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REVIEW ARTICLESPaul G. Barash, MD

Giovanni Landoni, MDSection Editors

Rotational Thromboelastometry (ROTEM)-Based Coagulation Management inCardiac Surgery and Major Trauma

Kenichi A. Tanaka, MD, MSc,* Daniel Bolliger, MD,† Ratna Vadlamudi, MD,‡ and Alastair Nimmo, MB§

3

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FOR MAJOR BLEEDING related to severe trauma, majorsurgery, or chronic anticoagulation, a rapid assessment of

hemostatic function is crucial so that optimal fluid replace-ments and blood transfusion can be administered without de-lays.1-6 Although the safety of blood products with regard toviral transmission risks has improved in recent years,7,8 trans-fusions of allogeneic erythrocyte and plasma products havebeen implicated in serious adverse events, including nosoco-mial infections, acute lung injury, and organ dysfunction.9-12

Obtaining conventional laboratory tests, such as the prothrom-bin time (PT), activated partial thromboplastin time (aPTT),and fibrinogen level, during acute bleeding is difficult becauseof a long turn-around time (�30 min).13,14 Furthermore, labo-atory PT/international normalized ratio and aPTT may not bearticularly useful in predicting bleeding after trauma or inva-ive procedures.15,16

The prime example of bleeding management is preemptivetransfusions of fresh-frozen plasma (FFP) and platelet concen-trates according to the erythrocyte requirement in major traumacases.17,18 This so-called “damage control resuscitation” (DCR;

able 1) originally was advocated for battlefield resuscitationn which laboratory testing and transfusion resources wereimited. However, plasma product transfusion according toCR became increasingly popular in US civilian trauma cen-

ers and operating rooms.17,19 The prevention of trauma-in-duced coagulopathy and subsequent nonsurgical bleeding is amajor advantage of DCR,20 but the DCR approach lacks aspecific target for replacement and a consideration for interin-dividual variability in coagulation factor levels and vascular(endothelial) responses. Implementing transfusion algorithmsbased on point-of-care (POC) coagulation testing can be effec-tive in decreasing transfusion requirements in elective or urgentcardiac surgical settings.2,5,21-23 In this review, the practical useof thromboelastometry is discussed relating to the diagnosis ofcoagulopathy and optimizing hemostatic interventions.

POC TESTING AND TIMING OFHEMOSTATIC INTERVENTION

PT (or international normalized ratio), aPTT, fibrinogenlevel (Clauss method and its modifications), and platelet countare the tests performed most commonly in managing perioper-ative bleeding. Except for the platelet count, these laboratorytests require a separation of plasma from whole blood before

testing, and, thus, a typical turn-around time is in the range of

ournal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 6 (Decemb

0-90 minutes.13,24 Abnormalities detected in these tests arefollowed by requests for specific blood components. The choiceof hemostatic therapies also affects the lag time before inter-vention. The time required for thawing FFP and cryoprecipitateis typically 30-60 minutes, but less time is needed for plateletconcentrates and thawed plasma. Factor concentrates, such asfibrinogen concentrate, and recombinant activated factor VII(rFVIIa) can be administered rapidly (�10 min) because theyare reconstituted in small volumes and infused irrespective ofblood type.

One of the key facts behind DCR is to prevent the delay oftransfusion therapy for patients in whom the risk of hemor-rhagic death is considerably greater than transfusion-associatedcomplications.25 However, a substantial number of patients

ay receive allogeneic plasma products inappropriately or inxcess, which collectively increase the risk for transfusion-elated adverse events.26 By implementing rapid POC coagu-ation testing, hemostatic interventions can be more individu-lized and goal directed (targeted) instead of indiscriminatepplications of DCR. Currently available POC coagulation testsre classified into 3 categories. The first category includes POChole-blood PT and aPTT for a rapid evaluation (5-10 min) oflasmatic coagulation. POC PT has been shown to have aeasonable agreement with plasma-based PT.13,27,28 However,

PT and aPTT are sensitive only to severe hypofibrinogenemia(�60-70 mg/dL) and are insensitive to FXIII deficiency or

From the *Department of Anesthesiology, University of PittsburghMedical Center, Pittsburgh, PA; †Department of Anesthesia and Inten-sive Care Medicine, University of Basel Hospital, Basel, Switzerland;‡Department of Anesthesiology, Emory University School of Medicine,Atlanta, GA; and §Royal Infirmary of Edinburgh, Edinburgh, UK.

Dr Bolliger was supported by a Myron B. Laver Grant, Departmentof Anaesthesia, University of Basel, Switzerland. Drs Tanaka, Bolliger,and Nimmo have received honoraria for consultation and/or lecturesfrom TEM International (Munich, Germany).

Address reprint requests to Kenichi A. Tanaka, MD, MSc, VisitingProfessor of Anesthesiology, Department of Anesthesiology, UPMCPresbyterian C-215, 200 Lothrop Street, Pittsburgh, PA 15213.E-mail: atlclot7@me.com

© 2012 Elsevier Inc. All rights reserved.1053-0770/2606-0022$36.00/0http://dx.doi.org/10.1053/j.jvca.2012.06.015Key words: rotational thromboelastometry, coagulation monitoring,

blood component transfusion, cardiac surgery, trauma

1083er), 2012: pp 1083-1093

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1084 TANAKA ET AL

fibrinolysis.29 Further, PT and aPTT have different sensitivitieso hemodilution-induced decreases in procoagulant factor lev-ls,15,16 and neither test reflects the total amount of thrombinhat can be generated in plasma.24 The second category includes

whole-blood platelet function tests, which are used increasinglyto monitor therapeutic responses to aspirin, clopidogrel, andother platelet adenosine-5=-diphosphate antagonists.30,31 Evalu-ting the extent of platelet inhibition by antiplatelet agents maye useful in optimizing the perioperative risks of thrombosisnd hemorrhage.32,33 Although a detailed discussion of plateletunction monitoring is beyond the scope of this review,lateletMapping will be discussed later as a modified techniquef thrombelastography (TEG; Haemonetics-Haemoscope,iles, IL).34 The third category includes TEG and rotational

thromboelastometry (ROTEM; TEM Systems, Raleigh, NC).These 2 systems are suitable for timely decision making (�20min) in hemostatic interventions.2,4-6 Indeed, the decrease ofpostoperative blood loss without increasing the blood compo-

Table 1. Damage Control Resuscitation

Early surgical control of bleeding sitesEarly transfusion of plasma, platelets, and erythrocytes; minimized

crystalloid usagePermissive hypotension (mean arterial pressure �60 mmHg)Correction of hypothermia and acidosisTimely use of CaCl2, THAM, and rFVIIa

Abbreviations: rFVIIa, recombinant factor VIIa; THAM, tris-hydroxy-ethyl aminomethane (alkalizer).

Pin

Blood

Light detector

Diode

Dataprocessor

Clo

t fir

mne

ss (m

m)

20

60

100

10

Alpha

CFT

CT

Fig 1. Basic principles of rotational thromboelastometry. For a r

placed with CaCl2 and a coagulation activator in the stationary cup. T

hanges the torque between the pin and the cup. The measured rot

econds), clot formation time (CFT; seconds), �-angle (degrees), amp

MCF; millimeters), and maximum lysis (ML; percent decrease in amplitud

ent usage or mortality has been shown in a recent meta-nalysis, including TEG and ROTEM.35 Rapid detection of

coagulopathy by TEG or ROTEM allows a timely preparation(thawing) of blood products or a prompt intervention usingplasma-derived or recombinant factor concentrate.4-6,36,37

COAGULATION TESTING ON ROTEM

The basic principles and technical aspects of TEG andROTEM have been reviewed elsewhere.14,38-40 In this article,the practical applications of ROTEM are described because thissystem currently offers comprehensive tests of coagulation. Forstandard ROTEM measurements, a citrated whole-blood sam-ple (300 �L) is placed in a plastic cup using an automatedipette (Fig 1). The sample is recalcified with CaCl2, 0.2

mmol/L (StarTEM; 20 �L) and activated with 20 �L of anEXTEM (tissue factor [TF]) or INTEM (ellagic acid) reagent.Subsequently, the plastic pin is immersed in the blood. Oncethrombin is generated in the blood, platelets are activated toexpress glycoprotein (GP) IIb/IIIa receptors, and fibrin isformed and polymerized. The interactions of GP IIb/IIIa recep-tors and polymerized fibrin increase the torque (viscoelasticity)between the cup and the rotating pin (at a 4.75° angle). Thebreakdown of fibrin strands by fibrinolysis decreases thetorque. The change in torque is detected optically and is pro-cessed by the microprocessor to trace the clot formation andbreakdown.

The commonly used ROTEM variables include coagulationtime (CT; seconds), clot formation time (seconds), �-angle(degrees), amplitude at 10 minutes after CT (A10; millimeters),

20 30 40 50 60

MCF ML

CT Clotting timeCFT Clot formation timeAlpha Alpha angleA10 Amplitude 10 min after CTMCF Maximum clot firmnessML Maximum lysis

Time (min)

nal thromboelastometric measurement, a citrated blood sample is

tating pin is lowered into the blood, and subsequent clot formation

al thromboelastometric variables include the coagulation time (CT;

e at 10 minutes after CT (A10; millimeters), maximum clot firmness

A10

otatio

he ro

ation

litud

e 60 min after MCF). (Color version of figure is available online.)

kav

a

b

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1085ROTEM IN COAGULATION MANAGEMENT

maximum clot firmness (MCF; millimeters), and maximumlysis (ML; percent decrease in amplitude 60 min after MCF;Fig 1). CT represents the onset of coagulation, whereas the clotformation time and �-angle represent the initial rate of fibrinpolymerization. MCF is a measurement of the maximal vis-coelastic strength of the clot. An ML �15% is used for thediagnosis of a premature breakdown of clot (hyperfibrinolysis).Normal ranges are summarized in Table 2.41 The referenceranges of TEG differ from those of ROTEM because of differ-ent sample types (citrated v noncitrated) and coagulation acti-vators (kaolin v INTEM or EXTEM).39

In addition to EXTEM and INTEM, several other tests canbe used in conjunction to diagnose specific coagulation prob-lems. FIBTEM is a modified EXTEM test (Fig 2A) withcytochalasin D, which inhibits platelet cytoskeletal reorganiza-tion and, thus, fibrin(ogen) binding to platelet GP IIb/IIIa.42 Bycombining EXTEM and FIBTEM, the differential diagnosis ofthrombocytopenia and/or hypofibrinogenemia is feasible within20 minutes (Fig 2B, C). APTEM is also a modified EXTEM, inwhich aprotinin inhibits plasmin in vitro if systemic fibrinolysiswas present (Fig 2D).37

HEPTEM contains heparinase in addition to the INTEMreagent. It is used as a pair with INTEM for the diagnosis ofsystemic heparin activity (Fig 2E).43 Although INTEM andaolin-activated TEG are intrinsic pathway tests, the sensitivitynd specificity are considerably different. Therefore, the cutoffalues for ROTEM cannot be applied simply to TEG.39

HEMOSTATIC MECHANISMS IN VIVO

In the event of a vascular injury (Fig 3A), a localizedhemostatic response is triggered by subendothelial collagen andTF, which are exposed to the circulating blood. Circulatingplatelets play a particularly important role in arterial hemosta-sis. The initial tethering of platelets to collagen is mediated byplatelet GP Ib/IX and the von Willebrand factor. A transientbinding of platelets to the von Willebrand factor becomesstabilized by collagen-induced platelet activation (via �2�1nd GP VI receptors).44 In parallel, a trace amount of thrombin

is generated by TF-FVIIa/FXa (extrinsic pathway). Thus, aden-osine-5=-diphosphate and thromboxane are released by colla-gen- and thrombin-activated platelets, forming the primaryhemostatic plug (Fig 3B). Subsequently, platelet aggregatesserve as catalytic surfaces and binding sites for coagulationresponses. Substrates (fibrinogen), proenzymatic factors (FII,

Table 2. Indications and Reference Rang

Tests Indicated to Evaluate

EXTEM, APTEM 2platelets, 2plasma factors, 1fibrinolysisFIBTEM 2fibrinogenINTEM, HEPTEM 2platelets, 2plasma factors, 1heparin

NOTE. Normal ranges (medians) are shown for EXTEM, FIBTEM, anreference range is used for HEPTEM. Data from Lang et al.41

Abbreviations: A10, amplitude at 10 minutes after coagulation timEXTEM, tissue factor reagent; FIBTEM, modified EXTEM test with cyreagent; INTEM, ellagic acid reagent; MCF, maximum clot firmness; Mprothrombin complex concentrate; TXA, tranexamic acid.

FIX, FX, FXI, FXIII), and accelerators (FV, FVIII) are con-

gregated (depicted as S-E-A in Fig 3C) on the activated plateletsurface to augment the local generation of thrombin and po-lymerized fibrin. After the initial activation of thrombin by theextrinsic pathway, the propagation of thrombin formationmainly involves the “intrinsic pathway.” Thrombin can activateFXI, which efficiently converts FIX to FIXa. On the activatedplatelet surface, FIXa in combination with thrombin-activatedFVIIIa becomes the major activator (intrinsic tenase) of FX.Subsequently, FXa and thrombin-activated FVa form a com-plex (prothrombinase), which exponentially increases the con-version of prothrombin (FII) to thrombin. Once activated byadenosine-5=-diphosphate-stimulated, each platelet expresses alarge number of GP IIb/IIIa receptors (�12,000) for fibrinogenbinding.45 Platelet-bound fibrinogen is converted to a fibrinmonomer by thrombin. Fibrin monomers are polymerized byplasma and platelet-derived FXIIIa, a transglutaminase, whichrequires thrombin-mediated activation.46 Polymerization of fi-rin on platelets stabilizes the primary hemostatic plug.47 On

ROTEM and TEG, major hemostatic responses involvingthrombin-activated platelets (GP IIb/IIIa), fibrin, and FXIIIaare reflected, although the contributions of the von Willebrandfactor, platelet GP Ib/IX, and other platelet agonists are mini-mal.

HEMOSTATIC INTERVENTIONS

It is well known that blood transfusion practice varies amongindividuals and institutions.48 In case of bleeding, FFP, plateletconcentrates, and cryoprecipitate often are transfused empiri-cally without laboratory testing. In addition to these allogeneicproducts, plasma-derived or recombinant factor concentrates,such as fibrinogen concentrates, prothrombin complex concen-trates, and rFVIIa, have been used for perioperative hemosta-sis.6,49 Recent clinical data have shown that ROTEM testing is

practical method to standardize the local transfusion prac-ice.5,50,51 Normal ranges of ROTEM testing are based on a

ulticenter study in healthy adult volunteers (Table 2).41

Hemostatic intervention(s) should be considered for nonsur-gical bleeding in the presence of abnormal ROTEM results.Threshold ROTEM values for interventions may vary amongdifferent types of vascular injury. In this section, several he-mostatic products are discussed in relation to ROTEM param-eters, but the availability of products differs among institutionsand countries. Therefore, it is prudent to validate or modify the

Rotational Thromboelastometric Tests

CT (s) CFT (s) A10 (mm) MCF (mm) ML (%)

2-74 (55) 46-148 (95) 43-65 (53) 49-71 (60) 0-18 (4)— — 9-24 (14) 9-25 (16) —

-246 (184) 40-100 (63) 44-68 (55) 52-72 (61) 0-12 (3)

EM. The EXTEM reference range is used for APTEM and the INTEM

PTEM, modified EXTEM test with aprotinin; CT, coagulation time;lasin D; FFP, fresh-frozen plasma; HEPTEM, heparinase plus INTEMximum lysis (percent decrease in amplitude 60 min after MCF); PCC,

es of

4

137

d INT

e; AtochaL, ma

herein-described algorithm for suitability at each institution.

1086 TANAKA ET AL

EA.

CT

B.

C.

MCF 9 mm

MCF 13 mm

MCF 38 mm

MCF 58 mm

MCF 4 mm

FIBTEM

10 30 min 10 30 min

10 30 min

10 30 min10 30 min

D.

10 30 min

10 30 min

ML 100%

CT 1500 s

E.

CT 205 s

ML 0%

EXTEM

FIBTEM EXTEM MCF 40 mm

min30 10

MCF 38 mmFIBTEM EXTEM

APTEM

HEPTEM INTEM

EXTEM Fig 2. Examples of rotational throm-

boelastometric tracings. (A) Normal

(EXTEM, FIBTEM): EXTEM-MCF (normal,

49-71 mm) and FIBTEM (normal, 9-25

mm). (B) Thrombocytopenia (EXTEM,

FIBTEM): platelet count 74 � 109/L and

fibrinogen 170 mg/dL. (C) Thrombocyto-

penia and hypofibrinogenemia (EXTEM,

FIBTEM): platelet count 57 � 109/L and

fibrinogen 78 mg/dL. (D) Systemic fibri-

nolysis (EXTEM, APTEM): normal ML is

<15%. (E) Heparin effect (INTEM,

HEPTEM): prolonged CT (1,500 s) at

INTEM (normal range, 137-246 s) is cor-

rected at HEPTEM (ie, CTINTEM/CTHEPTEM �

1.0 in the absence of heparin). APTEM,

modified EXTEM test with aprotinin; CT,

coagulation time; EXTEM, tissue factor

reagent; FIBTEM, modified EXTEM test

with cytochalasin D; HEPTEM, heparinase

plus INTEM reagent; INTEM, ellagic acid

reagent; MCF, maximum clot firmness;

ML, maximum lysis (percent decrease in

10 30 min 10 30 minamplitude 60 min after MCF). (Color ver-

sion of figure is available online.)

m

Dtmn

1087ROTEM IN COAGULATION MANAGEMENT

Platelets

The clot firmness of EXTEM shows the tensile strength ofthe whole-blood clot, which reflects the interaction betweenthrombin-activated platelets and polymerized fibrin via plateletGP IIb/IIIa receptors. For microvascular bleeding, EXTEM-and FIBTEM-A10 values can be used differentially to diagnosethe need for platelet transfusion or fibrinogen replacement.Thrombocytopenia (�50-100 � 109/L) is suspected when theEXTEM-MCF is �45 mm and the FIBTEM-MCF is �8-10mm (Table 3).5,52 When the FIBTEM-MCF is �10 mm, cryo-precipitate or fibrinogen is withheld unless bleeding is likelyto continue and lower fibrinogen levels. Platelet transfusionand fibrinogen replacement usually are indicated when theEXTEM-MCF is �35 mm.5,53 When the EXTEM-MCF is �45

m, severe thrombocytopenia (�50 � 109/L) is unlikely, buthereditary platelet dysfunction or antiplatelet effects of aspirinand P2Y12 antagonists (ticlopidine, clopidogrel, prasugrel, etc)may not be excluded. Platelet function tests can be used pre-operatively to screen high-risk patients. PFA-100 (Siemens,Tarrytown, NY) can be useful in screening patients with vonWillebrand disease or a platelet GP Ib defect (Bernard-Soulier

Vascular injuryBleeding

Event Primary hemostasisLocalization of factors

Thrombin generationFibrin polymerization

Elements CollagenTissue factor

Platelets ADP, ThromboxanevWF, FibrinogenFVII, FX, FII

Interventions FFP, PCCCryoprecipitateFibrinogenFXIII concentraterFVIIa

PlateletsCryoprecipitatevWF concentrateDesmopressin

(a) Vascular injury (b) Primary hemostasis (c) Coagulation

S-E-A S-E-A

Platelets (S) Fibrinogen(E) FII, FIX, FX, FXI, FXIII(A) FV, FVIII

Erythrocytes

Fig 3. Hemostatic processes and phase-specific interventions. (A)

Hemorrhage occurs after vascular injury. Extravascular (subendothe-

lial) collagen and tissue factor are exposed to the flowing blood.

Transfusion of erythrocytes is the initial intervention. The intact

vascular wall (blue), platelets (white ovals), erythrocytes (red circles),

and fibrin (green) are depicted. (B) Platelets adhere to the vascular

injury site by interacting with von Willebrand factor (vWF) by glyco-

protein Ib/IX receptors. Mural platelets are activated by collagen and

trace thrombin (by the extrinsic pathway involving factors VII [FVII],

X [FX], and II [FII]). They release adenosine-5=-diphosphate (ADP) and

thromboxane, stabilizing platelet-platelet interactions with fibrino-

gen. Thus, the primary (hemostatic) plug is established. Platelet

transfusion and measures to increase von Willebrand factor can

augment this process. (C) Activated platelet aggregates serve as a

catalytic surface and binding sites for coagulation responses. Sub-

strates (S; fibrinogen), proenzymatic factors (E; factors II, IX [FIX], X,

XI [FXI], and XIII [FXIII]), and accelerators (A; factors V [FV] and VIII

[FVIII]) are congregated. These factors can be replaced using fresh-

frozen plasma (FFP) or specific factor concentrates (see text for

details). PCC, prothrombin complex concentrate; rFVIIa, recombinant

factor VIIa.

syndrome).54 The VerifyNow system (Accumetrics, Inc., San s

iego, CA) and whole-blood impedance aggregometry (Mul-iplate, DynaBite, Munich, Germany) are used increasingly toonitor therapeutic responses to aspirin and P2Y12 antago-

ists.32,55 For TEG, PlateletMapping is available for the eval-uation of platelet inhibition by aspirin or clopidogrel.34,56-58 Forthis assay, a heparin-anticoagulated blood sample is used spe-cifically to inhibit thrombin, which masks the antiplatelet ef-fects of aspirin and clopidogrel. For PlateletMapping, fibrinpolymerization is achieved by the mixture of reptilase andactivated FXIII. Platelets are activated separately by the spe-cific platelet activator (arachidonic acid for aspirin and adeno-sine-5=-diphosphate for clopidogrel). Decreased maximum am-plitudes on PlateletMapping compared with kaolin-activatedTEG have been observed in perioperative patients with grossplatelet inhibition by aspirin or clopidogrel.59

Plasma and Prothrombin Complex Concentrate

The CT of EXTEM or INTEM can be used in determiningthe need for administering FFP or prothrombin complex con-centration (PCC). The latter refers to plasma-derived concen-trates of vitamin K-dependent factors (FVII, FIX, FX, pro-thrombin, protein C, and protein S).60 Coagulation factorreplacements are considered when CT values are prolonged(EXTEM-CT �100 s or INTEM-CT �240 s) and when resid-ual heparin effects, thrombocytopenia, and hypofibrinogenemiahave been addressed appropriately (Table 3). In patients whohave received intravenous heparin, a proper neutralization ofheparin can be confirmed by equal CT values between INTEMand HEPTEM (Fig 2E).43 Plasma or PCC can be used to correcta factor deficiency for a prolonged CT on HEPTEM.5

Similar to PT and aPTT, EXTEM-CT and INTEM-CT aredefined as the onset of blood coagulation after activation withTF and ellagic acid, respectively. However, ROTEM-CT val-ues are not equivalent to PT and aPTT. In trauma-inducedcoagulopathy, the correlation between the CT value and PT/aPTT was found to be rather poor (r � 0.47-0.53).61 Thereaction time (equivalent of CT) of kaolin-activated TEG hasbeen reported to correlate poorly with PT or aPTT.62,63 Abnor-mal PT/aPTT values (�1.5 times normal) are found frequentlywhen ROTEM parameters related to fibrin polymerization(EXTEM-A15 or clot formation time) are abnormal.61 Severehypofibrinogenemia (�60-70 mg/dL) can be the cause of pro-longed CT and PT/aPTT.

Fibrinogen-Rich Components

Cryoprecipitate is used commonly in North America forfibrinogen replacement. In many European countries, this prod-uct is no longer available, and plasma-derived fibrinogen con-centrate is used as a substitute.5,6,64 The minimal level offibrinogen previously was thought to be 80-100 mg/dL.65,66

However, higher fibrinogen levels (150-200 mg/dL) have beenrecommended in recent guidelines.67-69 It is plausible that aminimal fibrinogen level of 80-100 mg/dL is adequate forcongenital afibrinogenemia (ie, normal factor levels other thanfibrinogen), but higher fibrinogen levels (150-200 mg/dL) arenecessary for a multifactorial deficiency associated with peri-operative coagulopathy.70 There are several published data that

upport the efficacy of fibrinogen-rich components. In pediatric

2rummtm

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gcft

1088 TANAKA ET AL

cardiac surgical patients (body weight �8 kg), Miller et al71

reported that 24-hour chest tube drainage was greater afterplatelet and FFP transfusions compared with platelet and cryo-precipitate (39.8 v 20.2 mL/kg). These patients received FFP orcryoprecipitate when the platelet transfusion was not effectiveto correct microvascular bleeding. The post-treatment fibrino-gen level was 158 � 27 mg/dL in the platelet-FFP group versus37 � 67 mg/dL in the platelet-cryoprecipitate group. Moreecently, Rahe-Meyer et al72 reported that perioperative bloodsage (erythrocytes, FFP, and platelets) was decreased byaintaining a higher plasma fibrinogen level (mean, 360 � 60g/dL) using a purified fibrinogen concentrate compared with

he conventional management (mean fibrinogen, 210 � 30g/dL) for replacement of the ascending aorta.The FIBTEM test has been used commonly in ROTEM for

he clinical assessment of fibrin polymerization in whole blood.IBTEM-MCF is well correlated with plasma fibrinogen levelsr � 0.85-0.87).24,61 In trauma-induced coagulopathy, a FIB-EM-A10 of �5 mm was reported to be a good predictor of

ow plasma fibrinogen (�100 mg/dL), with a sensitivity of 91%nd a specificity of 85%.61 In patients after cardiopulmonaryypass (CPB), a FIBTEM-MCF of 10 mm was a good estimatef plasma fibrinogen at 200 mg/dL.24,61 For microvascularleeding, fluid resuscitation and blood loss continuously lower

Table 3. Hemostatic Interventions Based

EXTEM-M

Clot Firmness �35 mm

FIBTEM-MCF*�10 mm Cryo/fibrinogen �

Platelet 1 UCryo/

Pla�10 mm Platelets 1-2 U Platel

Diagnosis

Prolonged CT ValuesINTEM-CT/HEPTEM-CT ratio �1.0 Residual heparin ProtaEXTEM-CT �100 s orINTEM-CT �240 s Low coagulation factors FFP 1FIBTEM-A10 �5 mm Very low fibrinogen

(�100 mg/dL)Cryo/

Fibrinolysis Patterns†Fibrinolysis �20 min Fulminant fibrinolysis TXA 1Fibrinolysis 20-40 min Early fibrinolysis TXA 1Fibrinolysis �40 min Clot retraction or late

fibrinolysisUsua

Abbreviations: A10, amplitude at 10 minutes after coagulation timcoagulation time; EACA, �-aminocaproic acid; EXTEM, tissue factor replasma; HEPTEM, heparinase plus INTEM reagent; INTEM, ellagicconcentrate; TXA, tranexamic acid.

*FIBTEM-A10 at 8 mm may be used as a cutoff instead of FIBTEM-Mfibrinogen concentrate, 2 g, is administered. If FIBTEM-A10 is �5 mm

†EXTEM and APTEM are repeated after each therapeutic intervent‡Antifibrinolytic agents are used only if the risk of bleeding is great

coagulation.

lasma fibrinogen. Therefore, it is reasonable to maintain a

IBTEM-MCF at 10 mm using a cryoprecipitate or fibrinogenoncentrate (Table 3).

FIBTEM testing can be performed in heparinized sampleseg, during CPB), and, therefore, hypofibrinogenemia can beetected early so that the cryoprecipitate can be thawed orbrinogen concentrates can be prepared.5,50,51

Recombinant Activated Factor VIIa

The use of rFVIIa is indicated in hemophiliac patients whohave developed neutralizing antibodies against FVIII or FIX.73

Its use also is common in severe perioperative bleeding aftercardiac surgery and major trauma.74 The efficacy of rFVIIa toenerate thrombin depends on the available TF.75 High TFoncentrations in PT and EXTEM make these tests insensitiveor delineating the in vivo efficacy of rFVIIa in surgical pa-ients76 and in hemophiliac patients.77 Alternatively, diluted TF

(eg, innovin, 1:17,000) has been tried, with mixed results, inmonitoring the therapeutic response to rFVIIa in hemophilia.78-80

Kaolin-activated TEG has been used to evaluate the TF-indepen-dent hemostatic activity of rFVIIa in hemophilia.81,82 In nonhe-mophiliac surgical patients, rFVIIa continues to be used as asecond-line intervention after the failure of platelet and plasmatransfusions.76,83 In this regard, TEG and ROTEM can be used to

otational Thromboelastometric Results

rameters

EXTEM-MCF

35-45 mm �45 mm

ogen �

1 UCryo/fibrinogen

If bleeding is uncontrolled, consider FFP orPCC based on EXTEM-CT as below orconsider platelet transfusion in patientson P2Y12 inhibitors

Management

25-50 mg

L/kg or PCC 20 IU/kgogen as above

or EACA 5-10 g‡EACA 5 gtreatment is required

EM, modified EXTEM test with aprotinin; Cryo, cryoprecipitate; CT,; FIBTEM, modified EXTEM test with cytochalasin D; FFP, fresh-frozeneagent; MCF, maximum clot firmness; PCC, prothrombin complex

t 10 mm. For fibrinogen replacement, Cryo, 10 U, or plasma-deriveddose of Cryo or fibrinogen concentrate is doubled.

n the risk of thrombosis or worsening of disseminated intravascular

on R

CF Pa

fibrinteletet 1 U

mine

0-15 mfibrin

-2 gg or

lly no

e; APTagentacid r

CF a, the

ion.er tha

diagnose major causes of bleeding, such as thrombocytopenia,

s

tvccpf�ptn

oihC

ma

mmg8pfml

n

n

c

1089ROTEM IN COAGULATION MANAGEMENT

hypofibrinogenemia, and fibrinolysis, which preclude the opti-mal hemostatic effect of rFVIIa.76,84-86

Antifibrinolytic Therapy

Systemic fibrinolysis can be caused by an increased endo-thelial release of tissue plasminogen activator87 or by a de-creased protease inhibition of tissue plasminogen activator andplasmin.85 In ROTEM, hyperfibrinolysis is suspected when thedecrease of the amplitude over 1 hour is �15% of MCF (Table3, Fig 2D). The APTEM test is a modified EXTEM test withadded aprotinin (plasmin inhibitor) at ROTEM. The resolutionof fibrinolysis on APTEM compared with EXTEM confirmsongoing systemic fibrinolysis.14 In 15%-20% of patients withmajor trauma, overt hyperfibrinolysis is observed at ROTEMand TEG.36,37,88 Even in the absence of systemic fibrinolysis, afibrin clot tends to be more susceptible to a plasmin-mediatedbreakdown after hemodilution owing to a progressive loss ofendogenous fibrinolysis inhibitors.85 Using ROTEM, it may befeasible to use antifibrinolytic therapy selectively in patients atrisk for systemic fibrinolysis,89 which can be associated withevere injuries and increased mortality.37,88

ROTEM-BASED TRANSFUSION ALGORITHMS INCARDIAC SURGERY

Cardiovascular surgical patients are at increased risk forvascular thrombosis associated with atheromatous vascular dis-ease, atrial fibrillation, implanted coronary stents, and mechan-ical heart valves.90 Antiplatelet and antithrombotic therapiesoften are prescribed for preoperative patients. Balancing therisk of thrombosis against hemorrhage is one of the mostdifficult tasks for perioperative physicians.90,91 Intraoperatively,hese patients are anticoagulated with heparin for CPB orascular anastomosis. Hemorrhage and hemodilution decreaseirculating levels of coagulation factors and inhibitors.85 At theonclusion of surgery, heparin anticoagulation requires arompt reversal using protamine to establish hemostasis (clotormation). Antifibrinolytic therapy with tranexamic acid or-aminocaproic acid commonly is used during CPB as a pro-hylactic measure to decrease bleeding.92,93 However, theransfusion of allogeneic plasma and platelet products often isecessary to achieve hemostasis in complex CPB cases.83,93

Transfusion algorithms using TEG or ROTEM have beenshown previously to decrease postoperative blood loss andtransfusion requirements in cardiac surgery.2,22,23 An examplef ROTEM-based coagulation management in cardiac surgerys presented (Fig 4). EXTEM and FIBTEM are insensitive toeparin (�6 U/mL), and they can be tested toward the end ofPB (eg, rewarming).50,51 Based on EXTEM/FIBTEM results

(Table 3), hemostatic therapy after CPB can be planned inadvance, which may decrease the long interval from protamineadministration to hemostatic intervention(s). After the correc-tion of surgical bleeding and metabolic parameters (eg, pHstatus, body temperature), a ROTEM-based protocol allowspatient-specific hemostatic therapy targeted to replace deficientcoagulation element(s) rather than indiscriminately transfusingplatelets and plasma products.94

The initial approach to hemostasis generally involves the

restoration of plasma fibrinogen to the range of 150-200

g/dL (FIBTEM-MCF 8-10 mm; Table 3) with continuousntifibrinolytic therapy.5,6 Platelet transfusion is used in

patients with thrombocytopenia (EXTEM-MCF �45 mmand FIBTEM �8-10 mm) and those with platelet dysfunc-tion from antiplatelet therapy. Preoperative platelet functiontests may be helpful to diagnose and manage bleeding re-lated to platelet dysfunction.30,32 In patients who continuepreoperative vitamin K antagonist therapy and in those whounderwent extensive hemodilution or cell salvage, plasma orPCC may be necessary to restore procoagulant zymogens.EXTEM-CT values �100 seconds may indicate a procoagu-lant factor deficiency, particularly FVII, FIX, FX, and pro-thrombin (Table 3). INTEM-CT values �240 seconds alsomay be used to diagnose procoagulant factor deficiency, butexcess heparin or protamine can prolong INTEM-CT.43 As

uch as 20-30 mL/kg of plasma may be required to correctoderate-to-severe factor deficiency,95 whereas PCC can be

iven in smaller volumes (80 mL per 25-IU/kg dose for an0-kg person) to supplement key hemostatic factors.96,97 Inatients who required acute vitamin K antagonist reversalor cardiac surgery, PCC was shown to be hemostaticallyore effective by increasing plasma FX and prothrombin

evels compared with FFP.91,98

Additional clinical studies are necessary to establish thesafety and efficacy of plasma-derived and recombinant factorconcentrates in combination with conventional plasma andplatelet transfusions. The transfusion protocol based onROTEM and TEG should be useful in the evaluation of coagu-lopathy and in the patient-specific allocation of transfusion

Rewarming on CPB

Protamineadministration

EXTEM/FIBTEM

EXTEM/FIBTEM INTEM/HEPTEM

Order PLT, FFP or cryoprecipiate, if indicated (Table 3)

Hemostatic therapy oradditional protamine

Confirm coagulopathy and heparin neutralization

EXTEM/FIBTEMEvaluate therapeutic response, if indicated, INTEM/HEPTEM/APTEMor PLT function tests

Fig 4. Rotational thromboelastometry-based coagulation man-

agement in cardiac surgery. Early detection of coagulopathy and

preparations for hemostatic therapies are feasible using EXTEM and

FIBTEM in the late phase of cardiopulmonary bypass (CPB; at re-

warming). Clinical bleeding consistent with coagulopathy can be

confirmed after repeating EXTEM and FIBTEM and optimizing hepa-

rin neutralization (CTINTEM/CTHEPTEM � 1.0). If antifibrinolytic therapy is

ot used routinely, APTEM can be useful to exclude systemic fibri-

olysis as a cause of bleeding. Platelet (PLT) function tests should be

onsidered in patients who recently used aspirin and P2Y12 antago-

nists. APTEM, modified EXTEM test with aprotinin; CT, coagulation

time; EXTEM, tissue factor reagent; FFP, fresh-frozen plasma; FIB-

TEM, modified EXTEM test with cytochalasin D; HEPTEM, heparinase

plus INTEM reagent; INTEM, ellagic acid reagent.

products in cardiac surgical patients.2,22,23,48,50,51

rslaovbdhtaRaa

t(i

ppbcprpcswntlac

h(rfi

ag

b

1090 TANAKA ET AL

ROTEM-BASED TRANSFUSION ALGORITHMS INMAJOR TRAUMA

Most patients with major traumatic injuries are admitted withvarious degrees of cardiorespiratory and metabolic distur-bances. With an ongoing need for �4 U of erythrocyte con-centrates or a blood loss of �150 mL/min, DCR should betriggered to coordinate timely and sufficient provision of bloodproducts (Fig 5). Although damage-control surgery is pivotal tothe survival of patients with multiple injuries,99 massive fluidesuscitation often is required to counter systemic hypoperfu-ion and worsening acidosis.20,25 The rapid infusion of crystal-oid, albumin, or hydroxyethyl starch can lead to hypothermiand extensive hemodilution of erythrocytes, fibrinogen, andther coagulation factors and inhibitors.100 It is crucial to pre-ent the lethal triad of coagulopathy, hypothermia, and acidosisy early resuscitative and hemostatic therapies. In view ofynamic changes in the coagulation system and the paucity ofematologic information (eg, chronic antithrombotic therapy),he use of ROTEM is most practical for the comprehensivessessment of hemostatic function in trauma patients. InitialOTEM testing using EXTEM, FIBTEM, and APTEM allowsrapid evaluation of thrombocytopenia, hypofibrinogenemia,

nd the profibrinolytic state (Fig 2).The initial approach based on ROTEM involves the restora-

ion of plasma fibrinogen to the range of 150-200 mg/dLFIBTEM-MCF 8-10 mm) using plasma (when a large volume

Initiation of DCR

EXTEM/FIBTEM APTEM

Order PLT, FFP or cryoprecipiate, if indicated (Table 3)

Surgical intervention, if necessary

Evaluate therapeutic response, if indicated, add antifibrinolytic therapy

Continue monitoring until bleeding stopsif indicated, add INTEM or PLT function test

DCR with ROTEM-modifiedhemostatic therapy

EXTEM/FIBTEM APTEM

EXTEM/FIBTEM APTEM

Fig 5. Rotational thromboelastometry-based coagulation man-

agement in major trauma. At the initiation of a massive transfusion

protocol in major trauma patients, the use of EXTEM/FIBTEM/

APTEM allows a rapid evaluation of thrombocytopenia, hypofibrino-

genemia, and the profibrinolytic state. Specific component replace-

ment and antifibrinolytic therapy can be included in the damage

control resuscitation (DCR). Rotational thromboelastometric

(ROTEM) assessment can be repeated during and after surgical in-

tervention, if indicated. For persistent microvascular bleeding, plate-

let (PLT) function testing should be considered to evaluate the defect

in the primary hemostasis (eg, aspirin and P2Y12 antagonists). AP-

TEM, modified EXTEM test with aprotinin; EXTEM, tissue factor

reagent; FFP, fresh-frozen plasma; FIBTEM, modified EXTEM test

with cytochalasin D; INTEM, ellagic acid reagent.

s permitted), cryoprecipitate, or fibrinogen concentrates (Table

REN

oelastography-guided transfusion algorithm reduces trans-

f1

a2

3).4 Platelet transfusion is used in patients with thrombocyto-enia (EXTEM-MCF �45 mm) and those with suspectedlatelet dysfunction. Once residual heparin effects and hypofi-rinogenemia are excluded, EXTEM-CT values �100 secondsan be addressed with coagulation factor replacements usinglasma or PCC (Table 3). EXTEM-CT seems to be moreesponsive to hemodilution-induced factor deficiency com-ared with INTEM-CT or kaolin TEG R-time because in-reased FVIII in stress shortens contact-activated tests.16 Inevere injury, low EXTEM-MCF values (�35 mm consistentith thrombocytopenia and hypofibrinogenemia) are accompa-ied by a profibrinolytic state (ML �15%).36,37,88 The resolu-ion of clot breakdown on APTEM confirms systemic fibrino-ysis (Fig 2), and intravenous administration of tranexamiccid, 1-2 g, should be considered unless ongoing intravascularoagulation is suspected clinically (Table 3).89 A coexisting

hypocoagulable and profibrinolytic state in major trauma seemsto indicate the severity of illness, which demonstrates a corre-lation with mortality.37,57,88,101

Hemostatic interventions used in DCR are different amongtrauma centers based on the institutional blood usage policyand the availability of specific components and concen-trates.67,69,102,103 It is acceptable to initiate DCR early usingallogeneic plasma and platelet products if the risk of hemor-rhagic death is considered high.25 Once surgical controls ofemorrhage are attained, more individualized, goal-directedtargeted) transfusion is preferred because of the cumulativeisks of transfusion, including acute lung injury, multiple organailure, immunomodulation, thromboembolic complications,nfection, and death.10,12,26,104,105

CONCLUSIONS

Timely hemostatic interventions are pivotal in controlling co-agulopathy and bleeding after major surgery and trauma. How-ever, the risks of hemorrhage and transfusion-related complica-tions are to be weighed constantly against each other.12,25,26,104

ROTEM has become increasingly popular in perioperative coag-ulation management that involves the replacement of multiplecoagulation factors. Unlike hereditary hemorrhagic disorders,which usually involve a single factor replacement, perioperativehemorrhage in major surgery and trauma often demands sequen-tial treatments using multiple allogeneic components or factorconcentrates.4-6,83,100 Using the goal-oriented transfusion algo-rithm, clinicians appropriately may select necessary transfusioncomponent(s) instead of empirically administering all compo-nents, with potential hazardous effects.94 Recent clinical data havesupported the use of ROTEM or TEG in evaluating the clinicalefficacies of various hemostatic therapies, which had been seldomstudied.64,71,72 Further clinical investigations of hemostatic thera-pies under the guidance of ROTEM and TEG are warranted toestablish the safety, efficacy, and economic impact of various

hemostatic components.

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