmbH & Co. KG, Germany; andEssex Pharma GmbH, Germany.References1 Rossaint R, Bouillon B, Cerny V et al. Management of bleeding fol-lowing major trauma: an updated European guideline. Crit Care2010; 14: R522 Ganter MT, Pittet JF. New insights into acute coagulopathy intrauma patients. Best Pract Res Clin Anaesthesiol 2010; 24: 15–253 Fries D, Martini WZ. The role of fibrinogen in trauma induced coa-gulopathy (TIC). Br J Anaesth 2010; 105: 116–214 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma:mechanism, identification and effect. Curr Opin Crit Care 2007; 13:680–55 Chesebro BB, Rahn P, Carles M et al. Increase in activated proteinC mediates acute traumatic coagulopathy in mice. Shock 2009;32: 659–656 Hess JR, Brohi K, Dutton RP et al. The coagulopathy of trauma: areview of mechanisms. J Trauma 2008; 65: 748–547 Levrat A, Gros A, Rugeri L et al. Evaluation of rotation thrombelas-tography for the diagnosis of hyperfibrinolysis in trauma patients.Br J Anaesth 2008; 100: 792–78 Rugeri L, Levrat A, David JS et al. Diagnosis of early coagulationabnormalities in trauma patients by rotation thrombelastogra-phy. J Thromb Haemost 2007; 5: 289–959 Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF.Acute traumatic coagulopathy: initiated by hypoperfusion: modu-lated through the protein C pathway? Ann Surg 2007; 245: 812–810 Brohi K, Cohen MJ, Ganter MT et al. Acute coagulopathy oftrauma: hypoperfusion induces systemic anticoagulation andhyperfibrinolysis. J Trauma 2008; 64: 1211–711 Johansson PI, Stensballe J. Effect of haemostatic control resusci-tation on mortality in massively bleeding patients: a before andafter study. Vox Sang 2009; 96: 111–812 Roback JD, Caldwell S, Carson J et al. Evidence-basedpractice guidelines for plasma transfusion. Transfusion 2010doi:10.1111/j.1537-2995.2010.02632.x13 Scalea TM, Bochicchio KM, Lumpkins K et al. Early aggressive useof fresh frozen plasma does not improve outcome in criticallyinjured trauma patients. Ann Surg 2008; 248: 578–8414 Snyder CW, Weinberg JA, McGwin G Jr et al. The relationship ofblood product ratio to mortality: survival benefit or survivalbias? J Trauma 2009; 66: 358–6215 Riskin DJ, Tsai TC, Riskin L et al. Massive transfusion protocols: therole of aggressive resuscitation versus product ratio in mortalityreduction. J Am Coll Surg 2009; 209: 198–20516 Murad MH, Stubbs JR, Gandhi MJ et al. The effect of plasmatransfusion on morbidity and mortality: a systematic reviewand meta-analysis. Transfusion 2010 doi:10.1111/j.1537-2995.2010.02630.x17 Watson GA, Sperry JL, Rosengart MR et al. Fresh frozen plasma isindependently associated with a higher risk of multiple organfailure and acute respiratory distress syndrome. J Trauma 2009;67: 221–718 Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI,Gracias VH. Transfusion of fresh frozen plasma in critically ill sur-gical patients is associated with an increased risk of infection. CritCare Med 2008; 36: 1114–819 Welsby IJ, Troughton M, Phillips-Bute B et al. The relationship ofplasma transfusion from female and male donors withoutcome after cardiac surgery. J Thorac Cardiovasc Surg 2010doi:10.1016/j.jtcvs.2009.12.03520 Ganter MT, Hofer CK. Coagulation monitoring: current techniquesand clinical use of viscoelastic point-of-care coagulation devices.Anesth Analg 2008; 106: 1366–7521 Enriquez LJ, Shore-Lesserson L. Point-of-care coagulationtesting and transfusion algorithms. Br J Anaesth 2009; 103:i14–i2222 Theusinger OM, Nurnberg J, Asmis LM, Seifert B, Spahn DR.Rotation thromboelastometry (ROTEM) stability and reproducibil-ity over time. Eur J Cardiothorac Surg 2010; 37: 677–8323 Theusinger OM, Spahn DR, Ganter MT. Transfusion in trauma: whyand how should we change our current practice? Curr OpinAnaesthesiol 2009; 22: 305–1224 Schoechl H, Nienaber U, Hofer G et al. Goal-directed coagulationmanagement of major trauma patients using rotationthromboelastometry (ROTEM)-guided administration of fibrino-gen and prothrombin complex concentrate. Crit Care 2010; 14:R5525 Fenger-Eriksen C, Tonnesen E, Ingerslev J, Sorensen B. Mechan-isms of hydroxyethyl starch-induced dilutional coagulopathy.J Thromb Haemost 2009; 7: 1099–10526 Adam S, Karger R, Kretschmer V. Photo-optical methods can leadto clinically relevant overestimation of fibrinogen concentrationin plasma diluted with hydroxyethyl starch. Clin Appl ThrombHemost 2009 doi:10.1177/107602960934209027 Hiippala ST. Dextran and hydroxyethyl starch interfere with fibri-nogen assays. Blood Coagul Fibrinolysis 1995; 6: 743–6Editorial BJA105

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