Early Diagnosis of Clinically SignificantHyperfibrinolysis Using Thrombelastography

Velocity Curves

Matthew J Pommerening, MD, Michael D Goodman, MD, Danny L Farley, BS, Jessica C Cardenas, PhD,Jeanette Podbielski, BSN, Nena Matijevic, PhD, PharmD, Charles E Wade, PhD,John B Holcomb, MD, FACS, Bryan A Cotton, MD, MPH, FACS

BACKGROUND: Clot lysis values (LY30) determined by rapid thrombelastography (rTEG) predict postinjurytransfusion needs and mortality risk. However, the first derivative velocity curve values gener-ated by rTEG measuring lysisdmaximum rate of lysis (MRL) and total lysis (TL)dhave notbeen evaluated. Although recent data support use of antifibrinolytics in trauma, the popula-tion that would benefit remains poorly defined. The purpose of this study was to determine ifvelocity curves more accurately predict large volume transfusions and early mortality thanconventional rTEG values.

STUDY DESIGN: Conventional and velocity curve admission rTEG values of adult trauma patients were retro-spectively evaluated for their ability to predict early transfusion of RBC and plasma, substan-tial bleeding, massive transfusion, and mortality. Patient outcomes were compared accordingto hyperfibrinolysis diagnosed by velocity curve values and the conventional LY30 cutoff.

RESULTS: There were 1,625 patients included. Clot lysis values predicted early transfusion of RBC(p ¼ 0.003), but not plasma (p ¼ 0.298), within 3 hours of arrival. With respect to velocitycurves, MRL and TL predicted both early RBC and plasma transfusion (p < 0.05). All 3parameters predicted massive transfusion, but only MRL and TL predicted substantialbleeding (odds ratio [OR] 3.1 and 2.9, respectively). In addition, MRL was a stronger pre-dictor of 24-hour and 30-day mortality (p < 0.001) and was also available earlier after arrivalthan LY30 (p < 0.001).

CONCLUSIONS: Velocity curve measures of fibrinolysis are stronger predictors of early transfusion of bloodcomponents, bleeding, and mortality after trauma compared with conventional rTEG values.In addition, the MRL is more rapidly available after arrival, which may facilitate earlier diag-nosis and treatment of clinically significant hyperfibrinolysis. (J Am Coll Surg 2014;219:1157e1166. � 2014 by the American College of Surgeons)

CME questions for this article available athttp://jacscme.facs.org

Disclosure Information: Authors have to disclose. Timothy J Eberlein,Editor-in-Chief, has nothing to disclose.

Presented at the American College of Surgeons 99th Annual ClinicalCongress, Washington, DC, October 2013.

Received May 22, 2014; Revised July 29, 2014; Accepted July 29, 2014.From theDepartment of Surgery (Pommerening, Cardenas,Wade,Holcomb,Cotton) and the Center for Translational Injury Research (Pommerening, Far-ley, Cardenas, Podbielski, Matijevic, Wade, Holcomb, Cotton), The Univer-sity of Texas Health Science Center, Houston, TX, and the Department ofSurgery, University of Cincinnati, Cincinnati, OH (Goodman).Correspondence address: Bryan A Cotton, MD, MPH, FACS, Departmentof Surgery and Center for Translational Injury Research, The University ofTexas Medical School at Houston, 6410 Fannin St, UPB Suite 1100.20,Houston, TX 77030. email: bryan.a.cotton@uth.tmc.edu

1157ª 2014 by the American College of Surgeons

Published by Elsevier Inc.

Thrombelastography is a comprehensive coagulation assaythat measures real-time viscoelastic properties of the coag-ulation cascade. Coagulation parameters measured bythrombelastography, such as the maximum amplitude ofclot strength, have been shown to predict hemorrhageand mortality after traumatic injury and are increasinglybeing used to help guide resuscitation of severely injuredtrauma patients.1-4 Conventional coagulation tests, such asinternational normalized ratio (INR), prothrombin time(PT), and activated partial thromboplastin time (aPTT),measure only static plasma-based components of coagula-tion; however, thrombelastography measures the actualkinetic properties of clot formation and fibrinolysis. Inthis sense, thrombelastography provides a more compre-hensive description of the global hemostatic functional

http://dx.doi.org/10.1016/j.jamcollsurg.2014.07.943

ISSN 1072-7515/14

Abbreviations and Acronyms

IQR ¼ interquartile rangeLY30 ¼ percent lysis 30 minutes after MA is reachedMA ¼ maximum amplitudeMRL ¼ maximum rate of lysisMRTG ¼ maximum rate of thrombus generationMT ¼ massive transfusionrTEG ¼ rapid thrombelastographySB ¼ substantial bleedingTG ¼ thrombus generationTL ¼ total lysisTMRL ¼ time to maximum rate of lysisTMRTG ¼ time to maximum rate of thrombus generation

1158 Pommerening et al Early Diagnosis of Hyperfibrinolysis J Am Coll Surg

aspects of coagulation, which allows for early diagnosis ofcoagulopathies and identification of specific deficits incoagulation.5-11 When fast results are required, rapidthrombelastography (rTEG) is performed, and the resultsand visual tracing can be viewed on bedside computerscreens and interpreted in real time before the entiretest is finalized in the laboratory.Thrombelastography produces a tracing based on visco-

elastic properties of whole blood and generates a handfulof commonly used values that represent important com-ponents of the coagulation system. However, several othervalues are also calculated that are often overlooked or notused clinically. These include the first derivative valuesused to generate the conventional thrombelastographytracing and corresponding values, known as the para-metric velocity curves. These derivative values generate2 distinct curves measuring the velocity kinetics of 2 inte-gral components of coagulation, thrombus generation,and subsequent breakdown, or fibrinolysis.Fibrinolysis is an important component of the normal

homeostatic balance between clot formation and clotbreakdown. However, in the setting of trauma, increasedfibrinolytic activity represents a pathologic and inappro-priate response to hemorrhage that results in excessiveclot breakdown, coagulopathy, and increasedbleeding.12-15 Although present in only a minority oftrauma patients on admission, hyperfibrinolysis is associ-ated with large transfusion volumes and a significant in-crease in mortality.16 Antifibrinolytic agents, such astranexamic acid, have been suggested to improve survivalif given early after injury, but the evidence is conflictingand there are potential risks associated with adminis-tering these agents indiscriminately.17-21 More recent ev-idence indicates that tranexamic acid is safest and mosteffective only in patients with known hyperfibrinolysis,underscoring the importance of early diagnosis andintervention.18,22

In this study, we sought to evaluate if velocity curve pa-rameters are predictive of clinically important outcomesafter trauma. We hypothesized that the additional kineticinformation provided by these viscoelastic measures of he-mostatic potential may provide increased predictive valuefor early transfusion requirements and mortality that mayultimately help guide goal-directed therapy.

METHODS

Study setting

The institutional review boards at the University of TexasHealth Science Center at Houston and Memorial Her-mann Hospital approved this study. The Texas TraumaInstitute at Memorial Hermann Hospital is an AmericanCollege of Surgeons-verified level I trauma center locatedin the Texas Medical Center in Houston, TX. The 800-bed facility is the primary teaching hospital for the Uni-versity of Texas Health Science Center (UTHealth) andadmits more than 6,000 trauma patients annually, withthe most severely injured cared for in the 23-bed shock-trauma ICU.

Selection of participants

Using the institution’s Trauma Registry of the AmericanCollege of Surgeons database, we evaluated all adulttrauma patients admitted between September 2009 andFebruary 2011. Patients who arrived within 6 hours ofinjury at the institution’s highest-level trauma activationwere included. Patients who were younger than 18 years,had burn wounds greater than 20% total body surfacearea, or who died within 30 minutes of arrival wereexcluded. None of the patients at our institution receivedantifibrinolytic drugs for hyperfibrinolysis during the timeperiod this study was performed.

Laboratory setting and processing of specimens

Conventional rTEG values (activated clotting time,k-time, alpha angle, maximum amplitude, and lysis)and conventional coagulation tests (prothrombin time,partial thromboplastin time, fibrinogen, and plateletcount) were obtained on admission. All rTEG specimenswere run on a TEG 5000 Thrombelastograph (Haemo-netics Corporation). Blood specimens for rTEG were ob-tained as part of the usual blood samples acquired duringthe primary or secondary survey evaluation of all majortrauma activations. Laboratory processing of rTEG wasperformed as previously described.8 Briefly, anticoagula-tion was reversed by adding calcium chloride to citratedwhole blood in the TEG cup. Kaolin and tissue factorwere added to initiate coagulation as per the manufac-turer’s instructions for performing rTEG. Quality

Vol. 219, No. 6, December 2014 Pommerening et al Early Diagnosis of Hyperfibrinolysis 1159

controls were performed on the TEG analyzers every 8hours per the package insert from Haemonetics.

Conventional rapid thromboelastographyparameters

Rapid thrombelastography measures the kinetics,strength, and stability (rate of lysis) of the clot. The pa-rameters measured by rTEG are depicted on the conven-tional rTEG tracing in Figure 1. The activated clottingtime of rTEG (normal range, 0 to 118 seconds) is thetime in seconds between initiation of the test and initialfibrin formation and is increased with factor deficiencyand decreased with enzymatic hypercoagulopathy.23 Ther-value, or reaction time, is also another representationof the time to the beginning of clot formation. The alpha(a) angle, measured in degrees, (normal range, 66 to 82degrees) is the angle between the tangent line drawnfrom the base horizontal line to the beginning of thecross-linking process and represents the mean rate offibrin assembly. Therefore, an increased alpha angle rep-resents an increased rate of clot formation. The maximalamplitude (MA; normal range, 54 to 72 mm) is the great-est amplitude of the tracing and reflects the contributionof platelets, fibrinogen, and other coagulation factors toclot strength. High MA values correspond with states ofhypercoagulability. The G-value (normal range, 5.3 to12.4 Kdyn/cm2) is a measure of absolute clot strength(both enzymatic and platelet contributions) and isincreased in hypercoagulable states. Percent fibrinolysisat 30 minutes (LY30) (normal range, 0.0% to 7.5%) rep-resents the percent amplitude reduction at 30 minutesafter MA and reflects the degree of fibrinolysis.

Figure 1. Conventional rapid thrombelastography tralastography illustrates several parameters of hemosteters depict the kinetics of thrombus formation (ACT, K(LY30). ACT, activated clotting time; K, kinetic time;percent lysis 30 minutes after MA.

Velocity curves

In addition to conventional rTEG parameters, an addi-tional set of parameters is generated from the mathemat-ical first derivative values of rTEG. Known as velocitycurves, this set of parameters corresponds to the rate ofdevelopment of the tensile strength of the forming clotand subsequent dissolution via fibrinolysis. Although con-ventional rTEG values are descriptive of parameters suchas the time to clot initiation, the mean rate of clot forma-tion, and overall maximum clot strength, velocity curvesprovide more dynamic information about the rate or ve-locity at which these processes are occurring. In contrastto the conventional rTEG tracing typically used clinically,the first derivative velocity curves appear as 2 separatecurves representing the 2 competing processes of coagula-tion, thrombus generation, and fibrinolysis (Fig. 2).The positive curve above the horizontal axis represents

thrombus generation. The peak of the curve represents themaximum rate of thrombus generation (MRTG),measured in mm/min, and the distance on the x-axisfrom zero (marked with a horizontal arrow) depicts thetime to maximum rate of thrombus generation(TMRTG), or the time in minutes needed to reach themaximum rate of clot formation. The area under the ve-locity curve, thrombus generation (TG), is also calculatedand is an indirect measurement of clot strength, measuredin units of clot amplitude (mm). The subsequent curvebelow the horizontal axis depicts the same parameters,but for clot dissolution, or fibrinolysis. The negativepeak represents the maximum rate of lysis (MRL),measured in mm/min, with the distance on the x-axis rep-resenting the time the maximum rate of lysis occurs

cing. The conventional tracing of rapid thrombe-atic potential. Measured over time, these param-, alpha), thrombus strength (MA), and fibrinolysisa, alpha angle; MA, maximum amplitude; LY30,

Figure 2. Rapid thrombelastography (TEG) velocity curve tracing. Aset of parameters are also generated from the mathematical firstderivative of the conventional TEG tracing. These parametersdescribe formation of the thrombus, as well as lysis of thethrombus. MRTG, maximum rate of thrombus generation; MRL,maximum rate of lysis; TL, total lysis; TMRL, time to maximum rateof lysis; TMRTG, time to maximum rate of thrombus generation; TG,thrombus generation. (TEG Velocity Curve image from HaemoneticsCorporation, with permission.)

1160 Pommerening et al Early Diagnosis of Hyperfibrinolysis J Am Coll Surg

(TMRL). The area under this curve, total lysis (TL), is anindirect measurement of the total amount of lysis,expressed as total reduction in clot amplitude (mm).

Definitions and outcomes

Massive transfusion (MT) was defined as receiving 10 ormore units of red blood cells (RBC) in the first 6 hoursafter arrival. To reduce the inherent survival bias includedin the definition of MT, we also assessed patients by usingthe definition of substantial bleeding to account for earlyhemorrhagic deaths.24-28 Substantial bleeding (SB) wasdefined as receiving the first unit of RBCs within 2 hoursand more than 4 units of RBCs within the first 4 hours ofarrival, or hemorrhagic death within 6 hours. Patientswere considered as having a hemorrhagic death if theyreceived at least 1 unit RBC and died within 6 hours ofarrival. These definitions are supported by previouswork demonstrating that 80% of patients receiving MTdo so in the first 6 hours after arrival.29,30

Blood product delivery

Activation of our institution’s massive transfusion proto-col immediately delivers a cooler of 6 units of type Ored blood cells and 6 units of thawed AB plasma, alongwith a room temperature “tackle box” containing 1 unitof apheresis platelets. If necessary, before massive transfu-sion protocol cooler arrival, the trauma team may useproducts available in the Emergency Department bloodrefrigerator; this contains 4 units of type O red blood cells

and 4 units of thawed AB plasma at all times. Additionalcoolers and tackle-boxes of products (in the same numberand ratio) are delivered as soon as they are prepared (typi-cally every 10 to 15 minutes). This process continues untilthe physician cancels the protocol. Blood products areinitially transfused at a ratio of 1:1:1 plasma:RBC:plate-lets and then tailored to the patient’s condition andTEG results at the provider’s discretion. For patientsnot receiving products via massive transfusion protocol,it is routine practice at our institution to transfuse bloodproducts in similar high ratios of between 1:1 and 1:2plasma:RBC.

Statistical analysis

Each conventional rTEG and velocity curve parameterwas assessed for its ability to predict clinically importantoutcomes after injury. This was accomplished usingmultivariate regression analysis to control for importantpotential confounders associated with hemorrhage andmortality. In an effort to minimize the risk of falsely iden-tifying significant results with multiple comparisons, allregression variables were prespecified and judged a priorito be clinically sound. These variables included age, sex,mechanism of injury, weighted revised trauma score,Injury Severity Score, shock index, and base value.Stepwise regression modeling was used to construct a

multivariate linear and then a multivariate logistic regres-sion model evaluating the potential value of conventionalrTEG and velocity curve parameters for predicting trans-fusion outcomes and mortality. Multivariate linear regres-sion was used to evaluate blood and blood componenttransfusions as a continuous variable. For linear regres-sion, transfusion volumes used began at the most prox-imal time point for prediction, the first hour, andcontinued through 3 hours. Thrombelastography param-eters associated with early transfusion volumes were thentested with multivariate logistic regression to evaluatereceipt of clinically important volumes of products(namely, substantial bleeding and massive transfusion)as well as early (0 to 24 hours) and overall 30-day mortal-ity. For logistic regression, rTEG parameters were dichot-omized into normal and abnormal ranges using previouslydescribed cut points associated with clinically significantbleeding and early mortality.25 Corresponding thresholdvalues for velocity curves were identified using the corre-sponding conventional rTEG ranges and scatterplot anal-ysis to evaluate for inflection points associated withmortality. After our findings demonstrating the predictivevalue of fibrinolysis velocity curves, univariate analysis wasperformed to compare LY30 and MRL cutoffs as surro-gate markers of pathologic hyperfibrinolysis. Area under

Table 1. Demographics, Arrival Data, and Injury Severity

Variable All patientsLY30 � 3%(n ¼ 1,442)

LY30 > 3%(n ¼ 183) p Value

MRL � 0.5(n ¼ 1,477)

MRL > 0.5(n ¼ 148) p Value

Age, y (range) 33 (23e49) 34 (23e49) 26 (20e40) <0.001 31 (22e46) 33 (23e52) 0.235

Male sex, % 76.7 75.9 78.5 0.438 76.4 73.2 0.451

Blunt mechanism of injury, % 73.6 74.7 65.6 0.009 71.6 73.9 0.594

Initial SBP, mmHg (IQR) 130 (109e149) 130 (110e150) 128 (107e142) 0.074 130 (110e150) 120 (95e140) 0.006

Initial pulse, bpm (IQR) 98 (82e117) 98 (82e118) 96 (82e115) 0.485 97 (82e115) 98 (81e122) 0.430

Injury Severity Score (IQR) 16 (9e26) 16 (9e26) 17 (5e25) 0.730 14 (6e25) 18 (9e27) 0.025

Presence of shock(base excess � �5), % 29.0 28.0 32.5 0.303 24.5 41.2 0.001

Continuous variables represented as medians with interquartile range (IQR).ISS, Injury Severity Score; LY30, lysis 30 minutes after maximum amplitude is reached; MRL, maximum rate of lysis; SBP, systolic blood pressure.

Vol. 219, No. 6, December 2014 Pommerening et al Early Diagnosis of Hyperfibrinolysis 1161

the receiver operating curve analysis was used to comparethe predictive value of rTEG parameters.Continuous data are presented as medians with inter-

quartile range (IQR), with comparisons between groupsperformed using the Wilcoxon rank sum (Mann-WhitneyU test). Categorical data are reported as proportions and,where appropriate, tested for significance using chi-squareor Fisher’s exact tests. All statistical tests were 2-tailed,with p < 0.05 set as significant. STATA Statistical soft-ware (version 12.1; StataCorp) was used for analysis.

RESULTS

Patient characteristics

Nine thousand sixty-eight patients were admitted duringthe 18-month study period. Of these, 2,220 (24%)arrived as the highest level of trauma activation, and afterexclusion criteria, 1,625 patients were included in thefinal analysis. The majority of patients in the cohortwere young to middle-aged (median age 33 years, inter-quartile range [IQR] 23 to 49 years), male sex (76.7%),had sustained blunt trauma (73.6%), and were moder-ately to severely injured (median Injury Severity Score16 [IQR 9 to 26]), with a median weighted revisedtrauma score of 6.900 (IQR 2.930 to 7.840) (Table 1).A total of 29% of patients were considered to be in shockon arrival (base excess � �5), and 31% received at least 1unit of RBC or plasma within the first 24 hours. Substan-tial bleeding was present in 10% of patients and 5%received an MT. The overall 30-day mortality rate was11%, and 5% of patients died within the first 24 hoursafter arrival. Conventional rTEG and velocity curve pa-rameters obtained as part of the routine trauma panelon admission are shown in Table 2.

Hyperfibrinolysis

Using previously described cut-points, conventionalrTEG parameters were dichotomized into normal andabnormal ranges associated with clinically significant

bleeding and early mortality.25 For LY30, patients withadmission lysis values >3% were defined as having hyper-fibrinolysis, a cutoff we previously identified was associ-ated with a 2-fold increase in mortality and has sincebeen validated as a critical threshold for defining hyperfi-brinolysis and initiating antifibrinolytic therapy.16,26

Because LY30 > 3% amounts to the 90th percentile forfibrinolysis, the corresponding 90th percentile valueswere chosen as hyperfibrinolysis cutoffs for velocitycurves. Therefore, for velocity curves, hyperfibrinolysiswas defined as MRL > 0.5 mm/min and TL > 60 mmreduction in clot amplitude.A total of 22% of patients in the study cohort had some

degree of fibrinolysis (LY30 > 0%) detected by rTEG,and 11% of patients had hyperfibrinolysis at the time ofadmission, defined by LY30 > 3%. In contrast, all pa-tients had some degree of fibrinolysis detected by MRL,and 9% were classified as having hyperfibrinolysis byMRL > 0.5 mm/min. Characteristics for patients withhyperfibrinolysis defined by LY30 and MRL thresholdsare shown in Table 1. An LY30 > 3% was morecommonly associated with penetrating injuries and poorlydiscriminated injury severity and shock; MRL > 0.5 mm/min significantly discriminated increased injury severity,hypotension, and patients in shock.

Early transfusion of red blood cells and plasma

Using multivariable linear regression, each of the rTEGparameters was evaluated for its ability to predict earlytransfusion of RBC and plasma (Table 3). After control-ling for age, sex, mechanism of injury, base deficit,weighted revised trauma score, and Injury Severity Score,all 6 conventional rTEG parameters independently pre-dicted RBC transfusions within the first 3 hours afterarrival. With the exception of LY30 (coefficient 0.023;95%CI �0.021 to 0.067; p ¼ 0.298), conventionalrTEG parameters also predicted early transfusion ofplasma.

Table 2. Rapid Thrombelastography Parameters and Arrival Values

Parameter Definition Arrival value, median (IQR)

Conventional rTEG values

ACT Activated clotting time, sec 113 (105e128)

k-time Clot kinetic/time to reach 20 mm clot strength, min 1.5 (1.2e1.8)

a-angle Rate of clot formation, degrees 73 (68e76)

MA Maximum amplitude or maximum clot strength, mm 64 (59e68)

G-value Absolute clot strength/shear elastic strength, Kdyn/cm2 8.8 (7.2e10.5)

LY30 Percent lysis at 30 min after MA is reached, % 0.7 (0.1e1.8)

Velocity curve values

Thrombus generation

MRTG Maximum rate of thrombus generation, mm/min 13.2 (10.6e16.6)

TMRTG Time to maximum rate of thrombus generation, min 1.3 (1.2e1.9)

TG Total thrombus generated, mm 763 (709e811)

Fibrinolysis

MRL Maximum rate of lysis, mm/min 0.23 (0.18e0.31)

TMRL Time to maximum rate of lysis, min 32.8 (28.2e37.1)

TL Total lysis, mm 31 (22e45)

Continuous variables represented as median values with interquartile range (IQR).

1162 Pommerening et al Early Diagnosis of Hyperfibrinolysis J Am Coll Surg

Alternatively, when conducting the same analysis usingrTEG velocity curve parameters, none of the parametersmeasuring thrombus generation (MRTG, TMRTG, TG)were associated with early transfusion of RBC or plasma.However, for the velocity curve parametersmeasuring fibri-nolysis, MRL and TL were independently predictive ofearly RBC transfusions and, in contrast to LY30, also earlyplasma transfusions (Table 3). Given these findings and thesignificant morbidity and mortality associated with hyper-fibrinolysis in trauma, we then focused our analysis ondetermining if velocity curve measures of fibrinolysis aremore predictive of clinically significant hyperfibrinolysisthan the conventional rTEG parameter, LY30.

Substantial bleeding and massive transfusion

With respect to transfusions and bleeding, hyperfibrinol-ysis defined by LY30 > 3% was associated with receipt ofMT but not early transfusion of RBCs, plasma, or SB. Incontrast, hyperfibrinolysis defined by MRL > 0.5 mm/min was associated with early transfusion of RBCs andplasma, as well as MT and SB. Moreover, the risk forMT was significantly higher for patients with MRL >0.5 mm/min compared with LY30 > 3% (18.3% vs12.0%; p < 0.001) (Table 4). On multivariate analysiscontrolling for age, sex, mechanism of injury, base deficit,weighted revised trauma score, and Injury Severity Score,LY30 > 3% was independently associated with receipt ofMT but not SB. In comparison, MRL and TL were eachindependently associated with both MT and SB, high-lighting the additional predictive value of velocity curveparameters for early bleeding outcomes (Table 5).

Twenty-fourehour and 30-day mortality

Both LY30 and MRL were highly associated with 24-hourand 30-day mortality (Table 4). There was a nearly 10-fold higher incidence of 24-hour mortality associatedwith MRL > 0.5 mm/min compared with a 3-fold in-crease in mortality associated with LY30 > 3% (p <0.001). Similarly, MRL was also a stronger predictor of30-day mortality than LY30 (24.4% vs 18.0%; p <0.001). After controlling for confounders, all 3 measuresof fibrinolysis remained independent predictors of 24-hour and 30-day mortality (Table 5). Although not statis-tically significant, the odds of 24-hour mortality for MRL> 0.5 mm/min were double the odds of 24-hour mortal-ity for LY30 > 3%, again highlighting the idea that MRLmay be a better predictor of early outcomes after traumacompared with LY30.

Turnaround times for maximum rate of lysis andLY30

Previous studies have demonstrated the median time toreach MA is approximately 15 minutes (IQR13 to 19 mi-nutes), obligating that LY30 is not available until 45 mi-nutes (IQR 43 to 49 minutes) after initiation ofrTEG.8,31,32 We found that the median TMRL in thisstudy was 32 minutes (IQR 28 to 37 minutes), indicatingMRL is available for clinical use significantly earlier afterarrival than LY30 (p < 0.001).

DISCUSSIONThis is the first report evaluating the use of rTEG velocitycurves for predicting large volume transfusions and

Table 3. Multiple Linear Regression Model EvaluatingConventional Rapid Thrombelastography Parameters andVelocity Curves to Predict Early (0 to 3 Hours) Transfusion ofRed Blood Cells and Plasma

Variable Coefficient 95% CI p Value

RBC transfusions 0e3 h

Standard rTEG values

ACT 0.033 0.020, 0.046 <0.001*

k-time 0.659 0.435, 0.882 <0.001*

a-angle �0.116 �0.164, �0.067 <0.001*

MA �0.135 �0.180, �0.090 <0.001*

G-value �0.198 �0.312, �0.083 0.001*

LY30 0.072 0.025, 0.118 0.003*

Velocity curve values

MRTG �0.003 �0.008, 0.002 0.203

TMRTG �0.037 �0.099, 0.026 0.250

TG �0.000 �0.000, 0.000 0.305

MRL 1.375 0.777, 1.974 <0.001*

TMRL 0.025 �0.024, 0.073 0.316

TL 0.007 0.002, 0.012 0.006*

Plasma transfusions 0e3 h

Standard rTEG values

ACT 0.031 0.018, 0.043 <0.001*

k-time 0.655 0.442, 0.868 <0.001*

a-angle �0.110 �0.155, �0.064 <0.001*

MA �0.112 �0.155, �0.069 <0.001*

G-value �0.177 �0.285, �0.070 0.001*

LY30 0.023 �0.021, 0.067 0.298

Velocity curve values

MRTG �0.003 �0.008, 0.001 0.182

TMRTG �0.031 �0.090, 0.027 0.294

TG �0.000 �0.000, 0.000 0.206

MRL 0.715 0.143, 1.286 0.014*

TMRL 0.034 �0.011, 0.080 0.135

TL 0.006 0.001, 0.011 0.012*

Controlling for age, sex, mechanism, base value, Injury Severity Score, andweighted revised trauma score.*Significant.LY30, lysis 30 minutes after maximum amplitude is reached; MA,maximum amplitude; MRL, maximum rate of lysis; MRTG, maximum rateof thrombus generation; RBC, red blood cells; rTEG, rapid thrombelas-tography; TG, thrombus generation; TL, total lysis; TMRL, time tomaximum rate of lysis; TMRTG, time to maximum rate of thrombusgeneration.

Vol. 219, No. 6, December 2014 Pommerening et al Early Diagnosis of Hyperfibrinolysis 1163

mortality after traumatic injury. We hypothesized that theadditional kinetic information regarding the velocity ofclot formation and fibrinolysis may more accurately pre-dict clinically important outcomes. In 1,625 trauma pa-tients, we found that MRL and TL were bothindependently predictive of large volume transfusions(both SB and MT), as well as 24-hour and 30-day mor-tality. Compared with the traditional hyperfibrinolysiscutoff using LY30 > 3%, MRL > 0.5 mm/min was a

stronger predictor of early bleeding outcomes after traumaand was also available for interpretation earlier, indicatingthat MRL is a fast and valuable diagnostic tool that mayfacilitate earlier detection and goal-oriented treatment ofclinically significant hyperfibrinolysis.Early recognition of patients requiring massive transfu-

sion using viscoelastic hemostatic assays, such as rTEG, isassociated with reduced overall blood product usage aswell as increased survival.33-35 We have previously shownthat rTEG values are also available faster, are cheaperthan conventional coagulation tests, and are strongly asso-ciated with outcomes of interest to clinicians caring forseverely injured patients.25 In this study, we demonstratethat additional velocity curve parameters measured byrTEG are clinically useful and available faster than con-ventional rTEG values. Moreover, velocity curves areautomatically calculated with each and every rTEG sam-ple and therefore are available at no additional cost,further underscoring their potential value in the clinicalsetting.Compared with conventional rTEG tracings, velocity

curves contain kinetic parameters defined by sharp peaks,which may improve the resolution of rTEG to detectsmall but important changes in hemostatic potential.The well-defined peaks of velocity curves may improvethe signal-to-noise ratio and improve the ability to userTEG to identify coagulopathies and guide resuscita-tion.36 Our findings are paralleled by similar findingsfrom the Copenhagen group,31 who recently demon-strated that earlier amplitudes obtained before MA arecorrelated with hemorrhage and accurately identifytrauma-induced coagulopathy. Meyer and colleagues31

found that the amplitude of clot generation at 10 minutes(A10) reflects a more dynamic part of the hemostatic pro-cess than MA, suggesting that early amplitudes may pro-vide a means for earlier detection of coagulopathies andgoal-directed transfusion therapy. The same principlemay be applied to our results using an earlier measureof lysis to identify and target pathologic hyperfibrinolysis.As many centers have gained experience and interest in

guiding resuscitation with viscoelastic assays such asrTEG, defining a clear threshold for hyperfibrinolysishas been challenging. The manufacturer of TEG reportsthe normal range of fibrinolysis to be 0% to 7.5%; how-ever, we previously demonstrated that mortality increasessignificantly in patients with admission LY30 values aslow as 3%.16 In this study, 11% of patients had hyperfi-brinolysis by this threshold and this translated to a 3-fold increase in 24-hour mortality. These findings areconsistent with other studies reporting similar incidencerates and equally high mortality associated with hyperfi-brinolysis.12,37 In a recent study from the Denver Health

Table 4. Transfusion and Mortality Outcomes by Lysis 30 Minutes after Maximum Amplitude Is Reached and Maximum Rateof Lysis Measures of Hyperfibrinolysis

VariableLY30 � 3%(n ¼ 1,442)

LY30 > 3%(n ¼ 183) p Value

MRL � 0.5(n ¼ 1,477)

MRL > 0.5(n ¼ 148) p Value

Units of RBC at 3 h 0 (0e0) 0 (0e0) 0.341 0 (0e0) 0 (0e3) <0.001

Units of FFP at 3 h 0 (0e0) 0 (0e0) 0.367 0 (0e0) 0 (0e2) <0.001

Any transfusion, % 31.6 29.0 0.469 27.1 45.2 <0.001

Substantial bleeding, % 9.0 12.6 0.123 6.6 20.0 <0.001

Massive transfusion, % 4.9 12.0 <0.001 3.3 18.3 <0.001

24-h mortality, % 4.3 13.1 <0.001 2.3 20.0 <0.001

30-d mortality, % 9.9 18.0 0.001 6.6 24.4 <0.001

Continuous variables represented as medians with interquartile range (IQR).FFP, fresh frozen plasma; LY30, lysis 30 minutes after maximum amplitude is reached; MRL, maximum rate of lysis.

1164 Pommerening et al Early Diagnosis of Hyperfibrinolysis J Am Coll Surg

group, Chapman and colleagues26 demonstrated thatLY30 > 3% is a strong predictor of hemorrhage and mor-tality, and similarly concluded that fibrinolysis greaterthan 3% is a critical threshold for defining and treatingclinically relevant hyperfibrinolysis. Using this establishedLY30 threshold for increased mortality, we attempted toidentify an equivalent cut-point for MRL. In this study,this corresponded to an MRL of > 0.5 mm/min in asimilar percentage of patients (9%). It is important tonote that while both values were predictive of MT andmortality, MRL also predicted early transfusion of

Table 5. Multiple Logistic Regression Model PredictingLarge Volume Transfusion and Mortality Outcomes

Variable Odds ratio 95% CI p Value

Substantial bleeding*

LY30 > 3% 1.59 0.92, 2.75 0.100

MRL > 0.5 3.06 1.66, 5.62 <0.001

TL > 60 2.92 1.61, 5.29 <0.001

Massive transfusiony

LY30 > 3% 3.11 1.71, 5.64 <0.001

MRL > 0.5 5.77 2.91, 11.43 <0.001

TL > 60 5.58 2.85, 10.95 <0.001

24-h mortality

LY30 > 3% 4.14 2.26, 7.57 <0.001

MRL > 0.5 8.08 3.98, 16.41 <0.001

TL > 60 7.57 3.72, 15.40 <0.001

30-d mortality

LY30 > 3% 2.84 1.67, 4.83 <0.001

MRL > 0.5 3.51 1.89, 6.50 <0.001

TL > 60 4.55 2.47, 8.38 <0.001

Controlling for age, sex, mechanism, base value, Injury Severity Score, andweighted revised trauma score.*Substantial bleeding is defined as �1 U red blood cells (RBC) in the first2 h and >4 U RBC in the first 4 h after arrival, or hemorrhagic deathwithin 6 h.yMassive transfusion means a transfusion of �10 U RBCs in the first 6 hafter arrival.LY30, lysis 30 minutes after maximum amplitude is reached; MRL,maximum rate of lysis; TL, total lysis.

RBCs and plasma as well as SB. This is an importantfinding because it suggests that MRL may be more closelyassociated with early bleeding and coagulopathy, andtherefore could be a more valuable tool for early diagnosisof hyperfibrinolysis.Our findings have important implications given the

high mortality associated with hyperfibrinolysis and thenarrow window of time in which antifibrinolytic agentsmay offer a survival benefit. Fibrinolysis has been shownto play an integral role in the development of coagulopathyof trauma, and early infusion of an antifibrinolytic agent,such as tranexamic acid, has resulted in decreased mortal-ity.13 Currently, LY30 is the only measure of fibrinolysisused clinically that is included in the conventional rTEGtracing; however, the nature of LY30 as a finalized assess-ment of fibrinolysis means that it is one of the last param-eters to become available for interpretation. By definition,LY30 estimates the percent lysis 30 minutes after MA isachieved, which translates to 45 to 50 minutes (or longer)after initiation of rTEG. The fact that MRL is achievedjust after 30 minutes into the rTEG assay indicates thatthis value is available to clinicians significantly soonerthan LY30. Earlier identification of hyperfibrinolysis usingMRL could potentially reduce the time to activate amassive transfusion protocol and initiate infusion of anti-fibrinolytic agents. In addition, the earlier opportunity tovisualize and interpret rTEG velocity curve results mayenable physicians to customize resuscitation strategies tomore rapidly address patient-specific coagulopathies. Inthe critically injured, hemorrhaging patient, this seeminglysmall reduction in time to laboratory results may translateto significantly larger improvements in patient outcomes.There are important limitations to this study, namely,

that the data were obtained retrospectively and collectedfrom a single institution. In addition, the definitions forsubstantial bleeding and massive transfusion remaincontroversial and are not universally agreed on for pre-dicting trauma outcomes. However, we believe these

Vol. 219, No. 6, December 2014 Pommerening et al Early Diagnosis of Hyperfibrinolysis 1165

parameters accurately capture the intensity of bleedingand are therefore more clinically relevant than the lessfavored traditional cumulative blood transfused in 24hours. Moreover, the definition of substantial bleeding at-tempts to account for early hemorrhagic deaths and theinherent survival bias that confounds many traumastudies. Protocolized transfusion of blood products in pre-defined ratios may have also influenced our results, but itis important to note that this practice was often limited toonly the initial products transfused and/or patientsactively receiving MT protocols, after which productswere delivered and ordered based on clinical conditionand rTEG results. Finally, the use of velocity curves forpatient management is considered experimental and hasnot been evaluated in clinical settings or approved bythe FDA for clinical use. Larger prospective studies areneeded to validate our findings and better define how tooptimize use of velocity curves for patient care.

CONCLUSIONSFirst derivative velocity curves generated by rTEG provideadditional kinetic information regarding fibrinolysis thatis predictive of early bleeding and mortality after trauma.Compared with LY30, MRL is a more rapid, powerfulpredictor of bleeding and mortality that may facilitateearlier activation of MT protocols and treatment withantifibrinolytic agents in patients with clinically signifi-cant hyperfibrinolysis.

Author Contributions

Study conception and design: Cotton, Holcomb, Wade,Goodman, Pommerening

Acquisition of data: Farley, Pommerening, Cardenas,Podbielski

Analysis and interpretation of data: Pommerening,Cotton, Wade, Holcomb, Matijevic

Drafting of manuscript: Pommerening, GoodmanCritical revision: Pommerening, Cotton, Holcomb,Goodman, Wade, Cardenas, Podbielski, Matijevic

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