2011 viscoelastic coagulation testing-technology applications and limitations

R E V I EW

Viscoelastic coagulation testing: technology, applications,and limitations

Maureen A. McMichael1, Stephanie A. Smith2

1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, and 2Department of Biochemistry, College of Medicine, University of Illinois

at Urbana-Champaign, Urbana, IL, USA

Key Words

Hypercoagulability, ROTEM, Sonoclot,

thrombelastography, thromboelastometry

Correspondence

Maureen A. McMichael, Department of

Veterinary Clinical Sciences, College of

Veterinary Medicine, University of Illinois at

Urbana-Champaign, 1008 West Hazelwood

Dr., Urbana, IL 61802, USA

E-mail: [email protected]

DOI:10.1111/j.1939-165X.2011.00302.x

Abstract: Use of viscoelastic point-of-care (POC) coagulation instrumen-tation is relatively new to veterinary medicine. In human medicine, this

technology has recently undergone resurgence owing to its capacity to de-

tect hypercoagulability. The lack of sensitive tests for detecting hypercoag-

ulable states, along with our current understanding of in vivo coagulation,

highlights the deficiencies of standard coagulation tests, such as pro-

thrombin and partial thromboplastin times, which are performed on plate-

let-poor plasma. Viscoelastic coagulation analyzers can provide an

assessment of global coagulation, from the beginning of clot formation to

fibrinolysis, utilizing whole blood. In people, use of this technology has

been reported to improve management of hemostasis during surgery and

decrease usage of blood products and is being used as a rapid screen for

hypercoagulability. In veterinary medicine, clinical use of viscoelastic tech-

nology has been reported in dogs, cats, foals, and adult horses. This article

will provide an overview of the technology, reagents and assays, applica-

tions in human and veterinary medicine, and limitations of the 3 visco-

elastic POC analyzers in clinical use.

I. Introduction

II. Sonoclot

A. Technology

B. Variables

C. Reagents and assays

D. Application: human medicine

E. Application: veterinary medicine

F. Advantages and limitations

III. Thrombelastography

A. Technology

B. Variables





IV. Thromboelastometry

A. Technology

B. Variables





V. Viscoelastic testing

A. Advantages

B. Limitations

C. Comparison with standard plasma-based coagulation testing

D. Methods

VI. Conclusions

VII. References

Introduction

Hemostasis is a complex series of physiologic events

culminating in the formation of a fibrin clot through

the proteolytic action of thrombin on fibrinogen. Re-

cent advancements in the study of coagulation have

elucidated the important contribution of cells to the

hemostatic process. The cell-based model places em-

phasis on platelets and tissue factor-bearing cells while

also taking into account the contribution of membrane

surfaces, microparticles, enzyme systems, and endo-

thelial cells. An in-depth review of the cell-based

model of coagulation has been published previously.1

Our current understanding of in vivo coagulation

highlights the limitations of standard coagulation tests,

such as prothrombin time (PT) and activated partial

thromboplastin time (aPTT), which do not incorporate

cellular elements or only provide data on isolated com-

ponents of the coagulation cascade. Although valuable

140 Vet Clin Pathol 40/2 (2011) 140153 c2011 American Society for Veterinary Clinical Pathology

Veterinary Clinical Pathology ISSN 0275-6382

for examining specific components of enzymatic cas-

cades, these tests overlook such factors as rate of clot

formation, overall clot strength, and rate and degree of

dissolution, factors that represent significant interac-

tions essential to evaluation of the hemostatic system

in clinical patients.

In 1889 Hayem2 suggested that quantification of the

changes that occur in blood viscosity during clotting

could be utilized as the basis for a test that monitors co-

agulation function. Blood clots have both elastic and vis-

cous properties and technological methods have been

developed to assess these properties. Elasticity, or firm-

ness, refers to the reversible deformation of a material

under stress; the modulus of elasticity is a measure of

stiffness. Viscous properties, referring to stickiness or

thickness, cause blood to have high resistance to flow.

Elasticity of a blood clot is affected primarily by fibrin

and platelets in the sample.35 The first coagulovisco-

meter, a machine designed to detect viscous changes in

blood during clotting, was introduced in 1910 by Koff-

man.6 Significant improvements have occurred in the

evolution of the technology since that time.

Viscoelastic point-of-care (POC) devices provide in

vitro assessment of global coagulation, from beginning

of clot formation to fibrinolysis. Most conventional

coagulation tests end when the first fibrin strands are

developing, whereas viscoelastic coagulation tests begin

at this point and continue through clot development,

retraction, and lysis. An analogy, suggested by Hartert,7

compares coagulation testing to the building of a house;

conventional coagulation tests end with the laying of

the foundation, whereas viscoelastic testing provides

information about the entire house, including the speed

of the building process and the final strength of the

completed house. This technologymeasures the kinetics

of clot formation (the time needed for the clot to form),

the mechanical properties of the clot (tensile strength),

and the time to dissolution of the clot (fibrinolysis).

The tensile strength of the clot provides information

about the capacity of the clot to achieve hemostasis, and

the kinetics determine the adequacy of the quantitative

factors available for the clot to form.

The capability of utilizing whole blood in visco-

elastic kinetic testing is an additional advantage of this

approach for evaluating the coagulation system.

Whole blood contains cells that provide the charged

phospholipid cell surfaces necessary for enzymatic

reactions. It also provides the platelets that further

participate in coagulation by releasing granule con-

tents and providing a surface for amplification and

propagation of the clot.1

Clinically relevant benefits of viscoelastic testing of

clot dynamics are found in both human and veterinary

medicine. The use of viscoelastic coagulation analyzers

has resulted in improved management of hemostasis

during surgery, decreased usage of blood products,

rapid identification of mechanical (vessel) bleeding

postoperatively, more accurate anticoagulation

management, and rapid screening for hyper-

coagulability.810 This article will review the technol-

ogy, reagents, applications, and limitations of the

viscoelastic POC analyzers available for clinical use.

There are 3 instruments currently used in veteri-

nary and human medicine; the Sonoclot coagulation

and platelet function analyzer or Sonoclot (Sienco

Inc., Arvada, CO, USA), the TEG thrombelastograph

hemostasis analyzer or TEG (Haemonetics Corpora-

tion, Braintree, MA, USA), and the ROTEM (Penta-

pharm GmbH, Munich, Germany). The Sonoclot and

ROTEM measure changes in impedance to movement

of a vibrating probe immersed in a blood sample,

whereas TEG utilizes an oscillating cup with a fixed

probe or piston. The probe is a torsion wire in TEG

technology, whereas an optical detector is used by the

ROTEM. All 3 instruments measure the rate of fibrin

formation, clot strength, and clot lysis. The TEG and

ROTEM have become increasingly used in POC man-

agement of trauma and perioperative bleeding during

cardiac and liver transplantation in people.8,11,12 In

1966 the Haemoscope Corporation (now part of

Haemonectics Corporation) registered trademarks for

the terms thrombelastography and TEG; thus, these

terms are limited to evaluations done with the Haemo-

scope analyzers. Pentapharm GmbH has also registered

trademarks for the terms ROTEM and thromboelas-

tometry. The technology and data obtained are

similar; for the purposes of this review TE will refer

to analysis done with either the ROTEM or the TEG.

The variables recorded by the 3 instruments and the

associated terminology are summarized (Table 1).

Sonoclot

The Sonoclot analyzer, introduced by von Kaulla in

1975,13 uses whole blood or plasma. The instrument

detects viscoelastic changes that occur during clotting

(http://www.sienco.com/sonooverview.html).

Technology

The procedure begins with a hollow, disposable plastic

probe placed onto the transducer head before adding

the test sample, either whole blood or plasma, to a

cuvette. The sample is mixed automatically and

then the probe is immersed into the sample and begins

to oscillate. When the clot begins to form it impedes

the movement of the probe by creating a viscous

Vet Clin Pathol 40/2 (2011) 140153 c2011 American Society for Veterinary Clinical Pathology 141

McMichael and Smith Viscoelastic coagulation testing

drag, and this impedance is captured electronically as

resistance to motion that the probe encounters in the

blood sample.14

Variables

The Sonoclot analyzer provides information both

quantitatively and qualitatively as Sonoclot Signature

(SS; Figure 1). Coagulation reactions develop from the

beginning of the SS and continue throughout the liq-

uid phase. The end of the liquid phase is reported as

Onset in the SS (also called the SonACT) and is de-

fined as an upward deflection of 1.0mm calculated by

the instrument.14

The gradient of the first slope (R1) indicates theinitial rate of fibrin formation. This is the point where

identification of hypercoagulability is made and is the

reference point for anticoagulant management. There

is a variable shoulder between R1 and R2 that repre-sents the lag time before the start of contraction of the

fibrin strands by the action of platelets. The second

slope (R2) indicates platelet action resulting in contrac-tion of the clot, further fibrin formation, and fibrin po-

lymerization. The third slope (R3) is a downward slopeindicating platelet retraction and the clot pulling away

from the cuvette walls. R3 is an indicator of plateletnumber and function. As a normal clot retracts it tight-

ens and causes the SS to rise owing to increased im-

pedance of the probe to movement. Then at some later

time, the SS falls when the clot pulls away from the

inner surface of the probe or cuvette owing to loss of

impedance, allowing free movement of the probe.

Measurements of the time it takes for retraction and

the degree of retraction permit analysis of platelet

function.

Coagulation and fibrin gel formation are not

affected by hyperfibrinolysis or early clot breakdown,

but platelet function can be significantly reduced in

these circumstances owing to inhibition of platelet

function by plasmin. If poor clot retraction is the result

of plasmin inhibition of platelets, treatment of hyper-

fibrinolysis with plasmin inhibitor will improve the

abnormal clot retraction as observed on the SS. In this

case, the SS will lack the characteristic rise (R2) and fall(R3) associated with normal clot retraction owing toplasmin inhibition of platelet function.

Quantitative results are reported as activated clot

time (ACT) in seconds (s), clot rate (CR; D signal/s),platelet function (PF; no units), time to peak (TP; s),

and peak clot strength (PCS; clot signal). ACT is com-

parable to conventional plasma ACT.14 CR represents

the rate of clot formation and is the maximum slope of

the SS. PF is derived from the timing and quality of clot

retraction, is calculated using an algorithm performed

by the accompanying software program, and repre-

sents platelet function.15 TP is used to characterize clot

retraction, and faster TP times are correlated with

greater platelet function. PCS is the point in the

SS with the largest signal amplitude and represents

maximal clot stiffness. In people PCS is influenced by

fibrinogen concentration.

Figure 1. Sonoclot Signature. Shown are activated clotting time (Son-

ACT), clot rate, time to peak, clot retraction, and the 3 slopes, R1, R2, and

R3. ACT, activated clot time.

Table 1. Comparison of the coagulation variables recorded by the Sonoclot, TEG, and ROTEM.

Development of Clot Factors Affecting Clot Sonoclot TEG ROTEM

Initial fibrin formation Factor XII and XI activity; reflective of intrinsic

pathway if activators not used

SonACT Reaction time (R) Clot time (CT)

Development of clot or

rapidity of clot formation

Factor II and VIII activity, platelet count and function,

thrombin, fibrinogen, HCT

Clot rate (CR) Kinetics (K) and aangle (a)

Clot formation

time (CFT) and aangle (a)

Maximal clot strength Fibrinogen, platelet count and function, thrombin,

factor XIII activity, HCT

Peak amplitude

and time to peak

Maximum amplitude

(MA)

Maximum clot

firmness (MCF)

Fibrinolysis Hyperfibrinolysis R3 Clot lysis (CL30,

CL60)

Lysis (LY30, LY60)


McMichael and SmithViscoelastic coagulation testing

Reagents and assays

Cuvettes contain different coagulation activators or in-

hibitors depending on the type of analysis desired. A

cuvette without activator is frequently used to create

the initial SS (Figure 1). Celite, a contact activator, is

available in high concentration to measure ACT and

low concentration to accelerate analysis and creation

of the SS. Glass beadsheparinase are also available tomeasure coagulation in the absence and presence of

heparin.

Application: human medicine

One study comparing the Sonoclot with conventional

ACT instruments (eg, Hemochron; ITC, Edison, NJ,

USA) found the 2 instruments to be comparable.16 Use

of the Sonoclot analyzer has been reported during

cardiopulmonary bypass and liver transplant surgery

in people as a rapid method to monitor anticoagulant

therapy (Figure 2).10,17 It has also been used to identify

hypercoagulability and to evaluate platelet function in

high-risk human populations.18,19 The effects of spe-

cific anticoagulants, such as heparin, can be monitored

using the Sonoclot,20 and it is also being used to eval-

uate newer anticoagulants in human medicine.20

Application: veterinary medicine

In veterinary medicine, reports describing use of the

Sonoclot are limited. Normal values have been re-

ported in horses and foals, with foals demonstrating

increased PF compared with adult horses.21 Sonoclot

values measured in critically ill foals were evaluated

for prognostic capabilities. Foals with decreased CR or

slow clot formation on admission were more likely to

be euthanized or die.15

Advantages and limitations

The Sonoclot is reported to have better interoperator

reliability compared with the TEG.14 Sonoclot results

have been shown to be influenced by several variables,

including age, sex, and platelet count.22 Additional

studies showed poor reproducibility of some of the

measured variables, especially CR and PF.2327 Other

studies, however, have reported good reliability in pa-

tients undergoing cardiac surgery.25,26 In one study,

precision for the Sonoclot was similar to that for TE.27

The Sonoclot has only 1 cuvette and does not permit

duplicate samples to be run simultaneously. In addi-

tion, there does not appear to be a standardized proto-

col for new operators to adopt. Reports on the use of

the Sonoclot use different activators, variable periods

of warming, and variable holding times, and some use

fresh whole blood whereas others used whole

blood.15,16,20,28 The Sonoclot is the least expensive of

the 3 POC coagulation instruments.

Thrombelastography

Thrombelastography was first described by Hartert in

1948.29 Similar to the Sonoclot, TE assesses the visco-

elastic properties of whole blood under low shear

conditions and provides information about global

hemostatic function from the beginning of clot forma-

tion through clot retraction and fibrinolysis (http://

www.haemoscope.com/technology/index.html).

Technology

The TEG measures the physical properties of the clot

via a cylindrical cup heated to 371C that oscillates in10-second cycles. A pin held by a torsion wire is sus-

pended in the cup and is monitored for motion. As the

clot starts to form, fibrin strands develop between the

pin and the inner wall of the cup. This results in torque

on the immersed pin that is transmitted to the torsion

wire and converted to an electrical signal. As clot lysis

occurs the bonds between the pin and clot are broken,

resulting in decreased movement of the pin.

A mechanical electrical transducer converts the rota-

tion movement of the pin to an electrical signal that is

Figure 2. Abnormal Sonoclot Signature. (A) Part of a tracing before heparin administration. (B) Tracing after administration of heparin, demonstrating

later onset, lower clot rate, and lack of clot retraction.



displayed as a TEG tracing (Figure 3). There are 2 slots

for cups that can be run simultaneously for duplicate

sampling or with different reagents.

Variables

A graphical tracing of viscoelastic changes displays ini-

tial fibrin formation (reaction time, R), kinetics of fi-brin formation and development of the clot (K and aangle), and maximal strength of the fibrin clot (maxi-

mum amplitude [MA]) (Figure 3). Two additional

measurements representing fibrinolysis or clot lysis at

30 and 60 minutes (CL30, CL60) indicate clot stability

and are frequently absent from published tracings ow-

ing to the time required for normal fibrinolysis to occur.

Reaction time can be expressed in 2 equivalent

ways as distance in mm or time in minutes. The chart

speed of the TEG is 2mm/min; thus, time in minutes is

equal to the distance in mm divided by 2. In earlier re-

ports of studies using noncitrated blood R was definedas the time from initiation of the test to the point

where the curve is 1mm wide.30 Later, investigators

suggested using the point where the curve is 2mm

wide for citrated blood, and this is the most commonly

cited measurement for R today.3134 The time at whichR is measured is the point at which standard plasma-based clotting assays would end. Prolonged R is seenwith deficiencies in coagulation factors.

K and a angle (a) measure the rapidity of clotdevelopment from the beginning of the visible phase of

coagulation to a defined level of clot strength. K isthe time from initiation of clotting (2mm) until an

amplitude of 20mm is reached and is measured in

seconds. This aspect of the tracing is thought to be

affected by activities of factors (F)II and VIII, platelet

count and function, thrombin and fibrinogen concen-

trations, and HCT35,36 (http://www.haemoscope.com/

technology/index.html).

MA represents the maximal strength of the fibrin

clot and is recorded as the maximal width of the diver-

gence of the lines on the tracing. It indicates global clot

strength and is affected by fibrinogen, platelet count

and function, thrombin, FXIII, and HCT.35,36 It is mea-

sured as the difference in mm above baseline on the

tracing. Schematics frequently depicts the MA with a

double-headed arrow that goes both above and below

the baseline; although not technically correct, this is

most likely an attempt to help the reader visualize how

MA reflects overall clot strength.

Clot lysis, represented by CL30 and CL60, indi-

cates % lysis that has occurred at 30 and 60 minutes,

respectively, after MA has been reached and indicates

clot stability. High CL percentages correspond with

rapid fibrinolysis or platelet contraction.

Other analyses that have been reported utilizing

the TEG include TEG-index, coagulation index (CI), G(global clot strength), and total thrombin generation

(TTG). TEG-index was developed to compare celite-

activated whole blood with nonactivated (native)

whole blood from the same patient using the TEG.37

Celite activation of blood from normal patients had a

much faster onset of coagulation, faster clot rate, and

greater clot strength compared with native blood. The

theory was that inherent hypercoagulability in native

blood would nullify the differences between native

and celite-induced TE, reflecting in vivo hypercoagul-

ability in abnormal individuals. Statistically significant

differences between the 2 types of tracings were used

to develop an equation based on discriminant analysis

between people with normal hemostasis and cancer

patients.37 A higher TEG-index representing hyper-

coagulability was found in 98.9% of cancer patients in

the study.37,38 CI is a computer-calculated linear com-

bination of R, K, MA, and a angle and is thought toprovide an index of coagulation in one simple number,

rather than having to interpret all TEG variables.39

Adding all the TE values into a single number, while

simplifying interpretation, significantly diminishes the

capabilities of this technology to discriminate hemo-

static components, such as platelet function, factor

levels, and fibrinolysis.

Representing shear elastic modulus, G has alsobeen reported.40,41 This value is reported to represent

global coagulation in a single output number derived

from the following formula: G=5000MA/(100MA). Note that G is dependent only on MA; thus, likeMA it is a function of fibrinogen concentration, plate-

let count and function, thrombin concentration, FXIII

activity, and HCT. G increases exponentially compared

Figure 3. Schematic of thromboelastometry (ROTEM; top) and thromb-

elastography (TEG, bottom). ROTEM figure shows clot time (CT), clot for-

mation time (CFT), a angle (a), and maximum clot firmness (MCF). TEG figureshows reaction time (R), clot formation (K), a angle (a), and maximumamplitude (MA).



with MA, which permits more sensitive resolution at

high amplitudes.

TTG is calculated by measuring the area under the

thrombus velocity curve (dynes/cm2) and has been

shown to correlate with thrombinantithrombin com-

plex analysis, which is a marker of the amount of

thrombin generated.42

PlateletMapping is a trademarked TEG application

that measures % inhibition of platelet function com-

pared with maximal uninhibited platelet function. It

compares a tracing obtained when fibrinogen is

cleaved and cross-linked by reptilase and FXIIIa and

both thrombin and platelets are inhibited (represent-

ing fibrin formation without any contribution from

platelets) with that obtained after addition of platelet

agonists (when only thrombin is inhibited). The data

are adjusted based on a tracing obtained from whole

blood without any inhibitors (representing platelet

and fibrin function). The difference is a specific repre-

sentation of platelet function.43

Reagents and assays

Viscoelastic technology was originally designed as a

POCmonitoring method using native whole blood run

within minutes of collection. In the laboratory setting,

this approach is not practical; thus, citrated samples are

frequently used. A comparison study showed that TEG

measurements are not directly comparable between

native and citrated samples.44 Most tests are run either

using fresh whole blood or citrated whole blood; plate-

let-poor plasma may also be used. When citrated sam-

ples are used, delay in testing results in generation of

FXIIa, which is not calcium-dependent and, therefore,

not inhibited by citrate. As a consequence, recalcifica-

tion of a citrated sample results in thrombin generation

primarily as a function of FXIIa generation during stor-

age before recalcification rather than as a function of the

constituents present at the time of sample collection.45

Activators of coagulation available for use with the

TEG include kaolin, platelet mapping system reagents,

and a newRapidTEG reagent that contains tissue factor

and kaolin. Activation of intrinsic or extrinsic path-

ways can be achieved with kaolin or tissue factor, re-

spectively. Cups that contain heparinase are available

from the manufacturer to permit identification of non-

heparin-dependent coagulation abnormalities in the

presence of heparin.


The use of TEG analysis in a variety of clinical settings

has been reported in both human and veterinary

medicine (Figure 4). In human medicine TE has appli-

cability in managing trauma and surgical patients,

monitoring heparin therapy, and thrombophilia.

TEG has been used to assess the coagulation status

and to predict early transfusion requirements of trau-

ma patients.46 Tissue factor-activated TEG, marketed

as RapidTEG, is being used in emergency rooms as an

early diagnostic tool in trauma patients with suspected

coagulopathies.47 Recently, TEG was reported to be

more sensitive than plasma-based tests (eg, PT and

aPTT) in detecting hypercoagulable states in trauma

patients.48

TEG has also been repeatedly applied to human

surgical populations. In one study of patients who had

undergone cardiopulmonary bypass surgery, postoper-

ative bleeding was more accurately predicted by TEG

(87%) than conventional coagulation tests (51%) or

ACT (30%).49 TEG has been used to guide FVIIa ther-

apy in surgical patients,50 to monitor hemostasis dur-

ing liver transplantation51 and cardiac surgery, and to

limit unnecessary use of blood components.52 TEG has

been used to predict the need for antifibrinolytic ther-

apy in patients receiving liver transplant.53 The MA

recorded by TEG has been shown to be predictive of

postoperative thrombotic complications in surgical

patients.54 Heparinase has been reported for use with

TEG permitting identification of abnormal coagulation

in heparinized patients.55 In one study TEGwas able to

detect clot dissolution before changes were seen in

plasma fibrinogen concentrations.56


In animals normal TEG values have been reported for

healthy dogs57 and, more specifically, for normal Grey-

hounds,40 horses,58 and cats.59 Canine reference inter-

vals for kaolin-activated TEG have been reported.60

TEG results have also been described for dogs with

hemostatic disorders,41 disseminated intravascular

Figure 4. Abnormal TEG tracings. The center tracing is from a normal in-

dividual. Innermost tracing indicates a hypocoagulable state: R and K are

prolonged, and a and maximum amplitude (MA) are decreased. Outer-most tracing indicates a hypercoagulable state: R and K are shortened,

and a and MA are increased. Refer to Figure 3 for explanations of tracingsand abbreviations.



coagulation,33 parvoviral enteritis,61 neoplasia,62 and

immune-mediated hemolytic anemia (IMHA)63 and

for dogs admitted to an intensive care unit (ICU).64 In

the parvovirus and DIC studies, TEG identified hyper-

coagulability in the patient populations. In a study of

27 dogs admitted to an ICU compared with 31 normal

dogs, TEG results were abnormal in 52% of the ill

dogs.64 Dogs in hypercoagulable states had significant

increases in D-dimer and fibrinogen concentrations,

and there were significant correlations between MA

and fibrinogen concentration and between R and PT inthe dogs studied.64 In a population of retired racing

Greyhounds, all values except R and CL60 weresignificantly different compared with those in non-

Greyhound dogs.40 TEG results from Greyhounds in-

dicated hypocoagulable states, which may provide a

rationale for the increased tendency of this breed to

bleed postoperatively. Conventional coagulation tests

(PT, aPTT, ACT, and D-dimer) and TEG performed on

multiple samples from the same group of dogs once

weekly over 5 consecutive weeks were compared; a

high degree of variability in the standard coagulation

tests compared with TEG measurements was found.65

The capacity of tissue factor-activated TEG to identify

hemostatic alterations in canine whole blood with

varying dosages of low-molecular-weight heparin

(LMWH) has been studied and found to be a promis-

ing new method for clinical evaluation of LMWH-

dosing in dogs.66 The effect of LMWH on hemostasis

has also been reported in cats using TEG.67 Using TEG

hypercoagulability was identified in healthy Beagle

dogs after administration of prednisone, and Platelet-

Mapping has been used to detect platelet inhibition by

clopidogrel.68,69


In people a hypercoagulable state has been defined as

the presence of at least 2 of the following: shortened R,increased a, or increasedMA.46 As definitions have notbeen established yet for animals, comparisons among

published reports are challenging. Studies have used

different samples, including noncitrated whole blood

and citrated and recalcified blood, various intrinsic and

extrinsic activators, and different times from collection

to performing TEG anlaysis. Owing to the lack of

specific method details in published reports, critical

evaluation of results obtained with this technology is

difficult.

The TEG system is less costly to purchase than the

ROTEM, but provides only 2 channels. Use of this

equipment for human patients has been approved by

the US Food and Drug Administration (FDA).

Thromboelastometry

Rotational thrombelastography, termed thromboelas-

tometry, also assesses the viscoelastic properties of

whole blood under low shear conditions. The ROTEM

is a modification of classic thrombelastography. Like

the TEG, the ROTEM provides information about

global hemostatic function from the beginning of clot

formation through clot retraction and fibrinolysis

(http://www.rotem.de/site/index).

Technology

The technical aspects of the ROTEM are slightly differ-

ent from those of the TEG. There are 4 cylindrical cups

and an optical detector system that detects the signal of

a pin suspended in the blood sample cup. The cup is

stationary and the pin oscillates. As fibrin forms be-

tween the cup and the pin, the impedance of the rota-

tion of the pin is detected. As the blood clots the extent

of the pins oscillation is reduced; this is measured by

the angle of deflection of a beam of light directed at the

pin/wire transduction system. An ROTEM graphical

tracing is recorded (Figure 3). The 4 channels can be

used simultaneously allowing multiple specimens to

be sampled. In addition, the ROTEM is equipped with

an electronic pipette that permits consistency of dis-

pensing the sample.

Variables

Graphical displays of viscoelastic changes indicate ini-

tial fibrin formation (clotting time, CT), the kinetics of

fibrin formation and development of the clot (clot for-

mation time [CFT]; a angle), the maximum strength ofthe fibrin clot (maximum clot firmness [MCF]), and fi-

brinolysis at 30 and 60 minutes (clot lysis, LY30, LY60).

CT describes the time to initial fibrin formation and is

an indicator of plasma coagulation factor activity. CFT

corresponds to initial activation of platelets and fibrin-

ogen; a corresponds to the slope of the tangent and de-scribes the kinetics of clot formation. MCF is the

maximal amplitude in mm above baseline reached

during the test; MCF corresponds to the maximal clot

strength and depends on both platelet and fibrinogen

activation and the function of FXIII.

Other values that can be calculated using ROTEM

measurements have been reported and include maxi-

mum clot elasticity (MCE), global clot strength (G),

and a version of TTG focusing on derivative curves.

MCE is a calculated value derived from the MCF:

MCE= (100MCF)/(100MCF). G is calculated us-ing an equation identical to the one reported with the

TEG, with MCF replacing MA: G= (5000MCF)/



(100MCF). An alternative method of data analysis,somewhat comparable to calculation of TTG, utilizes

software developed to analyze the first derivative

measurements of whole blood clot formation.70 The

software produces a velocity profile consisting of

maximum velocity (MaxVel) and time to MaxVel. The

area under the velocity curve is also reported and is

thought to be a measure of G.70

Reagents and assays

Proprietary reagents available for use with the ROTEM

include INTEM (strong intrinsic pathway activation),

HEPTEM (strong intrinsic activation of coagulation in

the presence of heparinase to neutralize effects of hep-

arin in the sample), EXTEM (strong extrinsic pathway

activation), FIBTEM (strong extrinsic activation of co-

agulation in the presence of cytochalasin D, a platelet

inhibitor), APTEM (strong extrinsic activation of coag-

ulation in the presence of aprotinin, a fibrinolysis in-

hibitor), and ECATEM (direct activation of coagulation

with a snake-derived prothrombin activator). In order

to attribute an abnormal result to platelet or fibrinogen

abnormalities, a combination of EXTEM and FIBTEM

may be used. These reagents permit specific evaluation

of various components of the coagulation system.


The ROTEM has been applied to a variety of clinical

conditions in human patients and is FDA-approved. Ref-

erence intervals have been established for all values, and

the ROTEM has been shown to give reproducible results

when multiple testing centers were compared.71

In trauma patients, ROTEM analysis has aided in

early diagnosis of coagulation abnormalities.12 The

prognostic value of ROTEM use in the emergency

room has been reported, and CFT was found to be an

independent predictor of death72 and to have a good

negative predictive value with normal ROTEM values

unlikely to be associated with hemostatic disorders.73

ROTEM analysis has been used to assess bleeding risk

in patients receiving cardiopulmonary bypass.74

Outside the surgical setting, ROTEM analysis has

been used to assess the coagulation status in people

with type II diabetes.75 In a study of cancer patients,

there was significant correlation between standard lab-

oratory values and ROTEM results.76 The technology

has also been used to monitor fibrinogen concentrate

therapy in fibrinogen deficiency77 and to evaluate

neonatal hemostasis.78 ROTEM results were useful in

predicting outcome in a prospective cohort study in

septic patients79 and as a guide to blood transfusion

approaches in cardiac patients.74 The ROTEM is being

used to evaluate the capacity of LMWH to inhibit clot

formation in patients undergoing angioplasty and

stenting for carotid artery disease.80 Recently, Platelet-

Mapping developed for the TEG has been validated for

use on the ROTEM utilizing a slightly different con-

centration of the reagents.43


ROTEM analysis has been validated in horses with ref-

erence intervals established using citrated blood sam-

ples.81 Our laboratory has validated the ROTEM for

dogs using citrated and native blood using the INTEM

and EXTEM reagents. We are in the process of further

applying this technology to other species and diseased

populations (Figure 5).35,36,82


The use of a ball bearing system for power transduction

is thought to make the ROTEM less susceptible to

movement and vibration artifact. The presence of 4

channels allows up to 4 samples (or 2 with duplicates)

to be run simultaneously. The ROTEMwas designed to

be sturdy and easily transportable for bedside monitor-

ing. The electronic pipette can help to decrease

Figure 5. Abnormal ROTEM tracings. (A) A hypocoagulable state is indicated by prolonged clot time (CT) and clot formation time (CFT), decreased a, anddecreased maximum clot firmness (MCF). (B) A hypercoagulable state is indicated by shortened CT and CFT, increased a, and increased MCF. Refer toFigure 3 for explanations of tracings and abbreviations.



interoperator variability and makes the unit easier for

nonlaboratory personnel to use. The ROTEM is

more costly than the TEG and Sonoclot. Results from

the 2 TE instruments, the TEG and ROTEM, cannot be

compared directly.

Viscoelastic Testing

Advantages

Use of viscoelastic POC instruments offers several ad-

vantages, including evaluation of whole blood and,

therefore, the contribution of cells, rapid turn-around

times as most pertinent information is available within

30 minutes, and small sample volumes, usually

o0.5mL. Viscoelastic kinetic monitoring has the ad-ditional advantage of detecting hypercoagulability.

Normal fibrinolysis is slow and not seen on typical

tracings observed for up to 1 hour, but accelerated fi-

brinolysis can be identified on all 3 analyzers. Perhaps

the greatest strength of this technology is its capacity

to provide a global picture of the hemostatic process

as coagulation is extremely complex in vivo. The

summation picture provides an overall evaluation

of all the components, including the cellular ones, of

coagulation and is likely more clinically relevant than

isolated plasma-based testing.

Limitations

The recent introduction of viscoelastic coagulation

technology to veterinary medicine has resulted in sig-

nificant clinical use and multiple reports describing re-

sults obtained in several clinical populations. In many

cases this technology is being reported as if it is a single

diagnostic test with specific quantitative connotations.

Unfortunately, there has been little recognition that

viscoelastic monitoring, in particular with TEG, is a

means of acquiring data about coagulation, rather than

an individual diagnostic assay. The characteristics of

the sample analyzed along with other additives have

an enormous impact on interpretation of results. Re-

porting TEG results without considering sample char-

acteristics, use of activators of coagulation, and

sample-handling procedures that may have an impact

on the results would be comparable to reporting co-

agulation tests without delineating whether the test

performed was a PT, aPTT, or thrombin time. Different

tests and test conditions yield vastly different informa-

tion about the coagulation system.82

TE in general is not sensitive to mild coagulation

factor deficiencies or to mild defects of primary hemo-

stasis.80 In several investigations, little to no effect of

aspirin on TEG variables has been reported, even in the

presence of significantly prolonged bleeding times.83,84

Defects in primary hemostasis, such as those resulting

from treatment with aspirin or clopidogrel, can be de-

tected with the PlateletMapping assay.

Variations in HCT are known to affect the results of

TEwith increased and decreasedHCT leading to tracings

that indicate hypocoagulable and hypercoagulable

states, respectively.35,36,40,8587 These effects have been

reported in both in vitro dilution experiments and in

animals with anemia or erythrocytosis. Whether this is

truly a reflection of in vivo effects of RBC mass on co-

agulation, or simply an artifact of TE technology, is not

known at this time. Whole blood coagulation testing

requires that a defined volume of whole blood be dis-

pensed into the instrument; wide variations in HCT

consequently result in wide variations in the volume of

plasma loaded into the cup, which in turn has a marked

impact on the total amount of coagulation proteins

evaluated in the assay. Thus, HCT may be an important

confounder in interpretation of viscoelastic test results.

Note that in many studies results from diseased, and

possibly anemic, animals are compared with references

intervals established from animals with normal HCT.

Dogs with IMHA, cancer, and chronic disease are often

anemic; these populations are also reported to be in

hypercoagulable states using TEG technology.

These POC tests were designed to be performed

within minutes of collection on fresh, whole, noncit-

rated blood. POC tests often lack stringent quality

control that is applied to equipment in the clinical

pathology laboratory; this may be one reason that they

have been slow to gain favor clinically. Methods for

performing TE have not been standardized by the

Clinical and Laboratory Standard Institute, and this

has hampered widespread acceptance. In a recent

systematic review of TE studies, it was concluded that

of 10 prospective TE studies eligible to be included in

analysis only 5 reported measures of TEG accuracy.88

The overall quality of the studies was highly variable

as were variations in the methodology, reference stan-

dards, and definitions of hypercoagulability; meta-

analysis was not possible due to the wide variability in

reporting.

Comparison with standard plasma-based coagulation testing

Although a direct comparison between viscoelastic

and standard plasma-based test results is not possible,

several correlations have been reported.57,89 For

TEG, a significant correlation between MA and fibrin-

ogen concentration and platelet count has been

reported in both normal and hypercoagulable people

and dogs.37,51,64 Our laboratory recently reported



correlation between plasma-based tests and compara-

ble ROTEM values for normal dogs.82

Methods

In classic TE, activators were not used and clotting was

initiated by contact of the plasma component of the

blood with the steel cup. The charge of the metal was a

contact activator and resulted in production of FXIIa

and subsequent downstream enzymes. With the intro-

duction of plastic disposable cups, this activation

became less effective and was more likely to be repre-

sentative of a combination of contact activation,

platelet activation, which can vary considerably

depending on the level of preactivation of the sample,

and the low level of tissue factor that is present in

blood.45 In addition, performing all tests immediately

was not practical in many situations.

Anticoagulation with citrate had the advantage of

better stability compared with nonanticoagulated

blood; however, use of citrate has an impact on the

results.44,90 Investigators have reported tracings indi-

cative of hypercoagulability from citrated and recalci-

fied samples compared with tracings of noncitrated

samples.44 In addition to calcium, citrate chelates other

metallic ions, such as magnesium and zinc, which are

not added back upon recalcification and may have an

important impact on coagulation. Furthermore, if

citrated blood is recalcified in the absence of any

activator, the delay between sample collection and re-

calcification has a profound impact on the results.82

This phenomenon occurs because activation of FXII is

not calcium-dependent, and is not prevented by chela-

tion of calcium by citrate.45 The final TE tracing

obtained is a function of FXIIa activity in the sample

at the time of recalcification, which is dependent

on FXIIa generated by surfaces, including the needle,

syringe, and tube, to which blood was exposed and the

inhibition of FXIIa by plasma inhibitors, primarily C1

inhibitor, in the sample. Consequently, use of citrated

blood with recalcification without an activator

increases the variability of the results obtained.

Different types and concentrations of activators

can be used with each of these instruments. Depend-

ing on the target of activation, ie, contact or tissue fac-

tor activation, the specific activator, eg, celite, kaolin,

ellagic acid, and thromboplastin, and the concentra-

tion of activator used, test results will vary consider-

ably.91 Contact activation can be achieved using

kaolin, celite, or ellagic acid. Kaolin is a more potent

activator of contact pathway than celite,92 and use of

kaolin with both instruments has been reported.92 The

quality of kaolin, a clay mineral that activates the con-

tact pathway, differs among mining sites and depends

on impurities caused by the presence of other clays,

with wide variations between manufacturers.92 The

TEG-supplied reagent uses celite, whereas the RO-

TEM-supplied reagent uses ellagic acid. Relipidated tis-

sue factor or thromboplastin is used for activation of

the extrinsic pathway. The ROTEM reagents include a

tissue factor reagent (EXTEM) that may aid in consis-

tency of results. Reports with TEG describe dilution of

commercially available PT reagents, primarily Innovin

(Dade Behring, Marburg, Germany). Awide variety of

dilutions are reported.41,58,64,70 Our laboratory re-

cently compared several reagents used for initiating

coagulation during TE, revealing that the potency and

type of activator used strongly influence results.82 The

most profound effect was found on CT, which was ex-

pected as CT reflects the time to initial fibrin polymer-

ization and is primarily a function of the rate of initial

thrombin formation. Latter phases rely more on con-

tributions of platelets and fibrin polymerization than

on initial thrombin burst, and, thus, the type of activa-

tor had less of an impact on CFT and a. The impact onMCF was minimal.82

Temperature is an important variable in all coagu-

lation tests. Measurements should be made at 371C,and the cup and pin are both maintained at 371C. Coldcups, pins, or blood samples can slow reaction time

producing falsely prolonged values. Standardization of

sample warming procedures is essential for consis-

tency. Operator variability is another factor and it is

essential to establish instrument-specific and, in some

cases, operator-specific reference intervals using stan-

dardized activators for each species.58

Conclusions

Viscoelastic testing with the Sonoclot, TEG, and ROTEM

instruments is a new twist on an old technology and has

the potential to markedly improve evaluation and man-

agement of hemostatic abnormalities. Ideal procedures

for applying this technology and the patient populations

that could benefit most from viscoelastic testing are ar-

eas of active investigation in both human and veterinary

medicine, with many issues remaining to be definitively

resolved. For viscoelastic testing to be of optimal benefit,

standard protocols must be in place with respect to blood

collection, including method of venipuncture, va-

cutainer tubes used, and order of filling tubes; tempera-

ture, with the sample maintained at 371C at all times ormaintained at room temperature and then warmed to

371C; exact time from sample collection to assay;



activator type and concentration; and other laboratory

values, such as HCT.

Acknowledgments

The authors thank Elizabeth Rozanski, DVM, DACVIM, DAC-

VECC, Associate Professor, Cummings School of Veterinary

Medicine at Tufts University, for supplying the TEG tracings.

Disclosure: The authors have indicated that they have

no affiliations or financial involvement with any organiza-

tion or entity with a financial interest in, or in financial

competition with, the subject matter or materials discussed

in this article.

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