Introduction

Section 1

Allogenic blood product transfusions following cardiopulmonary bypass (CPB) are common due to the wide range of hemostatic insults associated with undergoing cardiac surgery. 

Major causes of significant bleeding following cardiac surgery include previous dual-antiplatelet therapy, oral anticoagulants, hypofibrinogenemia, residual heparin, prolonged CPB, and intraoperative hypothermia [1, 2].

Major causes of bleeding following cardiac surgery:

• previous dual-antiplatelet therapy

• oral anticoagulants

• hypofibrinogenemia

• residual heparin

• prolonged CPB

• hypothermia 

The subjectivity of diagnosing a microvascular bleeding combined with the lack of adequate testing of hemostasis may lead to indiscriminate transfusion practices.

Massive transfusion of blood products in the setting of excessive bleeding is associated with transfusion-related acute lung injury, transfusion-associated circulatory overload, transfusion-related immunomodulation, nosocomial infections, and increased morbidity and mortality [3, 4, 5, 6, 7].

The American Society of Anesthesiologists Practice Guidelines for Perioperative Blood Management emphasize employment of multimodal algorithms as strategies to reduce the usage of blood products [8]. 

Massive transfusion is associated with:

• transfusion-related acute lung injury

• transfusion-associated circulatory overload

• transfusion-related immunomodulation

• nosocomial infections

• increased morbidity and mortality

Transfusion algorithms should facilitate individualized goal-directed therapy, with intended improvements such as reduced transfusion of allogeneic blood products, reduced adverse outcomes, reduced mortality and increased cost-effectiveness. 

Evidence to support this approach exists in cardiac surgery [9, 10], trauma [11, 12, 13], postpartum hemorrhage [14], and liver transplantation surgery [15, 16]. 

Randomized-controlled trials (RCTs) demonstrate reduced blood transfusions and percentage of patients transfused when point-of-care-based algorithms are compared with standard laboratory coagulation testing in patients undergoing cardiac surgery (Category A2-B evidence) [17, 18, 19].

Intended improvements of using transfusion algorithms:

• reduced transfusion of blood products

• reduced adverse outcomes

• reduced mortality

• increased cost-effectiveness 

The value of standard laboratory coagulation tests during rapid decision-making processes in the operating room is limited due to the lack of real-time monitoring [20], with the turnaround time being at least 45 minutes [21, 22]. 

Therefore, the use of viscoelastic tests such as TEG to characterize coagulopathy and guide hemostatic therapy has been advocated [23] and is endorsed in guidelines for managing trauma, postpartum hemorrhage and severe perioperative bleeding [8, 24, 25].

Standard laboratory coagulation tests

• aPTT, PT, INR
  

• platelet count

• fibrinogen

Thromboelastography

In this section we will explore:

Section 2

• Fundamentals of hemostasis management

• Limitations of standard laboratory coagulation tests

• Fundamentals of thromboelastography

Hemostasis, also know as the arrest of bleeding from an injured blood vessel, requires the combined activity of:

Hemostasis

• Vascular factors

• Platelets

• Plasma coagulation factors

Hemostasis - Vascular factors

Vessel wall injury triggers the attachment and activation of platelets and the generation of fibrin polymers from fibrinogen. 

Platelets and fibrin combine to form a clot.

Hemostasis - Platelets I

Hemostasis - Platelets II

Platelet receptor for ADP (P2Y12-R), sends signals to suppress adenylate cyclase and promotes activation of the glycoprotein IIb/IIIa receptor (assembled on the activated platelet surface membrane).

Platelets provide surfaces for the assembly and activation of coagulation complexes and the generation of thrombin.

Fibrinogen binds to the glycoprotein IIb/IIIa complexes of adjacent platelets, connecting them into aggregates.

Thrombin converts fibrinogen into fibrin monomers, which polymerize into fibrin polymers that bind aggregated platelets into platelet-fibrin hemostatic plugs.

Hemostasis - Plasma coagulation factors

Coagulation cascade. (From Porwit A, et al. [eds]: Bone Marrow Pathology. Churchill Livingstone, Philadelphia, 2011.)

Due to its complexity, effective hemostasis management depends on the most complete information to make timely decisions on how to best approach a hemostatic imbalance.

Hemostasis Management

Maintaining hemostasis is a complex, dynamic and individualized process. 

Complications related to bleeding or thrombosis may result in increased:

• Pro-coagulant and anti-thrombotic therapies 

• Length of treatment and cost of care 

• Utilization of resources and cost of care

• Morbidity and mortality

Complications related to bleeding or thrombosis may result in increased:

• pro-coagulant and anti-thrombotic therapies 

• length of treatment and cost of care

• utilization of resources and cost of care

• morbidity and mortality

Traditional coagulation tests (i.e., PT, PTT, INR) are of limited value in the perioperative setting because they do not reflect current understanding of cell-based coagulation, providing a limited view of homeostasis.

Standard laboratory coagulation testing

Abnormal results (e.g., prolonged PTT) are not diagnostic of the underlying mechanism of coagulopathy (e.g., factor or fibrinogen deficiency, hypothermia, and heparinization all manifest with prolonged PTT).

Traditional coagulation tests do not show the mechanical properties of clot over time because PT and PTT both terminate at low thrombin levels and before fibrin is polymerized.

Traditional coagulation testing

• Lacks sensitivity and specificity in acute care settings 

• Inadequately reflects in vivo coagulation

• May result in inappropriate treatment

• May have a significant time delay in receiving results

TEG is a viscoelastic-based point-of-care in vitro coagulation testing, originally described as a whole blood assay in 1948 [26].

Thromboelastography I

TEG provides a comprehensive view of a hemostatic profile, assessing the hemostatic potential of whole blood, as compared to a traditional coagulation monitoring.

TEG can rapidly identify and quantify the underlying cause of coagulopathy such as thrombocytopenia, factor deficiency, heparin effect, hypofibrinogenemia, hyperfibrinolysis, and provide a goal-directed, individualized therapy (10, 19, 21).

TEG

• viscoelastic-based point-of-care in vitro coagulation testing

• provides a comprehensive view of a hemostatic profile 

• assesses the hemostatic potential of whole blood

• can rapidly identify and quantify the underlying cause of coagulopathy

Thromboelastography II

TEG results are available within minutes, which can be more readily used to guide clinical decisions when hemostatic abnormalities are suspected.

TEG measures viscoelasticity of whole blood from initiation of fibrin formation to maximal platelet clot strength and through fibrinolysis.

TEG

• measures viscoelasticity from initiation of fibrin formation to maximal platelet clot strength and through fibrinolysis

• provides qualitative information about platelet function rather than quantitative measures alone

• results are available within minutes

Thromboelastography Principles

Clot rate, strength, and stability help to assess patient's risk of bleeding or thrombotic events.

TEG measures clot strength over time, focusing on:

Graphical tracing and numerical results are reported for each measurement

• Clot rate (R, in mins) - time it takes  for first measurable clot to form.

• Clot strength (max. amplitude MA, in mm) - Strength of the clot.

• Clot stability (lysis LY30, in %) - breakdown of the clot.

time (mins)

Clot formation

Clot stability

Maximum amplitude

Clot
rate

Liquid state

Established VHA instruments such as TEG 5000 (TEG, Haemonetics Inc.) assess hemostasis properties by measuring shear forces between a pin and a blood-filled cup. Oscillation is generated by the cup [28]. 

In the past, VHA were associated with important limitations - in particular, limited consistency and sensitivity to vibration [29, 30, 31]. In addition, due to manual sampling and mixing, skilled technicians were needed to perform frequent calibration and cleaning procedures [32].

To overcome these limitations, Haemonetics recently developed a fully automated thromboelastograph, the TEG6s [33].  

TEG6s Hemostasis Analyzer

TEG6s (Haemonetics Inc.) assesses whole blood coagulation properties using the resonance method. 

A blood sample within a four-channel self-contained microfluidics cartridge is exposed to a sinusoidal motion range (20–500 Hz). As clotting proceeds, clot-strength-specific resonance frequencies are detected by a photodetector and converted into TEG-equivalent units. 

As compared to TEG 5000 the test setup of TEG6s is faster, portable, easy to maintain and does not require manual pipetting and mixing, allowing efficient POC coagulation monitoring in patients undergoing cardiac surgery [34]. 

The latter are used to generate TEG tracings, which are illustrating the viscoelastic change of the blood sample in real time [33].

TEG6s Hemostasis Analyzer - Resonance Techonlogy

The TEG6s system measures the clot viscoelasticity throughout the coagulation process.

New to the TEG system technology is the measurement of clot viscoelasticity using a resonance method.

To measure the clot strength with the resonance method, the sample is exposed to a fixed vibration frequency. With LED illumination, a detector measures up/down motion of the blood meniscus. The frequency leading to resonance is identified and then converted to the TEG system readout. Stronger clots have higher resonant frequencies and higher TEG readouts.

TEG 6s Hemostasis Analyzer

• assesses whole blood coagulation properties using the resonance method​ 

• blood sample within a 4-channel cartridge is exposed to a sinusoidal motion range (20–500 Hz)

• clot-strength-specific resonance frequencies are detected by a photodetector and converted into TEG-equivalent units

• stronger clots have higher resonant frequencies and higher TEG readouts

Interpretation of TEG results

Section 3

In this section we will explore:

• Global Hemostasis tracings and results

• Assays included on the TEG 6S cartridges

• How to interpret TEG results and tracings

TEG 6s assays are performed in microfluidic cartridges designed for simultaneous performance of multiple TEG assays. 

Global Hemostasis

Preparing the blood sample for the TEG 6s system analysis is relatively simple. There is no need for controlled pipetting or prior manipulation of reagents. 

The only requirement is to transfer a small, unmetered amount of blood to the loaded cartridge from a sample tube with citrate or heparin.

In this section, we will focus on 2 different multichannel assay cartridges: 

Multichannel assay cartridges

• TEG 6s Global Hemostasis Cartridge

• TEG 6s Global Hemostasis with Lysis Cartridge

The Global Hemostasis (GH) cartridges are utilized to assess the hemostatic properties of citrated blood samples using 4 different assays/reagents simultaneously, one in each of the four cartridge channels.

Global Hemostasis Assays I

For tests using the GH cartridges, use the citrate sample tube (blue top).

Global Hemostasis Assays II

CK

Kaolin

CRT

RapidTEG

Citrated Kaolin Heparinase (CKH) is similar to CK but with the addition of heparinase, to neutralize the effects of heparin in the blood. If there is heparin present, the R time for CK will be significantly longer than the R time for CKH.

The Citrated Rapid TEG (CRT) assay maximally accelerates the clotting process by simultaneously activating the intrinsic and extrinsic coagulation pathways, allowing for the maximum clot strength to be reached more quickly.

For the Citrated Kaolin (CK) assay, Kaolin-activated test methods are used to reduce variability and to reduce the running time of a native whole blood sample. 

CKH

CFF

The Citrated Functional Fibrinogen (CFF) assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

Global Hemostasis with Lysis 

The Global Hemostasis with Lysis Cartridge (GHL cartridge) contains 3 independent assays (CK, CRT and CFF) and the system output consists of a table of numerical values for parameters R, LY30, and MA. It does not contain Citrated Kaolin with Heparinase (CKH).

The CFF assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

The major difference between the GHL and the GH (Global Hemostasis) cartridges is that GHL cartridge is missing Citrated Kaolin with Heparinase (CKH). 

LY30 can only be measured using GHL and not the GH cartridge.

Global Hemostasis with Lysis Cartridge

• 3 independent assays (CK, CRT and CFF)

• parameters are R, LY30, and MA

• no Citrated Kaolin with Heparinase (CKH)

• LY30 cannot be measured using the Global Hemostasis (GH) cartridge

The analyzer displays visual tracings and numerical results. The numerical results are populated as they are finalized. The visual tracings develop continuously in real time.

Global Hemostasis Assays - Displaying Results

D - Parameter

E - Units

F - Result

Tracing interpretation framework

The analyzer will present numeric results and visual tracings for interpretation.

Interpreting results

Results are highlighted orange once they fall outside the reference range.

Let's look at the tracing on the right.

Is there a deficiency in:

• Clot Rate (R)?

• Clot Strength (MA)?

• Clot Stability (LY30)?

This tracing output is suggestive of an increased rate of fibrinolysis. 

Hover over the tracing to see the answer.

All tests are run simultaneously providing the advantage to select the most specific and timely information. 

Cyclic interpretation guide I

The greatest sensitivity to clotting factors and heparin is achieved with the R parameter of the CK and CKH tests.

Clot strength is most rapidly assessed with CRT, while CFF isolates fibrin contribution. 

Let's take a closer look at the cyclic interpretation guide designed to assist in determination of specific deficiencies at the next page.

CK (R) - clot initiation.

Used to guide clotting factor requirements.

Cyclic interpretation guide II

Kaolin

(CK)

Kaolin

Heparinase

(CKH)

RapidTEG

(CRT)

Functional

Fibrinogen

(CFF)

CRT (MA) - total clot strength (platelets AND fibrin).

Used in conjunction with CFF (MA) to guide platelet requirements

CKH (R) - used in conjunction with CK (R) to assess heparin effect.

CFF (MA) - fibrin only clot strength. Used to guide fibrinogen requirements.

Interpretation of TEG results - Summary

Parameters from each test are mapped to a results table and visual tracing output.

Analyze the results and try to identify any deficiencies in clot rate, strength, or stability. 

The simple interpretation framework identifies the most specific test and parameter for providing the most timely, sensitive, and specific information.

Use results parameters and tracing output to drive individual goal-directed therapy.

Results from the TEG6s analyzer should not be the sole basis for the diagnosis, but should be evaluated together with the patient's medical history, the clinical picture, and if necessary further hemostasis tests.

Platelet Mapping

Section 4

In this section we will explore:

• The functions and assays of the TEG6s Platelet Mapping Cartridge

• How to interpret Platelet Mapping output

Platelet Mapping

Platelet mapping can provide important information to help assess bleeding and ischemic risks in patients undergoing anti-platelt therapy. 

The CFF assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

Platelet mapping assays determine the Maximum Amplitude (MA) - a measure of clot strength - and the reduction in MA due to genetic factors or anti-platelet therapy.

For tests using Platelet Mapping Cartridge, use the heparin tube with the green top.  

Platelet Mapping ADP Cartridge

Platelet Mapping ADP Cartridge is used to assess platelet function. 

The CFF assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

This assay specifically determines the MA (Maximum Amplitude, a measure of clot strength) and the reduction in MA due to genetics, antiplatelet therapy, or surgical procedures, and reports it as percentage aggregation or percentage inhibition.

The Platelet Mapping ADP assay consists of blood modifiers - ADP platelet agonist and ActivatorF - which, when used on a heparinized blood sample, can measure the levels of platelet function. 

Platelet Mapping - Principles I

The assay uses the ADP agonist to assess platelet aggregation or inhibition. 

The CFF assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

Thrombin also converts fibrinogen into fibrin to create the fibrin mesh necessary for any clot formation, and converts Factor XIII to Factor XIIIa for fibrin cross linking. 

Since thrombin has been rendered inactive by heparin, ActivatorF is used to replace thrombin’s role in the conversion of fibrinogen to fibrin and Factor XIII to Factor XIIIa.

Since thrombin is the primary and most potent activator of platelets, its activity must be inhibited with heparin so that the platelet activating effects of ADP can be measured. 

Platelet Mapping

• thrombin is the primary and most potent activator of platelets

• thrombin activity is ihibited with heparin 

• after thrombin activity is inhibited, platelet activating effects of ADP can be measured

• now that the thrombin is inactive, ActivatorF is used to convert fibrinogen to fibrin and FXIII to FXIIIa

Platelet Mapping - Principles II

The CFF assay inhibits platelet aggregation, excluding its contribution to clot strength, and thereby measures fibrinogen contribution to clot strength.

With this cross-linked fibrin network as the foundation (represented by MA ActF), additional clot strength due to platelet-fibrin bonding related to the ADP (MA ADP) platelet receptor activation can be measured. 

The HKH reagent, a combination of Kaolin and Heparinase, generates test data for the uninhibited MA (MA K) resulting from thrombin activation of the blood sample, while the Heparinase neutralizes the effects of heparin.

Platelet Mapping

Click the button to see the key points

• Max Amplitude (MA) ActF represents the cross-linked fibrin network

• Max Amplitude (MA) ADP - additional clot strength due to platelt-fibrin bonding related to the ADP

• Kaolin and Heparinase (HKH) reagent generates test data for the uninhibited MA (MA K) 

Evaluating Platelet Function I

We are going to look at 3 elements:

Maximum Amplitude (MA) in the setting of platelets being fully activated by thrombin. This will be our baseline.

MA in the setting of platelets NOT being activated. Here we are evaluating fibrin only.

MA in the setting of platelets being activated by an agonist (ADP or Arachidonic Acid). 

0% Activation

0% - 100% Activation

100% Activation

Evaluating Platelet Function II

Clot Strength

Baseline

Reagent

Reference

Ranges

Test

Parameter

Clot Strength

Fibrin Only

Clot Strength

ADP Receptor Action

Hemostatic Activity

Tracings

Click on individual "Clot Strength" to show more or less

Evaluating ADP Response

Platelet receptor response to the platelet agonist ADP is relative to the baseline platelet and fibrin function. 

The closer the ADP response to the fibrin only result the stronger is the inhibition of that receptor. 

No inhibition

Moderate inhibition

Severe inhibition

Interpreting Platelet Mapping Output

Remember, the goal is to consider the inhibition relative to the maximum amplitude (MA) of the clot strength baseline.

Let's take a look at the example on the right of the screen. 

Notice that if there is a high thrombin-generated platelet MA, a 50% platelet inhibition may not put the agonist-generated platelet MA into the normal range. 

Platelet Mapping - Summary

Platelet Mapping determines the Maximum Amplitude (MA, a measure of clot strength) and the reduction in clot strength due to genetics or antiplatelet therapy.  

The result is reported as a percentage of reduction in clot strength.  

The Platelet Mapping assay uses agonists (ADP or arachidonic acid) to assess platelet aggregation or inhibition. 

When analyzing tracing results, identify the inhibition relative to the underlying baseline MA.

Clinical Scenarios

Now let's review some clinical scenarios

Section 5

Each scenario will represent a unique hemostatic profile

Let's analyze each TEG tracing before identifying the abnormality

Case 1

72 yo male is undergoing a CABG. At the end of the procedure surgeon is concerned  about diffuse bleeding. You decide to send a TEG sample. 

CK

CRT

CKH

CFF 

R (min)

K (min)

ANGLE(deg)

MA (mm)

What is the most likely deficiency here? 

Platelet deficiency: MA of the Rapid TEG (CRT) test is low. The functional fibrinogen (CFF) MA is normal. Combined these results are suggestive of a platelet deficiency.

Case 2

50 yo woman has arrived to the emergency room and has lost a significant amount of blood. You sent a TEG sample. 

CK

CRT

CKH

CFF 

R (min)

K (min)

ANGLE(deg)

MA (mm)

What is the most likely deficiency here? 

Factor deficiency: Both, the Kaolin (CK) test and the heparinase (CKH) rate are above the reference range. Heparinase (CKH) rate is not significantly shorter than the Kaolin (CK) rate, not suggesting the heparin effect.

Case 3

30 yo man  underwent major abdominal surgery with significant intraoperative blood loss. TEG sample was sent at the end of the procedure. 

CK

CRT

CKH

CFF 

R (min)

K (min)

ANGLE(deg)

MA (mm)

What is the most likely deficiency here? 

Fibrinogen deficiency: MA of the Functional Fibrinogen (CFF) test is low. This result is suggestive of fibrinogen deficiency.

Case 4

52 yo man  has been admitted following a motor vehicle accident. TEG sample was sent in the emergency department. 

CK

CRT

CFF 

R (min)

MA (mm)

What is the most likely deficiency here? 

Factors and Fibrinogen deficiency combined with hyperfibrinolysis: R time of the Kaolin (K) test is elevated. The MA of both the CFF and CRT are below the reference range. However, the CRT-MA is just slightly below the reference range. Kaolin LY 30 is increased, suggesting hyperfibrinolysis.  

LY30

(%)

Case 5

You are concerned about the bleeding risk associated with clopidogrel in a patient who is on dual anti-platelet therapy. You decide to perform a platelet mapping analysis.

Is the underlying hemostatic balance normal? 

The underlying hemostatic balance is hypercoagulable because HKH-MA is above the normal range. ADP-MA is normal, indicating no increased bleeding risk from ADP receptor inhibition.  AA-MA (arachidonic acid) is below the reference range, indicating that patient responds to aspirin.

HKH

ActF

ADP

AA

MA (mm)

Is the bleeding risk increased due to ADP inhibition?  

Does the patient respond to aspirin?  

TEG-guided transfusion algorithm

Section 6

As we learned in the Introduction section, the ASA Practice Guidelines for Perioperative Blood Management emphasize employment of multimodal algorithms as strategies to reduce the usage of blood products. 

Transfusion algorithms should facilitate individualized goal-directed therapy, with intended improvements such as reduced transfusion of allogeneic blood products, reduced adverse outcomes, reduced mortality and increased cost-effectiveness. 

On the next slide you can find a TEG-based transfusion algorithm. 

Clot Rate (R)

Clot Strength (MA)

Clot Stability (LY30)

CK-R normal?

AND

No

Yes

No

Yes

Yes

Administer

Protamine 

Administer

FFP

AND

No

No

Yes

Yes

Yes

Administer

Platelets

Administer

Fibrinogen

No

Yes

Administer

Platelets

+

Fibrinogen

Kaolin LY30 normal?

No

Consider

repeating TEG

Yes

Administer Antifibrinolytic agent

Kaolin LY30 high?

Yes

TEG-guided transfusion algorithm

CK-R high?

CKH-R normal?

AND

CK-R high?

CKH-R high?

CRT-MA normal?

CFF-MA normal?

CRT-MA low?

CFF-MA normal?

AND

CRT-MA normal?

CFF-MA low?

AND

CRT-MA low?

CFF-MA low?

AND

CK - Citrated Kaolin

CKH - Citrated Kaolin with Heparinase

CRT - Citrated Rapid TEG

CFF - Citrated Functional Fibrinogen

Treatment of hemostatic disorders I

While it is conceivable that transfusion algorithms facilitate individualized goal-directed therapy, it is not fully clear how much blood products to administer depending on a certain TEG result.

Royston et al. proposed a decision tree for administration of hemostatic components based on the heparinase-modifed thrombelastogram [18] (see table below).

The authors acknowledged a number of potential concerns and weaknesses in their pilot study, as well as a requirement of a larger, appropriately powered, multicenter study [18]. 

Treatment of hemostatic disorders II

Redfern et al. proposed another treatment algorithm. In their study, the recommended treatment and the amount of blood products to administer was based on the TEG results achieved with the TEG5000 Hemostasis Analyzer System (Haemonetics, Braintree, MA) [27].

Redfern et al., Ann Thorac Surg 2019;107:1313–8.

Gurbel et al. studied 300 patients undergoing coronary revascularization in a first validation study of the TEG6s system [32].

TEG6s measurements demonstrated high precision as well as a strong correlation with the results of the established TEG5000 [32]. 

Do the TEG5000 and TEG6s results correlate?

Full heparinization and TEG6s results

Erdoes et al. reported that TEG6s system appears to be feasible for point-of-care hemostasis assessment in cardiac surgery [35]. However, during full heparinization no results were determinable for MA CK, MA CRT, MA CFF, or R CK (partly determinable for MA CKH and R CRT). The authors concluded that while correlation with established laboratory parameters is adequate, only a few measurements could be performed during full heparinization [35].

Interestingly, Gurbel et al. did not report any influence of heparin administration on TEG6s parameters [32].

The conflicting results of the 2 studies regarding the influence of heparin administration on TEG6s parameters indicate the need for larger studies.

References

1. Fassl, J., et al., Transfusion of allogeneic blood products in proximal aortic surgery with hypothermic circulatory arrest: effect of thromboelastometry-guided transfusion management. J Cardiothorac Vasc Anesth, 2013. 27(6): p. 1181-8.

2. Bolliger, D. and K.A. Tanaka, Roles of thrombelastography and thromboelastometry for patient blood management in cardiac surgery. Transfus Med Rev, 2013. 27(4): p. 213-20.

3. Murphy, G.J., et al., Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation, 2007. 116(22): p. 2544-52.

4. Spiess, B.D., et al., Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion, 2004. 44(8): p. 1143-8.

5. Khan, H., et al., Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest, 2007. 131(5): p. 1308-14.

6. Buddeberg, F., B.B. Schimmer, and D.R. Spahn, Transfusion-transmissible infections and transfusion-related immunomodulation. Best Pract Res Clin Anaesthesiol, 2008. 22(3): p. 503-17.

7. Horvath, K.A., et al., Blood transfusion and infection after cardiac surgery. Ann Thorac Surg, 2013. 95(6): p. 2194-201.

8. Management, A.S.o.A.T.F.o.P.B., Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology, 2015. 122(2): p. 241-75.

9. Görlinger, K., et al., First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology, 2011. 115(6): p. 1179-91.

References (continued)

10. Weber, C.F., et al., Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology, 2012. 117(3): p. 531-47.

11. Nardi, G., et al., Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs. Crit Care, 2015. 19: p. 83.

12. Schöchl, H., et al., Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care, 2011. 15(2): p. R83.

13. Spahn, D.R., TEG®- or ROTEM®-based individualized goal-directed coagulation algorithms: don't wait--act now! Crit Care, 2014. 18(6): p. 637.

14. Mallaiah, S., et al., Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage. Anaesthesia, 2015. 70(2): p. 166-75.

15. Leon-Justel, A., et al., Point-of-care haemostasis monitoring during liver transplantation reduces transfusion requirements and improves patient outcome. Clin Chim Acta, 2015. 446: p. 277-83.

16. Roullet, S., et al., Management of bleeding and transfusion during liver transplantation before and after the introduction of a rotational thromboelastometry-based algorithm. Liver Transpl, 2015. 21(2): p. 169-79.

17. Ak, K., et al., Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg, 2009. 24(4): p. 404-10.

18. Royston, D. and S. von Kier, Reduced haemostatic factor transfusion using heparinase-modified thrombelastography during cardiopulmonary bypass. Br J Anaesth, 2001. 86(4): p. 575-8.

19. Shore-Lesserson, L., et al., Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg, 1999. 88(2): p. 312-9.

20. Afshari, A., Evidence based evaluation of immuno-coagulatory interventions in critical care. Dan Med Bull, 2011. 58(9):p. B4316.

21. Görlinger, K., et al., Management of hemorrhage in cardiothoracic surgery. J Cardiothorac Vasc Anesth, 2013. 27(4 Suppl):p. S20-34.

22. Haas, T., et al., Comparison of thromboelastometry (ROTEM®) with standard plasmatic coagulation testing in paediatric surgery. Br J Anaesth, 2012. 108(1): p. 36-41.

23. Weber, C.F., et al., Hemotherapy algorithms for coagulopathic cardiac surgery patients. Clin Lab, 2014. 60(6): p. 1059-63.

24. Kozek-Langenecker, S.A., et al., Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol, 2013. 30(6): p. 270-382.

25. Spahn, D.R., et al., Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care, 2013. 17(2): p. R76.

26. Hartert, H., Blood coagulation studies using thromboelastography, a new evaluation technique. Klin Wochenschr, 1948. 26(37-38): p. 577-83.

27. Redfern, R.E., et al., Thrombelastography-Directed Transfusion in Cardiac Surgery: Impact on Postoperative Outcomes. Ann Thorac Surg, 2019. 107(5): p. 1313-1318.

References (continued)

28. Ganter, M.T. and C.K. Hofer, Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg, 2008. 106(5): p. 1366-75.

29. Adler, M., et al., Thromboelastometry and Thrombelastography Analysis under Normal Physiological Conditions - Systematic Review. Transfus Med Hemother, 2017. 44(2): p. 78-83.

30. Nagler, M., et al., Impact of changes in haematocrit level and platelet count on thromboelastometry parameters. Thromb Res, 2013. 131(3): p. 249-53.

31. Nagler, M., et al., Consistency of thromboelastometry analysis under scrutiny: results of a systematic evaluation within and between analysers. Thromb Haemost, 2014. 111(6): p. 1161-6.

32. Gurbel, P.A., et al., First report of the point-of-care TEG: A technical validation study of the TEG-6S system. Platelets, 2016. 27(7): p. 642-649.

33. Bliden, K.P., et al., Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis, 2017. 43(4): p. 437-445.

34. Dias, J.D., et al., New-Generation Thromboelastography: Comprehensive Evaluation of Citrated and Heparinized Blood Sample Storage Effect on Clot-Forming Variables. Arch Pathol Lab Med, 2017. 141(4): p. 569-577.

35. Erdoes, G., et al., Next generation viscoelasticity assays in cardiothoracic surgery: Feasibility of the TEG6s system. Plos One, 2018. 13(12):e0209360.

References (continued)