thromboelastography and thromboelastometry in assessment of fibrinogen … · 2018. 5. 28. ·...

Review ArticleThromboelastography and Thromboelastometry inAssessment of Fibrinogen Deficiency and Prediction forTransfusion Requirement: A Descriptive Review

Henry T. Peng ,1,2 Bartolomeu Nascimento,3 and Andrew Beckett4

1Defence Research and Development Canada, Toronto Research Centre, Toronto, Ontario, Canada2Research Institute of Xi’an Jiaotong University, Hangzhou, Zhejiang, China3Sunnybrook Health Sciences Centre, Department of Surgery, University of Toronto, Toronto, Canada4Royal Canadian Medical Services, Ottawa, Ontario, and McGill University, Montreal, Quebec, Canada

Correspondence should be addressed to Henry T. Peng; [email protected]

Received 28 May 2018; Revised 28 September 2018; Accepted 6 November 2018; Published 25 November 2018

Academic Editor: Francois Berthiaume

Copyright © 2018 Henry T. Peng et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG)and RotationalThromboelastometry (ROTEM) have been increasingly used to diagnose fibrinogen deficiency and guide fibrinogentransfusion in trauma and surgical bleeding patients. We conducted a comprehensive and comparative review on the technologiesand clinical applications of two typical functional fibrinogen assays using TEG (FF TEG) and ROTEM (FIBTEM) for assessment offibrinogen level and deficiency, and prediction of transfusion requirement. Clot strength and firmness of FF TEG and ROTEMFIBTEM were the most used parameters, and their associations with fibrinogen levels as measured by Clauss method rangedfrom 0 to 0.9 for FF TEG and 0.27 to 0.94 for FIBTEM. A comparison of the interchangeability and clinical performance of thefunctional fibrinogen assays using the two systems showed that the results were correlated, but are not interchangeable betweenthe two systems. It appears that ROTEM FIBTEM showed better associations with the Clauss method and more clinical use formonitoring fibrinogen deficiency and predicting transfusion requirements including fibrinogen replacement than FF TEG. TEGand ROTEM functional fibrinogen tests play important roles in the diagnosis of fibrinogen-related coagulopathy and guidance oftransfusion requirements. Despite the fact that high-quality evidence is still needed, the two systems are likely to remain popularfor the hemostatic management of bleeding patients.

1. Introduction

Fibrinogen is perhaps the most important protein inhemostasis, as the final stage of the coagulation cascade isconverted to fibrin by thrombin and cross-linked by factorXIII. It also induces platelet activation and aggregation viabinding to glycoprotein IIb/IIIa receptors on the surface ofplatelets, acting as the bridge for stable clot formation [1].During major bleeding, fibrinogen is the first clotting factorto reach critically low levels below the normal physiologicallevel of around 2 to 4 g/L, which is associated with increasedbleeding, coagulopathy, and in turn worsened clinical out-comes [2–5]. Fibrinogen is an independent predictor ofmortality in major trauma patients [6].

Thromboelastography (TEG; Haemonetics Corporation,Haemoscope Division, Nile, Illinois, USA) and RotationalThromboelastometry (ROTEM; Tem Innovations GmbH,Munich, Germany; succeeded by Instrumentation Labora-tory, Bedford, MA, USA) are two point-of-care systems forhemostatic tests in whole blood [7]. Both have been increas-ingly used to diagnose fibrinogen deficiency [8], predict riskof bleeding and mortality, and guide fibrinogen transfusionin trauma [9], cardiac surgery [10], liver transplantation[11], and postpartum bleeding [12]. TEG- and ROTEM-based algorithms have been widely used to direct fibrinogenadministration in different settings leading to reductionin transfusion needs, costs, adverse outcomes, and evenmortality [13–16] although a recent review indicated that the

HindawiBioMed Research InternationalVolume 2018, Article ID 7020539, 24 pageshttps://doi.org/10.1155/2018/7020539

http://orcid.org/0000-0001-5276-9573

https://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1155/2018/7020539

2 BioMed Research International

benefit of reduced blood products (red blood cells, freshfrozen plasma, and platelet) and improved morbidity inbleeding patients with the application of TEG- or ROTEM-guided transfusion strategies were primarily based on tri-als of elective cardiac surgery involving cardiopulmonarybypass, with low-quality evidence [17]. Similarly, a systematicreview and meta-analysis of the use of TEG and ROTEM ingoal-directing treatment with allogeneic blood products inbleeding patients found that the amount of transfused redblood cells, fresh frozen plasma, and bleeding volume wasreduced in the TEG- or ROTEM-guided groups compared tothe control groups either treated at the clinician’s discretionor based on conventional coagulation tests (CCTs), whereasthere were no differences in platelet transfusion andmortality[18]. Furthermore, a randomized clinical trial has concludedthat TEG-guided massive transfusion protocol for severetrauma improved survival compared with that guided byCCTs (i.e., prothrombin time [PT]/international normalizedratio [INR], fibrinogen, and D-dimer) and utilized lessplasma and platelet transfusion during the early phase ofresuscitation [19].

Nevertheless, another recent review on routine use ofviscoelastic blood tests for diagnosis and treatment of coag-ulopathic bleeding concluded that TEG and ROTEM testsonly reduced red blood cells and platelet transfusion in adultsundergoing cardiac surgery [20]. Meta-analyses across allindications (trauma, cardiac surgery, and liver transplan-tation) have shown that TEG and ROTEM tests are cost-saving and more effective than standard laboratory tests intrauma patients and patients undergoing cardiac surgery [21].Moreover, studies, including ours, have shown that TEG andROTEM provide different results for diagnosing coagulopa-thy and guiding transfusion [22–24]. Further evaluation ofTEG- or ROTEM-guided transfusion in prospective case-matched studies and different patient categories with low riskof bias is needed. Alternatively, TEG and ROTM have alsobeen used to study the effects of fibrinogen supplementationon hemostasis in an in vitromodel of dilutional coagulopathy[25], the correction of dilutional coagulopathy by fibrinogenconcentrate in orthopedic patients [26], and hypothermiccoagulopathy [27] as well as in patient blood [28].

Although the role of TEG and ROTEM in diagnosisof coagulopathy, prediction of transfusion and mortality inbleeding patients has been reviewed [12, 29]. This paperis focused on the studies on TEG and ROTEM functionalfibrinogen tests: FF TEG and ROTEM FIBTEM for the diag-nosis of fibrinogen deficiency and prediction of transfusionrequirements in bleeding patients. A follow-up paper will befocused on the use of FF TEG and ROTEM FIBTEM to guidefibrinogen replacement and monitor its hemostatic effects.

The paper is structured into four major sections. Thefirst session describes the principles of the two systems andvarious commercially available tests with an emphasis onfunctional fibrinogen tests. The second session reviews theuse of TEG and ROTEM for measurement of functional fib-rinogen levels in relation to fibrinogen concentration assays.The third session discusses the diagnosis of fibrinogen relatedcoagulopathy and prediction of transfusion requirements indifferent clinical settings. Finally, the review compares the

two systems in terms of reagents, parameter values, andclinical uses.

2. Principles of TEG and ROTEM FunctionalFibrinogen Tests

TEG 5000 (Haemonetics Corporation, Haemoscope Divi-sion, Niles, IL, USA) and ROTEM delta (InstrumentationLaboratory, Bedford, MA, USA) are the most used vis-coelastic hemostasis analyzers. Both systems measure theviscoelastic properties of blood as it clots under low shearstress based on pin-and-cup technology, but there are pri-mary hardware differences between the two [68]. The TEGanalyzer has a pin suspended by a torsion wire, wherein acup oscillates through 4.75 degree/5 seconds. In contrast, theROTEM analyzer has an immobile cup, wherein a pin/wiretransduction systemoscillates through 4.75 degree/6 seconds.It has been suggested that the ROTEM system uses a ball-bearing system for power transduction, which makes itless susceptible to movement and vibration [69] and thatthe automatic pipetting may ensure less variations amongoperations [70].

In addition to the differences in instrument, the twoviscoelastic point-of-care systems used different reagents forvarious tests and applications [68]. Specifically, the functionalfibrinogen reagent for TEG is composed of lyophilized tissuefactor and a platelet inhibitor (abciximab) that binds toglycoprotein IIb/IIIa receptors to inhibit platelet aggregationand exclude the platelet contribution to clot strength [71].However, it could contain kaolin or celite instead of tissuefactor [32, 43]. ROTEM fibrinogen assay uses two solutionscalled ex-tem andfib-tem [71].The ex-tem solution contains acombination of recombinant tissue factor and phospholipidsthat activates the extrinsic pathway of the coagulation system,while the fib-tem solution contains CaCl2 as a recalcificationreagent and a platelet inhibitor (cytochalasin D) that inhibitsactin/myosin-system. A new reagent called fib-tem pluscontains 2 platelet inhibitors, cytochalasin D, which inhibitsplatelet cytoskeletal reorganization, and tirofiban, which isa glycoprotein IIb/IIIa inhibitor similar to abciximab thatprevents fibrinogen from binding to glycoprotein IIb/IIIareceptors on the surface of platelets and platelet aggregation[48]. Furthermore, single portion reagents composed of alllyophilized reagents required for each ROTEM test have beendeveloped [72].

Although multiple parameters can bemeasured for bloodcoagulation and fibrinolysis, maximum amplitude MA inTEG and maximum clot strength MCF in ROTEM havebeen mostly used as a direct measure of fibrinogen functions.According to each manufacturer, the normal range of MAas measured by FF TEG using citrated blood is 11-24 mm(Guide to functional fibrinogen) and the normal range ofMCF as measured by ROTEM FIBTEM assay is 7-24 mm(Instructions for use of fib-tem). In addition, the clot firmnessat 5, 10, and 15 min after CT (A5, A10, and A15) has beenreported.

It should be noted that new and fully automated (nopipetting) TEG and ROTEM systems (TEG 6s and ROTEMsigma) are now commercially available. Both work with

BioMed Research International 3

4-channel cartridges based on different mechanisms. TEG6s uses a new technology called coagulation resonanceanalysis and works with two types of cartridges. One is aglobal hemostasis cartridge to perform four tests (kaolinTEG, kaolin TEG with heparinase, RapidTEG, and FF TEG)simultaneously and the other is a Platelet Mapping cartridgeto perform theTEGPlateMapping test (kaolinTEG, activatorF (ActF), adenosine diphosphate (ADP), and arachidonicacid (AA) [73, 74]. ROTEM sigma operates on the provenpin and cup technology as ROTEM delta, but uses two typesof cartridges containing lyophilized beads reagents insteadof liquid reagents for four tests per cartridge (cartridge 1:FIBTEM, EXTEM, INTEM, APTEM; cartridge 2: FIBTEM,EXTEM, INTEM, HEPTEM) [75].

3. Methods

A PubMed search was completed for the TEG and ROTEMstudies involving functional fibrinogen tests. The searchtermswere as follows: thrombelastogra∗ or thromboelastogra∗or TEG and fibrinogen, thromboelastomentr∗ orthrombelastromentr∗ or ROTEM and fibrinogen. Thespecific clinical use/interest of TEG and ROTEM (e.g.,trauma, cardiac surgery, transfusion, hypofibrinogenemia,hypo, and hyperfibrinolysis) was also used as keywords inthe search. Abstracts were used to determine the relevanceand when appropriate, further review of the original articleswas warranted. Additional publications were selected fromthe cross-references listed in the original papers and fromthe citing articles, and additional search was made throughMedline, Scopus, and Institute of Scientific Informationdatabases for those topicswith limited findings fromPubMed.The search was primarily focused on human studies.

We analyzed the correlations between functional fibrino-gen assays, i.e., Clauss method and FF TEG or ROTEMFIBTEM tests, and the accuracies (sensitivity, specificity, andarea under receiver operating characteristic (ROC) curve) ofFF TEG and ROTEM FIBTEM for the detection of hypofib-rinogenemia and prediction of bleeding and transfusion.Furthermore, data were extracted and pooled from differenttrials where FF TEG MA, ROTEM FIBTEM MCF versusplasma fibrinogen concentration data were reported. Linearregression with 95% confidence interval was then performedusing SigmaPlot Version 13.0 (Systat Software, Inc., San Jose,California, USA). We also calculated likelihood ratios of FFTEG and ROTEM FIBTEM for the diagnosis of hypofibrino-genemia defined as plasma fibrinogen level < 1.5 g/L usingthe following formula: sensitivity/(1-specificity) [76]. Meta-analysis of the clinical benefit of functional fibrinogen assaysusing TEG and ROTEM within their different uses could notbe conducted due to the small sample size and heterogeneityof studies.

4. Measurement of FibrinogenLevels and Functions

TEG has been used to study in vitro effects of fibrinogenon coagulation of plasma deficient in coagulation factors

and diluted by colloids [77, 78], and the effect of a car-diopulmonary bypass system with biocompatible coating onfibrinogen levels [38]. ROTEM has been used to determinethe usefulness of fibrinogen substitution to reverse dilutionalcoagulopathy in in vitro and in vivomodels [79–81]. All thesestudies showed that, to various extents, fibrinogen improvedclot strength (MA or MCF), clot formation (R or CT), andclot propagation (Alpha) as measured by TEG or ROTEM.

Clinical studies showed variable correlations betweenmaximum clot strength/firmness and fibrinogen levels assummarized in Table 1. The correlation coefficients rangefrom 0 (no significant correlation) [37] to 0.9 (strong cor-relation) [42] for FF TEG and 0.27 [3] to 0.94 [47] forROTEM FIBTEM. The correlations between A5, A10, or A15and fibrinogen levels have also been reported [34, 44, 45, 51,53, 57, 59]. These early values of clot firmness can providefast and reliable prediction of MCF to guide haemostatictherapy in severe bleeding [82]. Other ROTEM tests (e.g.,EXTEM) showed certain degrees of correlations with plasmafibrinogen concentrations as well [50, 55]. Both FF TEGand ROTEM FITBEM have been used in clinical settings oftrauma [30, 32–34, 46], cardiac surgery [36, 37, 39, 49, 52],liver transplantation [42, 54], and pregnancy [43, 59]with dif-ferent popularities. In addition, ROTEM FIBTEM has beenused for assessment of fibrinogen function in neurosurgery[60], burn injury [61], and cirrhosis [62].The variations in thecorrelations could be due to the differences in study popula-tion and range of fibrinogen concentrations as most TEG andROTEM tests were performed using TEG 5000 and ROTEMdelta with the same reagent and procedures as recommendedby their manufacturers. For example, one study reportedno significant correlations between either TEG functionalfibrinogen level (FLEV) or maximal amplitude (MA) andClauss fibrinogen level at baseline or 10min postprotamine incardiac surgery patients [37]. The different correlations werealso reported for children at different ages [40, 41].

Figure 1(a) shows the correlation between plasma fibrino-gen concentration measured by the Clauss method and FFTEG MA based on the data extracted from several studies.Overall correlation from pooled literature data was strong.Similarly, Figure 1(b) shows an overall strong correlationbetween the Clauss fibrinogen and FIBTEM MCF frompooled data extracted from the literature.

The Clauss assay is considered a standard functional testfor fibrinogen concentration by determination of the timein seconds to clot formation following addition of excessthrombin [83]. Other methods such as prothrombin time-derived method [56] and enzyme-linked immunosorbentassay (ELISA) [83] are also used. ELISAdoes not discriminatebetween functional and non-functional immunoreactive fib-rinogen protein, and even some degraded forms of fibrinogen[84].

The Clauss method is limited to only small concen-trations of heparin (which inactivates thrombin throughanti-thrombin III), which is a serious limitation in cardiacsurgery. It may be affected by fibrin degradation products,polymerization inhibitors as other inhibitors of fibrin for-mation [85]. Its turnaround time is approximately 40 min[86]. In comparison, TEG and ROTEM function fibrinogen


Table1:Summaryof

correlations

betweenfunctio

nalfi

brinogen

(FF)

TEG/ROTE

MFIBT

EMandfib

rinogen

levels.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

FFTE

G

Trauma

Arand

omized

controlledtrialoftraum

apatientsa

tris

kof

significanth

emorrhage(

n=45,ISS=18-29)

receivingeither

6gfib

rinogen

concentrate

(RiaSTAP�

)orp

lacebo

(normalsalin

e).C

itrated

who

lebloo

dwas

collected

from

ther

ando

mized

traumapatientsa

tadm

ission,

1-,3-,11-,

23-and

47-h

post-

infusio

ntim

e.

Standard

FFTE

Gwas

perfo

rmed

onac

ompu

teriz

edTE

GHem

ostasis

Syste

m5000

(Haemon

etics

Corpo

ratio

n,Haemoscope

Division

,Niles,IL,U

SA)

accordingto

manufacturer’s

protocol.Specifically,

500

𝜇Lof

theb

lood

samplew

aspipette

dinto

aFFvialwhich

contains

lyop

hilized

tissuefactorw

ithplateletinhibitor

(abcixim

ab)a

ndgentlymixed

byinversionfivetim

es,

andthen

340𝜇Lof

them

ixture

from

theFF

vialwas

addedinto

aTEG

cuppre-warmed

to37∘Ccontaining

20𝜇Lof

0.2M

calcium

chlorid

e.Plasmafib

rinogen

levelswe

remeasuredby

thes

tand

ardvonClauss

metho

d.

FFTE

GMAstr

onglycorrelated

with

Claussfib

rinogen

concentrationdeterm

ined

bySpearm

an’scorrelation(𝜌=0

.75,

p<0.00

1).FFTE

GK,A

lpha

show

edmod

eratec

orrelatio

nswith

fibrin

ogen

concentration(𝜌=-0.46

and0.40

,p<0.00

1),

whileTE

GFF

CL30

onlyshow

edwe

ekcorrelations

with

fibrin

ogen

concentration(𝜌=0

.21,p=

0.00

4).

[30,31]

Aprospectiveo

bservatio

nalstudy

oftraumapatients

(n=68),with

amedianISSof

23.5.C

itrated

who

le-blood

samples

were

obtained

from

the

patientso

narriv

alto

thee

mergencydepartmentand

with

inthefi

rst5

days

ofadmissionto

thes

urgical

intensivec

areu

nit.

TheF

Fandkaolin

TEGassays

were

perfo

rmed

onthe

TEG5000

device

inthetraum

aresearch

labo

ratory.Th

eFF

TEGassaymeasuresthe

FFlevel(FL

EV),which

isextrapolated

from

theM

Afib

rinogen

value.Plasma

fibrin

ogen

levelswe

remeasuredby

thesta

ndardvon

Claussmetho

d.

Sign

ificant

correlations

betweenTE

GFL

EVandClauss

fibrin

ogen

levels(R2=0.87,p<0.00

01)and

betweenTE

GFF

MAandClaussfib

rinogen

levels(R2=0.75,p<0.00

01).

Mod

erateinverse

correlationbetweenFL

EVandK(R2=0.35,

p<0.00

01),betweenFL

EVandalph

a(R2

=0.70,p<0.00

01).

[32]

Aprospectiveo

bservatio

nalstudy

of251critically

injuredtraumapatientsw

itham

edianISSof

9(1-19)

atas

ingleLevel1

traumac

enter.Citrated

who

lebloo

dwas

collected

from

thep

atientso

narriv

aland

at2,3,4,6,12,24,48,72,96,and

120haft

eradmission.

Forthe

kaolin

TEG,340𝜇Lkaolin-activated

bloo

dwas

transfe

rred

totheT

EGcup,pre-warmed

to37∘Cand

containing

20𝜇Lof

0.2M

CaC

l 2.For

theFF

TEG,500

𝜇Lof

citrated

bloo

dwas

addedto

theF

Fvial(kaolin

+glycop

rotein

IIb/IIIaantagonist)

andmixed;340𝜇Lwas

then

transfe

rred

totheTE

Gcup.Plasmafib

rinogen

concentrationwas

assayedby

thev

onClaussmetho

d.

FLEV

calculated

byanalyticalsoftw

arethrou

gha

transfo

rmationof

theF

FMAto

approxim

atethe

concentrationof

functio

nalfi

brinogen

correlates

with

stand

ardClaussfib

rinogen

(R2=0.57,p<0.00

1),sim

ilartoMA

(R2=0

.44-0.64

,p<0.00

1)bette

rthanthek

aolin

TEGmeasures

offib

rinogen

functio

n(kinetictim

eand

angle)

(R2=0

.01,

p=0.095;andR2

=0.03,p=

0.00

4)

[33]

Aprospectiveo

bservatio

nalstudy

of182trauma

patientsw

itham

edianISSof

17(9-26).C

itrated

bloo

dwas

sampled

immediatelyup

onarriv

al.

TheF

FTE

Gwith

tissuefactora

ctivator

andap

latelet

inhibitor(Re

oPro,a

GPIIb/IIIa

inhibitor)was

perfo

rmed

byaTE

G5000

Hem

ostasis

AnalyzerS

ystem

usingTE

GAnalyticalSoftw

areversion4.2.3

(Haemon

eticsC

orp.,B

raintre

e,MA),accordingto

the

manufacturer’s

recommendatio

ns.

FFTE

GMA,A

5,A10

hadmod

eratec

orrelatio

nwith

fibrin

ogen

concentrationdeterm

ined

bySpearm

an’s

correlation(𝜌=0

.64,0.68,0.68,p<

0.01).

[34,35]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

Cardiac

surgery

Aprospectiveo

bservatio

nalstudy

of117

patients

operated

forischemicheartd

isease.Bloo

dwas

collected

before

cardiopu

lmon

arybypass

FFTE

Gtestwas

cond

uctedusingfunctio

nalfi

brinogen

reagent(lyop

hilized

tissuefactorw

ithplateletinhibitor-

glycop

rotein-IIb/IIIa

receptor

blocker).A

nalytical

softw

arec

alculatedthefun

ctionalfi

brinogen

level

(FLE

V)throu

ghthetransform

ationof

theM

Avalue.

Fibrinogen

levelswe

reassessed

bythev

onClauss

metho

d.

Amod

eratec

orrelatio

nwas

foun

dbetweenfib

rinogen

level

andFF

TEGFL

EVwith

aSpearman

correlationcoeffi

ciento

f0.476(p<0.00

01).

[36]

Aprospectives

tudy

of160cardiacs

urgery

patients.

Bloo

dwas

collected

atbaselin

e,priorto

heparin

isatio

nand10

min

postprotam

ine

administratio

n

TEG-fu

nctio

nalfi

brinogen

testwas

cond

uctedwith

nativ

eblood

usingthefun

ctionalfi

brinogen

reagent

(lyop

hilized

tissuefactorw

ithplateletinhibitor-

glycop

rotein

IIb/IIIareceptor

blocker).A

nalytical

softw

arec

alculatesthe

functio

nalfi

brinogen

level

(FLE

V)throu

ghthetransform

ationof

theM

Avalue.

Fibrinogen

levelswe

reassessed

with

citrated

bloo

dby

thevonClaussmetho

dusingFibrinogen-C

XL(H

emosiL;Instrum

entatio

nLabo

ratory,B

edford,M

A,

USA

)perform

edon

theA

CLTO

P300CT

Sanalyser

(Instr

umentatio

nLabo

ratory,B

edford,M

A,U

SA).

Nosig

nificantcorrelatio

nbetweentheT

EGFL

EVandthe

Claussfib

rinogen

levelatthe

baselin

e(R2

=0.10

6)and10

min

postprotam

ine(

R2=0

.025)and

betweentheT

EGFF

MAand

theC

laussfi

brinogen

concentrationattheb

aseline(R2

=0.061)

and10

min

postprotam

ine(R2=0

.26)

[37]

Aprospectives

tudy

of60

electiv

epatientso

perated

forischemicheartd

iseasew

ithCP

Bandrand

omly

assig

nedto

agroup

with

aheparin-coatedCP

Bsyste

mor

agroup

with

acon

ventional(no

n-coated)

circuit.Bloo

dwas

collected

from

right

after

indu

ctionof

generalanesth

esia,2-h

postop

eration,

andsecond

posto

perativ

eday.

FFTE

Gtestwas

cond

uctedby

mod

ified

TEGwith

plateletinhibitio

n(H

aemoscope

Corpo

ratio

n,Niles,IL,

USA

).Plasmafib

rinogen

levelswe

redeterm

ined

bya

Claussmetho

dno

tspecified.

Spearm

an’scorrelationanalysisshow

edam

oderatelyp

ositive

correlationbetweenperio

perativ

eClaussfi

brinogen

leveland

FFTE

GMA(n=6

0,r=0.40

8,p=

0.002)

[38]

Aprospectiven

on-rando

mized

study

of51

cardiac

surgerypatients.Citrated

(3.2%)b

lood

collection

tubesw

ereused

fora

llsamples

3tim

epoints:(1)

baselin

e;(2)rew

armingon

cardiopu

lmon

arybypass;

(3)p

ostb

ypass.

FLEV

assays

were

determ

ined

byTE

G5000

hemostasis

analyzersinaccordance

with

company’sprotocol

utilizing

thep

rovidedfunctio

nalfi

brinogen

reagentvials

(heparinasecups

were

used

fora

llbypasssamples).

Plasmafib

rinogen

levelswe

remeasuredusingthe

Claussmetho

d(Trin

iCLO

TFibrinogen

Kitwith

Destin

yMax

Coagulatio

nAnalyzer;Tcoag,Bray,Ireland

).

Asim

plelinearregressionmod

elshow

edas

trong

correlation

betweenthes

tand

ardlabo

ratory

assay(C

lauss)andthe

functio

nalfi

brinogen

level(FL

EV)assay

(r=0.76;p<0.00

01)

ofthefi

brinogen

values

attheb

aseline.Similarc

orrelatio

nwas

seen

atther

ewarmingandpo

stbypass.FLE

Vvalues

were

consistently

higher

than

thes

tand

ardlabo

ratory

assay.

[39]

Aprospectiveo

bservatio

nalstudy

of105child

renless

than

5yearso

fage

undergoing

congenitalh

eart

surgerywith

CPB.

Citrated

bloo

dwa

scollected

before

andaft

erbypass.

FFTE

Gwas

perfo

rmed

ontheT

EG5000

hemostasis

analyzersw

ithfunctio

nalfi

brinogen

reagentv

ialand

heparin

aseT

EGcup(H

aemon

etics,Niles,IL)b

yas

ingle

technician,w

ithin

20min

ofcollectionof

thes

amples.

Fibrinogen

levelswe

redeterm

ined

bytheC

lauss

metho

don

platelet-poo

r,centrifuged

bloo

dsamples

(STA

Fibrinogen,D

iagn

osticaStago).

Linear

correlationcoeffi

cientsbetweenFF

TEGMAand

fibrin

ogen

levelswe

re0.36

(p<0.00

1)before

and0.52

after

bypass(p=0

.02).

[40]

Aretro

spectiv

eand

observationalstudy

of119

child

renyoun

gerthan10

yearso

ldun

dergoing

congenitalcardiac

surgerywith

CPB.

Bloo

dwas

collected

twiced

uringsurgery,aft

eranesthesia

indu

ctionandCP

B.

ROTE

MFIBT

EMwas

perfo

rmed

accordingto

manufacturer’s

procedure.Fibrinogen

concentration

was

measuredby

afullyautomated

device

(Diagn

ostica

Stago,Asnieres,France).

Post-

CPBfib

rinogen

levelswe

reno

tcorrelatedwith

post-

CPB

FIBT

EMMCF

ininfants(r=0.155,p=

0.197,0.155),w

hereas

they

were

correlated

with

FIBT

EMMCF

inchild

renolderthan

12mon

ths(r=0.311,p=

0.031).

[41]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

Livertransplantatio

n(LT)

Aprospectives

tudy

of27

consecutiveadultL

Tpatients.Bloo

dsamplew

astakenfrom

anarteria

llin

eatthe

timeo

fthe

skin

incisio

n(th

ebaseline)and

30min

after

graft

reperfusion

Thew

holebloo

dwas

analyzed

with

TEG5000

hemostasis

analyzer

accordingto

them

anufacturer’s

instr

uctio

ns.P

lasm

afibrinogen

levelw

eremeasured

with

amod

ified

Claussmetho

dusingac

oagulatio

nanalyzer

(STA

-REv

olutionEx

pertserie

shem

ostasis

syste

m,D

iagn

osticaStago,Parsippany,N

J,USA

)

FFTE

GMAcorrelated

stron

glywith

thep

lasm

afibrinogen

levelatthe

baselin

e(Spearm

an’scorrelationcoeffi

cient𝜌

=0.90,

p<0.01);ho

wever,thec

orrelatio

nredu

cedaft

ertheg

raft

reperfusion(𝜌=0

.58,p<

0.01).Th

esam

ecorrelations

were

seen

betweenFF

TEGFL

EVandthep

lasm

afibrinogen

level.

[42]

Pregnancy

Aprospectives

tudy

of21

healthy,term

parturients

schedu

ledfore

lectivecesarean

delivery.Freshwho

lebloo

dwas

draw

nfrom

each

patient.

Mod

ified

TEGwas

perfo

rmed

with

360mLof

1%celite-activ

ated

who

lebloo

dandwith

5mLof

(2mg/mL)

ReoP

ro�(plateletaggregatio

ninhibitor)addedto

355

mLof

1%celite-activ

ated

who

lebloo

dwith

in4min

ofbloo

dcollection.

Thep

lasm

afibrinogen

concentration

was

measuredby

theC

laussq

uantitativ

efib

rinogen

assayusingthrombinderiv

edfrom

bovine

plasma

(Ortho

Diagn

ostic

Syste

mInc.,

Raritan,N

J).

Linear

regressio

nanalysisrevealed

TEGMAas

asignificant

predictoro

fthe

plasmafi

brinogen

level,with

anadjuste

dR2

of0.49,and

aslope

offib

rinogen

level=

9.56×

MA+150.68

[43]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

ROTE

MFIBT

EM

Trauma

Rand

omized


apatientsa

tris

kof

significanth

emorrhage(

n=45,ISS=18-29)

receivingeither

6gfib

rinogen

concentrate

(RiaSTAP�

)orp

lacebo

(normalsalin

e).C

itrated

who

lebloo

dwas

collected

from

ther

ando

mized

traumapatientsa

tadm

ission,

1-,3-,11-,

23-and

47-h

post-

infusio

ntim

e.

Standard

ROTE

MFIBT

EMwas

perfo

rmed

ona

ROTE

Mdelta

syste

maccordingto

manufacturer’s

protocol.Specifically,

analyses

were

perfo

rmed

using300

𝜇Lof

citrated

who

lebloo

dand20𝜇Lof

ex-te

mtogether

with

20𝜇Lof

fib-te

mfollo

wingthep

rocedu

reas

recommendedby

thec

ompany.P

lasm

afibrinogen

levels

were

measuredby

thesta

ndardvonClaussmetho

d.

ROTE

MFIBT

EMMCF

stron

glycorrelated

with

Clauss

fibrin

ogen

concentrationdeterm

ined

bySpearm

an’s

correlation(𝜌=0

.87,p<

0.00

1).R

OTE

MFIBT

EMCF

T,Alpha

show

edmod

eratec

orrelatio

nswith

fibrin

ogen

concentration

(𝜌=-0.41

and0.54,p<0.00

1),w

hileCT

andLI30

weekly

correlated

with

fibrin

ogen

concentration(𝜌=-0.29,p<0.00

1and0.20,p=0

.003).

[30,31]

Aprospectives

tudy

of517adulttraum

apatientsw

ithas

ystolic

bloo

dpressure

(SBP

)of<

90mmHganda

medianISSof

14(8–27).C

itrated

bloo

dwas

collected

with

in20

min

ofarriv

alin

thee

mergency

department(ED

).

Bloo

dsamples

were

analyzed

with

in2hof

bloo

ddraw

,with

aRO

TEM

delta

instr

ument,at37∘C.

Twoseparate

ROTE

Massays

were

perfo

rmed

fore

achpatient,the

EXTE

M,m

easurin

gtissuefactor-initiated

clottin

g,and

theFIBT

EM,w

iththea

ddition

ofcytochalasin

D,a

plateletinhibitora

sper

manufacturer’s

protocols.

Fibrinogen

levelswe

redeterm

ined

with

theC

lauss

metho

dusingSTAFibrinogen

(Stago,A

snieressur

Seine,France)a

ndSiem

ensTh

rombin(Sysmex

UK,

Milton

Keynes,U

K)reagents.

EXTE

MandFIBT

EMmeasureso

fA5andmaxim

alclot

form

ation(M

CF)w

eres

ignificantly

correlated

with

Clauss

fibrin

ogen

levels,

andthec

orrelatio

nsbetweenFIBT

EMA5

andMCF

were

slightly

stron

gerthanEX

TEM

(r2=0.44

vs.

0.35

and0.27

vs.0.26).E

XTEM

andFIBT

EMA5gave

areceiver

operatingcharacteris

ticcurvea

reaof

0.8(95%

confi

denceinterval0.7–0

.9,p<

0.00

1)ford

iscrim

inating

patientsw

ithadmissionfib

rinogen

levelsbelow1.5

g/L.

[3]

Aretro

spectiv

estudy

of358traumapatientsw

itha

medianISSof

26(17–34).Citrated

bloo

dwas

collected

atadmissionanddu

ringthefi

rst12-hcare.

EXTE

MandFIBT

EMwe

reperfo

rmed

inasta

ndardized

fashionwith

in30

min

ofbloo

dcollection.

Fibrinogen

concentrationwas

measuredby

theC

lausstechn

ique,

STA-

Fibrinogen.

Correlatio

nsbetweenfib

rinogen

concentrationandFIBT

EMA5atadmission(Spearman

coeffi

cient𝜌

=0.858)and

durin

gcare

(𝜌=0

.824),no

bloo

dprod

uctg

roup

(𝜌=0

.772)and

bloo

dprod

uctg

roup

(𝜌=0

.823).

[44]

Aprospectiveo

bservatio

nalcoh

ortstudy

of182

traumapatientsw

itham

edianISSof

17(9

to26).

Bloo

dwas

sampled

immediatelyup

onarriv

alat

hospitaland

kept

atroom

temperature.

EXTE

M,INTE

MandFIBT

EMassays

were

perfo

rmed

with

citrated

bloo

daccordingto

them

anufacturer’s

recommendatio

ns1h

after

sampling.

Fibrinogen

concentrationhadmod

eratec

orrelatio

nswith

A5,

A10

andMCF

ofEX

TEM

(𝜌=0

.65-0.68),IN

TEM

(𝜌=0

.62-0.68)and

FIBT

EM(𝜌=0

.68).

[34]

Aprospectiveo

bservatio

nalstudy

of88

trauma

patientsw

ithan

ISSof22

(12-34).Bloo

dsamples

were

collected

immediatelyaft

erthep

atient’sarriv

alto

the

traumaroom

andat6,12

and24

haft

eradmission

EXTE

M,INTE

MandFIBT

EMwe

reperfo

rmed

at37∘C

inparallelw

iththec

itrated

bloo

dwith

in2handaft

er15

min

ofcollectionin

asta

ndardizedway.Fibrin

ogen

levelswe

reassayedaccordingto

Clausstechniqu

eusin

gFibriquick�reagent(Biom

erieux).

Asig

nificantcorrelatio

nwas

foun

dbetweenfib

rinogen

levels

andEX

TEM

CT(r=0.40

,p<0.00

1),A

15(r=0

.69,p<

0.00

1),

betweenfib

rinogen

levelsandIN

TEM

A15

(r=0

.66,p<

0.00

1),

andbetweenfib

rinogen

levelsandFIBT

EMA10

(r=0

.85,

p<0.00

1)

[45]

Aprospectivec

ohortstudy

of334blun

ttraum

apatients(ISS≥

15or

Glasgow

Com

aScore≤

14).

Citrated

bloo

dwas

collected

atho

spitaladm

ission.

ROTE

MEX

TEM

andFIBT

EMtests

were

perfo

rmed

accordingto

manufacturer’s

guides.P

lasm

afib

rinogen

concentrationwas

measuredusingtestkitsfrom

Siem

ensH

ealth

care

AG,E

rlangen,G

ermany.

EXTE

MandFIBT

EMMCF

show

edstr

ongcorrelations

with

fibrin

ogen

concentration(𝜌=0

.79and0.81,respectively,

p<0.00

1).

[46]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

Cardiac

surgery

Aprospective,ob

servationalpilo

tstudy

of35

patientsu

ndergoingelectiv

ecardiacs

urgery

oncardiopu

lmon

arybypassforc

yano

ticcongenital

heartd

isease.Bloo

dsamples

were

collected

after

indu

ctionof

anesthesia.

EXTE

M,INTE

MandFIBT

EMwe

reperfo

rmed

with

citrated

bloo

daft

errecalcificationwith

20𝜇LCaC

l 2.

Fibrinogen

concentrationassaywas

notp

rovided.

Fibrinogen

concentrationshow

edas

ignificantcorrelatio

nwith

ROTE

MFIBT

EMMCF

(Pearson

coeffi

cientr=0

.94,p<

0.00

1),but

notw

ithEX

TEM

MCF

(r=0

.077,p=0

.67)

and

INTE

MMCF

(r=0

.162,p=

0.37).

[47]

Aprospectiveo

bservatio

nalstudy

of30

patients

undergoing

cardiacs

urgery

with

cardiopu

lmon

ary

bypass(C

PB).Citrated

bloo

dwas

draw

natthe

beginn

ingof

surgery(pre-C

PB),20

minutes

before

weaningfrom

CPBand5minutes

after

heparin

neutralization.

TEGwith

thefun

ctionalfi

brinogen

reagent(FF

TEG),

ROTE

Mwith

fib-te

m(FIBTE

M)and

fib-te

mplus

containing

twoplateletinhibitors:cytochalasin

Dand

tirofi

ban(FIBTE

MPL

US)

were

runfora

minim

umof

30min.Fibrin

ogen

concentrationwas

measuredusing

theClaussmetho

dandph

oto-op

ticaldeterm

inationon

theAC

LTo

p700(In

strum

entatio

nLabo

ratory,M

ilan,

Italy)a

ndQFA

thrombinreagent(Instr

umentatio

nLabo

ratory).

Sign

ificant

positivec

orrelatio

nswe

refoun

dbetweenMCF

orMAandfib

rinogen

concentration(allp<

0.00

1);the

highest

correlationwas

with

FIBT

EMPL

USMCF

(Spearman

coeffi

cient𝜌

=0.70),followe

dby

FIBT

EM(𝜌=0

.66)

andFF

TEG(𝜌=0

.56).

[48]

Aprospectives

tudy

of157patientsu

ndergoing

cardiacs

urgery

with

CPB.

Citrated

bloo

dwe

recollected

atbaselin

e(beforeindu

ctionof

anaesth

esia)

andatthee

ndof

CPB(afte

rprotamine

administratio

n).

Who

lebloo

dFIBT

EMwas

perfo

rmed

usingaR

OTE

Mdevice

accordingto

them

anufacturer's

instr

uctio

nsat

each

timep

oint.P

lasm

afib

rinogen

concentrationwas

measuredusingtheC

laussm

etho

dandwho

lebloo

dfib

rinogen

concentrationwas

calculated

asplasma

fibrin

ogen

concentration×(100−haem

atocrit)/100.

TheS

pearman

correlationcoeffi

cientb

etwe

enFIBT

EMMCF

andplasmafi

brinogen

concentrationwas

0.68

atbaselin

eand

0.70

after

protam

ine,whilethatbetweenFIBT

EMMCF

and

who

lebloo

dfib

rinogen

concentrationwas

0.74

atbaselin

eand

0.72

after

protam

ine(allp<

0.00

1).

[49]

Aprospectiveo

bservatio

nalstudy

of35

patients

undergoing

electiv

ecardiac

surgerywith

CPB.

Citrated

bloo

dwas

collected

from

atthreedifferent

timep

oints:preoperativ

ely(

immediatelybefore

anesthesiaindu

ction),and

at1-and24-h

post

operation.

Kaolin

TEGandRO

TEM

EXTE

M,INTE

M,FIBTE

Mwe

recond

uctedwith

thecitrated

bloo

dwith

in1h

after

thecollection,

accordingto

them

anufacturer’s

instr

uctio

ns.F

ibrin

ogen

concentrationwas

measuredby

asta

ndardmetho

d(not

specified).

Correlatio

nsbetweenfib

rinogen

concentrationandEX

TEM

MCF

(Pearson

coeffi

cientr=0

.71,p<

0.00

05),IN

TEM

MCF

(r=0

.53,p=0

.001),FIBT

EMMCF

(r=0

.79,p<

0.00

05)w

ere

foun

dat1-h

postop

erationandcorrelations

between

fibrin

ogen

concentrationandTE

GK(r=-0.52,p=0

.002),

Alpha

(r=0

.53,p=0

.001),TE

GMA(r=0

.63,p<

0.00

05),

EXTE

MMCF

(r=0

.58,p=

0.00

1),INTE

MMCF

(r=0

.63,

p<0.00

05),FIBT

EM(r=0

.50,p=

0.003)

at24-h

postop

eration.

[50]

Aretro

spectiv

eobservatio

nalstudy

of1077

patients

undergoing

cardiacs

urgery

with

CPB.

Citrated

bloo

dwas

collected

durin

gther

ewarmingph

ase(≥36∘ C).

EXTE

MandFIBT

EMwe

recond

uctedat37∘Cas

per

manufacturer’s

reagentsandprocedures.Fibrin

ogen

concentrationwas

measuredby

theC

laussm

etho

dusingSTAREv

olution(Stago,P

aris,

France).

Claussfib

rinogen

concentrationwas

correlated

stron

glywith

EXTE

MMCF

andA10

(Spearman

coeffi

cient𝜌

=0.68and0.70;

p<0.01)and

FIBT

EMMCF

andA10

(𝜌=0

.78and0.78;p<0.01).

Thec

orrelatio

nwas

relatedinverselyto

hemoglobin

concentration(p<0.01).

[51]

Arand

omized

controlledtrialof116

high-risk

patientsu

ndergoingcardiacs

urgery

with

CPB.

Bloo

dwas

collected

at20

min

beforeremovalof

theaortic

cross-clam

p(baseline)andaft

erplaceboor

fibrin

ogen

administratio

n.

FIBT

EMtestwas

cond

ucted.

Fibrinogen

concentrations

were

measuredaccordingto

apho

to-opticalClauss

metho

d,with

acoagulatio

nanalyser

(ACL

TOP700),a

calib

rator(Hem

osilNormalCon

trol),

andathrom

bin

reagent(Hem

osilQFA

thrombin).

Linear

regressio

nanalyses

show

edagood

associationbetween

FIBT

EMMCF

andClaussfib

rinogen

concentrationatthe

baselin

epop

ulation(R2=0

.66,p=

0.00

1),w

hich

redu

cedto

R2=0

.16(p=0

.003)infib

rinogen-sup

plem

entedsubjects.

[52]

Aprospectiveo

bservatio

nalstudy

of110

patients

undergoing

cardiacs

urgery

with

CPB.

Citrated

who

lebloo

dwas

sampled

from

acentralveno

uslin

eor

from

thee

xtracorporealcirc

uitatp

re-C

PB,

on-C

PB,post-C

PB.

ROTE

Massays

ofIN

TEM,E

XTEM

,FIBTE

Mand

HEP

TEM

were

perfo

rmed

at37∘Cby

certified

bioanalyticaltechnicians.

Plasmalevelsof

fibrin

ogen

were

measuredusingthe

Clausstechniqu

eon

acoagulationanalyzer

(BCS

,Dade

BehringInc.,

Germany)

usingtheM

ultifi

bren

U-Reagent

accordingto

manufacturer’s

specificatio

ns.

Thefi

brinogen

leveland

FIBT

EMA10

were

significantly

correlated

fora

lldatapo

ints(Pearson

coeffi

cientr=0

.81;

p<0.05).Th

eirc

orrelatio

nwas

stron

gero

n-CP

Batam

ean

hemoglobinof

83g/L(r=0.87)and

post-

CPB(m

ean

hemoglobin88

g/L;r=0.74)thanpre-CP

B(m

eanHem

oglobin

105g/L;r=0.66

).

[53]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

Livertransplantatio

n(LT)

Aretro

spectiv

eobservatio

nalstudy

of282patients

receivingliver

transplantation.

Citrated

bloo

dwas

collected

at1h

after

indu

ctionof

generalanesth

esia,1

haft

erthefi

rstsurgicalincision

,30min

after

hepatectom

y,30

min

after

graft

reperfusion,

andaft

erhepatic

artery

anastomosis.

ROTE

Mtests

(EXT

EM,INTE

MandFIBT

EM)w

ere

routinelyperfo

rmed

accordingto

them

anufacturer’s

instr

uctio

ns.F

ibrin

ogen

concentrationwas

measured

usingtheD

adethrom

binreagent(Siem

ensH

ealth

care

Diagn

ostics,Erlangen,G

ermany)

andan

automatic

coagulationanalyzer

(Sysmex

CA-700

0,Siem

ens

Health

care

Diagn

ostics,Erlangen,G

ermany).

Fibrinogen

was

theprim

arydeterm

inanto

fFIBTE

MMCF

,accoun

tingfor7

3%of

thev

ariability.How

ever,insevere

hypo

fibrin

ogenem

ia(fibrinogen<1g

/L),fib

rinogen

accoun

ted

only22%

ofFIBT

EMMCF

varia

bility.Spearm

an’scorrelations

betweenfib

rinogen

concentrationandEX

TEM

MCF

(𝜌=0

.66,

p<0.00

1),INTE

MMCF

(𝜌=0

.65,p<

0.00

1),FIBTE

MMCF

(𝜌=0

.83,p<

0.00

1).

[54]

Aretro

spectiv

eobservatio

nalstudy

of295patients

(254

livingdo

norsand41

LTpatients).C

itrated

bloo

dwas

collected

from

1haft

erindu

ctionof

generalanesth

esia,1

haft

ersurgicalincisio

n,30

min

after

hepatectom

y,30

min

after

graft

reperfusion,and

after

hepatic

artery

anastomosis.

Thes

amea

sabo

ve

FIBT

EMMCF

significantly

correlated

with

fibrin

ogen

concentrationwith

ahighestSpearm

an’scoeffi

cient(𝜌=0.84,

p<0.00

1),followe

dby

EXTE

MMCF

(𝜌=0

.67,p<

0.00

1),

INTE

MMCF

(𝜌=0

.66,p<

0.00

1).

[55]

Aprospectives

tudy

of253patientsreceiving

orthotop

icliver

transplantation.

Citrated

bloo

dsamples

were

collected

after

indu

ctionof

general

anesthesia,atthe

endof

theh

epatectomy,20

minutes

after

graft

revascularization,

and90

minutes

after

graft

revascularization.

Theb

lood

samples

were

teste

djustaft

ercollectionby

ROTE

Mgammadevice

operated

accordingto

manufacturerinstructio

nsandwith

thetypea

ndconcentrationof

reagentsas

provided

byPentapharm

(Mun

ich,Germany).F

ibrin

ogen

concentrationwas

measuredby

prothrom

bintim

e-deriv

edmetho

d,with

values

below2g/Lbeingcheckedby

theC

laussm

etho

don

acoagulometer

(KC-

1A,A

melu

ng,L

emgo,G

ermany)

usingfib

rinogen

reagent(Diagn

osticaStago,Asnieres,

France)a

ccording

tothem

anufacturer’s

instr

uctio

ns.

FIBT

EMMCF

correlated

with

fibrin

ogen

level(Spearm

an’s

correlationcoeffi

cient𝜌

=0.70).

[56]

Aprospectiveo

bservatio

nalstudy

of20

patients

undergoing

orthotop

icliver

transplantation.

Bloo

dsamples

were

takenatthefollowingpo

intsdu

ring

OLT

:the

beginn

ingof

thed

issectio

nph

ase,thee

ndof

dissectio

nph

ase,10

min

into

thea

nhepaticph

ase,

10min

into

ther

eperfusio

nph

ase,and1h

after

dono

rgraft

reperfusion.

FIBT

EMwas

perfo

rmed

with

citrated

bloo

dwith

in4h

ofcollectionaccordingto

themanufacturer’s

instr

uctio

ns.C

laussfi

brinogen

assaywas

perfo

rmed

onaCA

-1500analyzer

(Sysmex,M

ilton

Keynes,U

K).

Therew

asas

ignificantcorrelatio

nbetweenFIBT

EMMCF

and

Claussfib

rinogen

concentration(Pearson’scorrelation

coeffi

cientr

=0.75,p≤

0.01).

[23]

Aprospectiveo

bservatio

nalstudy

of23

patients

undergoing

orthotop

icliver

transplantation.

Bloo

dsamples

were

collected

after

indu

ctionof

general

anaesth

esia,d

uringhepatectom

y,attheanhepatic

stage,30–

60min

after

graft

revascularization,

atthe

endof

surgery,and24

haft

ersurgery

ROTE

Mtests

(EXT

EM,INTE

M,FIBTE

MandAPT

EM)

were

perfo

rmed

intheo

peratin

gtheatre

andby

the

anaesth

esiologists

treatingthep

atientsa

ccording

tothe

manufacturer’s

instr

uctio

nsusingequipm

entand

test

reagentsprovided

byPentapharm

GmbH

.Plasm

afib

rinogen

concentrationwas

determ

ined

bytheC

lauss

metho

dperfo

rmed

onAC

LTo

pautomates

(Instr

umentatio

nLabo

ratory,Lexington

,MA,U

SA)

ROTE

MFIBT

EMA10

correlated

with

Claussfib

rinogen

(r=0

.74,p<0.00

01),on

lyslightly

stron

gerthanEX

TEM

A10

(r=0

.72,p<

0.00

01)

[57]


Table1:Con

tinued.

Clinicalsettings

Stud

ypo

pulatio

nandbloo

dsample

TEGandRO

TEM

metho

dsRe

sults

Ref.

Aretro

spectiv

estudy

of40

1patientsw

houn

derw

ent

liver

transplantation.

Bloo

dwas

sampled

at1h

after

indu

ctionof

generalanaesthesia,1

haft

ersurgical

incisio

n,30

min

after

hepatectom

y,and30

min

after

graft

reperfusionandaft

erhepatic

artery

anastomosis.

ROTE

Mtests

were

perfo

rmed

accordingto

the

manufacturer’s

instr

uctio

ns,u

singequipm

entand

test

reagents

provided

byTem

InternationalG

mbH

.Fibrin

ogen

level

was

measuredusingtheD

adeTh

rombinRe

agent

(SiemensH

ealth

care

Diagn

ostics)andan

automatic

coagulationanalyser

(Sysmex

CA-700

0,Siem

ens

Health

care

Diagn

ostics).

Thec

orrelations

ofFIBT

EMA5,A10,M

CFwith

fibrin

ogen

levelswe

redeterm

ined

usingSpearm

an’srank

correlation

coeffi

cients(𝜌=0.75,0.76

and0.75,respectively,p<

0.00

1).

[58]

Postp

artum

Aprospectiveo

bservatio

nalstudy

of91

women

atthe

third

trim

estero

fpregn

ancy:37with

postp

artum

haem

orrhage(stu

dygrou

p)and54

with

outabn

ormal

bleeding

(con

trolgroup

).Citrated

bloo

dwas

collected

from

women

atthethird

trim

estero

fpregnancy.

Standard

FIBT

EMwas

carriedou

tbyclinicians

with

the

bloo

dsamples

inthed

eliveryroom

.Fibrin

ogen

assay

was

forp

lasm

acon

centratio

nwith

in5min

after

samplingwith

aSTA

Rautomated

coagulationanalyser

(Diagn

osticaStagoInc.,

Franconville,France)

A5,A15

andMCF

were

significantly

lowe

rintheh

aemorrhage

grou

pthan

incontrol(p<

0.00

01)and

stron

glycorrelated

with

fibrin

ogen

levelsbo

thgrou

ps(Spearman’scorrelation

coeffi

cient𝜌

=0.84–0

.87,p<

0.00

01).

[59]

Neurosurgery

Aprospectiveo

bservatio

nalstudy

of92

patients

undergoing

emergent

neurosurgery

ROTE

Manalyses

were

perfo

rmed

with

inmin

ofbloo

dsamplingby

anesthesianu

rses

orph

ysicians

trainedto

perfo

rmtheR

OTE

Mtests

accordingto

the

manufacturer’s

instr

uctio

ns.P

lasm

afib

rinogen

concentrationwas

determ

ined

byClaussmetho

d(Siemens-DadeBe

hringHealth

care

Diagn

ostics,

Marbu

rg,G

ermany).

Therew

asas

trong

correlationbetweenPT

TandIN

TEM

CT(r=0

.76)asw

ellasb

etwe

enfib

rinogen

concentrations

and

FIBT

EMMCF

(r=0

.70).

[60]

Burn

injury

Aprospectiveo

bservatio

nalstudy

of20

consecutive

patients.Citrated

bloo

dwas

collected

immediately

after

admission,

12,24and48

haft

eradmission.

Four

ROTE

Mtests

(INTE

M,E

XTEM

,FIBTE

Mand

APT

EM)w

erep

erform

edsim

ultaneou

slyon

the

four-chann

elRO

TEM

intheICUwardlabateach

time

point.Plasmafib

rinogen

levelw

asdeterm

ined

byClauss

metho

dusingan

automated

coagulationanalyzer

(STA

-REv

olution,

Stago,Asnieres,France).

Fibrinogen

leveland

FIBT

EMMCF

were

with

inther

eference

rangeun

til24

haft

erbu

rninjury,but

increasedsig

nificantly

after

48h.Th

erew

asa

significantcorrelatio

nbetweenFIBT

EMMCF

andfib

rinogen

level(Spearm

an’scorrelationcoeffi

cient𝜌

=0.714,p<0.00

1).

[61]

Cirrho

sis

Across-sectionalsingle-centre

study

involving60

patientsw

ithalcoho

liccirrho

sis,24patientsw

ithcholestatic

cirrho

sisandac

ontro

lgroup

of50

healthy

volunteers.B

lood

samples

were

takenatadmission.

ROTE

MFIBT

EMassaywas

perfo

rmed

with

citrated

bloo

dwith

in1h

after

collectionusingas

etof

stand

ard

reagentsaccordingto

them

anufacturer’s

recommendatio

ns.C

laussfi

brinogen

assaywas

perfo

rmed

usingaBC

S�XP

automated

coagulation

analyzer

(SiemensH

ealth

care

Diagn

osticsG

mbH

,Marbu

rg,G

ermany).

Inallcirr

hosis

patients,FIBT

EMMCF

stron

glycorrelated

with

fibrin

ogen

concentration(r=0

.72-0.77,p<0.00

1).

[62]

CPB=

Cardiop

ulmon

aryBy

pass;ISS=InjurySeverityScore;Livertransplantatio

n=LT


Meyer 2015Peng 2018 Gottumukkala 1999

Lu 2014r=0.77, p<0.00195% Confidence Interval

4 6 8 102Clauss fibrinogen level (g/L)

0

10

20

30

40

50

60

70FF

TEG

MA

(mm

)

(a)

Blasi 2012Peng 2018

Meyer 2015Solomon 2013

Ranucci 2016 r=0.77, p<0.00195% Confidence Interval

0

10

20

30

40

50

ROTE

M F

IBTE

M M

CF (m

m)

2 4 6 80Clauss fibrinogen level (g/L)

(b)

Figure 1: Correlations of Clauss fibrinogen level with FF TEGMA (a) and with ROTEM FIBTEMMCF (b).The correlation coefficients wereobtained through linear regression of all data extracted from the literature. The data were pooled from different clinical studies involving atotal of 275 patients for the correlation between Clauss fibrinogen level and FF TEG MA [30, 35, 42, 43] and a total of 626 patients for thecorrelation between Clauss fibrinogen level and ROTEM FIBTEM MCF [30, 35, 48, 52, 56]. The means ± standard deviations of FF TEGMA and Clauss fibrinogen level in (a) are 20.14±8.28 mm and 2.71±1.32 g/L. Themeans ± standard deviations of ROTEM FIBTEMMCF andClauss fibrinogen level in (b) are 15.40±7.86 mm and 2.74±1.22 g/L.

assays can be completed in 15 min and can provide rapidand accurate detection of hyperfibrinolysis [87]. Anotheradvantage of TEG and ROTEM is that they can be used forfully heparinised patients, e.g., when on cardiopulmonarybypass, with the use of a heparinase TEG cup or heparinase.In vitro studies showed that FF TEG MA was unaffected byheparin levels up to 2.8 IU/mL, but was reduced at 5.6 IU/mLof heparin in blood even performed in heparinase TEG cups[71], while ROTEM FIBTEMMCFwas insensitive to heparinup to a concentration of 4 IU/ml in whole blood, but thendeclined to values less than 50%of baseline at 8 IU/mL [88]. Aclinical study in pediatric cardiac surgery validated the use ofFIBTEM in the presence of very high heparin concentrations(400 IU/kg bodyweight) [89].

The correlations between Clauss fibrinogen concentra-tion and FF TEG MA or ROTEM FIBTEM MCF couldbe affected by a number of factors in addition to heparinconcentration. As elucidated in Table 1, different reagents andinstruments produced by Stago, Siemens, and Instrumenta-tion Laboratory are used to quantify fibrinogen concentra-tion. It is known that there can be systematic differencesbetween the fibrinogen concentrations obtained with variouscommercial kits [90]. The different detections used in theClauss method and resuscitation fluids administered mayaffect the correlation [91, 92].This is likely due to the fact thatFIBTEM test is more affected than fibrinogen concentrationassays by the fluids [93]. Solomon et al. examined correlationsbetween ROTEM FIBTEMMCF and Clauss fibrinogen con-centration as determined using photo-optical, mechanical,and electromechanical detections in cardiac surgery patients

[91]. The correlations obtained from the photo-optical andelectromechanical methods (r=0.82 and 0.81) were greaterthan the mechanical method (r=0.73 and 0.71). Fenger-Eriksen et al. assessed fibrinogen levels in plasma dilutedin vitro with different fluids (isotonic saline, hydroxyethylstarch, and human albumin) using an antigen determination,three photo-optical Clauss methods, one mechanical Claussmethod, a prothrombin-derived method, and viscoelasticmeasurement through ROTEM [92]. The fibrinogen levelswere overestimated using the photo-optical Clauss methodsas a result of the dilution with hydroxyethyl starch, whereasROTEM FIBTEM MCF was reduced by the dilution and toa lesser extent by human albumin. The former was ascribedto an unexplained interference with the optical source byhydroxyethyl starch and the latter was due to impairmentof fibrin polymerization induced by the fluid. In addition,the fibrinogen measurement by the Clauss method for thesame set of plasma samples can vary within and betweenlaboratories [94].

On the other hand, it was found that plasma fibrinogenlevel (FLEV) estimated by FF TEG was on average 1.0 g/Lhigher than that determined by the Clauss method in bothsurgical patients and healthy controls [95]. This is consistentwith other reports of higher TEGFLEVvalues than theClaussvalues in cardiac surgery [39] and overestimation of plasmafibrinogen level in liver transplantation when the plasmafibrinogen level becomes less than 1 g/L [42].

In our subgroup analysis of trauma patients who receivedfibrinogen concentrate versus placebo (i.e., normal saline),the correlation coefficients are not as significantly altered


between the two groups (0.68 versus 0.67 for FF TEG and0.88 versus 0.82 for ROTEM FIBTEM). This is in contrastwith patients undergoing liver transplantation [42, 54] andcardiac surgery [52, 91] where the correlation was impairedby severe hypofibrinogenemia and fibrinogen replacement.Specifically, the correlations between FIBTEM MCF andClauss fibrinogen concentration decreased from r=0.71-0.82to 0.33-0.59 after administration of fibrinogen concentratein patients undergoing complex cardiovascular surgery [91].In addition, hyperfibrinogenemia (>4 g/L) could impair thecorrelation between ROTEM FIBTEM MCF and fibrinogenlevels as reported in major upper gastrointestinal surgery[96].Therefore, the discrepancymay be due to the differencesin the range of plasmafibrinogen concentrations among thesestudies (e.g., interquartile range of 1.88-3.63 g/L in our studyvs. 0.77-1.38 g/L in the liver transplantation study). Similarcorrelations were reported between FIBTEM clot amplitudeand fibrinogen concentration (r=0.86) at admission and thendecreased correlations (r=0.43 and 0.63) after admission inthe trauma patients receiving fibrinogen concentrate [44].

It should be noted that the concentration measurementsby the Clauss method and other plasma fibrinogen assayscannot be the same as the clot strength of whole bloodmeasured by TEG and ROTEM. Apparently, fibrinogen is notthe only contributor to clot amplitude in these FF TEG andROTEM FIBTEM assays, which may impose some limita-tions on FF TEG and ROTEM FIBTEM for the assessmentof fibrinogen deficiency. Activated FXIII and hematocritcould have an impact on clot firmness as well and affect thecorrelations [49, 96–99]. Postoperative FXIII levels correlatedto FIBTEM MCF more significantly than fibrinogen levelsin patients undergoing major upper gastrointestinal surgery[96]. However, the same study also showed a significant cor-relation between platelet count and ROTEM FIBTEM MCF(r=0.55), which implied that the test might be profoundlyimpaired by incomplete inhibition of the platelet contributionto the clot strength. Furthermore, FXIII levels might affect FFTEG as well [98].

In addition, Ogawa et al. reported a higher correlationbetween ROTEM FIBTEM MCF and Clauss plasma fibrino-gen at lower hematocrit (<25%) than at higher hematocrit(>30%) (r =0.88 and 0.67, resp.) in cardiac surgery [99].In contrast, Solomon et al. found no significant differencesbetween the lowest haematocrit group (<25%) and the higherhaematocrit groups (25-27.9%, 28-29.9%, and >30%) forFIBTEM MCF or fibrinogen concentrations in whole bloodand plasma, and thus the hematocrit effect appeared to benegligible [49]. FF TEG has shown hypocoagulable states inpatients with cyanotic congenital heart disease mainly due toimpaired fibrinogen function negatively affected by elevatedhaematocrit [100].

In addition toMA, other TEG parameters, e.g., estimatedfunctional fibrinogen level (FLEV) and kinetic time K andAlpha, kaolin TEGK andAlpha, have shown different extentsof correlations with fibrinogen concentration [32, 33, 47].Kornblith et al. confirmed a significant correlation betweenFF TEG FLEV and the Clauss fibrinogen assay in traumapatients in agreement with the published findings from Harret al., but the correlation as assessed by linear regression was

weaker (R2= 0.57 vs. 0.87) [32, 33]. In addition, differentcorrelations of FLEV with kaolin TEG MA (R2= 0.44-0.64vs. 0.80), K (R2= 0.01 vs. 0.35), and Alpha (R2= 0.03 vs. 0.70)were reported in their studies likely due to different statisticalmethods (linear vs. polynomial regression). The correlationswere affected by fibrinogen concentration, decreases at lowand high ranges [32]. FF TEG FLEV was diminished andnegatively correlated to haematocrit [100].

We observed moderate correlations of Clauss fibrino-gen concentration with FF TEG K and Alpha (Spearman’scorrelation 𝜌=-0.46 and 0.40) and with ROTEM FIBTEMCFT and Alpha (𝜌=-0.41 and 0.54) in trauma patients [30].Furthermore, there were weak correlations of fibrinogenconcentration with ROTEM FIBTEM CT (𝜌=-0.29), andwith FF TEG CL30 and ROTEM FIBTEM LI30 (𝜌=0.21 and0.20).The correlations between K/CFT, Alpha and fibrinogenconcentration are consistent with their measurement of theactivity of clotting factors, in particular fibrinogen [101], andare comparable with or stronger than the reported correla-tions between FFTEGK/Alpha and fibrinogen concentration[32, 33]. A linear correlation was observed between the clotshear elasticity G calculated fromFFTEGMA and functionalfibrinogen levels measured by the Clauss method in bothwhole blood (R2=0.605) and platelet-poor plasma (R2=0.94)[102].

Among all the parameters, the strongest correlationsbetween FF TEG MA/ROTEM FIBTEM MCF and plasmafibrinogen concentration have been reported [32, 33, 103],suggesting these parameters are most useful for monitoringthe role of fibrinogen in hemostasis of bleeding patients.

Together with kaolin TEG, FF TEGhas been used to char-acterize functional fibrinogen to platelet ratio and was founduseful in preoperatively identifying thrombotic complicationin patients undergoing microvascular free tissue transferin head and neck surgery [104]. FF TEG MA correlatedwith a number of biomarkers of endothelial activation anddamages such as syndecan-1, thrombomodulin and proteinC, and plasminogen activator inhibitor-1 (r=-0.37, p<0.001)in patients with severe sepsis [105].

5. Diagnosis ofCoagulopathy/Hypofibrinogenemia andPrediction of Blood Transfusion

Table 2 summarizes the predictive accuracy of FF TEG andROTEM FIBTEM in various clinical settings. MA and MCFare the main parameters used for the predictions of hypofib-rinogenemia and blood transfusions.Theprediction accuracywas evaluated by sensitivity, specificity, and area under thereceiver operating characteristic curve (AUC) and variateregression analyses. Different cut-off values of fibrinogenconcentrations ranging from 1 to 1.8 g/L were used to definehypofibrinogenemia. Traditionally, a plasma fibrinogen levelof 1 g/L was established for fibrinogen replacement in patientswith congenital fibrinogen deficiency, whereas the thresholdvaried from 0.8 to 2.0 g/L in patients with acquired fibrinogendeficiency [14]. In contrast, a critical fibrinogen concentrationof 2.29 g/L was identified in trauma below which a significant


Table2:Clinicalevaluatio

nof

TEGandRO

TEM

functio

nalfi

brinogen

tests

ford

iagn

osisof

coagulop

athy

(hypofi

brinogenem

ia),predictio

nof

transfu

sionrequ

irementsandmortality.

Clinicalsettings

Stud

ydesig

nandpatients

Bloo

dcollectionandanalysis

Find

ings

Ref.

FFTE

G

Trauma

Rand

omized


apatientsa

tris

kof

significanth

emorrhage(

n=45,ISS=18-29)

receivingeither

6gfib

rinogen

concentrate

(RiaSTAP�

)orp

lacebo

(normalsalin

e)

Citrated

who

lebloo

dwas

collected

from

the

rand

omized

traumap

atientsa

tadm

ission,

1-,3-,11-,

23-a

nd47-h

post-

infusio

ntim

e.Standard

FFTE

Gwas

perfo

rmed

onacompu

teriz

edTE

GHem

ostasis

Syste

m5000

(Haemon

eticsC

orpo

ratio

n,Haemoscope

Division

,Niles,IL,U

SA)a

ccording

tothemanufacturer’s

protocol.

FFTE

GMApredictedhypo

fibrin

ogenem

ia(fibrinogen

concentration<1g

/L)and

24-h

plasmatransfusio

nwith

high

accuracies

(AUC=

0.95,p=0

.002

andAU

C=0.70,p=0

.042).

[30,31]

Aprospectives

tudy

of182adulttraum

apatientsw

itham

edianISSof

17(9-26)

Bloo

dwas

sampled

immediatelyup

onarriv

alto

traumac

entre

andevaluatedin

tissuefactor-activ

ated

andplateletinhibitedTE

G(i.e.FF

TEG)p

recisely1h

after

samplingby

ahem

ostasis

analyzer

syste

m(TEG

5000

,Haemon

eticsC

orp.,B

raintre

e,MA)a

ccording

tothem

anufacturer’s

recommendatio

ns.A

llanalyses

were

cond

uctedat37∘C.

Sensitivity,specificity

andAU

Cof

FFTE

GMAford

etectio

nof

fibrin

ogen<1.5

g/Lwe

re77%,81%

and0.869,respectiv

ely.FF

TEGMAwas

also

aunivaria

tepredictorsof

massiv

etransfu

sion(>10

units

ofRB

Cs)at6

and24

hwith

oddratio

sof

0.79,0.82andmortalityat28

days

with

ahazardratio

of0.84.

[35,63]

Cardiac

surgery

Aprospectiveo

bservatio

nalstudy

of105child

renless

than

5yearso

fage

undergoing

congenitalh

eart

surgerywith

CPB

Who

lebloo

dsamples

were

collected

viaind

welling

arteria

lcathetersbefore

andaft

erCP

B.FF

TEGand

kaolin

heparin

aseT

EGwe

reperfo

rmed

ontheT

EG5000

with

company’sreagentsby

asingletechnician,

with

in20

min

ofcollectionof

thes

amples.P

lasm

afib

rinogen

levelswe

redeterm

ined

bytheC

lauss

metho

dusingthecommercialreagentsand

instr

ument(STAFibrinogen,D

iagn

osticaStago).

FFTE

GMApredictedhypo

fibrin

ogenem

ia(fibrinogen

concentration<2g/L)

with

AUCof

0.71

(95%

CI0.59-0.83)

[40]


Table2:Con

tinued.

Clinicalsettings

Stud

ydesig

nandpatients

Bloo


Find

ings

Ref.

ROTE

MFIBT

EM

Trauma

Rand

omized


apatientsa

tris

kof

significanth

emorrhage(

n=45,ISS=18-29)

receivingeither

6gfib

rinogen

concentrate

(RiaSTAP�

)orp

lacebo

(normalsalin

e)

Citrated

who

lebloo

dwas

collected

from

thetraum

apatientsa

tadm

ission,

1-,3-,11-,

23-a

nd47-h

post-

infusio

ntim

e.Standard

ROTE

MFIBT

EMwas

perfo

rmed

onaR

OTE

Mdelta

syste

m(Tem

Inno

vatio

nsGmbH

,Mun

ich,Germany;succeeded

byInstr

umentatio

nLabo

ratory,B

edford,M

A,U

SA)

accordingto

them

anufacturer’s

protocol.

ROTE

MFIBT

EMMCF

predictedhypo

fibrin

ogenem

ia(fibrinogen

concentration<1g

/L)and

24-h

plasma

transfu

sionwith

high

accuracies

(AUC=

0.96,p<0.00

1)and

AUC=

0.72,p=0

.023).

[30,31]

Aprospectiveo

bservatio

nalstudy

of88

trauma

patientsa

nmedianISSscoreo

f22(12-34)

Bloo

dsamples

were

collected

immediatelyaft

erthe

patient’sarriv

alto

thetraumar

oom

(H0)

andat6h

(H6),12h(H

12)a

nd24

h(H

24)afte

radm

ission,

representin

gatotalof

270samples.Th

eROTE

Mmeasurementsandsta

ndardcoagulationtests

were

perfo

rmed

with

in2hof

collectionof

bloo

dsamples.


andAU

Cof

FIBT

EMA10

ford

etectio

nof

fibrin

ogen<1g

/Lwe

re91%,85%

and0.96,respectively.

[45]

Aretro

spectiv

eanalysis

ofdatafrom

323p

atients

with

aninjury

severityscore(

ISS)≥16

(20-50)

Bloo

dsamples

were

takenim

mediatelyup

onadmissionto

ER.R

OTE

Manalyses

(EXT

EM,

INTE

M,FIBTE

M)w

eretypicallyperfo

rmed

atthe

bedsidew

ithin

minutes

ofsamplec

ollection.

Fibrinogen

concentrationwas

measuredby

the

Claussmetho

d(STA

-Fib�assay(Roche

Diagn

ostics

GmbH

);op

ticalread-out),usingaS

TA-C

ompact�

machine

(Roche

Diagn

osticsG

mbH

,Vienn

a,Au

stria).


andAU

Cof

FIBT

EMA10/M

CFfor

predictio

nof

massiv

etransfusio

n(≥10

units

RBCtransfu

sedin

24h)

63.3/77.5

%,83.2/74.9%,0.83/0.84

(95%

CI0.78-0.87/0.79-0.88),sim

ilartofib

rinogen

concentration

[64]

Aprospectivec

ohortstudy

of517traumap

atients

with

amedianISSof

14(8-27)

Bloo

dwas

draw

nfrom

either

thefem

oralvein

orantecubitalfossa

into

a2.7-mLcitrated

vacutainer

with

in20

min

ofarriv

alin

thee

mergency

department(ED

).RO

TEM

tests

were

perfo

rmed

with

in2hof

bloo

ddraw

with

aROTE

Mdelta

instr

ument,at37∘C.


andAU

Cof

FIBT

EMA5ford

etectio

nof

fibrin

ogen<1.5

g/L87%,70%

and0.8(95%

CI0.7-0.9)

[3]

Aprospective,sin

gle-center,n

on-in

terventio

nal,

non-controlled,op

enclinicalstu

dyof

50tra

uma

patientsw

itham

edianISSof

13(4-66)

Bloo

dwas

collected

atho

spitaladm

ission,

3-and

24-h

after

admissionandanalyzed

byRO

TEM

assays

(EXT

EMandFIBT

EM).EX

TEM

was

considered

positiveifo

neof

thefou

rprin

ciplep

aram

eters(CT

,CF

T,MCF

,and

Maxim

umLysis)g

reater

than

20%

oftheexpected

highesto

rlow

estn

ormalvalueo

fthe

manufacturern

ormalvaluer

anges(CT≥94,C

FT≥

190,MCF≤40

,ML≤12).FIBT

EMwas

considered

positiveifM

CFwas

atleast2

0%sm

allerthanthe

expected

meanno

rmalvalue(MCF≤7).


andAU

Cof

FIBT

EMMCF<7mm

with

inno

rmalEX

TEM

patientsa

re100%

,90.2%

,0.951

and

0%,87.5

%,0.563

forp

redictions

ofcoagulop

athy

(INR≥

1.3)

andmortalityat30

days

[65]

Aprospectives

tudy

of182adulttraum

apatientsw

itham

edianISSof

17(9-26)

Bloo

dwas

sampled

immediatelyon

hospitalarrival.

FIBT

EMassays

were

perfo

rmed

with

citrated

bloo

dprecise

ly1h

after

samplingaccordingto

the

manufacturer’s

recommendatio

ns.F

ibrin

ogen

level

was

determ

ined

byClaussmetho

d.


andAU

Cof

FIBT

EMMCF<10

mm

were

80%,89%

and0.889ford

etectio

nof

fibrin

ogen<1.5

g/L.

[35]


Table2:Con

tinued.

Clinicalsettings

Stud

ydesig

nandpatients

Bloo


Find

ings

Ref.

Aprospectivec

ohortstudy

of334blun

ttraum

apatients(ISS≥

15or

Glasgow

Com

aScore≤

14).

Citrated

bloo

dwas

collected

atho

spitaladm

ission.

ROTE

Mtests

were

perfo

rmed

accordingto

the

manufacturer’s

instr

uctio

ns,u

singequipm

entand

testreagentsprovided

byTem

InternationalG

mbH

.Lo

gisticr

egressionmod

elswe

reused

toevaluate

ROTE

Mtests

forp

redictionof

24-h

deathand6-h

transfu

sions.

FIBT

EMMCF

with

acut-offof

7mm

predictedtheneed

for

RBCtransfu

sionwith

anod

dratio

of0.92

(95%

CI0.87–0.98)

[46]

Cardiac

surgery

Aprospective,ob

servationalpilo

tstudy

of35

patientsu

ndergoingelectiv

ecardiacs

urgery

oncardiopu

lmon

arybypass(C

PB)for

cyanotic

congenitalh

eartdisease

Citrated

bloo

dwas

collected

after

indu

ctionof

anesthesiaandanalyzed

byRO

TEM.N

odetails

were

provided.Fibrin

ogen

concentrationassaywas

not

provided.

ROTE

MFIBT

EMMCF

ishighly

predictiv

eofh

ypofi

brinogenem

ia(fibrinogen<1.5

g/L)

(AUC=

0.99).

[47]

Arand

omized,placebo

-con

trolledtra

ilof

116high-risk

patientsu

ndergoingcardiacs

urgery

with

CPB

ROTE

MFIBT

EMwas

perfo

rmed

20min

before

removalof

thea

ortic

cross-cla

mp,aft

erfib

rinogen

supp

lementatio

n.Fibrinogen

concentrations

were

measuredup

onarriv

alin

ICUaccordingto

aph

oto-op

ticalClaussmetho

d.

FIBT

EMMCF

with

theb

estcut-offvalueo

f14mm

yieldeda

good

discrim

inativep

ower

forsevereb

leedingwith

anAU

Cof

0.721,sensitivity

of80%,specificity

of72%

[52]

Aretro

spectiv

eobservatio

nalstudy

of1077

patients

undergoing

cardiacs

urgery

with

CPB.

Citrated

bloo

dwas

collected

durin

gther

ewarming

phase(≥36∘C)

.EXT

EMandFIBT

EMwe

recond

uctedat37∘Cas

perm

anufacturer’s

reagentsand

procedures.Fibrin

ogen

concentrationwas

measured

bytheC

laussm

etho

dusingSTAREv

olution(Stago,

Paris

,France).

Theo

ptim

alFIBT

EMA10

cut-o

ffford

iagn

osisof

afibrinogen

concentration<1.5

g/Lwas≤8mm

with

anAU

Cof

0.95.

[51]

Aprospectiveo

bservatio

nalstudy

of110

patients

undergoing

cardiacs

urgery

with

CPB.

Citrated

who

lebloo

dwas

sampled

from

acentral

veno

uslin

eorfrom

thee

xtracorporealcirc

uitat

pre-CP

B,on

-CPB

,post-C

PB.R

OTE

Massays

ofIN

TEM,E

XTEM

,FIBTE

MandHEP

TEM

were

perfo

rmed

at37∘Cby

certified

bioanalytical

technicians.Plasmalevelsof

fibrin

ogen

were

measuredusingtheC

lausstechn

ique

ona

coagulationanalyzer

(BCS

,DadeB

ehrin

gInc.,

Germany)

usingtheM

ultifi

bren

U-Reagent

accordingto

manufacturer’s

specificatio

ns.

Anon

-CPB

FIBT

EMA10≤10

mm

identifi

edpatientsw

itha

post-

CPBClaussfib

rinogen

of≤1.5

g/Lwith

asensitivity

of0.99

andap

ositive

predictiv

evalueo

f0.60.

[53]

Aretro

spectiv

eand

observationalstudy

of119

child

ren<10

yearso

ldun

dergoing

congenitalcardiac

surgerywith

CPB.

Bloo

dwas

collected

twiced

uringsurgery,aft

eranesthesiaindu

ctionandCP

B.RO

TEM

EXTE

Mand

FIBT

EMwe

reperfo

rmed

with

citrated

bloo

daccordingto

them

anufacturer’s

recommendatio

ns.

Intraoperativ

eexcessiv

ebloo

dlosswas

defin

edas

estim

ated

bloo

dloss≥50%

ofestim

ated

bloo

dvolume.Lo

gisticr

egressionmod

elsw

ereu

sedto

identifypredictorsfore

xcessiv

eblood

loss.

Post-

CPBFIBT

EMCA

10<5m

mpredictedmassiv

eblood

loss

with

anod

dratio

of11.1(95%

CI2.6-47.3,p=0

.001)and

AUC

of0.83.

[41]


Table2:Con

tinued.

Clinicalsettings

Stud

ydesig

nandpatients

Bloo


Find

ings

Ref.

Livertransplantatio

n(LT)

Aretro

spectiv

eobservatio

nalstudy

of295patients

(254

livingdo

norsand41

LTpatients).

Citrated

bloo

dwas

collected

from

1haft

erindu

ction

ofgeneralanesth

esia,1

haft

ersurgicalincisio

n,30

min

after

hepatectom

y,30

min

after

graft

reperfusion,

andaft

erhepatic

artery

anastomosis.

ROTE

M�tests

(EXT

EM,INTE

MandFIBT

EM)w

ere

routinelyperfo

rmed

accordingto

them

anufacturer’s

instr

uctio

ns.F

ibrin

ogen

concentrationwas

measured

usingtheD

adethrom

binreagent(Siem

ens

Health

care

Diagn

ostics,Erlangen,G

ermany)

andan

automaticcoagulationanalyzer

(Sysmex

CA-700

0,Siem

ensH

ealth

care

Diagn

ostics,Erlangen,

Germany).

FIBT

EMMCF<8m

mpredictedhypo

fibrin

ogenem

ia(fibrinogen<1.2

8g/L)

with

asensitivity

of82%,a

specificityof

90%

andAU

Cof

0.94.

[55]

Aprospectives

tudy

of253patientsreceiving

orthotop

icliver

transplantation.

Citrated

bloo

dsamples

were

collected

after

indu

ction

ofgeneralanesth

esia,atthe

endof

theh

epatectomy,

20min

after

graft

revascularization,

and90

min

after

graft

revascularization.

Theb

lood

samples

were

teste

djustaft

ercollectionby

ROTE

Mgammadevice

operated

accordingto

manufacturerinstructio

nsand

with

thetypea

ndconcentrationof

reagentsas

provided

byPentapharm

(Mun

ich,Germany).

Fibrinogen

concentrationwas

measuredby

the

PT-derived

metho

d,with

values

below2g/Lbeing

checkedby

theC

laussmetho

d.


andAU

Cof

FIBT

EMA10

ford

etectio

nof

plasmafi

brinogen

level(<1.3

g/L)

86%,55%

and0.801

[56]

Aretro

spectiv

e,sin

gle-centre,observatio

nalstudy

of243a

dultliver

transplant

patients

Bloo

dsamples

were

collected

immediatelyup

onadmissionto

ICUandon

cedaily

until

thes

eventh

posto

perativ

eday.R

OTE

Mtests

inclu

ding

EXTE

M,

INTE

M,and

FIBT

EMwe

reperfo

rmed.Stand

ard

labo

ratory

tests

(PT,aPTT

,fibrinogen)w

ere

perfo

rmed

usingaBC

SAnalyzer(Siem

ens

Health

care

Diagn

osticsP

rodu

ctsG

mbH

,Erla

ngen,

Germany).

FIBT

EMA10/M

CFpredictedpo

stoperativ

ebleedingwith

asensitivity

of90/90%

,specificity

of33/32%

,AUCof

0.636/0.632,bette

rthanfib

rinogen

concentrationwith

74%,

39%

and0.531

[66]

Aprospectiveo

bservatio

nalstudy

of23

patients

undergoing

orthotop

icliver

transplantation.

Bloo

dsamples

were

collected

after

indu

ctionof

generalanaesthesia,d

uringhepatectom

y,atthe

anhepatic

stage,30–

60min

after

graft

revascularization,

atthee

ndof

surgery,and24

haft

ersurgery.RO

TEM

tests

(EXT

EM,INTE

M,FIBTE

MandAPT

EM)w

ereperfo

rmed

intheo

peratin

gtheatre

andby

theanaesth

esiologists

treatingthe

patientsa

ccording

tothem

anufacturer’s

instr

uctio

nsusingequipm

entand

testreagentsprovided

byPentapharm

GmbH

.Plasm

afib

rinogen

concentrationwas

determ

ined

bytheC

laussm

etho

dperfo

rmed

onAC

LTo

pautomates

(Instr

umentatio

nLabo

ratory,L

exington

,MA,U

SA).

ROTE

MFIBT

EMA10≤8mm

predictedhypo

fibrin

ogenem

ia(fibrinogen<1g

/L)w

ithas

ensitivity

of0.83,specificity

of0.35,and

AUCof

0.61,w

orse

than

EXTE

Mwith

correspo

nding

values

of0.83,0.75and0.84

[57]


Table2:Con

tinued.

Clinicalsettings

Stud

ydesig

nandpatients

Bloo


Find

ings

Ref.

Aretro

spectiv

eof4

01patientsw

houn

derw

entliver

transplantation.

Bloo

dwas

sampled

at1h

after

indu

ctionof

general

anaesth

esia,1

haft

ersurgicalincisio

n,30

min

after

hepatectom

y,and30

min

after

graft

reperfusionand

after

hepatic

artery

anastomosis.

Atotalof1125

FIBT

EMtests

were

perfo

rmed

accordingto

the

manufacturer’s

instr

uctio

ns.F

ibrin

ogen

levelw

asmeasuredusingtheD

adeTh

rombinRe

agent

(SiemensH

ealth

care

Diagn

ostics)andan

automatic

coagulationanalyser

(Sysmex

CA-700

0,Siem

ens

Health

care

Diagn

ostics).

ROCcurvea

nalysis

show

edthatac

ut-offvalueo

fFIBTE

MA5

at4mm

andA10

at5mm

predictedfib

rinogen<1g

/Lwith

asensitivity

of81%

and76%,specificity

of77%

and82%,A

UC

of0.86

and0.87

[58]

Postp

artum

hemorrhage

Aprospectiveo

bservatio

nalstudy

of91

women

atthe

third

trim

estero

fpregn

ancy:37with

postp

artum

haem

orrhage(stu

dygrou

p)and54

with

outabn

ormal

bleeding.

Standard

FIBT

EMwas

carriedou

tbyclinicians

with

citrated

bloo

dsamples

inthed

eliveryroom

.Plasm

afib

rinogen

was

assayedwith

in5min

after

sampling

with

aSTARautomated

coagulationanalyser

(Diagn

osticaStagoInc.,

Franconville,France)

accordingto

stand

ardprocedures.

Acut-o

ffvalueo

fA5andA15

at6mm

provided

ansensitivity

of100%

forb

othparameters,as

pecificity

of85

and88%,and

AUCof

0.96

and0.97,respectivelyto

detectafi

brinogen

level

<1.5

g/Lin

postp

artum

haem

orrhage.

[59]

Aprospectiveo

bservatio

nalpilo

tstudy

inclu

ding

217

healthypregnant

women

Bloo

dsamples

were

collected

upon

admissionto

the

deliveryroom

forlabor

andwith

in1h

after

vaginal

delivery.AllRO

TEM

tests

were

perfo

rmed

with

the

recommendedreagentsandin

accordance

with

the

manufacturer’s

procedures.Fibrin

ogen

levelswe

remeasuredwith

STA-

fibrin

ogen

reagent(Ro

che

Diagn

osticsG

mbH

,Mannh

eim,G

ermany)

using

Claussmetho

d.

TheA

UCof

ROTE

MFIBT

EMMCF

forp

redictionof

postp

artum

hemorrhaged

efinedas

bloo

dloss≥500mLwas

0.52

(95%

confi

denceinterval0.41–0.64

,p=0

.699),sim

ilarto

thep

redictivep

ower

offib

rinogen

levels(AUC=

0.53,95%

confi

denceinterval0.40–

0.65,p=0

.644

).

[67]

Neurosurgery

Aprospectiveo

bservatio

nalstudy

of92

patients

undergoing

emergent

neurosurgery

Bloo

dwas

sampled

intheop

eratingtheatero

ncitrated

tubesa

ndRO

TEM

analyses

were

perfo

rmed

with

inmin

ofbloo

dsamplingby

anesthesianu

rsesor

physicians

trainedto

perfo

rmtheR

OTE

Mtests

accordingto

them

anufacturer’s

instr

uctio

ns.P

lasm

afib

rinogen

concentrationwas

determ

ined

byClauss

metho

d(Siemens-DadeBe

hringHealth

care

Diagn

ostics,Marbu

rg,G

ermany).

Then

eedfortransfusio

n(≥

3PR

BCs)was

bestpredictedby

EXTE

MandFIBT

EMMCF

(AUCof

0.72

and0.71,

respectiv

ely)

andby

fibrin

ogen

concentration(AUCof

0.70),

with

asensitivity

of38.2,33.3

,25.6%

andspecificityof

85.1,

96.2and100%

.

[60]

AUC=

Areau

nder

thereceiver

operatingcharacteris

ticcurve;CI

=Con

fidence

Interval;C

PB=C

ardiop

ulmon

aryBy

pass;ICU

=Intensiv

eCareU

nit;ISS=

Injury

SeverityScore


increase inmortality occurred [106].The discrepancy impliesthat the negative impact of fibrinogen deficiency in traumamay have been underestimated. It should also be notedthat hypofibrinogenemia prevalence in major bleeding variesacross clinical contexts [107].

Most clinical studies are prospective observational, whilea few are retrospective and randomized controlled. Samplesize ranged from 23 to 1077 patients. In contrast withROTEM, FF TEG has been used less to detect hypofibrino-genemia and predict blood transfusion requirements with afocus on trauma patients. Among various clinical settings,ROTEM FIBTEM has been mostly used in trauma, cardiacsurgery, and liver transplantation with best predictive powerfor hypofibrinogenemia (fibrinogen <1.5 g/L) (AUC=0.99)in cardiac surgery [47]. Furthermore, several studies haveshown that FF TEG and ROTEM FIBTEM could predictbleeding and transfusion requirements in trauma [63, 64],cardiac surgery [52], and liver transplantation [58, 66] withvarious accuracies. It appeared that ROTEMwould have bet-ter predictive accuracy than TEG because it has greater speci-ficity for some common coagulopathies in cardiac surgery,such as fibrinogen deficiency. The averaged likelihood ratioof FF TEG MA for diagnosis of hypofibrinogenemia is4.71±2.18 based on a number of studies [30, 35, 40], while thecorresponding value of ROTEM FIBTEM MCF is 9.24±2.64calculated from the literature [30, 35, 55].

Two studies evaluated ROTEM devices in patients withpostpartum hemorrhage (PPH). One study provided data onthe ability of ROTEM FIBTEM to predict hypofibrinogene-mia (<1.5 g/L) [59]; the other evaluated the predictive powerof ROTEM FIBTEM and Clauss fibrinogen for PPH andfound no associations between the prepartum coagulationparameters and blood loss defined as blood loss ≥ 500 mL[67]. Alternatively, one study showed that FF TEG MAwith a cut-off value of 12.1 mm could predict obstetriccomplications in nonpregnant dysfibrinogenemia patientswith a sensitivity of 100%, specificity of 69.2%, and AUC of0.923, but could not distinguish patients with bleeding andnonbleeding symptoms [108].

Only a few studies demonstrated ROTEM FIBTEM pro-vided faster and better prediction than plasma fibrinogenconcentration formassive transfusion [64] and bleeding [66],respectively. ROTEM FIBTEM provided early prediction ofmassive transfusion in trauma similar to the most predic-tive laboratory parameters (e.g., fibrinogen and hemoglobinconcentrations) [64]. A separate study comparing standardfibrinogen measurement methods (i.e., Clauss method andthrombin clotting time) with ROTEM FIBTEM in patientswith cirrhosis suggested FIBTEM as a promising alternativeto standard plasma fibrinogen measurement in cirrhoticpatients, especially in evaluating fibrin polymerization disor-ders in these patients [62].

There is insufficient evidence or low-quality evidencefor the benefits of TEG and ROTEM for the prediction ofbleeding and adverse outcomes beyond that achieved usingroutinely measured baseline factors or conventional coag-ulation tests (CCTs) except for rapidity. ROTEM EXTEMand FIBTEM were no better than routine laboratory testsfor detecting differences between surviving and nonsurviving

critically ill patients [109]. ROTEM FIBTEM was unableto predict PPH and not superior to CCTs in a prospectiveobservational study of 217 healthy pregnant women [67].On the other hand, ROTEM FIBTEM was not a good testto predict the presence of acute coagulopathy of traumadefined as an international normalized ratio (INR) > 1.3 ora fibrinogen level < 1.5 g/L unless combined with EXTEM,and either of the tests could predict the need for emergentblood product transfusions (defined as ≥5 units of red bloodcells (RBC) and ≥3 units of plasma within the first 24 hof care) [65]. The use of CCTs such as INR in trauma hasbeen severely criticized due to the lack of association withbleeding and blood transfusion. It has been reported thatINR overestimated coagulopathy should not be used to guideblood transfusion in stable trauma and surgical patients [110].

Finally, if fibrinogen deficiency has a causal relationshipwith bleeding and adverse clinical outcomes, it is sensibleto suggest that TEG and ROTEM functional fibrinogen teststhat improve clinical prediction for fibrinogen-related bleed-ing may also have the potential to predict adverse clinicaloutcomes. However, randomized trials are needed to providehigh-quality evidence for the role of TEG and ROTEMin diagnosis, management, and monitoring of fibrinogenfunction and replacement in bleeding patients.

It is noteworthy that recently two large randomized trials,CRASH-2 (Clinical Randomisation of an Antifibrinolyticin Significant Haemorrhage 2) [111] and WOMAN (WorldMaternal Antifibrinolytic) [112], provide high-quality evi-dence for the early use of tranexamic acid for a survivaladvantage to many bleeding patients. An in vitro studyshowed that the antifibrinolytic reduced fibrinogenolysis inaddition to the correction of fibrinolytic effects on TEG (MA,LY) values in the presence of tissue plasminogen activator[113].

6. Comparison between TEG and ROTEM forFunctional Fibrinogen Assays

A number of studies compared the reagents and devicesbetween FF TEG and ROTEM FIBTEM. Solomon et al.showed that FF TEG MA was larger than FIBTEM MCFwhen performed with either their standard assay reagents(lyophilized tissue factor and abciximab on TEG and acombination of ex-tem and fib-tem on ROTEM) or the sameassay reagent [71]. In addition, the FF TEG reagent producedhigher values than the FIBTEM reagent on both TEG andROTEM. Schlimp et al. compared different fibrinogen assaysin eliminating platelet effects on TEG MA and ROTEMMCF. It was found that abciximab based on glycoproteinIIb/IIIa inhibition was less effective at inhibiting the plateletcontribution to clot strength than cytochalasin D based onprevention of platelet cytoskeletal reorganization, resulting inlarger FF TEGMA compared to ROTEM FIBTEMMCF andaffecting their correlations and changes with fibrinogen con-centration. In addition, the combination of both inhibitionsprovided the most accurate assessment of the clot strengthand fibrinogen function [114]. It has been speculated that theROTEM FIBTEM reagent might contain stabilizing agents(e.g., dimethyl sulfoxide) and more tissue factors than the


FF TEG reagent [115]. These results are consistent with otherstudies comparing TEG and ROTEM functional fibrinogenassays forwhole blood from surgical patients [48, 116], traumapatients, and healthy volunteers [91, 114].

However, the differences between FF TEG MA andROTEMFIBTEMMCFobtained using the same reagents [71,115] imply that TEG system itself may also be a contributingfactor. The hardware differences between the two systemsinclude the mechanisms for cup/pin rotation, detection ofthe rotation, cup materials, and interior surface properties[117, 118].

Meyer et al. compared different TEG and ROTEMtests including FF TEG and FIBTEM, and Clauss methodfor detection of trauma-induced coagulopathy and goal-directed transfusion therapy [34]. Specifically, FF TEG andROTEM FIBTEM early amplitudes (A5, 10) and MA/MCFhad similar correlations with Clauss fibrinogen level andcould differentiate coagulopathic and transfused patientsfrom noncoagulopathic and nontransfused patients.

Pruller et al. compared fibrinogen assays using FF TEGand ROTEM FIBTEM in surgical patients in terms oftheir MA and MCF values, and correlations with Claussfibrinogen level [116]. It was found that FF TEG MA washigher than ROTEM FIBTEMMCF and their MA and MCFcorresponded to different Clauss fibrinogen levels. The FFTEGMA showed a weaker correlation with Clauss fibrinogenthan ROTEM FIBTEMMCF (R2=0.542 vs. 0.671).

Different TEG (Rapid, Kaolin, and FF) and ROTEMtests (EXTEM, INTEM, and FIBTEM) were compared fortheir sensitivity to detect fibrinolysis induced by tissue plas-minogen activator in whole blood [119]. Compared to othertests, FF TEG and ROTEM FIBREM provided more rapiddetection of fibrinolysis, but FF TEG detected changes inclot strength as well. Comparison of tissue factor-triggeredROTEM FIBTEM and EXTEMwith contact-activated kaolinTEG in patients undergoing liver transplantation showedthe highest and lowest hyperfibrinolysis detection rates byFIBTEM and kaolin TEG, respectively, suggesting the effectsof coagulation activators and platelet inhibitors on sensitivityto identifying hyperfibrinolysis [120].

In contrast with hyperfibrinolysis detection, we foundonly kaolin TEG and ROTEM EXTEM as the methodsof measuring hypofibrinolysis (also called fibrinolysis shut-down) instead of FF TEG and ROTEM FIBTEM. In onestudy of 914 trauma patients (ISS≥15), the threshold forhypofibrinolysis was determined for EXTEM ML at 5.5%with a sensitivity of 61.6% and specificity of 58.4% [121]. Thestudy reported 29.9% hypofibrinolysis. In another study of550 severe trauma patients with a median ISS of 19, EXTEMML<3.5% was selected to define hypofibrinolysis with asensitivity 42.5% and specificity 76.5% [122]. The methodidentified 25.6% hypofibrinolysis. A number of studies haveused TEG in particular kaolin TEG LY30<0.81% to detecthypofibrinolysis in trauma patients with a median ISS of25 [123, 124]. These studies reported fibrinolysis phenotypeswith different prevalence: hypofibrinolysis at 29.9%, 25.6%,and 46%; physiologic fibrinolysis at 63.0%, 70.7%, and 36%.The ROTEM method indicated physiologic fibrinolysis as

the predominant phenotype with 63% [121] and 71% [122]followed by hypofibrinolysis, while the TEG method showedhypofibrinolysis as the most common phenotype with 46%followed by physiologic fibrinolysis with 36% [124]. Thediscrepancy could be the difference in patients’ characteristics(e.g., ISS) and the method itself (tissue factor-activatedROTEMEXTEM vs. contact-activated kaolin TEG). A recentretrospective analysis of the Pragmatic, Randomized Opti-mal Platelet and Plasma Ratios (PROPPR) trial found 61%of hypofibrinolytic patients as determined by kaolin TEGLY30<0.9%, followed by 22% of hyperfibrinolytic patientsbased on LY30≥3% [125]. The study also suggested thathypofibrinolysis did not reflect shutdown of enzymaticfibrinolysis with hypercoagulability, but rather a type ofcoagulopathy characterized by fibrinolytic activation withconcurrent fibrinogen consumption and platelet dysfunction.

There is a lack of studies to compare the utilities ofTEG and ROTEM for diagnosis of coagulopathy, predictionof mortality, and the requirement for massive transfusion,although both have been reported useful [45, 126]. Weconducted a comparative study of functional fibrinogenassays using TEG and ROTEM in trauma patients [30] todetermine (1) their interchangeability of the key parametervalues obtained by the two systems in all trauma patientsas well as severe trauma patients randomized to receivetheir fibrinogen concentrate or placebo (normal saline), and(2) utility of each system for predicting clinical outcomesand monitoring any changes in coagulation profiles in thetrauma patients randomized for treatment with fibrinogenconcentrate or placebo. In addition, a crossover analysis(ex-tem and fib-tem on TEG) was conducted to confirmwhether the assay reagents or the device could contribute tothe observed differences. Overall, we found that TEG andROTEM parameter values were correlated, being strongestbetween MA and MCF, but were significantly different, andtheir agreement fell outside acceptable limits and thus theirvalues were not interchangeable, arguably due to differencesin both devices and assay reagents used. Specifically, ROTEMFIBTEM MCF had a higher correlation with Clauss fibrino-gen (𝜌=0.87 vs. 0.75) and lower value than FF TEG MA(17.1±8.0 mm vs. 22.4±7.5 mm). Clinically, TEG MA andROTEM MCF showed reasonable predictive accuracy forplasma transfusion, but poor accuracy for any red bloodcells and cryoprecipitate transfusions. Both well predictedhypofibrinogenemia (fibrinogen concentration < 1 g/L) withAUC of 0.95 and 0.96. ROTEM FIBTEM MCF seems to bemore consistent with the duration of the between-group dif-ference as indicated by fibrinogen levels than FF TEGMA. Inaddition, ROTEM FIBTEM detected changes in coagulationtime (CT) and clot lysis (LI30) over hospitalization time as aresult of fibrinogen treatment.

In a study similar to ours, TEG and ROTEM werecompared for functional fibrinogen assays in trauma todetermine specific cut-offs of TEGMAand ROTEMMCF foran increased risk of receiving a transfusion [35]. It was foundthat FF TEGMA and ROTEM FIBTEMMCF correlated well(𝜌=0.71, p<0.001) and had the same correlation coefficientwith Clauss fibrinogen level (𝜌=0.64, p<0.001). Figure 2shows a strong correlation between FFTEGMAand ROTEM


Peng 2018Meyer 2015

r=0.77, p<0.00195% Confidence Interval

0

10

20

30

40

50

ROTE

M F

IBTE

M M

CF (m

m)

10 20 30 40 500FF TEG MA (mm)

Figure 2: Comparison of FF TEGMA values and ROTEM FIBTEMMCF values.The correlation coefficientwas obtained through linearregression of pooled data from Peng 2018 [30] and Meyer 2015[35]. MCF=0.8384MA-1.065 (R2=0.5938). The means ± standarddeviations of FF TEGMAandROTEMFIBTEMMCF are 20.63±7.11mm and 16.23±7.73 mm (n=363).

FIBTEMMCF (r=0.77, p<0.001) based on the pooled data ofour study [30] and Meyer et al. [35], but a larger FF TEGMAthan ROTEM FIBTEM MCF on average (20.63±7.11 mm vs.16.23±7.73mm, n=363, p<0.001).

7. Conclusions

TEG and ROTEM functional fibrinogen tests play importantroles in diagnosis of fibrinogen-related coagulopathy andtransfusion requirements including fibrinogen replacement.The clot strength of FFTEGandROTEMFIBTEM is themostused parameter for discrimination of fibrinogen deficienciesand their correlations with Clauss fibrinogen levels are varieddepending on patient population and range of fibrinogenconcentrations. When using FF TEG and ROTEM FIBTEMto diagnose fibrinogen deficiency and predict transfusionrequirements other variables such as hematocrits, factorXIII levels and fibrinogen concentrate ranges should betaken into consideration. Both TEG and ROTEM have beenused to detect systemic fibrinolysis (physiologic, hypo, andhyperfibrinolysis). Studies comparing FF TEG and ROTEMFIBTEM suggest a stronger correlation of the latter withplasma fibrinogen concentration, likely due to its moreeffective elimination of platelet contribution to clot strength.We should be aware that the studies supporting the use TEGand ROTEM are limited for trauma and surgical bleedingpatients. Even without robust clinical data, TEG and ROTEMare likely to remain popular for the hemostatic managementof bleeding patients.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

References

[1] J. H. Levy, F. Szlam, K. A. Tanaka, and R. M. Sniecienski,“Fibrinogen and hemostasis: A primary hemostatic target forthe management of acquired bleeding,” Anesthesia & Analgesia,vol. 114, no. 2, pp. 261–274, 2012.

[2] D. Fries and W. Z. Martini, “Role of fibrinogen in trauma-induced coagulopathy,” British Journal of Anaesthesia, vol. 105,no. 2, pp. 116–121, 2010.

[3] C. Rourke, N. Curry, S. Khan et al., “Fibrinogen levels duringtrauma hemorrhage, response to replacement therapy, andassociation with patient outcomes,” Journal of Thrombosis andHaemostasis, vol. 10, no. 7, pp. 1342–1351, 2012.

[4] Y. Kimura, S. Kimura, S. Sumita, andM. Yamakage, “Predictorsof hypofibrinogenemia in blunt trauma patients on admission,”Journal of Anesthesia & Clinical Research, vol. 29, no. 2, pp. 242–248, 2015.

[5] K. Inaba, E. Karamanos, T. Lustenberger et al., “Impact offibrinogen levels on outcomes after acute injury in patientsrequiring a massive transfusion,” Journal of the AmericanCollege of Surgeons, vol. 216, no. 2, pp. 290–297, 2013.

[6] Z. K. McQuilten, E. M.Wood,M. Bailey, P. A. Cameron, and D.J. Cooper, “Fibrinogen is an independent predictor of mortalityin major trauma patients: A five-year statewide cohort study,”Injury, vol. 48, no. 5, pp. 1074–1081, 2017.

[7] D. Whiting and J. A. Dinardo, “TEG and ROTEM: technologyand clinical applications,” American Journal of Hematology, vol.89, no. 2, pp. 228–232, 2014.

[8] C. J. Schlimp andH. Schochl, “The role of fibrinogen in trauma-induced coagulopathy,” Hamostaseologie, vol. 34, no. 1, pp. 29–39, 2014.

[9] S. Figueiredo, A. Tantot, and J. Duranteau, “Targeting bloodproducts transfusion in trauma: What is the role of thromboe-lastography?”Minerva Anestesiologica, vol. 82, no. 11, pp. 1214–1229, 2016.

[10] K.Gorlinger, L. Shore-Lesserson,D.Dirkmann,A.A.Hanke,N.Rahe-Meyer, andK. A. Tanaka, “Managementof hemorrhage incardiothoracic surgery,” Journal of Cardiothoracic and VascularAnesthesia, vol. 27, no. 4, pp. S20–S34, 2013.

[11] K. Goerlinger, “Coagulation management during liver trans-plantation,”Hamostaseologie, vol. 26, no. 3, pp. S64–S75, 2006.

[12] M. Ranucci, B. Martinez, D. Colella, and D. Haxhiademi, Point-of-care tests for severe hemorrhage: A manual for diagnosis andtreatment, Cham: Springer International Publishing, 2016.

[13] D. Spahn, G. Spahn, and P. Stein, “Indications and Risks ofFibrinogen in Surgery and Trauma,” Seminars in Thrombosisand Hemostasis, vol. 42, no. 02, pp. 147–154, 2016.

[14] J. H. Levy, I. Welsby, and L. T. Goodnough, “Fibrinogen as atherapeutic target for bleeding: A review of critical levels andreplacement therapy,” Transfusion, vol. 54, no. 5, pp. 1389–1405,2014.

[15] J. H. Levy and L. T. Goodnough, “How I use fibrinogenreplacement therapy in acquired bleeding,” Blood, vol. 125, no.9, pp. 1387–1393, 2015.

[16] J. Stensballe, S. R. Ostrowski, and P. I. Johansson, “Viscoelasticguidance of resuscitation,” Current Opinion in Anaesthesiology,vol. 27, no. 2, pp. 212–218, 2014.

[17] A. Wikkelsø, J. Wetterslev, A. M. Møller, and A. Afshari,“Thromboelastography (TEG) or rotational thromboelastom-etry (ROTEM) to monitor haemostatic treatment in bleedingpatients: a systematic review with meta-analysis and trialsequential analysis,”Anaesthesia, vol. 72, no. 4, pp. 519–531, 2017.


[18] M. Fahrendorff, R. S. Oliveri, and P. I. Johansson, “The useof viscoelastic haemostatic assays in goal-directing treatmentwith allogeneic blood products - A systematic review andmeta-analysis,” Scandinavian Journal of Trauma, Resuscitation andEmergency Medicine , vol. 25, no. 1, article no. 39, 2017.

[19] E. Gonzalez, E. E. Moore, H. B. Moore et al., “Goal-directedhemostatic resuscitation of trauma-induced coagulopathy apragmatic randomized clinical trial comparing a viscoelasticassay to conventional coagulation assays,”Annals of Surgery, vol.263, no. 6, pp. 1051–1059, 2016.

[20] G. F. Serraino and G. J. Murphy, “Routine use of viscoelasticblood tests for diagnosis and treatment of coagulopathic bleed-ing in cardiac surgery: Updated systematic review and meta-analysis,” British Journal of Anaesthesia, vol. 118, no. 6, pp. 823–833, 2017.

[21] P. Whiting, M. Al, M. Westwood et al., “Viscoelastic point-of-care testing to assist with the diagnosis, management andmonitoring of haemostasis: A systematic review and cost-effectiveness analysis,”Health TechnologyAssessment, vol. 19, no.58, pp. 1–228, 2015.

[22] A. Sankarankutty, B. Nascimento, L. T. da Luz, and S. Rizoli,“TEG� and ROTEM� in trauma: Similar test but differentresults?”World Journal of Emergency Surgery, vol. 7, 2012.

[23] M. Coakley, K. Reddy, I. Mackie, and S. Mallett, “TransfusionTriggers in Orthotopic Liver Transplantation: A Comparisonof theThromboelastometry Analyzer, theThromboelastogram,and Conventional Coagulation Tests,” Journal of Cardiothoracicand Vascular Anesthesia, vol. 20, no. 4, pp. 548–553, 2006.

[24] S. Rizoli, A. Min, A. P. Sanchez et al., “In trauma, conventionalROTEMandTEG results are not interchangeable but are similarin clinical applicability,” Military Medicine, vol. 181, no. 5, pp.117–126, 2016.

[25] N. Schafer, A. Driessen, U. Bauerfeind et al., “In vitro effectsof different sources of fibrinogen supplementation on clotinitiation and stability in a model of dilutional coagulopathy,”Transfusion Medicine, vol. 26, no. 5, pp. 373–380, 2016.

[26] M. Mittermayr, W. Streif, T. Haas et al., “Hemostatic changesafter crystalloid or colloid fluid administration during majororthopedic surgery: The role of fibrinogen administration,”Anesthesia & Analgesia, vol. 105, no. 4, pp. 905–917, 2007.

[27] M. Durila, P. Lukas, M. Astraverkhava, and T. Vymazal, “Eval-uation of fibrinogen concentrates and prothrombin complexconcentrates on coagulation changes in a hypothermic in vitromodel using thromboelastometry and thromboelastography,”Scandinavian Journal of Clinical & Laboratory Investigation, vol.75, no. 5, pp. 407–414, 2015.

[28] B. Schenk, A. K. Lindner, B. Treichl et al., “Fibrinogen sup-plementation ex vivo increasesclot firmness comparable toplatelet transfusion in thrombocytopenia,” British Journal ofAnaesthesia, vol. 117, no. 5, pp. 576–582, 2016.

[29] L. T. Da Luz, B. Nascimento, A. K. Shankarakutty, S. Rizoli,and N. K. J. Adhikari, “Effect of thromboelastography (TEG�)and rotational thromboelastometry (ROTEM�) on diagnosis ofcoagulopathy, transfusion guidance and mortality in trauma:Descriptive systematic review,”Critical Care, vol. 18, no. 5, 2014.

[30] H. T. Peng, B. Nascimento, andH. Tien, “A comparative analysisof functional fibrinogen assays using teg and rotem in traumapatients enrolled in the fiirst trial,” Panamerican Journal ofTrauma, Critical Care & Emergency Surgery, vol. 7, pp. 143–157,2018.

[31] B. Nascimento, J. Callum, H. Tien et al., “Fibrinogen in theinitial resuscitation of severe trauma (FiiRST): a randomized

feasibility trial,” British Journal of Anaesthesia, vol. 117, no. 6, pp.775–782, 2016.

[32] J. N. Harr, E. E. Moore, A. Ghasabyan et al., “Functionalfibrinogen assay indicates that fibrinogen is critical in correctingabnormal clot strength following trauma,” Shock, vol. 39, no. 1,pp. 45–49, 2013.

[33] L. Z. Kornblith, M. E. Kutcher, B. J. Redick, C. S. Calfee, R. F.Vilardi, and M. J. Cohen, “Fibrinogen and platelet contribu-tions to clot formation: Implications for trauma resuscitationand thromboprophylaxis,” Journal of Trauma and Acute CareSurgery, vol. 76, no. 2, pp. 255–263, 2014.

[34] A. S. P. Meyer, M. A. S. Meyer, A. M. Sørensen et al.,“Thrombelastography and rotational thromboelastometry earlyamplitudes in 182 trauma patients with clinical suspicion ofsevere injury,” Journal of Trauma and Acute Care Surgery, vol.76, pp. 682–690, 2014.

[35] M. A. S. Meyer, S. R. Ostrowski, A. M. Sørensen et al.,“Fibrinogen in trauma, an evaluation of thrombelastographyand rotational thromboelastometry fibrinogen assays,” Journalof Surgical Research, vol. 194, no. 2, pp. 581–590, 2015.

[36] I. Fluger, K. Maderova, M. Simek, R. Hajek, J. Zapletalova,and V. Lonsky, “Comparison of functional fibrinogen assess-ment using thromboelastography with the standard von claussmethod,” Biomedical Papers, vol. 156, no. 3, pp. 260-261, 2012.

[37] S. Agarwal, R. I. Johnson, and M. Shaw, “A comparison offibrinogenmeasurement using TEG� functional fibrinogen andClauss in cardiac surgery patients,” International Journal ofLaboratory Hematology, vol. 37, no. 4, pp. 459–465, 2015.

[38] I. Fluger, K. Maderova, M. Simek, R. Hajek, J. Zapletalova,and V. Lonsky, “The effect of a cardiopulmonary bypass systemwith biocompatible coating on fibrinogen levels determined bythe TEG-functional fibrinogen method: Preliminary results,”Perfusion, vol. 26, no. 6, pp. 503–509, 2011.

[39] M. Fabbro, J. T. Gutsche, T. A. Miano, J. G. Augoustides, andP. A. Patel, “Comparison of Thrombelastography-Derived Fib-rinogen Values at Rewarming and Following CardiopulmonaryBypass inCardiac SurgeryPatients,”Anesthesia& Analgesia, vol.123, no. 3, pp. 570–577, 2016.

[40] N. K. Gautam, C. Cai, O. Pawelek, M. B. Rafique, D. Cattano,and E. G. Pivalizza, “Performance of functional fibrinogenthromboelastography in children undergoing congenital heartsurgery,” Pediatric Anesthesia, vol. 27, no. 2, pp. 181–189, 2017.

[41] E. Kim, H. S. Shim, W. H. Kim et al., “Predictive Value ofIntraoperative Thromboelastometry for the Risk of Periopera-tive Excessive Blood Loss in Infants and Children UndergoingCongenital Cardiac Surgery,” Survey of Anesthesiology, vol. 61,no. 1, p. 17, 2017.

[42] S. Yang Lu, K. A. Tanaka, E. Abuelkasem, R. M. Planinsic, andT. Sakai, “Clinical applicability of rapid thrombelastographyand functional fibrinogen thrombelastography to adult livertransplantation,” Liver Transplantation, vol. 20, no. 9, pp. 1097–1105, 2014.

[43] V. N. R. Gottumukkala, S. K. Sharma, and J. Philip, “Assessingplatelet and fibrinogen contribution to clot strength usingmodified thromboelastography in pregnantwomen,”Anesthesia& Analgesia, vol. 89, no. 6, pp. 1453–1455, 1999.

[44] J.-S. David, M. Durand, A. Levrat et al., “Correlation betweenlaboratory coagulation testing and thromboelastometry ismod-ified duringmanagement of trauma patients,” Journal of Traumaand Acute Care Surgery, vol. 81, no. 2, pp. 319–327, 2016.


[45] L. Rugeri, A. Levrat, J. S. David et al., “Diagnosis of early coag-ulation abnormalities in trauma patients by rotation thrombe-lastography,” Journal of Thrombosis and Haemostasis, vol. 5, no.2, pp. 289–295, 2007.

[46] H. Tauber, P. Innerhofer, R. Breitkopf et al., “Prevalence andimpact of abnormal ROTEM� assays in severe blunt trauma:Results of the ’Diagnosis and Treatment of Trauma-InducedCoagulopathy (DIA-TRE-TIC) study’,” British Journal of Anaes-thesia, vol. 107, no. 3, pp. 378–387, 2011.

[47] V. Bhardwaj, P. Malhotra, S. Hasija, U. K. Chowdury, andN. Pangasa, “Coagulopathies in cyanotic cardiac patients: Ananalysis with three point - Of - care testing devices (Throm-boelastography, rotational thromboelastometry, and sonoclotanalyzer),”Annals of Cardiac Anaesthesia, vol. 20, no. 2, pp. 212–218, 2017.

[48] C. Solomon, E. Baryshnikova, C. J. Schlimp, H. Schochl, L. M.Asmis, and M. Ranucci, “Fibtem plus provides an improvedthromboelastometry test for measurement of fibrin-based clotquality in cardiac surgery patients,”Anesthesia & Analgesia, vol.117, no. 5, pp. 1054–1062, 2013.

[49] C. Solomon, N. Rahe-Meyer, H. Schochl, M. Ranucci, and K.Gorlinger, “Effect of haematocrit on fibrin-based clot firmnessin the FIBTEM test,” Blood Transfusion, vol. 11, no. 3, pp. 412–418, 2013.

[50] A. Espinosa, R. Stenseth, V.Videm, andH. Pleym, “Comparisonof three point-of-care testing devices to detect hemostaticchanges in adult elective cardiac surgery: A prospective obser-vational study,” BMC Anesthesiology, vol. 14, no. 1, 2014.

[51] H. S. Mace, N. Lightfoot, S. McCluskey et al., “Validityof Thromboelastometry for Rapid Assessment of FibrinogenLevels in Heparinized Samples during Cardiac Surgery: ARetrospective, Single-center, Observational Study,” Journal ofCardiothoracic and Vascular Anesthesia, vol. 30, no. 1, pp. 90–95, 2016.

[52] M. Ranucci and E. Baryshnikova, “Fibrinogen supplementationafter cardiac surgery: Insights from the Zero-Plasma trial(ZEPLAST),” British Journal of Anaesthesia, vol. 116, no. 5, pp.618–623, 2016.

[53] G. Erdoes, G. Gerster, G. Colucci, H. Kaiser, L. Alberio,and B. Eberle, “Prediction of post-weaning fibrinogen statusduring cardiopulmonary bypass: An observational study in 110patients,” PLoS ONE, vol. 10, no. 5, 2015.

[54] H. Seo, J.-H. Choi, Y.-J. Moon, and S.-M. Jeong, “FIBTEM ofthromboelastometry does not accurately represent fibrinogenconcentration in patients with severe hypofibrinogenemia dur-ing liver transplantation,” Annals of Transplantation, vol. 20, pp.342–350, 2015.

[55] S.-M. Jeong, J.-G. Song, H. Seo, J.-H. Choi, D.-M. Jang, andG.-S. Hwang, “Quantification of Both Platelet Count andFibrinogen Concentration Using Maximal Clot Firmness ofThromboelastometry during Liver Transplantation,”Transplan-tation Proceedings, vol. 47, no. 6, pp. 1890–1895, 2015.

[56] A. Blasi, J. Beltran, A. Pereira et al., “An assessment ofthromboelastometry to monitor blood coagulation and guidetransfusion support in liver transplantation,” Transfusion, vol.52, no. 9, pp. 1989–1998, 2012.

[57] S. Roullet, J. Pillot, G. Freyburger et al., “Rotation thromboelas-tometry detects thrombocytopenia and hypofibrinogenaemiaduring orthotopic liver transplantation,” British Journal ofAnaesthesia, vol. 104, no. 4, pp. 422–428, 2010.

[58] J.-G. Song, S.-M. Jeong, I.-G. Jun, H.-M. Lee, and G.-S. Hwang,“Five-minute parameter of thromboelastometry is sufficient to

detect thrombocytopenia and hypofibrinogenaemia in patientsundergoing liver transplantation,”British Journal ofAnaesthesia,vol. 112, no. 2, pp. 290–297, 2014.

[59] C. Huissoud, N. Carrabin, F. Audibert et al., “Bedside assess-ment of fibrinogen level in postpartum haemorrhage bythrombelastometry,” BJOG: An International Journal of Obstet-rics & Gynaecology, vol. 116, no. 8, pp. 1097–1102, 2009.

[60] C. Ellenberger, N. Garofano, G. Barcelos, J. Diaper, G. Pavlovic,and M. Licker, “Assessment of Haemostasis in patients under-going emergent neurosurgery by rotational Elastometry andstandard coagulation tests: a prospective observational study,”BMC Anesthesiology, vol. 17, no. 1, 2017.

[61] E. Schaden,D. Hoerburger, S. Hacker, P. Kraincuk,D.M. Baron,and S. Kozek-Langenecker, “Fibrinogen function after severeburn injury,” Burns, vol. 38, no. 1, pp. 77–82, 2012.

[62] D. Vucelic, R. Jesic, S. Jovicic et al., “Comparison of standardfibrinogen measurement methods with fibrin clot firmnessassessed by thromboelastometry in patients with cirrhosis,”Thrombosis Research, vol. 135, no. 6, pp. 1124–1130, 2015.

[63] P. I. Johansson, A. M. Sørensen, C. F. Larsen et al., “Lowhemorrhage-related mortality in trauma patients in a Leveli trauma center employing transfusion packages and earlythromboelastography-directed hemostatic resuscitation withplasma andplatelets,”Transfusion, vol. 53, no. 12, pp. 3088–3099,2013.

[64] H. Schochl, B. Cotton, K. Inaba et al., “FIBTEM provides earlyprediction of massive transfusion in trauma,” Critical Care, vol.15, no. 6, 2011.

[65] M. L. Tonglet, J.-L. Poplavsky, L. Seidel, J. M. Minon, V. D’Orio,and A. Ghuysen, “Thromboelastometry in trauma care: a placein the 2018 Belgian health care system?” Acta Clinica Belgica:International Journal of Clinical and Laboratory Medicine, pp.1–7, 2018.

[66] T. M. Dotsch, D. Dirkmann, D. Bezinover et al., “Assessmentof standard laboratory tests and rotational thromboelastometryfor the prediction of postoperative bleeding in liver transplanta-tion,” British Journal of Anaesthesia, vol. 119, no. 3, pp. 402–410,2017.

[67] L. Kaufner, A. Henkelmann, C. Von Heymann et al., “Canprepartum thromboelastometry-derived parameters and fib-rinogen levels really predict postpartum hemorrhage?” Journalof Perinatal Medicine, vol. 45, no. 4, pp. 427–435, 2017.

[68] H. Schochl, W. Voelckel, A. Grassetto, and C. J. Schlimp,“Practical application of point-of-care coagulation testing toguide treatment decisions in trauma,” Journal of Trauma andAcute Care Surgery, vol. 74, no. 6, pp. 1587–1598, 2013.

[69] W. Schobersberger, D. Fries, M. Mittermayr et al., “Changesof biochemical markers and functional tests for clot formationduring long-haul flights,” Thrombosis Research, vol. 108, no. 1,pp. 19–24, 2002.

[70] L. Anderson, I. Quasim, M. Steven et al., “Interoperator andintraoperator variability of whole blood coagulation assays: Acomparison of thromboelastography and rotational thromboe-lastometry,” Journal of Cardiothoracic and Vascular Anesthesia,vol. 28, no. 6, pp. 1550–1557, 2014.

[71] C. Solomon, B. Sørensen, G. Hochleitner, J. Kashuk, M.Ranucci, and H. Schochl, “Comparison of whole blood fibrin-based clot tests in thrombelastography and thromboelastome-try,” Anesthesia & Analgesia, vol. 114, no. 4, pp. 721–730, 2012.

[72] N. Rahe-Meyer, C. Solomon, M. Vorweg et al., “Multicentriccomparison of single portion reagents and liquid reagents for


thromboelastometry,” Blood Coagulation & Fibrinolysis, vol. 20,no. 3, pp. 218–222, 2009.

[73] P. A. Gurbel, K. P. Bliden, U. S. Tantry et al., “First report of thepoint-of-care TEG: A technical validation study of the TEG-6Ssystem,” Platelets, vol. 27, no. 7, pp. 642–649, 2016.

[74] J. D. Dias, E. I. Haney, B. A. Mathew, C. G. Lopez-Espina,A. W. Orr, and M. A. Popovsky, “New-Generation Throm-boelastography: Comprehensive Evaluation of Citrated andHeparinized Blood Sample Storage Effect on Clot-FormingVariables,”Archives of Pathology& LaboratoryMedicine, vol. 141,no. 4, pp. 569–577, 2017.

[75] K. Gorlinger, J. Iqbal, D. Dirkmann, and K. A. Tanaka, “Wholeblood assay: Thromboelastometry,” Management of BleedingPatients, pp. 37–64, 2016.

[76] D. A. Grimes and K. F. Schulz, “Refining clinical diagnosis withlikelihood ratios,”The Lancet, vol. 365, no. 9469, pp. 1500–1505,2005.

[77] V. G. Nielsen, B. M. Cohen, and E. Cohen, “Effects of coagu-lation factor deficiency on plasma coagulation kinetics deter-mined via thrombelastography�: Critical roles of fibrinogen andfactors II, VII, X and XII,” Acta Anaesthesiologica Scandinavica,vol. 49, no. 2, pp. 222–231, 2005.

[78] V. G. Nielsen, “Colloids decrease clot propagation and strength:Role of factor XIII-fibrin polymer and thrombin-fibrinogeninteractions,” Acta Anaesthesiologica Scandinavica, vol. 49, no.8, pp. 1163–1171, 2005.

[79] D. Fries, P. Innerhofer, C. Reif et al., “The effect of fibrinogensubstitution on reversal of dilutional coagulopathy: An in vitromodel,” Anesthesia & Analgesia, vol. 102, no. 2, pp. 347–351,2006.

[80] D. Fries, A. Krismer, A. Klingler et al., “Effect of fibrinogen onreversal of dilutional coagulopathy: A porcine model,” BritishJournal of Anaesthesia, vol. 95, no. 2, pp. 172–177, 2005.

[81] C. Fenger-Eriksen, E. Anker-Møller, J. Heslop, J. Ingerslev, andB. Sørensen, “Thrombelastographic whole blood clot formationafter ex vivo addition of plasma substitutes: Improvements ofthe induced coagulopathy with fibrinogen concentrate,” BritishJournal of Anaesthesia, vol. 94, no. 3, pp. 324–329, 2005.

[82] K. Gorlinger, D. Dirkmann, C. Solomon, andA. A. Hanke, “Fastinterpretation of thromboelastometry in non-cardiac surgery:Reliability in patients with hypo-, normo-, and hypercoagula-bility,” British Journal of Anaesthesia, vol. 110, no. 2, pp. 222–230,2013.

[83] U. Kalina, H.-A. Stohr, H. Bickhard et al., “Rotational throm-boelastography for monitoring of fibrinogen concentrate ther-apy in fibrinogen deficiency,” Blood Coagulation & Fibrinolysis,vol. 19, no. 8, pp. 777–783, 2008.

[84] I. J. Mackie, A. S. Lawrie, S. Kitchen et al., “A performanceevaluation of commercial fibrinogen reference preparations andassays for clauss and PT-derived fibrinogen,” Thrombosis andHaemostasis, vol. 87, no. 6, pp. 997–1005, 2002.

[85] S. C. Koh, C. Y. Chew, O. A. Viegas, M. Choo, and S. S. Ratnam,“Influence of circulatingD-dimer levels on assays of fibrinogen,”ANNALS Academy of Medicine Singapore, vol. 23, pp. 856–860,1994.

[86] L. M. Asmis, “Coagulation factor concentrates,” in Perioperativehemostasis: Coagulation for anesthesiologists, C. E.Marcucci andP. Schoettker, Eds., pp. 177–204, Springer, Berlin, Heidelberg,2015.

[87] H. Schochl, W. Voelckel, and C. Solomon, “Detection andimpact of hyperfibrinolysis in trauma,” Wiener KlinischeWochenschrift, vol. 122, no. 5, pp. S11–S13, 2010.

[88] R. Gertler, G. Wiesner, P. Tassani-Prell, S.-L. Braun, and K.Martin, “Are the point-of-care diagnostics MULTIPLATE andROTEM valid in the setting of high concentrations of heparinand its reversal with protamine?” Journal of Cardiothoracic andVascular Anesthesia, vol. 25, no. 6, pp. 981–986, 2011.

[89] B. S. Romlin, H. Wahlander, M. Synnergren, F. Baghaei, andA. Jeppsson, “Earlier detection of coagulopathy with throm-boelastometry during pediatric cardiac surgery: A prospectiveobservational study,”Pediatric Anesthesia, vol. 23, no. 3, pp. 222–227, 2013.

[90] A. M. H. P. Van Den Besselaar, C. J. J. Van Rijn, C. M.Cobbaert et al., “Fibrinogen determination according to Clauss:Commutability assessment of International and commercialstandards and quality control samples,” Clinical Chemistry andLaboratory Medicine, vol. 55, no. 11, pp. 1761–1769, 2017.

[91] C. Solomon, J. Cadamuro, B. Ziegler et al., “A comparisonof fibrinogen measurement methods with fibrin clot elasticityassessed by thromboelastometry, before and after administra-tion of fibrinogen concentrate in cardiac surgery patients,”Transfusion, vol. 51, no. 8, pp. 1695–1706, 2011.

[92] C. Fenger-Eriksen, G. W. Moore, S. Rangarajan, J. Ingerslev,and B. Sørensen, “Fibrinogen estimates are influenced bymeth-ods of measurement and hemodilution with colloid plasmaexpanders,” Transfusion, vol. 50, no. 12, pp. 2571–2576, 2010.

[93] D. Winstedt, C. Solomon, A. Hillarp, T. Lundahl, and U.Schott, “Intraoperative Hydroxyethyl Starch and its Effectson Different Fibrinogen Measurements,” Clinical and AppliedThrombosis/Hemostasis, vol. 22, no. 7, pp. 641–647, 2016.

[94] C. Solomon, E. Baryshnikova, A. Tripodi et al., “Fibrinogenmeasurement in cardiac surgery with cardiopulmonary bypass:Analysis of repeatability and agreement of Clauss methodwithin and between six different laboratories,” Thrombosis andHaemostasis, vol. 112, no. 1, pp. 109–117, 2014.

[95] A. Agren, A. T. Wikman, A. Ostlund, and G. Edgren, “TEG�functional fibrinogen analysis may overestimate fibrinogenlevels,”Anesthesia & Analgesia, vol. 118, no. 5, pp. 933–935, 2014.

[96] O.Thomas, H. Rein, K. Strandberg, and U. Schott, “Coagulativesafety of epidural catheters after major upper gastrointestinalsurgery: advanced and routine coagulation analysis in 38patients,” Perioperative Medicine, vol. 5, no. 1, 2016.

[97] C. J. Schlimp, J. Cadamuro, C. Solomon, H. Redl, and H.Schochl, “The effect of fibrinogen concentrate and factor XIII onthromboelastometry in 33% diluted blood with albumin, gela-tine, hydroxyethyl starch or saline in vitro,” Blood Transfusion,vol. 11, no. 4, pp. 510–517, 2013.

[98] V. G. Nielsen, W. Q. Gurley, and T. M. Burch, “The Impactof Factor XIII on Coagulation Kinetics and Clot StrengthDetermined by Thrombelastography,” Anesthesia & Analgesia,vol. 99, no. 1, pp. 120–123, 2004.

[99] S. Ogawa, F. Szlam, D. Bolliger, T. Nishimura, E. P. Chen,and K. A. Tanaka, “The Impact of Hematocrit on FibrinClot Formation Assessed by Rotational Thromboelastometry,”Anesthesia & Analgesia, vol. 115, no. 1, pp. 16–21, 2012.

[100] A. S. Jensen, P. I. Johansson, L. Bochsen et al., “Fibrinogenfunction is impaired inwhole blood frompatientswith cyanoticcongenital heart disease,” International Journal of Cardiology,vol. 167, no. 5, pp. 2210–2214, 2013.

[101] H. T. Peng and S. G. Rhind, “Thromboelastographic Studyof Psychophysiological Stress,” Clinical and Applied Thrombo-sis/Hemostasis, vol. 21, no. 6, pp. 497–512, 2015.

[102] R. C. Carroll, R. M. Craft, J. J. Chavez, C. C. Snider, R. K. Kirby,and E. Cohen, “Measurement of functional fibrinogen levels


using the Thrombelastograph,” Journal of Clinical Anesthesia,vol. 20, no. 3, pp. 186–190, 2008.

[103] A. Rizza, Z. Ricci, C. Pezzella et al., “Kaolin-activated throm-boelastography and standard coagulation assays in cyanoticand acyanotic infants undergoing complex cardiac surgery: aprospective cohort study,” Pediatric Anesthesia, vol. 27, no. 2, pp.170–180, 2017.

[104] R. J. Parker, K. A. Eley, S. Von Kier, O. Pearson, and S.R. Watt-Smith, “Functional fibrinogen to platelet ratio usingthromboelastography as a predictive parameter for thromboticcomplications following free tissue transfer surgery: A prelimi-nary study,”Microsurgery, vol. 32, no. 7, pp. 512–519, 2012.

[105] S. R. Ostrowski, N. Haase, R. B. Muller et al., “Associationbetween biomarkers of endothelial injury and hypocoagulabil-ity in patients with severe sepsis: A prospective study,” CriticalCare, vol. 19, no. 1, 2015.

[106] J. S. Hagemo, S. Stanworth, N. P. Juffermans et al., “Prevalence,predictors and outcome of hypofibrinogenaemia in trauma: Amulticentre observational study,” Critical Care, vol. 18, no. 2,2014.

[107] Z. K. McQuilten, M. Bailey, P. A. Cameron et al., “Fibrinogenconcentration and use of fibrinogen supplementation withcryoprecipitate in patients with critical bleeding receivingmassive transfusion: a bi-national cohort study,” British Journalof Haematology, vol. 179, no. 1, pp. 131–141, 2017.

[108] J. Zhou, Y. Xin, Q. Ding et al., “Thromboelastographypredicts risks of obstetric complication occurrence in(hypo)dysfibrinogenemia patients under non-pregnantstate,” Clinical and Experimental Pharmacology and Physiology,vol. 43, no. 2, pp. 149–156, 2016.

[109] A. Larsson, N. Tynngard, T. Kander, J. Bonnevier, andU. Schott,“Comparison of point-of-care hemostatic assays, routine coag-ulation tests, and outcome scores in critically ill patients,”Journal of Critical Care, vol. 30, no. 5, pp. 1032–1038, 2015.

[110] S. P. McCully, L. J. Fabricant, N. R. Kunio et al., “The inter-national normalized ratio overestimates coagulopathy in stabletrauma and surgical patients,” Journal of Trauma andAcute CareSurgery, vol. 75, no. 6, pp. 947–953, 2013.

[111] H. Shakur, I. Roberts, and R. Bautista, “Effects of tranexamicacid on death, vascular occlusive events, and blood transfusionin trauma patients with significant haemorrhage (CRASH-2): arandomised, placebo-controlled trial,” The Lancet, vol. 376, no.9734, pp. 23–32, 2010.

[112] H. Shakur, I. Roberts, B. Fawole et al., “Effect of earlytranexamic acid administration on mortality, hysterectomy,and other morbidities in women with post-partum haemor-rhage (woman): An international, randomised, double-blind,placebo-controlled trial,” The Lancet, vol. 389, pp. 2105–2116,2017.

[113] A.Godier, K. Parmar, K.Manandhar, andB. J. Hunt, “An in vitrostudy of the effects of t-PA and tranexamic acid on whole bloodcoagulation and fibrinolysis,” Journal of Clinical Pathology, vol.70, no. 2, pp. 154–161, 2017.

[114] C. J. Schlimp, C. Solomon, M. Ranucci, G. Hochleitner, H.Redl, and H. Schochl, “The effectiveness of different functionalfibrinogen polymerization assays in eliminating platelet contri-bution to clot strength in thromboelastometry,” Anesthesia &Analgesia, vol. 118, no. 2, pp. 269–276, 2014.

[115] C. J. Schlimp, C. Solomon, G. Hochleitner, J. Zipperle, H.Redl, and H. Schochl, “Thromboelastometric maximum clotfirmness in platelet-free plasma is influenced by the assay used,”Anesthesia & Analgesia, vol. 117, no. 1, pp. 23–29, 2013.

[116] F. Pruller, A. Munch, A. Preininger et al., “Comparison of func-tional fibrinogen (FF/CFF) and FIBTEM in surgical patients– a retrospective study,” Clinical Chemistry and LaboratoryMedicine (CCLM), vol. 54, no. 3, 2016.

[117] V. G. Nielsen, “A comparison of theThrombelastograph and theROTEM,” Blood Coagulation & Fibrinolysis, vol. 18, no. 3, pp.247–252, 2007.

[118] T. Tomori, D. Hupalo, K. Teranishi et al., “Evaluation of coagu-lation stages of hemorrhaged swine: Comparison of thromboe-lastography and rotational elastometry,” Blood Coagulation &Fibrinolysis, vol. 21, no. 1, pp. 20–27, 2010.

[119] J. N. Harr, E. E.Moore, T. L. Chin et al., “Viscoelastic hemostaticfibrinogen assays detect fibrinolysis early,” European Journal ofTrauma and Emergency Surgery, vol. 41, no. 1, pp. 49–56, 2014.

[120] E. Abuelkasem, S. Lu, K. Tanaka, R. Planinsic, and T. Sakai,“Comparison between thrombelastography and thromboelas-tometry in hyperfibrinolysis detection during adult liver trans-plantation,” British Journal of Anaesthesia, vol. 116, no. 4, pp.507–512, 2016.

[121] L. S. Gall, P. Vulliamy, S. Gillespie et al., “The S100A10 Path-way Mediates an Occult Hyperfibrinolytic Subtype in TraumaPatients,” Annals of Surgery, p. 1, 2018.

[122] J. C.Gomez-Builes, S. A. Acuna, B.Nascimento, F.Madotto, andS. B. Rizoli, “Harmful or Physiologic,” Anesthesia & Analgesia,vol. 127, no. 4, pp. 840–849, 2018.

[123] H. B.Moore, E. E. Moore, E. Gonzalez et al., “Hyperfibrinolysis,physiologic fibrinolysis, and fibrinolysis shutdown: the spec-trum of postinjury fibrinolysis and relevance to antifibrinolytictherapy,”The Journal of Trauma and Acute Care Surgery, vol. 77,no. 6, pp. 811–817, 2014.

[124] H. B. Moore, E. E. Moore, I. N. Liras et al., “Acute FibrinolysisShutdown after InjuryOccurs Frequently and IncreasesMortal-ity: AMulticenter Evaluation of 2,540 Severely InjuredPatients,”Journal of the American College of Surgeons, vol. 222, no. 4, pp.347–355, 2016.

[125] J. C. Cardenas, C. E. Wade, B. A. Cotton et al., “Teg Lysis Shut-down Represents Coagulopathy in Bleeding Trauma Patients,”Shock, p. 1, 2018.

[126] R. Carroll, R. Craft, and R. Langdon, “Early Evaluation of AcuteTraumatic Coagulopathy by Thrombelastography,” Journal ofVascular Surgery, vol. 51, no. 1, p. 280, 2010.

Stem Cells International

Hindawiwww.hindawi.com Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawiwww.hindawi.com

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwww.hindawi.com Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwww.hindawi.com

Submit your manuscripts atwww.hindawi.com

https://www.hindawi.com/journals/sci/

https://www.hindawi.com/journals/mi/

https://www.hindawi.com/journals/ije/

https://www.hindawi.com/journals/dm/

https://www.hindawi.com/journals/bmri/

https://www.hindawi.com/journals/jo/

https://www.hindawi.com/journals/omcl/

https://www.hindawi.com/journals/ppar/

https://www.hindawi.com/journals/tswj/

https://www.hindawi.com/journals/jir/

https://www.hindawi.com/journals/jobe/

https://www.hindawi.com/journals/cmmm/

https://www.hindawi.com/journals/bn/

https://www.hindawi.com/journals/joph/

https://www.hindawi.com/journals/jdr/

https://www.hindawi.com/journals/art/

https://www.hindawi.com/journals/grp/

https://www.hindawi.com/journals/pd/

https://www.hindawi.com/journals/ecam/

https://www.hindawi.com/

https://www.hindawi.com/

thromboelastography and thromboelastometry in assessment of fibrinogen … · 2018. 5. 28. ·...

Documents