Trauma--Coagulopathy in Trauma, Optimising Haematological Status

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DOI: 10.1177/14604086080912662008; 10; 109Trauma

Vickie McDonald and Kim RylandCoagulopathy in trauma: optimising haematological status

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Trauma 2008; 10: 109123

Coagulopathy in trauma: optimisinghaematological statusVickie McDonald and Kim Ryland

It is estimated that 10 000 people per year die following trauma in England and Wales

and 3040% do so due to uncontrolled haemorrhage. By the time the patient reaches

hospital, coagulopathy is often already installed and needs to be corrected promptly to

prevent further haemorrhage and allow effective treatment of injuries. The

coagulopathy is multifactorial with the leading causes being acidosis, hypothermia

and massive transfusion. Early recognition of the condition is imperative using

standard coagulation testing; however, there are limitations in this setting. Newer

methods of testing global haemostasis using thromboelastography are becoming

more popular but need further validation. Treatment of coagulopathy requires a

multidisciplinary approach. Blood product transfusion remains the cornerstone of

management but newer pharmacological agents such as recombinant factor VIIa areincreasingly being used. Here we review the pathogenesis, investigation and

management of the coagulopathy of trauma.

Key words: Coagulopathy; trauma; lethal triad; transfusion; fresh frozen plasma;

platelets; fibrinogen; rVIIa

Background

The UK Trauma Audit and Research Network

(TARN) estimates that in England and Wales alone,

10 000 people per year die following injury (TARN,

2008). Worldwide, trauma accounts for 10% of allfatalities and is the leading cause of death in

individuals aged between 1 and 44 years (CDC:

Web-Based Injury Statistics Query and Reporting

System, 2002). Haemorrhage continues to be a

primary cause of death independent of the mechan-

ism of injury and accounts for the majority of

potentially preventable early in-patient deaths

(Kauvar et al., 2006). Although trauma care has

improved, 3040% of patients who die do so as a

result of uncontrolled traumatic haemorrhage

(Sauaia et al., 1995b; Holcomb, 2004; Kauvar andWade, 2005). In the pre-hospital setting,this figure rises to 3356% of cases with exsanguina-tion being the most common cause of death amongstthose found dead at the scene by emergency medical

personnel (Sauaia et al ., 1995a). Haemorrhagicshock also contributes significantly to the mortalityof those suffering central nervous system injuries,raising deaths in this group 2- to 3-fold (Manleyet al., 2001).

Haemorrhagic shock and volumes of blood lossare predictors of poor outcome; early hypotension(systolic blood pressure 590mmHg in initialassessment phases) is a marker of late mortality.Multi-organ failure (MOF) and sepsis are morelikely in these groups with 24 and 39% of patientsrespectively developing these complications

(Heckbert et al., 1998; Franklin et al., 2000). In thecontext of trauma, the combination of acidosis,hypothermia and coagulopathy is referred to as thelethal triad (Hoyt et al., 1994; Gentilello andPierson, 2001).

Tissue damage in trauma is massive and uncon-trolled and the interval between haemorrhage andresuscitation measures, including blood product

Address for correspondence: Vickie McDonald, HaemostasisResearch Unit, University College London Department ofHaematology, 1st Floor 51 Chenies Mews, London WC1E6HX, UK. E-mail: [email protected]

Haemostasis Research Unit, University College LondonDepartment of Haematology, University College London,London, UK.

SAGE Publications 2008Los Angeles, London, New Delhi and Singapore 10.1177/1460408608091266

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replacement, is variable. Coagulopathy is oftenalready present by the time patients reach theaccident and emergency department (Brohi et al.,2003; Hardy et al., 2006). Overt coagulopathy affectsat least 1 in 4 seriously injured trauma patients(MacLeod et al., 2003). It is directly proportionalto injury severity, haemorrhagic shock, massiveresuscitation and transfusion (Bickell et al., 1994;Brohi et al ., 2003; MacLeod et al ., 2003;MacLeod et al., 2004). The pathogenesis is complexand multi-factorial.

It is clear the recognition and prompt manage-ment of coagulopathy is essential if survivalfollowing trauma is to be improved.

Methods

Electronic databases were searched (Cochrane

Central Register of Controlled Trials, MEDLINE,EMBASE) and abstract databases for the AmericanSociety of Haematology meetings, the BritishSociety of Haematology meetings, the EuropeanHaematology Society and the International Societyon Thrombosis and Haemostasis. Key words usedfor the search included: coagulopathy trauma,haemorrhage trauma, hypothermia coagulation,acidosis coagulation, trauma coagulation, transfu-sion trauma, FFP trauma, Cryoprecipitate trauma,fibrinogen trauma. The search was completed inJanuary 2008 and there were no language

restrictions.

Coagulation cascade

Haemostasis and clot formation require the inter-action between a number of different procoagulantand anticoagulant mechanisms. The key elementsrequired for haemostasis include: the blood vesseland its supporting structures; platelets and theplatelet-vessel interaction; fibrin generation andregulation of the clot size by coagulation factor

inhibitors and the fibrinolytic system (Goodnightand Hathaway, 2001). In a normal individual, thereis a constant balance of procoagulant and antic-oagulant activity to avoid pathological thrombosisor haemorrhage.

Our current understanding of coagulation is nowbased around the cell-based model of haemostasison phospholipid surfaces rather than the traditional

coagulation cascade with intrinsic and extrinsicpathways (Hoffman and Monroe III, 2001). Thecell-based model describes three phases of coagula-

tion: initiation, amplification and propagation(Figure 1).

During the initiation phase, endothelial cell

damage leads to exposure of tissue factor (TF)which binds avidly to factor VII leading to itsactivation (VIIa). The TF-VIIa complex activatesfactors IX (IXa) and X (Xa). Factor Xa activates

factor V (Va) and together these form the prothrom-binase complex which generates small amounts ofthrombin (IIa) from prothrombin (II). Occurring

concurrently with this, platelets adhere to the sub-endothelial matrix at the site of injury and areactivated. They provide a phospholipid surface forcoagulation factor activity.

During the amplification and propagationphases, factor IIa activates factors VIII, IX andXI. Factor IXa with its cofactor FVIIIa form the

tenase complex which converts factor X into factorXa which, in turn, combines with factor Va toconvert further prothrombin into thrombin.Thrombin then converts fibrinogen in to fibrin,which is cross-linked by the activity of factor XIII.

This leads to stable clot formation.The localisation of thrombus formation is under

the control of several enzymes and cell surfacereceptors. Antithrombin inactivates factors IIa, Xa,

IXa, XIa and XIIa. Its activity is increased42000

fold by the activity of heparin. Thrombomodulin isa receptor on endothelial cell surfaces that inacti-vates thrombin. Tissue factor pathway inhibitor

inhibits the TF/VIIa/Xa complex and is found onendothelial cell surfaces. The protein C and Ssystem inactivates the cofactors in the coagulation

cascade, namely factors Va and VIIIa. Protein Cis activated by the thrombinthrombomodulincomplex.

The fibrinolytic system leads to localised break-

down of fibrin. Tissue plasminogen activator (tPA)and urokinase-type plasminogen activator (uPA)

are activated by the presence of fibrin andkallikrein, respectively. They convert plasminogeninto plasmin which breaks down fibrin into fibrindegradation products including D-Dimers.Plasminogen activator inhibitor (PAI-1) and

Thrombin activatable fibrinolysis inhibitor (TAFI)inhibit the activation and activity of the fibrinolyticsystem.

110 V McDonald and K Ryland

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Pathophysiology of coagulopathyin trauma

Massive haemorrhage in trauma results fromtwo main elements: traumatic injury and

a coagulopathy. Coagulopathic bleeding is usuallymultifactorial. Causes include: consumption ofclotting factors and platelets; dilution of clotting

factors due to fluid resuscitation; dysfunction ofclotting factors from acidosis or hypothermia;

Tissue Factor-Bearing Cell

IX

IIa

IIX

TFVIIa

Va

Xa

IIa


TFIXVIIa

IXa

II

VIIaTFPI

TFXa


VaVIIIa

Activated PlateletXIa

TF VIIa

Xa

VaV

VIIIAvWFVIIIa + Free vWF

XI

XIaVPlatelet

Va

TFPI = tissue factor pathway inhibitor.

IX

IIa

Xa

VaVIIIa

Activated Platelet

II

XIa

X

IXa

IXa

VIIaTF

(a)

(b)

(c)

Figure 1 The cell-based model of haemostasis: (a) initiation; (b) amplification; (c) propagation. Reproduced from

A cell-based model of coagulation and the role of factor VIIa. Blood Reviews 17: S1S5, 2003, with kind permission

from Elsevier and Hoffman M

Coagulopathy in trauma 111

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thrombocytopenia with platelet dysfunction; hyper-

fibrinolysis and the development of secondary

disseminated intravascular coagulation. Additional

co-morbidities and medication or drug consumption

may confound the problem.

Dilution and consumption of clotting factors

Massive blood loss is arbitrarily defined as the loss ofone blood volume within a 24 h period (Mollisonet al ., 1997) although other, more convenient,definitions include 50% blood volume loss within3 h (Spahn et al., 2007) or a rate of loss of 150 mL/min (Fakhry and Sheldon, 1994). Red cell transfu-sion is likely to be required when 3040% of theblood volume has been lost. Massive blood loss leadsto significant reductions in the levels of clotting

factors that cannot be compensated for in the acutesetting. Loss of 1.42 times blood volume leads to areduction in fibrinogen to51 g/L while loss of twicethe blood volume leads to reduced levels ofprothrombin, factor V, Factor VII and platelets(Hiippala, 1998). In order to maintain cardiac outputand circulating blood volume, colloid, crystalloidand packed red cells are usually given in the acutesetting. In vitro data show that thrombin generation,fibrin formation and platelet activation appear to bereduced after haemodilution with normal saline,lactate ringers solution, HES and hypertonic

saline. Lactate Ringers and normal saline had lesseffect on these parameters than HES and hypertonicsaline (Brummel-Ziedins et al., 2006). The greaterthe molecular weight of HES, the greater theimpairment on coagulation (de Jonge and Levi,2001).

Previously, thrombocytopenia was the main com-plication when whole blood was used to resuscitatepatients, (Miller et al., 1971); however, the main issuearound massive transfusion now is the loss ofcoagulation factors. Packed red cells in the UKcontain around 30 m L residual plasma

(OShaughnessy et al., 2004b). Data suggests thatin adult patients receiving over 10 units of packed redcells, the prothrombin time (PT) and activatedpartial thromboplastin time (APTT) increase aftera median of 12 units and thrombocytopenia developsafter a median of 20 units transfusion (Leslie andToy, 1991).

During trauma, massive TF exposure leads toearly clot formation at the sites of injury. Activationof the coagulation system and fibrinolytic systemleads to early consumption of clotting factors(Rossaint et al., 2006).

Hypothermia

Hypothermia is defined as a core temperature of535C. It is a common finding in trauma patientson admission to hospital and has been shown to beassociated with a worse outcome (Ferrara et al.,1990). In a study of patients undergoing hipreplacement, hypothermia led to clinically signifi-cant increases in bleeding (Schmied et al., 1996).In a prospective review of trauma patients in theUSA who had received 10 unit of red cells,

temperature under 34

C was associated withan increased risk of developing life threateningcoagulopathy (defined as PT and APTT 42xnormal controls) with OR of 8.7 (p 0.007)(Cosgriff et al., 1997). This effect was additive toother risk factors for coagulopathy such as acidosis,injury severity score and hypotension (systolicBP 570 mmHg). In animal studies hypothermiahas been shown to cause thrombocytopenia,

platelet function defects (Yoshihara et al., 1985;Pina-Cabral et al ., 1985) and to prolong thebleeding time (Valeri et al., 1987; Oung et al.,

1993). Hypothermia has also been shown inhuman studies to prolong the bleeding time andcause platelet function defects (Valeri et al., 1992;Michelson et al ., 1994), in particular, reducedplatelet aggregation and adhesion (Wolberg et al.,2004). Hypothermia reduces the activation ofplatelets via the vWF-GP 1b-IX-V interaction(Kermode et al., 1999) and also reduces coagulationfactor enzymatic function even in the presence of

normal antigen levels (Johnston et al ., 1994).There is evidence to suggest that the haemostaticdefects seen between 37C and 33C are in the

main due to platelet defects, while those occurringbelow 33C are due to a combination of plateletdefects and coagulation factor dysfunction

(Wolberg et al., 2004). Coagulation tests performedat 37C may underestimate the extent ofthe coagulopathy in vivo (Reed et al ., 1992;De Waele et al., 2003).


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Acidosis

Metabolic acidosis is commonly seen in traumapatients and may result from tissue injury, hypoxiaand massive transfusion. In patients who havereceived a massive transfusion (410 units packedRBC) with an injury severity score (ISS) of425 anda pH of57.10, there is a 49% chance of developinga life threatening coagulopathy (Cosgriff et al.,1997). There is evidence to show that acidosis leadsto reduced activity of clotting factors, reducedthrombin generation and reduced clot stability.A reduction in pH from 7.4 to 7.1 reduced factorVIIa activity by 90% and the FVIIa tissue factorcomplex by 55% (Martini et al ., 2007). LowpH leads to increased clot formation time andreduced alpha angle although clot strengthappeared to be normal on thromboelastography.(Engstrom et al., 2006).

Anaemia

The contribution of red cells (RBC) to the haemo-static process is poorly defined but there have beenpublished reports that they may activate platelets(Santos et al., 1991; Quaknine-Orlando et al., 1999).Red cells marginalise platelets within the bloodvessel and this rheological effect ensures plateletshave access to damaged endothelium. The optimalhaematocrit for RBC to sustain haemostasis isunclear (Spahn et al., 2007); however, reductions inhaematocrit lead to prolonged bleeding times(Hellem et al., 1961; Valeri et al., 2001). There isconflicting evidence on the role of RBC in the coagu-lation process with one study using thromboelasto-graphy not confirming that a low haematocritcompromises clot formation and stability in vitro(Iselin et al., 2001) while another study suggeststhat RBC may contribute to clot formation byproviding a phospholipid surface for coagulationfactor activation (Peyrou et al., 1999). Proteins onthe surface of RBC may activate factor IX therebytriggering activation of factor X and thrombingeneration (Iwata and Kaibara, 2002; Kaibaraet al., 2005).

Disseminated intravascular coagulation (DIC)

The scientific subcommittee on DIC for theInternational Society for Thrombosis and

Haemostasis defines DIC as an acquired syndromecharacterised by the intravascular activation ofcoagulation with loss of localisation arising fromdifferent causes (Taylor Jr et al., 2001). Traumamay cause DIC but the frequency varies with thetrauma type. The incidence of DIC in patients withhead injuries is much higher than those who have noCNS damage and the mechanism is thought to bedue to systemic tissue factor release (Hulka et al.,1996). DIC results from several simultaneouspathologic mechanisms. Firstly, widespread expo-sure of tissue factor on endothelial cells andmononuclear cells leads to excessive thrombingeneration. Secondly, anticoagulant mechanismsand fibrinolytic pathways are dysfunctional (Levi,2007). This, in turn, leads to consumption ofplatelets and clotting factors leading to a secondarycoagulopathy with thrombocytopenia and pro-longed PT and APTT. The ISTH have proposed adiagnostic algorithm for DIC based on plateletcount, fibrin degradation products, prolongedPT and fibrinogen level. The inherentproblem with this in the context of trauma isthat there may be other reasons for lowfibrinogen or prolonged clotting times and thefibrin-related markers will be elevated due to thetrauma itself.

Activation of fibrinolysis and the protein C system

The fibrinolytic system is activated during traumawith release of tPA from the endothelium(Schneiderman et al., 1991; Kooistra et al., 1994).Reduced levels of PAI-1 are also seen early intrauma (Brohi et al., 2007b). Acceleration of fibrindegradation has been documented in pigs in trauma(Martini et al., 2005).

A recent study has also shown that levels ofprotein C fall early in trauma and that the severityof the reduction is related to the degree of acidosis.It is also related to an increase in thrombomodulin(Brohi et al., 2007b). The authors propose that upon

endothelial cell damage, thrombomodulin is expo-sed and binds to thrombin to activate protein C.This leads to a shift towards systemic anti-coagulant rather than fibrin generation. In addition,thrombin may also activate the complement systemwhich is a powerful mediator of tissue injury(Ganter et al., 2007).


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Clinical and laboratory diagnosisof coagulopathy

The diagnosis and management of coagulopathy andongoing bleeding requires both clinical andlaboratory input. The inability of standard

laboratory tests to keep pace with the clinical pictureis well recognised: patients who are actively bleeding and receiving blood products are undergoingrapid physiological changes and thus the actualcoagulation status of the patient may be verydifferent from that reflected in the laboratory results.However, coagulation monitoring should still playan essential part in the directed care of traumapatients. A pro-active anticipatory approach isrequired for a successful outcome to be achieved asrescue correction is more difficult than prevention.

Clinical assessment

Generalised non-surgical bleeding from cannulationsites, mucosal surfaces, skin edges and woundsindicate that a marked coagulopathy is alreadypresent. At this point, the PT will generally bebelow the safe level of 3040% normal (Ketchumet al., 2006). Coagulopathy of this nature is complexand proves very challenging.

Clinical grading systems such as that used by theAmerican College of Surgeons (ACS) have beendevised in order to help assess the extent of

haemorrhage in trauma patients and thus identifythose patients at high risk of coagulopathy andfurther bleeding (Spahn et al., 2007). A systolic bloodpressure (SBP) of570 mmHg may be used to predictpost-traumatic coagulopathy. It is, however, unclearwhether this represents a function of the injuryseverity or occurs as a direct consequence of bleedingitself (Cosgriff et al., 1997).

Laboratory testing

For optimal management, a series of simple, reliable

and easily accessible tests are required. The PT andAPTT are still the main screening tools used asmarkers of developing coagulopathy in the traumasetting. There is strong data to show that earlycoagulopathy predicts mortality in trauma with botha prolonged PT and APTT on arrival at hospitalbeing independent risk factors for mortality. Thepresence of an abnormal PT time on admission is

associated with a tripling of the mortality rate, anddeaths tend to occur early (MacLeod et al., 2003).

It is important to recognise that the International

Normalised Ratio (INR) should not be used in thissetting. The INR has been specifically developed asa means of standardising PT results using different

thromboplastins in order to monitor Vitamin Kantagonist use (warfarin).

Fibrinogen should be estimated using a func-

tional assay such as the Clauss method. Derivedfibrinogen values are calculated from the PT and areunreliable when the PT is prolonged. The derived

method overestimates the fibrinogen level comparedto the Clauss (Mackie et al., 2003).

The relationship between the PT, APTT and

individual clotting factor levels have been studied.It has been suggested that the PT is a more reliableindicator of non-haemostatic levels of clotting

factors than the APTT (Yuan et al., 2007). AnAPTT 1.5 times the normal value equates to FactorVIII, IX, XI activity51520 iu/dL; a PT 1.5 times the

normal value represents FII, V, VII and X levels of515 iu/dL. However, in the context of multiple factordeficiencies the PT and APTT values may be

significantly deranged despite only moderate reduc-tions in factor levels (5060 iu/dL).

There has been increasing interest in using point-

of-care (POC) devices and tests of global haemos-tasis. POC devices have the obvious advantage ofbeing readily accessible to the treating clinician.

Whether near-patient tests of PT and APTT areaccurate in trauma and haemorrhage is yet asunknown (Brohi et al., 2007a). Blood gas analysers

have been used as POC devices for Hb measurementin the emergency setting. There are a variety ofmachines available but the results may be unreliable

(McNulty et al., 1995). If used the results should beinterpreted with caution and not used as a substitutefor formal laboratory measurements.

Global haemostasis tests potentially allow amore physiological picture to be gained withdynamic assessment of the clotting cascade.

Thromboelastography techniques would seem tolend themselves well to being used as POC devices in

trauma centres.ROTEM and TEG analyse whole blood

samples by measuring changes in elastic shearstresses seen during clot formation and subsequentfibrinolysis. Information is provided on the initia-

tion and propagation of coagulation, fibrin-platelet


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interaction, clot firmness and fibrinolysis (Hartert,

1948; Whitten and Greilich, 2000). The methodsand parameters measured have previously beendescribed in detail (Salooja and Perry, 2001; Fries

et al., 2002; Luddington, 2005; Roche et al., 2006).Thromboelastography (Figure 2) has theoretical

advantages over standard laboratory tests including

the analysis of whole blood, rapidity of results (asquickly as 10 min depending on the parametersmeasured), and the ease of operation. The validityof using ROTEM as a POC device has been shown

in both cardiac surgery and liver transplantation(Kang et al ., 1985; Royston & von, 2001;Luddington, 2005).

There have been studies on the correlation

between PT, APTT, fibrinogen and platelet levelswith various ROTEM parameters such as clotformation time (CFT) and clot amplitude (CA).

A recent study showed that thromboelastography isfeasible in early trauma and ROTEM changes wereespecially marked in those who are more severelyinjured (Rugeri et al., 2007). It is difficult to draw

further conclusions about the characterisation ofcoagulopathy from these results (Brohi et al., 2007a).

TEG has been shown to be predictive of the need

for transfusion in hypocoagulable trauma patients(Kaufmann et al., 1997).The existence of both hypo-and hypercoagulable states post-trauma as measured

by thromboelastography have been demonstrated(Kaufmann et al., 1997; Schreiber et al., 2005).

However, the current use of these devices must betreated with caution as there are issues surrounding

accuracy, reproducibility and quality control. There

is an initial period of instability of samples ifanalysed within 30 min of collection. In addition, asignificant change towards hypercoagulability isobserved when the same sample is repeatedlyanalysed over time (Vig et al., 2001). The use ofcitrated blood compared to native blood may alsoaffect results (Zambruni et al ., 2004). Robustquality control is essential so staff need to beadequately trained, with a formal StandardOperating Procedure (SOP) in place. Unless theseissues are addressed it may be difficult to ensure thevalidity of results.

Treatment modalities

Historically, there has been a relative neglect of thetreatment of coagulopathy in trauma patients

because it was often thought to have been aby-product of resuscitation but the coagulopathicsyndrome can be detected from early initial assess-ment of trauma patients within minutes of arrivingat hospital. (Hess, 2007; Brohi et al., 2007a). As ourunderstanding of the pathogenesis has increased,attention has been focused on the need to try andcorrect coagulopathy.

Every trauma patient should be managed accord-ing to current guidelines such as the AdvancedTrauma Life Support Guidelines published by theAmerican College of Surgeons. European guidelineson the management of bleeding following majortrauma have also been recently published (Spahnet al ., 2007). These guidelines comprehensivelyreview the use of colloid versus crystalloid asresuscitation fluids and discuss the concept ofpermissive hypotension in trauma patients(excluding those with traumatic brain injuries). Itis important to remember that in addition to red celland coagulation factor support, treatment shouldalso be directed towards control of acidosis andhypothermia in order to try and attain the optimalenvironment for haemostasis.

This review will focus on correction of coagulo-pathy and control of bleeding using blood productsand pharmacological agents.

Packed red cell transfusion

The management of haemorrhagic shock necessi-tates the transfusion of red blood cells. For patients

a

Platelet (MA)

Platelet function

Clot strength (G)

Reaction

time

Amplitude(min)

Time (min)

Enzymatic

(R)

Fibrinogen

(K, a)

Thrombolysins

(Ly30, EPL)

FibrinolysisCoagulation

Clot stability

Clot breakdown

Clot

kinetics

Figure 2 Schematic of thromboelastography (TEG)

tracing parameters. Key: R reaction time, K clot

formation time, CLT clot lysis time, MAmaximum

amplitude, aangle of slope (Reproduced with kind

permission of Medicell Ltd)


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with no coagulopathy who do not require massive

transfusion, reduced exposure to blood products isdesirable; however, for those with a coagulopathy,restrictive use of blood products may be detrimental.Early red cell transfusion may be advantageous,increasing cardiac output and preserving oxygen

carrying capacity (Dutton and Carson, 2006).In addition, as discussed earlier, red cells maycontribute to the haemostatic process.

However, RBC transfusion has been shown to beassociated with the development of MOF, increasedintensive care (ICU) admissions and length of stay,increased acute respiratory distress syndrome

(ARDS), increased length of hospital stay, andincreased mortality (Moore et al., 1996; Sauaiaet al., 1996; Durham et al., 2003; Malone et al.,2003; Plurad et al., 2007). A study from a Germancentre showed that levels of cytokines that can

mediate MOF (IL-6, IL-10) are significantly ele-vated in trauma patients who have received 415units of packed RBC compared to those that havereceived 515 units (Hensler et al ., 2003). Theincreased red cell requirement and increase in

inflammatory cytokines may merely reflect greaterinjury severity.

There are no randomised controlled trials com-paring transfusion regimes in trauma and there is nointernational consensus regarding the optimal red

cell transfusion trigger. Some groups do not give aspecific transfusion trigger, but suggest that the

indications for red cell transfusion should bedifferent in different phases of resuscitation(Dutton and Carson, 2006). The British

Committee for Standards in Haematology (BCSH)guidelines on massive blood loss (due to all causes)recommend a target Haemoglobin (Hb) of48 g/dL.The European guidelines on the management ofbleeding following trauma currently recommend a

target Hb of 79 g/dL (Grade 1C). Both of theseshould clearly be used in the context of theindividual patient but give guidance on consid-ering an appropriate trigger. The Transfusion

Requirements in Critical Care (TRICC) trial didnot detect statistically significant benefits in termsof MOF and post-traumatic infections when restric-tive (trigger Hb 57 g/dL) and liberal transfusionregimens (trigger Hb 510 g/dL) were compared

(Hebert et al ., 1999; McIntyre et al ., 2004).However, this study was not designed to addressthe trauma subgroup question directly.

Platelet transfusion

There is no direct evidence to support a particularplatelet threshold in the bleeding patient.Spontaneous haemorrhage does not usually occurin medical conditions causing thrombocytopeniauntil the platelet count falls below 50 109/L.Platelet function decreases exponentially below thislevel (Norfolk et al., 1998; Stainsby et al., 2000b;Samama et al., 2005; Stainsby et al., 2006). Theconsensus from The National Institutes of Health(NIH) meeting was that bleeding is unlikely to becaused by thrombocytopenia when the platelet countwas 50 109/L or above (Consensus ConferencePlatelet Transfusion Therapy, 1987).

The BCSH guidelines recommend a plateletthreshold of475 109/L in massive transfusion(410 units packed RBC). The European Guidelinesrecommend that platelets are administered to main-tain a platelet count450 109/L (Grade 1C), or over

100 109/L in patients with multiple trauma who arebleeding severely or have traumatic brain injury(Grade 2C). Evidence to suggest thresholds of100 109/L in these patients is weak (Fresh frozenplasma, cryoprecipitate and Platelet AdministrationPractice Guidelines, 1994).

Fresh frozen plasma transfusion

Fresh frozen plasma, once thawed, contains nearnormal levels of clotting factors, both procoagulant

and anticoagulant. (Stanworth, 2007), althoughthere is some dilution effect by the addition of citrateanticoagulant solution.

As with platelets, there is little direct evidence forthe clinical efficacy of FFP in trauma patients(Stanworth et al., 2004); however, when a patient isbleeding and has abnormal coagulation then trans-fusion of fresh frozen plasma would seem clinicallyappropriate. Recently work has been performed onsamples from patients who have been given plasmafor bleeding during major surgery (Schols et al.,2008). The data showed that transfusion of

FFP increased thrombin generation and that alack of improvement of thrombin generation orfibrinogen was associated with ongoing bleeding.Interestingly, the authors used doses of FFP lowerthan would be recommended in the UK.

The use of FFP is currently recommended forpatients with massive bleeding or significant bleedingcomplicated by coagulopathy, defined as PT or


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APTT 41.5 times normal (Stainsby et al., 2000a;Spahn et al., 2007). There have been reviews offormularic transfusion of FFP in a set ratio to RBCin this patient group (Hirshberg etal., 2003; Ho etal.,2005) to try and avoid dilution of coagulationfactors. The BCSH guidelines anticipate the needfor FFP after 11.5 times blood volume replacementand recommend a dose of 1215 mg/kg. TheEuropean guidelines initial recommended dose is1015 mL/kg but further doses may be requireddepending on the degree of ongoing haemorrhage(Grade 1C). Repeat coagulation testing shouldalways be performed after administration ofplasma products to assess the response and furtherproduct replacement.

Administration of fibrinogen

The evidence for the use of fibrinogen concentratescomes from indirect sources. Hypofibrinogenaemiain bleeding patients responds to the administrationof fibrinogen (Counts et al., 1979; Gilabert et al.,1985; Shima et al., 1997) and animal models haveshown fibrinogen can improve the effects ofdilutional coagulopathy (Fries et al., 2005); how-ever, there are no randomised controlled trials in thetrauma setting.

Current UK guidelines recommend replacementof fibrinogen when the serum concentration falls tobelow 1 g/L (OShaughnessy et al., 2004a). This can

be administered in the form of cryoprecipitate orfibrinogen concentrates. Cryoprecipitate is madefrom pooled plasma. One adult therapeutic dose(two pools or 10 single donor units) provides 34 gof fibrinogen (Stainsby et al., 2006). However, inmassive haemorrhage, the response may be variableand higher doses of 1520 units (50mg/kg) havebeen suggested in European Guidelines (Spahnet al., 2007). Repeated doses may be required ifthere is ongoing bleeding and consumption ofcoagulation factors. Fibrinogen levels shouldbe monitored regularly to help assess the need for

re-treatment (OShaughnessy et al., 2004c).Fibrinogen concentrate (HaemocomplettanP CSL Behring) is also made from pooledpatient plasma. During processing, the plasmaundergoes additional viral inactivation steps inorder to try and reduce the transmission of infection.It is, as yet, unlicensed in the UK and consent for itsuse should be acquired where possible. Suggested

doses are 34 g (Spahn etal., 2007) which, again, mayneed to be repeated depending on the patientsfibrinogen concentration and ongoing bleeding.

All products derived from human blood carry arisk of transmission of infectious agents, ABOincompatibility, circulatory overload, allergic reac-tions. In the case of platelets and FFP, TRALI(transfusion-related acute lung injury) may be anadditional complication.

Recombinant factor VIIa

Recombinant factor VIIa (rVIIa) NovoSeven

Novo Nordisk is manufactured using recombinantDNA technology. Pharmacokinetic studies intrauma patients have shown a half life of 23 hwith a two compartment model (Klitgaard et al.,2006). The half-life showed high intrapatient and

interpatient variability and the main variableinfluencing half-life was transfusion requirement.Recombinant VIIa binds to tissue factor and leadsto localised thrombin generation. It can alsoactivate factors IX and X on the surface of platelets,independent of tissue factor, but the tissue factordependent mechanism is more efficient (Gabrielet al., 2004). It is not currently licensed for use intrauma patients.

The evidence for rVIIa use is limited and anecdotalbut is increasing. In a randomised control trial ofpatients suffering from blunt trauma, rVIIa reduced

RBC usage by 2.6 units (p50.05) and reducedthe need for massive transfusion from 33 to 14%(p50.03). Patients were given a first dose (300 mcg/kg) of rVIIa after eight units of transfusion anda second and third dose (100 mcg/kg) at 1 and 3 h(Boffard et al., 2005). The patients were treatedconcurrently with red cells, FFP and fibrinogenas required. In a similar study by the same group,patients with penetrating trauma received thesame dosing schedule. The results showed a trendto reduced transfusion requirements but this wasnot statistically significant. There was no

statistically significant difference in mortality orthromboembolic disease in either blunt or penetrat-ing groups who had or had not received rVIIa.Post hoc subgroup analysis from this study, exclud-ing patients with traumatic brain injury, has shownthat coagulopathic patients may derive particularbenefit from the use of rVIIa with a reduction in redcell, FFP and platelet usage; however, the study was


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not originally powered to detect such differences

(Rizoli et al., 2006).In another (non-randomised) study patients were

given rVIIa (40150 mcg/kg) for haemorrhage withclinical coagulopathy (Dutton et al., 2004). Sixty

percent of patients who received rVIIa survivedinitial resuscitation; however, 28% of these diedgiving an overall survival of 43%. When comparing

with historical controls the authors could find nooverall survival advantage in those receiving rVIIa;however, the number of adequately matched con-trols was small. Interestingly, the authors were ableto draw out a subgroup of patients who did not

appear to respond to rVIIa: lower mean pH (7.02versus 7.29), lower base excess (13.4 versus 4.7),higher lactate (11.3 versus 5.2) and lower plateletcount (median 86 versus 140) and reduced reversal

of PT following rVIIa administration. There is other

data to support the effect of acidosis, hypothermiaand thrombocytopenia on the efficacy of rVIIa

(Meng et al., 2003; Marietta et al., 2006).Administration of fibrinogen to haemodiluted

patient plasma ex vivo increases the velocity ofwhole blood clot formation as detected by TEG

following rVIIa administration (Fenger-Eriksen

et al., 2005). Therefore, every effort should bemade to reduce the effects of, or achieve thecorrection of, factors that may attenuate the functionof rVIIa such as hypothermia, severe acidosis,

hypocalcaemia, low haematocrit and hypofibrino-

genaemia. Recommended targets, where possible,prior to administration of rVIIa are: platelets450 109/L, fibrinogen 0.51.0 g/L, pH! 7.2, PCV40.24 (Vincent et al., 2006).

Recent literature has suggested that lower doses(20 mcg/kg) of rVIIa may be as effective as higherdoses with clearly significant financial implications.Statistically significant reductions in red cell, FFP

and platelet usage were reported with an overallmortality of 25%; however, this was a non-randomised study (Bauza et al., 2007).

A risk benefit assessment should be made in those

patients with coronary artery disease or a history ofsignificant thromboembolic disease. The currentEuropean guidelines recommend using rVIIa as an

adjunct to the surgical control of bleeding ifconventional therapies have failed. A dosing sche-dule of 300 mcg/kg followed by further doses of

100 mcg/kg at 1 and 3 h as required is suggested(Vincent et al., 2006).

In the future, molecular changes to rVIIa maylead to improved kinetics and superior clinicaloutcomes and several products are presently inearly clinical trials.

AntifibrinolyticsAntifibrinolytics such as tranexamic acid, aprotininand aminocaproic acid have been widely used incardiac surgery to reduce post-operative bleedingand there is evidence that they reduce blood loss(Henry et al., 2001). Tranexamic acid and amino-caproic acid are lysine analogues that block theactivation of plasminogen. Aminocaproic acid isnot available in the UK. Aprotinin is currently notbeing marketed worldwide and the UK commissionon Human Medicines has withdrawn its license.This is following reports from the Canadian BARTstudy that aprotinin gave a 2x increase in renalfailure requiring dialysis in patients undergoingCABG, a 55% increase in the risk of MI or heartfailure in patients undergoing primary CABG and a181% increase in CVA and encephalopathy com-pared to tranexamic acid or aminocaproic acid(Mangano et al., 2006). Further evaluation is beingundertaken.

In the Cochrane review of antifibrinolytics drugsfor acute traumatic injury, only two trials metinclusion criteria and there was no evidence thatthey improve outcomes in the trauma setting (Coatset al ., 2004). The CRASH-2 trial is currently

underway which aims to randomise 2000 traumapatients with or at risk of significant haemorrhageto received tranexamic acid or placebo. The endpoints of the trial will be death, vascular events andtransfusion requirements.

Other pharmacological agents

Prothrombin complex concentrate (Octaplex

Octapharma, Beriplex CSL Behring) containsfactors II, VII, IX and X. There is no evidence oftheir efficacy in trauma in humans and their use innot recommended except for specific clinical cir-cumstances, for example warfarin reversal.

Thromboprophylaxis

The risk of thromboembolic disease (TED) follow-ing trauma is high. Studies show that the risk is


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nearly 60% in patients who do not receiveprophylaxis (Geerts et al., 1994). The highest riskgroups appear to be those with spinal cord injuries,lower limb and pelvic fractures and those who areimmobile for a prolonged period of time (Velmahoset al., 2000; Azu et al., 2007). Once the patient isstable and is no longer at significant risk of bleedingthey should be considered for thromboprophylaxispreferably in the form of low molecular weightheparin. If heparin is contraindicated then mechan-ical devices should be considered where possible(Geerts et al., 2004) but they alone have not beenshown to reduce the incidence of massive or fatalpulmonary embolism.

Summary

The coagulopathy of trauma is a clinical syndromewhich is receiving increasing recognition for its rolein haemorrhage following trauma. It is a majorcontributing factor to patient morbidity and mor-tality. Prompt recognition and treatment of thesyndrome with blood products and pharmacologi-cal agents is vital in order to control bleeding,reduce further transfusion requirements and allowdefinitive surgical treatment of the patient.

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Trauma--Coagulopathy in Trauma, Optimising Haematological Status