1. Clinical Utility of Thromboelastography (TEG)
Lowell Chambers, MD

2. Secondary Hemostasis (Coagulation Cascade)
CLASSIC COAGULATION CASCADE
INTRINSIC PATH
(PTT)
EXTRENSIC PATH
(PT)
XII
XIIa XI
XIa
VIIa + TF IX
IXa +
VIIIa X Xa + Va
Gradually described from ex-vivo lab experiences between s and noted to rely heavily on hepatically produced, systemically circulating serine proteases
Ca++
Prothrombin (II)
Thrombin (IIa)
Fibrinogen (I)
Fibrin (Ia) 2

3. Secondary Hemostasis (Coagulation Cascade)
PHYSIOLOGIC PATHWAY
VIII
Platelet
Thrombin
VII + TF IX
IXa +
VIIIa* V X Xa + Va
XIII (transglutaminase) II
Thrombin XI
XIa
Subsequently learned that in-vivo the physiologically functioning cascade was more dependent on the exposure of subendothelial tissue factor and platelet activation.
Ca++
XIIIa
Cross-
Linked*
Fibrin
Fibrinogen
Fibrin 3

4. Cell-Based Hemostasis

5. Challenges in Coagulation Evaluation
Evaluation of Platelet Function
Monitoring of New generation anticoagulants
Determination of Hyperfibrinolytic States

6. Coagulopathy of Trauma
Hyper-
fibrinolysis
Prot. C Activation
ACIDOSIS
Impaired Clotting Factor Function
Impaired Platelet Function C O A G U L P T H Y
HYPOTHERMIA
Increased
TF Release
CNS Injuries
DIC
HIGH ISS
Long Bone
Fxs
Fat Embolism
Initially described in 2003
Dilution of Clotting
Factors & Platelets
HYPOTENSION
Increased
IVF & PRBCs
Hess J,… Hoyt D, … Bouillon B. J Trauma 2008; 65:748-54 6

7. Coagulopathy of Trauma
¼ Significant Trauma patients
4x increased mortality
Multifactorial
Currently addressed with:
Whole Blood
1:1:1 Massive Transfusion Protocols
Hess J,… Hoyt D, … Bouillon B. J Trauma 2008; 65:748-54

8. Coagulopathy of Trauma
¼ Significant Trauma patients
4x increased mortality
Multifactorial
Currently addressed with:
Improved
Outcomes
Whole Blood
1:1:1 Protocols
Hess J,… Hoyt D, … Bouillon B. J Trauma 2008; 65:748-54

9. Consequences of Overtransfusion
Waste
ALI / MSOF
Thrombosis

10. Hyperfibrinolysis in Trauma
See in 2-34% of Trauma Pts
Increased risk with increased ISS, need for transfusion, etc…
Associated with increased mortality
Napolitano L,… Moore EE. J Trauma Acute Care Surg 2013; 74:

11. Fibrinolyis in Trauma
Kashuk J, Moore EE, et al. Ann Surg 2010; 252:434-44

12. Hyperfibrinolysis in Trauma
Napolitano L,… Moore EE. J Trauma Acute Care Surg 2013; 74:

13. Randomized, multicenter trial (Europe, Asia, Africa)
20,127 trauma pts in 274 hospitals
Inclusion criteria:
TA (1gm over 10 min. then another gm over 8hr) versus Placebo
Hemorrhagic Shock (SBP < 90, HR > 110)
High risk of substantial bleeding
Within 8 hr of injury

14. Tranexamic Acid in Trauma
All cause mortality reduction of 1.5%.
Lancet 2010; 376:23-32

15. Tranexamic Acid in Trauma
Lancet 2010; 376:23-32
NNT = # needed to treat
All cause mortality reduction of 1.5% with TXA. +
No harm from TXA
Low Cost (~$6.00/gm)
Potential to save ,000
lives annually world-wide
(NNT1 = 67)

16. TXA in Trauma Cheap Safe Effective
SO WHY NOT USE ROUTINELY IN BLEEDING TRAUMAS ?
Added to WHO “Essential Medications List” in 2011
Napolitano L,… Moore EE. J Trauma Acute Care Surg 2013; 74:

17. CRASH-2 Problems
This observation has led most to desire more selective use of TXA
Napolitano L,… Moore EE. J Trauma Acute Care Surg 2013; 74:

18. Deficiencies in Current Coag. Assessment of Severely Injured Trauma Pts
No rapid, reliable assessment of hyperfibrinolysis
Incomplete assessment of Coagulopathy of Trauma
Lack of Qualitative Platelet Evaluation
Lack of rapid Coag. Assessment
Inability to assess when switch from hypo to hypercoagulable occurs

19. Thrombelastography (TEG)
A viscoelastic point of care hemostatic assay
Provides a graphic presentation of clot formation & lysis
Johansson PI, et al. Scan J Trauma, Resus, & Emerg Med 2009; 17:45.

20. Hemostasis Monitoring with the TEG® System
Measures entire clotting process
Measures: ∆Clot strength / time
Facilitates RAPID assesment of entire coagulation process.
Rate of clot formation
Strength of clot
Stability of clot
Hemostatic
status

21. TEG - History Initial description in 1948 (H Hartert)
Important role in development of open heart surgery and liver transplantation
Hartert H. Klin Wochenschr 1948; 26:577-83
Dr. Kurt von Koulla
& Hartert TEG
Dr. Swan recruited a research fellow Dr. Koulla from Germany who brought the Hartert instrument with him to U of Colorado
1950s Dr. Henry Swan &
Hypothermic Open Heart Procedures
1960s Dr. Thomas Starzl &
Liver Transplantation

22. TEG Method
0.36 ml whole blood 37oC in a heated, kaolin-containing cup
Pin is suspended into cup and connected to a detector system (torsion wire)
Cup is oscillated at an angle to the pin
Fibrin forms between the cup and pin
Formation of fibrin results in transmitted rotation from the cup to the pin
Tracing is generated as a result of pin’s movement
Pattern & duration of different aspects of tracing provides information on the clotting and lysis process
(after being collected in Citrate – if delay in running > 3 min)

23. TEG Tracing and Clotting Process
Time (min) ║
Time
Continuous monitoring of clotting process
Generates parameters that relate to each phase

24. Analytical Software Graphical Representation
Kinetics
of clot
development
LY30
K = time between 2 & 20 mm aplitude
Percent lysis
30 minutes
after MA
Reaction time,
first significant
clot formation
Achievement
of certain clot
firmness
Maximum amplitude –
maximum strength of
clot 24

25. TEG Parameters: R Reaction time (4 – 8 min) FFP rVIIa PCC FFP +
Platelets
R=reaction time=period from 0-2 mm amplitude. Corresponds with the initiation phase & clotting factor function. MA=maximum amplitude – Corresponds with Final Clot Strength & therefore Clotting Factor and Platelet function.
LMWH
LMWH +
ASA

26. TEG Parameters: K and angle () Rate of clot growth
K: Clot kinetics (0 - 4 min)
K=kinetics=period from 2-20 mm amplitude. Reflects the amplification phase. Alpha angle the slope between R & K. Smaller alpha corresponds with longer K which is associated with low fibrinogen levels.
4-8 min
FFP
Cryoprecipitate

27. TEG Parameters: MA Maximum clot strength
Maximum amplitude
(54 – 72 mm)
Platelets
Normal R with low MA = platelet need.
ASA

28. TEG Parameters: LY30 Clot Breakdown
Lysis at 30 minutes
(0 – 7.5%)
TXA
ACA
Ly = Clot lysis after certain time (most common eg= 30 minutes). Increased LY30 seen with hyperfibrinolytic states. Can help select trauma and general surgery patients who will benefit from TXA, etc… .

29. TEG: Basic Patterns

30. Hemostasis Monitoring with the TEG® System
Measures entire clotting process
Measures: ∆Clot strength / time
Rate of clot formation
Strength of clot
Stability of clot
Hemostatic
status

31. Primary clinical applications over the last several decades have been in hepatic and cardiac surgery patients

32. Clinical Experience with standard TEG
Majority of experience is with Cardiac & Liver Surgery
> 20 clinical studies with > 4500 pts in last 25 years
Varying quality (3 rand. clin. trials)
Uniform findings of superiority of TEG over routine coagulation tests.
Johansson PI, et al. Scan J Trauma Resus Emerg Med. 2009; 17:45

33. Standard TEG in Massive Tranfusion
European Prospective Trial
n=832 massively bleeding pts (21% trauma)
TEG-guided patients:
More applicable to General Surgeons and others of us who aren’t Transplant or Cardiac surgeons was a prospective trial published in 2009 out of Copenhagen
20% VS 32% mortality
> FFP
> Plts
Johansson PI, et al. Vax Sang 2009; 96:111-8

34. TEG in Trauma
Johansson PI, et al. Scan J Trauma Resus Emerg Med. 2009; 17:45

35. TEG in Trauma
Differentiates different etiologies of the Coagulopathy of Trauma
Quicker & more accurate than coags.
Permits ID of Hyperfibrinolysis
Differentiates hyper VS hypocoagulability
Gives info. on coag status with newer
anticoag. agents
Johansson PI, et al. Scan J Trauma Resus Emerg Med. 2009; 17:45

36. RapidTEG Tissue Factor added to Kaolin in cup
Cuts processing time by ~ 50%:
r-TEG 19.2 min to completion
TEG 29.9 min “
Coags 34.1 min “
Software available facilitating viewing of TEG on monitor in ICU/OR
real-time so initial information available within minutes.
Jeger V, et al. J Trauma 2009; 66:1253-7
Holcomb JB, et al. Ann Surg 2012; 256:476-86

37. r-TEG Tracing Comparison
RapidTEG
Standard TEG
Differences: R range: 0-1 min
& use ACT

39. U Colorado Experience
Preliminary Study: Randomized prospective trial underway
More “Goal Directed” Therapy “LEAN” Goals met c blood products needed
Kashuk JL, Moore EE, et al. Transfusion 2012; 52:23-33

40. U Colorado Case Study 38 yo F auto VS ped. patient
HD unstable from intra-abd bleeding
Emergent Trauma Lap.
Initial r-TEG in OR
- PRBCs for hemorrhagic shock
- FFP for prolonged ACT
- Platelets for depressed MA
- 5 gm EACA for elevated LY30

41. U Colorado Case Study Intra-abd. Bleeding controlled but still “oozey”
2nd r-TEG in OR
- Improved coagulopathy (improved ACT)
- Improved platelet function (improved MA)
- Persistent Fibrinolysis (Sign. Increased LY30 still)
Additional EACA administered

42. U Colorado Case Study Pt continued to stabilize “Oozing” resolved
3rd r-TEG in OR

43. Ann Surg 2012; 256:476
U Texas Experience demonstrated good correlation with TEG & coags with TEG being a slightly better predictor of need for massive transfusion.

44. r-TEG U Texas Experience…
Holcomb JB, et al. Ann Surg 2012; 256:476

45. U Texas Approach Unstable Pt: 1:1:1 Transfusion
Once surgical hemostasis achieved:
Holcomb JB, et al. Ann Surg 2012; 256:476

46. Baylor Approach ~ 10 year experience with TEG-directed resusc.
Use conventional TEG rather than r-TEG
Mattox believes in the KISS principal !!
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

47. Baylor Experience In October 2009 instituted 1:1:1 MTP
Reviewed outcomes 21 months before & after
Compared outcomes with TEG-directed VS reflexive 1:1:1 MTP
Dr. Mattox and his colleagues represented a unique experience as they were already utilizing TEG when most hadn’t even heard of it and were just getting started with modern MTPs
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

48. Baylor Experience
MTP associated with stat. significant increased FFP utilization and a trend toward overall increased blood utilization.
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

49. Baylor Experience
No improved survival in MTP with increased FFP utilization
Some subsets of MTP with worse outcomes
Furthermore they found that the more aggressive blood product administration associated with the MTP did not translate to improved survival or other outcome measures. In fact some subsets experienced statistically significant increased mortality with the MTP VS TEG-guided resuscitation.
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

50. Baylor Approach
In other words they use their 1:1:1 Massive Transfusion Protocol to determine what blood bank sends them but once TEG-data is available they use it to guide how much of the products they actually transfuse
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

51. ? Mt Carmel Approach
> 3.0% TXA
Baylor approach (with modification in accordance with U Texas & Colorado experiences with improved outcomes when TXA is used for LY-30s > 3%) is the one which makes the most sense to me. Its simple, combines the benefits of MTPs & TEG, and keeps it simpler for the lab techs and cheaper for the system by using standard TEG & is the only one validated with mortality data.
Tapia NM, … Mattox KL, Suliburk J. J Trauma Acute Care Surg 2013; 74:

52. U Texas Approach
Holcomb JB, et al. Ann Surg 2012; 256:476

53. TEG & PE risk assessment
Prospective Study with 2,070 consecutive Cat. 1 Trauma Alerts ( ) at U Texas, Houston
All had r-TEG
53 (2.5%) PEs at median of 6 days (range 2-31 days)
Sens. 82%
Spec. 53%
Cotton B, … Holcomb J. J Trauma Acute Care Surg 2012; 72:1470-7

54. TEG & PE risk assessment
Sens. 49%
Spec. 87%
Cotton B, … Holcomb J. J Trauma Acute Care Surg 2012; 72:1470-7

55. Prospective Blinded Cohort Study
240 pts undergoing major non-cardiac surgery
Routinely drew ran TEG 2 hr postop & followed
12 thrombotic complications in 10 pts
(6 MI, 2 DVT, 2 PE, 2 CVA)

56. TEG & Postop Thrombosis

57. TEG & Postop Thrombosis

58. TEG & Postop Thrombosis
What to do based on these findings: ? Early ASA, ? Increased prophylaxis, ? Plavix

59. New Anticoagulant Monitoring
Holcomb JB, et al. Ann Surg 2012; 256:476

60. TEG & LMWH LMWH not typically monitored
Anti-Xa levels used when needed:
TEG Delta R (with & without heparinase) appears to be a better index of LMWH dose adequacy
Limited availability
Inconsistent data
White H, et al. Blood Coag & Fibrinolysis 2012; 23:304-10
Van PY, … Schreiber M. J Trauma 2009; 66:

61. TEG & LMWH R < 0.4 associated with DVT & calls for LMWH dose
No difference in Antifactor X values between the 2 groups but a delta R on TEG was associated with DVT. More study is needed but TEG may provide an easier and more accurate means of measuring the adequacy of LMWH dosing for prophylaxis and therapy. It may also provide a means of monitoring some of the newer anticoagulants.
Van PY, … Schreiber M. J Trauma 2009; 66:

62. Anti-platelet issues
Surgical issue: risk of bleeding VS risk of ischemic events
Medical / Cardiac Issue: variance of response
Current “Gold Standard” in platelet monitoring is Light Transmission Platelet Aggregometry (LTA) :
Requires specialized labs
Poorly standardized between labs
Not routinely used clinically
Numerous studies demonstrate increased bleeding risk with operations performed on platelet inhibition. Leading cause for successful litigation against Gen Surgeons. On flip side other studies showing increased ischemia risks in stopping anti-platelet therapy for surgery – led to a number of consensus statements from Cardiology, Anesthesia and Surgical Societies (including the American College of Chest Physicians) emphasizing the need to continue antiplatelet therapy in the periop. period.
Forgetting the issue of surgery there appears to be enough variation of the cytochrome P-450 system such that some patients on Plavix will have essentially no platelet inhibition & therefore remain at risk for ischemic events while others will be hyperresponders placed at increased risk for bleeding with standard dosing.
In light of this it would be very beneficial to have an effective method of monitoring the effects of antiplatelet drugs
Agarwal S, et al. Anesthesiology 2006; 105:676-83

63. Conventional TEG & Antiplatelets
Not helpful
Kaolin-induced thrombin generation overshadows any platelet effect
Lab & clinical experiences have demonstrated normal TEG MAs in specimens with definitive platelet inhibition on LTA
Conventional TEG is performed on blood collected in Citrated tubes. Coag. is stimulated with the addition of Kaolin. This results in significant thrombin generation from the clotting cascade which overwhelms the ability to detect the relatively smaller contribution brought about by platelet activation.
MA = maximum amplitude LTA = Light Transmission Aggregometry
Agarwal S, et al. Anesthesiology 2006; 105:676-83

64. Platelet Mapping
Modified TEG c Heparin added to prevent thrombin activity.
Then add ADP or Arachidonic Acid to determine the contribution of the ADP & TxA2 receptors.
Correlates well with the unwieldy standard of Light Transmission Aggregometry.
Platelet mapping is a modification of TEG which appears to correlate well with LTA but is a much more clinically usable.
Unlike standard TEG the blood is collected in a heparinized tube. Concurrent with this a standard TEG specimen is collected in citrate.
Mylotte D, et al. Cardiovasc Hematolog Agents Med Chem 2011; 9:14-24
Agarwal S, et al. Anesthesiology 2006; 105:676-83

65. Platelet Mapping
Unlike standard TEG the blood is collected in a heparinized tube. This specimen is then divided into 3 of the TEG cups. The first of these has heparinase in it to offset the heparin’s effect. This then has Kaolin placed in it and is run like normal producing a normal maximal amplitude representing the maximum platelet function the patient’s blood is able to produce with max. thrombin generation. This is indicated by the black tracing.
The second cup contains “Activator F (reptilase & Factor XIIIa)” alone in order to measure the contribution of fibrin to the MA. This is represented by the red tracing.
The final cup also contains Activator F but also contains a platelet activator (either ADP if it is Plavix therapy being evaluated or Arachidonic Acid if it is ASA therapy being evaluated). This is represented by the Blue Tracing.In cases where there is dual therapy 2 separate traces (4 in all) are run, one with each of the agonists.
The resulting clot MA is dependent on platelets stimulated by the added agonists, is sensitive to any antiplatelet agent in the blood, and provides a measure of the extent of platelet inhibition. The more closely the MA of theActivated Specimen approximates the kaolin-stimulated MA the less inhibition that is present.

66. Platelet Mapping Minimal Platelet Inhibition:
- minimal risk of bleeding
- ischemia risk
Severe Platelet Inhibition:
- risk of bleeding
- minimal ischemia risk
Wohlauer MV, Moore EE, et al. J Am Coll Surg 2012; 214:
Agarwal S, et al. Anesthesiology 2006; 105:676-83

67. Platelet Mapping
% Inhibition = [(MAADP or AA – MAFibrin) / (MAThrombin – MAFibrin) X 100]
The computer calculates and generates the % Inhibition being afforded by the Antiplatelet medication.
% Inhibition = [(MAADP – MAFibrin) / (MAThrombin – MAFibrin) X 100]
>50% Inhibition Response
30-50% Inhibition Partial Response
< 30% Inhibition Lack of Response
Agarwal S, et al. Anesthesiology 2006; 105:676-83

68. TEG vs LTA vs PFA 91% Correlation between LTA & TEG65 60
PFA = Platelet Function Analyzer
91% Correlation between LTA & TEG
Agarwal S, et al. Anesthesiology 2006; 105:676-83

69. TEG vs LTA vs PFA Agarwal S, et al. Anesthesiology 2006; 105:676-83
Patients taking both ASA and Plavix had 100% response on LTA and on TEG c AA but not TEG c ADP
Agarwal S, et al. Anesthesiology 2006; 105:676-83

70. Preop Antiplatelet Assessment
Current Anesthesia Policy at U of Wales:
“Allows for informed rather than empirical platelet transfusions.”
< 30% Platelet inhibition: proceed with surgery
> 30% Platelet Inhibition: wait or administer platelets
Conservative measure chosen based on earlier LTA data associating platelet inhibitions above 40% with increased bleeding risk during CABG
Kauer J, et al. British J Anaesthesia; 2009; 103:304-5

71. Post PCI J Am Coll Cardiol 2005; 46:1820-6 (n 38) (n 154)
Percutaneous Coronary Intervention. The existence of a high level of individual variability in platelet responsiveness to antiplatelet therapy has been confirmed in a number of clinical studies. As many as ## have been shown to be nonresponders and are therefore at increased risk post PCI MI. Currently them majority of post PCI patients are therefore treated with both Plavix and ASA. Despite this recurrent ischemic events still occur in 8-10 of cases. Additonally this may pose an increased risk of bleeding in patients who respond to Plavix alone.
Feeling that “one size doesn’t typically fit all” an Interventional Cardiology group out of Baltimore has recently, through NIH grants, been investigating the utility of TEG in their post-PCI pts. Their Initial experience in 2005 was dubbed the Platelet Reactivity in Patients and Recurrent Events Post-Stenting and was published in 2005 in the J of the American College of Cardiology. In a prospective observational study they followed 192 post PCI patients (100% of which were on ASA and 84% of which were also on Plavix) over a 6 month interval – demonstrating an association between an MA > 65 on routine TEG & post stenting thrombosis.

72. Post PCI Gurbel PA, et al. J Am Coll Cardiol 2005; 46:1820-6
A high MA on TEG was noted to be the most sensitive and specific risk factor for thrombosis outperforming even LTA. An MA > 72 was associated with a 58% rated of thrombosis as compared to ~ 10% for MA & 2% for MA < Is significant to note that this is consistent with the observation of McCrath, et al who observed increased post op (non cardiac surgery) ischemic complications with MA > 65.
BEWARE HOWEVER THE STUDY WAS (IN ADDITION TO THE NIH) PARTIALLY FUNDED BY HAEMOSCOPE – THE TEG MANUFACTURER.
A subsequent study funded only by the NIH confirmed these findings and demonstrated possible additional utility to Platelet mapping over traditional TEG. (Am Heart J 2010; 160:346-54).
So there is some evidence that TEG can be helpful in tailoring the antiplatelet therapy of all PCI patients – not just the ones undergoing surgery.
Gurbel PA, et al. J Am Coll Cardiol 2005; 46:1820-6

73. Clinical Utility of TEG
Direct resuscitation of severely injured pts
Guide anticoagulation therapy
Guide anti-platelet therapy