1. Hemostasis and TEG® Technology
Copyright © Haemoscope Corporation

2. Hemostasis Issues Facing Clinicians
Before surgery
Is there a coagulopathy present and how should it be treated
Prophylactic treatment / Autologous platelet plasmapheresis
During surgery
What coagulopathy is developing
After surgery
If the patient is bleeding, is it due to
Surgical
Excess of heparin
Coagulopathy and how it should be treated Ü
The purpose of this slide is to present the hemostasis issues confronting the clinician during surgery, and later to show how the TEG® instrument addresses these issues.
1. Should every patient be treated prophylactically with antifibrinolytic drugs before surgery.
2. Only approximately 5% of patients undergoing CPB exhibit fibrinolysis; should the 95% be treated prophylactically because of the 5%.
3. Should platelet phoresis be performed without first checking whether or not the patients' platelets are fully functional.
4. Coagulopathy develops during surgery due to the surgery; should we not check during the surgery what coagulopathy is developing and treat the coagulopathy then, or be prepared for the necessary treatment immediately post-surgery.
5. We should know within ten minutes at most post-protamine whether patient bleeding is due to coagulopathy, a residual of heparin, or surgical causes. If it is a coagulopathy, it most likely will be consistent with any coagulopathy observed while the patient is on the pump. It is necessary to keep in mind that a coagulopathy does not start post-protamine but develops during surgery, while the patient is on the pump. Thus it is important to monitor the patient while he is on the pump and detect if any coagulopathy is developing, worsening, or improving, and thus to be ready to treat the patient immediately post-protamine.
In this slide presentation we:
1. will show how the TEG® instrument addresses these issues.
2. will cover TEG® technology.
3. will show why the TEG® system can reduce blood transfusion and reduce reexploration rate.
4. will illustrate TEG® technology by monitoring a three-month-old pediatric patient undergoing valve repair.
5. will introduce a protocol which is being used in a multicenter clinical trial, and present the results of this study. The centers involved are Mount Sinai Medical Center in New York, Royal Brompton and Harefield NHS in London, and the Heart Institute in Mumbai, India.
The results, as presented in at the ASA and in Anesthesiology News and Anesthesia and Analgesia, show a dramatic reduction in the use of blood product transfusion of 30% and reexploration of 50% through monitoring with the TEG® system.
The following slides show how the TEG® system addresses these issues.

3. Normal Hemostasis…
… is controlled activation of clot formation and clot lysis that stops hemorrhage without permitting inappropriate clotting (thrombosis). Ü
The purpose of this slide is to provide a definition of normal hemostasis.
Normal hemostasis is the capability of the hemostatic system to control activation of clot formation and clot lysis in order to prevent hemorrhage without causing thrombosis. This basic definition of normal hemostasis shows that:
1. There are two systems involved simultaneously in hemostasis: the procoagulant system and the fibrinolytic system.
2. The presence or absence of hemorrhage or thrombosis depends on a delicate balance between the procoagulant system and the fibrinolytic system. Excess of procoagulants will result in thrombosis; too much activation of fibrinolysis will result in hemorrhage.
3. Any instrument that measures coagulation that does not measure the balance between the two systems will not be able to provide accurate information on patient hemostasis and may provide misleading information or artifacts.
E.g.: Prothrombin time (PT), and partial thromboplastin time (PTT), are elongated in the presence of fibrinolysis due to the presence of an excess of plasmin which biodegrades factors V, VIII, IX and XI, or due to an excess of fibrinogen degradation products, FDPs, that act as an anticoagulant. FDPs inhibit platelet aggregation and prevent the normal cross-linking of fibrin, which is necessary to render clots insoluble. The elongation of PT and PTT due to fibrinolysis are not distinguishable from the elongation that reflects a defect in the intrinsic or extrinsic pathways.
These observations should serve as a reminder to not base therapy on static end-points and isolated coagulation tests that measure one or part of one of the hemostasis systems and not the net sum of all components involved with both the procoagulant and fibrinolytic systems.
 An example is the risk of measuring one part of the hemostasis system and ignoring the others, or not taking into account the balance between the two, is the case of secondary fibrinolysis, where the prothrombotic state induces the endothelium to release TPA, an enzyme that activates plasminogen into plasmin, which breaks down the clot.
If, for example, tests are run to measure fibrinolysis, eg, D-Dimer or FDP tests, those tests will show high fibrinolytic activities and, if these patients are treated accordingly with antifibrinolytic drugs, these patients will most likely clot or die as in the case of a three-month-old baby on ECMO in one of the university hospitals. The proper treatment in this case is anticoagulant agents such as heparin, LMWH, or coumadin to treat the hypercoagulable state.
In the following slides we will show how the two systems are initiated simultaneously and how they are controlled, and we will show how to measure the balance between the two systems, the prothrombotic system and the fibrinolytic system.
Laposata et al. University of Pennsylvania Medical School/Mass.General Hospital

4. Hemostasis Components
The purpose of this slide is to show the three components that are involved in hemostasis: blood vessels, platelets and coagulation proteins.
The proper interaction of the three components produces a dynamic equilibrium that maintains blood in a fluid state.
For example, the first layer of lining of the vascular system, intima, has a monolayer of endothelial cells which are the most antithrombogenic tissue in existence. The nonthrombogenic property of the endothelial cells is due in part to the secretion of prostacyclin, a potent inhibitor of platelet aggregation, and acts as a powerful vasodilator; to heparin or heparinoids which stimulate ATIII to inhibit thrombin by 100- to 1000-fold; and to the release of Tissue Plasminogen Activator (TPA)in breaking down a clot if it should happen to be formed.
The inactivated platelets have a disk-like shape and smooth surface. This platelet surface can also be referred to as a nonthrombogenic surface because it lacks the phospholipid surface platelet factor 3 (PF3), which is necessary for the enzymatic reaction of the coagulation cascade.
Once the endothelial cells have been damaged, the platelets and coagulation proteins are activated by the subendothelial collagen surface and by tissue factor (TF) enzyme. Collagen has a negatively charged surface that activates platelets and initiates the intrinsic pathway (surface activation) by activating factor XII, while TF together with factor VII, initiates the extrinsic pathway. These will be shown in slides 4 and 5.

5. The Procoagulant Cascade
Slides 4 and 5 will show the mechanism by which the hemostasis system activates the procoagulant cascade and the fibrinolytic systems simultaneously, as well as how to control the activation of these systems to create a delicate balance between the procoagulant system and the fibrinolytic system.
Slide 4. The Cascade. This slide shows the intrinsic, extrinsic and common pathways that are involved in the clotting cascade. Blood coagulation is believed to be predominantly initiated by the extrinsic pathway through the presence of TF, which is a cell-surface glycoprotein responsible, together with factor VII, for initiating the extrinsic pathway of coagulation.
The purpose of this slide is to show the interaction between the intrinsic and extrinsic pathways in the process involving hemostasis. Factor XII activated by subendothelium collagen, which initiates the intrinsic pathway also activates plasminogen into plasmin and thus initiates the intrinsic fibrinolytic pathway. The damaged endothelial cells release tissue plasminogen activator (TPA) which activates plasminogen into plasmin and thus initiates the extrinsic fibrinolytic pathway. Whether the hemostasis system is activated by the intrinsic or extrinsic pathway or a combination of both, both the procoagulant and fibrinolytic systems are activated simultaneously and the balance between the two systems will determine whether the patient will have normal hemostasis, bleed or develop thrombosis.
Once the coagulation cascade is activated, whether through the intrinsic pathway, the extrinsic pathway, or a combination of both, thrombin is formed. The thrombin cleaves soluble fibrinogen into fibrin monomers, which spontaneously polymerize to form protofibril strands that undergo linear extension, branching, and lateral association leading to the formation of a three dimensional network of fibrin fibers. The three-dimensional network of fibrin fiber, together with platelet GPIIb/IIIa receptor bonding forms the final clot. A unique property of this network structure is that it behaves as a rigid elastic solid, capable of resisting the deforming shear stress of circulating blood.

6. The Hemostasis Process
This slide shows the hemostasis process to be extremely complex, with multiple interactions between factors, which includes the coagulation and fibrinolytic proteins, platelets, activators and inhibitors.
This slide also shows how the hemostasis system controls the activation of clot formation and clot lysis so that these systems do not proceed uncontrolled. This is accomplished by numerous positive and negative inhibitor and activator feed-back mechanisms. Eg: an excess of TPA will be inhibited by the release of plasminogen activator inhibitor (PAI). Eg.: an excess of TF VII complex will be controlled and inhibited by the release of TF Pathway Inhibitor (TFPI), etc.
Another mechanism that keeps hemostasis balanced is the interaction between factors which results in one factor compensating for the deficiencies of another. Eg: high levels of fibrinogen can compensate for lower levels of platelet number or function.
From the above observations, one concludes that the actual factor level or quantity as measured by an assay do not reflect their actual functional activities, which depends on the presence and activity of activators and inhibitors. The conclusion from the above observation is that there is no single factor or process that is static or works in isolation.
The conclusion from the above observations is that there is no system available at this time to measure such a complicated dynamic and interactive system, a multitude of hemostatic proteins interacting with each other and with cellular elements especially platelet surfaces, platelet releases.
Is it possible that hemostasis is seen to be so complex because it is still not thoroughly understood. Perhaps this is why new inhibitors and activators are continuously being discovered and developed. Is it possible that hemostasis is still shrouded in the fog of the unknown, a mystery that is currently in the process of being deciphered.
In the meantime, a patient is bleeding in the O.R., in the trauma center, or in the I.C.U., and there is no system in existence at this moment that can measure such a complicated system within the short time of 5-10 minutes. In the meantime, the clinician must decide what to do; what the proper treatment is. Perhaps the final observation of this slide has the seed of an indication of another way of looking at hemostasis to find the solution; that is, out of this complicated process only one product is produced, and that is the clot.

7. The Clot
The only end result of the activated coagulation protein is the fibrin strand which, together with activated platelets, forms fibrin-platelet bonding to produce the final clot.
The strength and stability of the clot, that is its physical properties, determine its ability to do the work of hemostasis, which is to mechanically impede hemorrhage.
The clot is in essence a damage control device, a temporary stopper, which gradually dissolves during vascular recovery. Ü
The clot is a mechanical device, developed for a specific purpose, to adhere to the damaged vascular system, at a specific strength, to resist the shear force of the circulating blood, until the recovery of the damaged vascular system. Therefore the physical properties of the clot determine whether the clot will be strong and stable enough to do the mechanical work necessary to stop hemorrhage without inducing thrombosis. In essence, the clot is a damage-control device, a temporary stopper, which gradually dissolves during vascular recovery.
The question is whether a patient's hemostasis can produce a clot that has the capacity to perform the work of hemostasis, which is to stop hemorrhage without introducing thrombosis.
This is exactly what the TEG® system was designed to do, which is to measure the time it takes for initial fibrin formation, the time it takes for the clot to reach its maximum strength, the actual maximum clot strength, and the clot's stability.
In summary, the clot is the elementary machine of hemostasis, and the TEG® analyzer measures the ability of the clot to perform this mechanical work throughout its structural development. During such measurements, the TEG® system will indicate what blood components or drugs are needed to correct any defect in the developing clot to enable it to perform its mechanical work of hemostasis.
Approximately 75-85% of the strength of the clot is contributed by platelets, 15-25% by the cross-linked fibrin fiber three-dimensional clot network. Platelets have been shown to affect the mechanical strength of fibrin by at least two ways. First, by acting as nodes branching points, they significantly enhance fibrin structure rigidity. Second, by the platelet actomyosin's exerting a "tugging" force on fibers, the rigidity of the fibrin structure is further increased. Platelet actomyosin is a muscle protein that is part of a cytoskeleton-mediated contractility apparatus. The platelet integrin GPIIb/IIIa appears crucial in anchoring polymerizing fibers to the underlying cytoskeletal contractile apparatus in activated platelets, thereby mediating the transfer of mechanical force.

8. TEG® Technology Slides 7-8. TEG® Technology
In the presentation of TEG® technology, we will show how the TEG® instrument measures the mechanical properties of the developing clot:
1. The time until initial fibrin formation.
2. The kinetics of the initial fibrin clot to reach maximum strength.
3. The ultimate strength and stability of the fibrin clot and therefore its ability to do the work of hemostasis, that is mechanically impede hemorrhage without permitting inappropriate thrombosis.
Slide 7. TEG® technology is consistent with recent advances in the understanding of hemostasis by analyzing the functional activities of the cellular elements, such as platelet cytoplasmic granules and platelet surfaces, in conjunction with plasma components. Because the TEG® instrument monitors the shear elasticity of clotting blood, a physical property, the TEG® instrument is sensitive to all the interacting cellular and plasmatic components such as coagulation and fibrinolytic factors, activators, and inhibitors, that may effect the rate or structure of a clotting sample and its breakdown. This is accomplished with the use of a special cylindrical cup that holds the blood and that is oscillated through an angle of 4°45'. Each rotation cycle lasts 10 seconds, which includes a one-second rest period at the end of the excursion. A pin is suspended in the blood by a torsion wire and is monitored for motion. The torque of the rotating cup only affects the immersed pin after fibrin-platelet bonding has linked the cup and pin together. The strength and rate of these fibrin-platelet bonds affects the magnitude of the pin motion such that strong clots move the pin directly in phase with the cup motion. As the clot retracts, or lyses, these bonds are broken and the transfer motion from cup to pin is diminished. The resulting hemostasis profile is therefore a measure of the time it takes for the first fibrin strand to be formed, the kinetics of clot formation, strength of clot and dissolution (the ability to perform the work of hemostasis).

9. Clot Kinetics
This slide shows the resultant hemostatic profile and the formal definition of the TEG® parameters:
R measures the time until the onset of clotting; this is the point at which all other coagulation instruments stop measuring.
K measures the time until the tracing amplitude reaches 20 mm.
α measures the angle between the tangent line drawn from the curve to the split point and the tracing's horizontal line, in degrees.
MA measures the maximum amplitude.
LY30 and LY60 measure the rate of amplitude reduction 30 minutes and sixty minutes after MA.
It is important to mention here that PT, PTT, ACT, TT, fibrinogen level, etc., stop measuring at the first stage of coagulation, where the first clot is formed, ignoring the kinetics of the clot to reach its maximum strength, the strength of the clot, and dissolution of the clot. In summary, the conventional coagulation test parameters measure the static end-point of blood coagulation but provide no information about the dynamics of clot formation, strength and stability.
For clinical evaluation, these are the most important parts of hemostasis, the parts that determine whether the formed clot has the mechanical strength and stability to do the work of hemostasis, that is impede blood loss without permitting inappropriate thrombosis.
This is illustrated by two studies, one by Dr. Gravlee et al which shows the inability of conventional coagulation tests to predict hemorrhage, and one by Dr. Spiess et al which shows that the TEG® instrument is highly predictive (87%) of post-cardiopulmonary bypass coagulopathies. Slides on these studies follow:

10. TEG® Data Related to Pathways

11. Formal Definition of TEG® Parameters
R is the time of latency from the time that the blood was placed in the TEG® analyzer until the initial fibrin formation. a
The a value measures the rapidity (kinetics) of fibrin build-up and cross-linking, that is, the speed of clot strengthening. K
K time is a measure of the rapidity to reach a certain level of clot strength MA
MA, or Maximum Amplitude, is a direct function of the maximum dynamic properties of fibrin and platelet bonding via GPIIb/IIIa and represents the ultimate strength of the fibrin clot. CI
Coagulation Index is linear combination of the above parameters.
LY30
LY30 measures the rate of amplitude reduction 30 minutes after MA. This measurement gives an indication of the stability of the clot.
Interpretation of the TEG® parameters is easy and straightforward. Each TEG® parameter, R, K, α, MA and LY30, represents a different aspect of the patient's hemostasis. In general, an elongated R means that it takes longer for the first fibrin strand to be formed and therefore an elongated R represents a factor deficiency and can be corrected by administering FFP. α measures the rapidity (kinetics) of fibrin buildup and cross-linking, that is the speed of clot strengthening. K, or K time, is a measure of the rapidity of reaching a certain level of clot strength (20 mm amplitude). K and α (K,α) both measure similar information and both are affected by the availability of fibrinogen, which determines the rate of clot buildup; by the presence of factor XIII, which enables cross-linking; and, to a lesser extent, by platelets. Therefore an elongated K and reduced α represents a low level of fibrinogen (factor XIII is rarely deficient) and can be corrected by administering CRYO, which has both. MA measures the strength of clot and is affected by platelet number and function and, to a lesser extent, by fibrinogen level. Therefore a small MA represents thrombocytopenia or platelet dysfunction and can be corrected by administering platelets. However MA and (K, α) are correlated due to the interaction between fibrinogen fiber and platelets which together form the fibrin-platelet bonding to produce the final clot. Therefore there is a compensatory effect between fibrinogen level and platelets. A low level of fibrinogen will be compensated for, to some extent, by a high level of platelet number and function, and vice versa. Therefore in borderline cases when both fibrinogen level and platelets are at the low limit of the normal range, either CRYO or platelets will correct patient hemostasis.
In the case of cardiac surgery when MA is small, infusion with platelets alone will correct the coagulopathy in most cases because platelets are affected by most if not all cardiac surgical procedures. In such a situation, the rule of thumb is that, if MA is small, treat with platelets (platelet units also contain fibrinogen,). After minutes take another sample; if the new TEG® sample tracing still shows abnormal (K,α), follow platelet infusion with CRYO.
LY30 greater than 7.5% represents hyperfibrinolysis and may be corrected by administering antifibrinolytic drugs such as Amicar®, tranexamic acid or aprotinin.
For further information on the interpretation of the TEG® parameters, please read the first two chapters in the user manual.

12. Pattern Recognition
Pattern recognition of various coagulopathies. We also provide a linear index of R, K, MA and α, called the Coagulation Index, C.I., which provides a global view of patient coagulation. If the C.I. is between -3 and +3, patient coagulation is normal; if the C.I. is less than -3, the patient is hypocoagulable; if the C.I. is more than +3, the patient is hypercoagulable.
Note that hypercoagulability in D.I.C. Stage 1 is usually initiated with the presence of TF, forming a prothrombotic state which in turn stimulates the endothelium to release TPA to counteract the prothrombotic state, to break down the clot and create an anticoagulant state in the form of FDP as described above.

13. Recombinant Factor VIIa - before
6 ½ yo male, respiratory failure due to pulmonary hemorrhage following 2 doses of TPA, 23 h apart (for suspected veno-occlusive disease, accompanying grade III graft vs host disease on days 33 and 34 post matched unrelated donor bone marrow transplant for ALL in second remission).
Following TPA doses, patient received platelets, plasma and red cells with ongoing good correction of lab coag parameters (PT INR , PTT sec, fibrinogen , platelets , hematocrit 25-30).
Intubated 12 hrs after second dose of TPA and had ongoing bleeding from the airway, despite good coagulation laboratory tests.
TEG® analysis showed a major coagulopathy.
Recombinant factor Viia 200 mg/kg was administered. R K MA
3—8
1—3
51—69
19.4
5.6
9.4
“Normalization of TEG® tracing and cessation of bleeding after infusion of recombinant Factor VIIa in a child with pulmonary hemorrhage and complex coagulopathy post tissue plasminogen activator infusion”
Boshkov et al, abstract presented at Am Soc Hem Dec 2002

14. Recombinant Factor VIIa - after
Clinical bleeding stopped and did not resume. TEG® analysis showed dramatic correction of coagulopathy post infusion.
Lab values after infusion of rVIIa showed very little change (PT INR 1.13, PTT 34.6, fibrinogen 151, platelets 81). R K MA
3—8
1—3
51—69
8.0
2.1
55.4

15. Recombinant Factor VIIa - superimposed
This shows the overlaid TEG® tracings before infusion (blue) and after infusion (yellow). “This suggests that correction of TEG® parameters may correlate with clinical efficacy.”
This paper confirms previous reports that suggest high dose rVIIa may be useful in refractory hemorrhage accompanying multifactorial coagulopathy, and has also been reported in hemophilia patients with inhibitors and in complex coagulopathies treated with blood products.

16. Sepsis
This section presents a series of actual cases, patient samples with coagulopathies, as well as several induced coagulopathies, as we’ll explain. We will discuss causes and treatment of these coagulopathies, and show the effects of treatment on the tracing.
Sepsis
This is an example of a patient with sepsis – and its resultant prothrombotic state.
We know that sepsis activates monocytes with an accompanying release of TF. In this tracing, the R is short, K is normal, alpha is high, and MA is high. It seems that we have enzymatic, as well as platelet, hypercoagulability. We can even see the trend for secondary fibrinolysis.
The patient was already in the OR. The clinicians were informed of the highly prothrombotic state. They examined the patient, found sepsis, and took her back to her room, where she was treated with antibiotics for the sepsis and LMWH to reduce the probability of an ischemic event.

17. Sepsis - after Sepsis – after
Several days later, you can see that the R is 7.4, the MA is large, but closer to normal, and CI is normal. So the assessment based on the higher MA is that the patient is only slightly prothrombotic, and that it was safe to proceed with surgery. The surgery – CABG – was performed without any hemostasis complications.

18. Sepsis (superimposed before and after)
Superimposition of the before and after tracings shows the contrast.

19. Extreme Hypercoagulability
This example shows a patient with extreme hypercoagulability, as indicated by the high Coagulation Index of Although the TEG® analysis showed a prothrombotic state, the clinicians chose to ignore it and took the patient into surgery. He had a clotted graft, and next day had a stroke. The ischemic event could have been prevented by treating with 1:0.5 heparin to protamine ratio instead of a 1:1 ratio. This ratio will keep the patient slightly anticoagulated until the hypercoagulability diminishes or patient is treated with additional heparin or platelet inhibitor drugs.

20. Clot Breakdown with Urokinase
Primary fibrinolysis
This is a typical tracing showing primary fibrinolysis, evidenced by the shape of the tracing showing rapid clot breakdown. In this example it is induced by adding urokinase to blood, which activates plasminogen into plasmin.
Primary fibrinolysis is treated with antifibrinolytic drugs, versus the secondary fibrinolysis as shown in Stage 1 of D.I.C. which should be treated with anticoagulants -- heparin, LMWH, coumadin, or platelet inhibiting drugs -- depending on the situation.
_____________________old…………………….
Urokinase-treated blood sample with 10 ul. of Abbokinase® by Abbott Laboratories; observe the breakdown of the clot induced by the presence of UK. This illustrates the state of primary fibrinolysis, which can be treated by antifibrinolytic drugs, versus the secondary fibrinolysis as shown in Stage 1 of D.I.C. which should be treated with heparin, LMWH or coumadin, depending on the situation, to inhibit thrombin.

21. Amicar and Urokinase Combined
Counteracting primary fibrinolysis
This slide shows the same primary fibrinolytic tracing with a “normal” tracing superimposed. This normal tracing is also induced, where 30ul Amicar® and 10ul urokinase were added to the sample. Amicar® inhibits the fibrinolytic activity of urokinase. This shows how in vitro testing can be used as a method of differential diagnosis. By adding components such as FFP, cryo, or pharmacological agents such as Amicar® to patient blood, you can prove, in vitro, which treatment will be most effective in vivo, namely which reagents will normalize the TEG® tracing.
The TEG® system is helpful also in determining which patients need prophylactic treatment. Instead of administering Amicar to all cardiac surgical patients, TEG® analysis identifies the 5-7% of those patients who exhibit hyperfibrinolysis and benefit from treatment with a bolus of 5g of Amicar, instead of penalizing the remaining 95% of patients by treating with unneeded prophylactic drugs.
old……………
30 ul Amicar® and 10 ul UK-treated blood sample produces output that closely matches the normal tracing. Amicar® inhibits the fibrinolytic activity of UK. This demonstrates in vitro testing as a method of differential diagnosis. By adding components such as FFP, CRYO or pharmacological agents such as Amicar® to patient blood, the clinician can prove, in vitro, which treatment will be most effective for the patient.

22. ReoPro Effect Reopro effect
This slide shows a blood sample treated with 5 ul ReoPro superimposed on the same blood sample without ReoPro. ReoPro is one of the GPIIb/IIIa platelet inhibitors used today. In the same class are Integrilin and Aggrastat.
These tracings:
·        illustrate the effect of platelet inhibition on MA
·        show that TEG® analysis can measure its effect and finally,
·        demonstrates that platelet number is not synonymous with platelet function.
5 ul ReoPro®-treated blood sample superimposed on the same blood sample without the addition of ReoPro®. This illustrates the effect of the ReoPro® platelet inhibition agent on TEG® MA, and that TEG® analysis can measure its effect and finally, ReoPro®-modified TEG® analysis shows that platelet number is not synonymous with platelet function.
Rationale for ReoPro®-modified TEG® Analysis:
Since all platelet-fibrin(ogen) interaction is mediated via platelet integrin GPIIb/IIIa receptor, it is possible to abrogate the platelet contribution to the TEG® instrument with c7E3 (ReoPro®) an antibody fragment that inhibits clot retraction and abolishes platelet aggregation by binding to fibrin(ogen) receptors GPIIb/IIIa on platelets. The MA of TEG® whole blood performed in the presence of high concentration of c7E3 is a function of effective fibrinogen level.
Therefore, when a high concentration of ReoPro® is used, 5 ul of 2 mg/ml concentration of ReoPro® is pipetted into the TEG® cup, the MA measures functional fibrinogen level (MAR) or non platelet components of TEG® clot strength. Thus, MA with whole blood without ReoPro® (MAW) minus MA with ReoPro® (MAR) equals the specific contribution of the platelets to MA (MAP). By using the ReoPro®-Modified TEG® parameters together with the standard TEG® parameters, the following parameters can be computed:
MAW = MA of whole blood; measures the maximum strength of clot.
MAR = MA with ReoPro®; measures functional fibrinogen level or non platelet component of clot strength.
MAP = MAW-MAR; measures unique contribution of platelets to strength of clot.
Similarly:
αW = α of whole blood; measures kinetics of clot development.
αR = α with ReoPro®; measures the contribution of functional fibrinogen level or non platelet component to the kinetics of clot development.
αP = αW-αR; measures unique contribution of platelets to the kinetics of clot development.
When a tracing of an active ReoPro® sample is displayed or a ReoPro® sample is stored in the database, the program displays the value of the FLEV (Functional Fibrinogen Level). When exactly two samples are selected to be displayed in Multiple Tracing mode, whether they are active channels or from the database, if one of the samples is a ReoPro® sample, then additional data, MAP, ANGP and FLEV, appear in the upper right-hand section of the tracing.

23. AMI – before treatment AMI – before treatment
This is a tracing of a patient with AMI. When treated with streptokinase, a thrombolytic drug, the results are shown next.

24. AMI – immediately post treatment
The effect of the streptokinase is shown by the low MA and then the immediate “breaking” of the tracing.
We have anecdotal evidence from one surgeon who says that if the patient does not respond that way, but instead produces a normal tracing after treatment with streptokinase, they will typically have a recurrence of the heart attack.

25. AMI – during recovery AMI – during recovery
This shows the hemostasis during recovery. Notice that all the tracing parameters are approaching normal.

26. Mitral Valve Replacement (Complicated history with numerous conditions)
This patient had a very complicated history with numerous conditions, including GI bleeding, cancer, renal dysfunction and dialysis. The tracing shows fibrinolysis, as indicated by the EPL value, and the patient was treated accordingly with aprotinin. The aprotinin dosing was a 1 million KIU bolus and 2 million KIU in pump prime. Although there are also indicators of a slightly prothrombotic state (short R, high angle and elevated MA), the patient was being prepared to be anticoagulated and a long pump time was anticipated.

27. Mitral Valve Replacement (2)
This tracing was taken while the patient was on the pump. The slight prothrombotic state has diminished into a tendency to bleed and continues to exhibit hyperfibrinolysis.

28. Mitral Valve Replacement (3)
This sample was taken close to rewarming. Because the patient’s hemostasis continued to deteriorate, including a higher level of fibrinolysis, another bolus of 1 million KIU was given.

29. Mitral Valve Replacement (4)
This sample was taken post protamine, and is approaching normal. No further treatment was given.

30. Mitral Valve Replacement (5)
The patient in the ICU shows continuing hemostasis improvement.

31. Marfan Syndrome/Aneurism
President Lincoln had Marfan syndrome. This is a genetic defect that expresses itself in an elongated face and limbs, but and with brittle collagen. This leads to a tendency toward aneurism.
This particular patient already had one aneurism prior to this one. The platelet count was 16,000. MA and CI are low.

32. Marfan Syndrome/Aneurism (2)
Here the patient is on the pump, and the MA is lower still – no platelet function discernable – probably mostly fibrin. CI is very low, and R is slightly increased, attributable to low phospholipid surfaces to support the enzymatic reaction.

33. Marfan Syndrome/Aneurism (3)
This sample was taken during re-warming, and the platelet dysfunction is deteriorating. 12 units of platelets were given while the patient was still on the pump.

34. Marfan Syndrome/Aneurism (4)
Post protamine all parameters are approaching normal. The patient was oozing, and typically would not be treated to allow time for the heparin/protamine to be metabolized. New platelets are forming, platelets are rewarming, coming back into circulation, etc. However, in this case, the Marfan syndrome was a concern, and another 6 units of platelets were administered.

35. Marfan Syndrome/Aneurism (5)
After treatment, post-op everything looks normal. The patient’s first hour chest tube drainage was less than 100 cc.

36. 2 mo old baby/Fontan heart surgery -1
2 month-old baby/Fontan heart surgery
This case is a two-month old baby with Fontan heart surgery – very complicated and long. He starts out slightly prothrombotic.

37. 2 mo old baby/Fontan heart surgery -2
2 month-old baby/Fontan heart surgery (2)
Post protamine, the baby was bleeding and the tracing shows fibrinolysis. Normally Amicar would be given and the need for platelets would be evaluated later. But, in the case of an infant, with a low blood volume of only 270 cc, Amicar was given. A few minutes later, platelets, and still a few minutes later cryo.

38. 2 mo old baby/Fontan heart surgery -3
2 month-old baby/Fontan heart surgery (3)
He bounced back and stopped bleeding. If blood product had been given without first inhibiting fibrinolysis with Amicar, the clot that formed would immediately dissolve and the bleeding would continue unabated.

39. 2 mo old baby/Fontan heart surgery -4
2 month-old baby/Fontan heart surgery (4)
This shows all three tracings superimposed – baseline, while bleeding, and after treatment.

40. High contractility - 1 High contractility
These four tracings represent what you might see due to high contractility as a result of high platelet number and activation due to surface activation.
This is an interesting tracing that is typically only seen in artificial surface device cases. You see clot breakdown that is not smooth -- as opposed to that in fibrinolyis, which is an enzymatic reaction. Instead it is a sudden break due to platelets that are highly activated platelets by the artificial surfaces and cause the platelets to highly contract. The clot is broken down by the high platelet contractility force.
It is possible that besides the platelet activation, we have the additional interaction of the activated white cells and red cell hemolysis, and need to treat these as well.

41. High contractility - 2 High contractility (2)
The literature refers to this as a “stairway” tracing or a “whiskey cork.” This is not an enzymatic reaction. MA has actually reached a high value and then breaks down. It looks like secondary fibrinolysis, but, in reality, the shape is due to platelet contractility.
In this case the platelet count was 500,000 per ul – very high. The platelets were activated by the negative surface of the artificial heart/heart assist device, resulting in a very high contractility force. It was this force breaking down the clot, not the constant rate of an enzymatic reaction

42. High contractility - 3 High contractility (3)
This tracing shows that the patient is very prothrombotic – MA is very high – with a tremendous amount of platelet activation. Despite anticoagulation with heparin, the R is normal due to a high concentration of phospholipid surfaces on the highly activated platelets. In this case the INR was 5, suggesting a state of anticoagulation. INR is based on plasma and ignores the role of platelets. This patient has half a million platelets per ul, all activated, providing so many phospholipid surfaces to support enzymatic reactions, that R is normal, even while INR shows anticoagulation. In actuality, the patient is very prothrombotic.
Based on the INR, the clinicians reduced the coumadin dose, and, as a result, the patient had a stroke.

43. Monitoring Hirudin with TEG® Analysis
This shows the results from a study in the UK measuring Hirudin using the TEG® system with ecarin in the TEG® sample cup. The correlation factor, r2 is .99, which shows a high degree of correlation between the amount of Hirudin given and the value of the TEG® R parameter.
Von Kier, Wade, and Royston, Royal Brompton and Harefield NHS Trust, Harefield, UK

44. Monitoring Anti-Xa with TEG® Analysis
A study at Duke Medical Center used the TEG® system to monitor low molecular weight heparin instead of using anti-factor Xa testing.
We know that low molecular weight heparin inhibits factor Xa, but also inhibits tissue factor pathways and thrombin. The anti-Xa test is very complicated and not readily available. TEG® analysis can show the net product of all the LMWH effects on patient hemostasis.
We can see that R at baseline – before giving anti Xa – is 0, showing no inhibition of Factor Xa before giving low molecular weight heparin.
The second time point (12 hours) shows residual low molecular weight heparin based on both TEG® analysis and anti-Xa testing, even though it is claimed that the effects of LMWH diminish after 12 hours. This indicates that we should use the R value or anti-Xa test before using epidural drugs, rather than using a constant of 12 hours.
The third point, immediately after giving low molecular weight heparin, shows an elongated R and higher inhibition of Factor Xa.
The fourth point (12 hours later) again shows a residual LMWH effect.
Although the anti-Xa test shows the effects of low molecular weight heparin, TEG® analysis is more effective. It measures the multiple effects of low molecular weight heparin at the point of care within 15 minutes.
Klein, et al. Duke University Medical Center

45. TEG® Tracing Schematic
This slide shows schematic representations of the critical TEG® clotting parameters. It shows normal and coagulopathy patterns.
Tracing 1.       Normal. This indicates that no coagulopathy is present, so if the patient is bleeding profusely in the presence of a fully functional clot, it is most likely surgical bleeding.
Tracings 2 and 3. This tracing is the same as 1 as far as K, angle, MA, and LY30, but the R is elongated. However, tracing 2 is seldom seen clinically because of the interactive nature of hemostasis. If R is elongated, the thrombin production rate is so slow that angle, K, and MA will be affected. Keep in mind that thrombin, in addition to cleaving fibrinogen into fibrin, is also the most potent platelet activator on whose surface the enzymatic reaction occurs. Therefore, in the presence of such an elongated R, more often the resulting tracing will be similar to tracing 3. The elongated R has to be corrected first. Ten to fifteen minutes post-transfusion, another sample is run to determine the effectiveness of the treatment and to further evaluate the resulting tracing. The exception to this rule is when patient hemostasis is activated by artificial surfaces or damaged endothelium, and the platelets are activated, releasing ADP, which recruits other platelets in the absence of thrombin.
Tracing 4.       The R is slightly elongated, but MA is very small. The slight elongation of R is due to the fact that platelets provide the surface where the enzymatic reaction takes place. Therefore, it appears likely that proper treatment such as platelets will normalize R as well as MA.
Tracing 5.    This is a typical primary fibrinolysis pattern, in which the R is slightly elongated and the MA is small and decreasing. Fibrinolysis has to be treated with antifibrinolytic drugs before evaluating R, K, alpha, and MA, unless these parameters show hypercoagulability, in which R and K are small, and MA and alpha are large. In that case, the fibrinolysis is referred to as secondary fibrinolysis, in that it is secondary to hypercoagulability. In secondary fibrinolysis, antifibrinolytic agents are contraindicated, since, under these circumstances, fibrinolytic activation prevents microvascular fibrin deposit and should be treated with anticoagulant drug therapy.
old……
In this schematic of tracings, the assumption is that tracing 1 represents a normal tracing; therefore, if the patient is bleeding profusely in the presence of a fully functional clot, the reason most likely surgical. Tracing 2 is the same as 1 as far as K, α, Ma and LY30, but the R is elongated can be corrected by the administering of FFP. However tracing 2 is seldom seen clinically because of the interactive nature of hemostasis. If R is elongated, thrombin rate production is so slow that α, K and MA will be affected. Keep in mind that thrombin, in addition to cleaving fibrinogen into fibrin, also is the most potent platelet activator on whose surface the enzymatic reaction occurs. Therefore, in the presence of such an elongated R, more often the resulting tracing will be similar to tracing 3. Therefore the elongated R has to be corrected first with FFP. Ten to fifteen minutes post-transfusion another sample is run to determine the effectiveness of the treatment and to further evaluate the resulting tracing.
In tracing 4, the R is slightly elongated but MA is very small. The slight elongation of R is due to the fact that platelets provide the surface where the enzymatic reaction takes place. Therefore it appears likely that treating with platelets will normalize R as well as MA.
Similarly, in the case of tracing 5, a typical fibrinolysis pattern, where the R is slightly elongated and the MA is small and decreasing, fibrinolysis must be treated before evaluating R, K, α and MA unless these parameters show hypercoagulability, where R and K are small, and MA and α are large. In this case, the fibrinolysis is referred to as secondary fibrinolysis, in that it is secondary to hypercoagulability, and an antifibrinolytic agent is contraindicated since, in these circumstances, fibrinolytic activation prevents microvascular fibrin deposit. In such cases, depending on the clinical situation, hypercoagulability may be treated with anticoagulant drug therapy such as heparin, low molecular weight heparin, or warfarin but not antifibrinolytic drugs.

46. Standard Protocol for Cardiovascular Applications
Baseline tracing on induction
1 sample with kaolin and heparinase (heparinase in case of heparin presence or contamination)
At rewarming (approx 36°) on CPB
1 sample with kaolin and heparinase
*10 min post protamine, 2 TEG® columns needed
1 sample with kaolin only Ü
Standard Protocol for Cardiovascular Applications, self-explanatory.

47. Post Protamine
Looking at only the R parameter, if the samples with and without heparinase are the same, the patient has received enough protamine to reverse heparin.
If both tracings are normal and the patient is bleeding, the reason is surgical.
If the R without heparinase is elongated and the heparinase tracing is normal and the patient is bleeding, the bleeding is due to excess of heparin.
If the tracing with heparinase shows a coagulopathy, the patient is treated accordingly. Most likely coagulopathies will be consistent with those observed during monitoring while the patient is on the pump. Ü
Post-protamine, self-explanatory.

48. Suggested Therapy Algorithm
Copyright © 2002 Haemoscope Corp.

49. Sampling Protocol (Cardiovascular)
Sampling Protocol — All samples are Kaolin activated
Sample #
When
Cup type 1
On induction
Heparinase bonded (blue) cup and pin 2
At rewarming (approx 36°C) on CPB
3 & 4
10 min post protamine
Split sample:
Plain (clear) cup and pin
5 & 6
Post op
Copyright © 2002 Haemoscope Corp.

50. TEG® Results Interpretation (If HIT, treat with Hirudin)
Sample #
Measures If
Suggested Treatment 1
Baseline hemostasis profile
Prothrombotic state: AT III deficiency or others
(To test for AT III deficiency, see AT III protocol)
AT III or FFP
Antifibrinolytic drugs are contraindicated unless patient treated with Plavix, ReoPro, Aggrastat, or Integrilin, in which case Aprotinin is recommended. 2
Coagulopathy, if any, developed during bypass phase
Coagulopathy
Treat hyperfibrinolysis. See protocol below.
Order blood product. See protocol below.
3 & 4
Post-CPB hemostasis profile
Heparin reversal
Heparinase R and Plain R are within normal limits, heparin is effectively reversed
None
Heparinase R normal, Plain R above normal limits, heparin is not completely reversed
Protamine
See protocol below
5 & 6
Post-op hemostasis profile
Normal
Coagulopathy / heparin rebound
Copyright © 2002 Haemoscope Corp.

51. Suggested Treatment Treatment protocol TEG® value Clinical cause
R between min
 clotting factors
x 1 FFP or 4 ml/kg
R between min
 clotting factors
x 2 FFP or 8 ml/kg
R greater than 14 min
 clotting factors
x 4 FFP or 16 ml/kg
MA between mm
 platelet function
0.3mcg/kg DDAVP
MA between mm
 platelet function
x5 platelet units
MA at 40 mm or less
 platelet function
x10 platelet units
 less than 45°
 fibrinogen level
.06 u/kg cryo
LY30 at 7.5% or greater, C.I. less than 3.0
Primary fibrinolysis
antifibrinolytic of choice
LY30 at 7.5% or greater, C.I. greater than 3.0
Secondary fibrinolysis
anticoagulant of choice
LY30 less than 7.5%, C.I. greater than 3.0
Prothrombotic state
Copyright © 2002 Haemoscope Corp.

52. Plavix Monitoring with TEG® Analysis
(Orange) large tracing is MA with kaolin&heparinase
(Green) middle tracing shows inhibition by Plavix
(White) innermost tracing shows MA attributed to fibrinogen

53. Aspirin Monitoring with TEG® Analysis
White tracing shows MA with kaolin & heparinase
Green tracing shows MA inhibition after aspirin

54. Reduced Hemostatic Factor Transfusion Using Heparinase-modified [TEG® Analysis] During Cardiopulmonary Bypass (CPB)
Stephen von Kier and David Royston
Group
Actual
Predicted
C (n=30)
DT (n=30)
C (TEG®)
DT (lab)
Pts transfused 10 5 2 12
FFP 16 1 22
Platelets 9 8
Study by Stephen von Kier and Dr. Royston of Royal Brompton and Harefield NHS, London. They concluded in their abstract presented at the ASA conference in October, 1998, "Use of heparinase-modified TEG® was associated with a three-fold reduction in use of hemostatic factors resulting in more appropriate ordering of products and greatly reduced costs."

55. Benefit of Intraoperative TEG® Algorithm to Reduce Platelet Transfusion Associated Adverse Outcome in Higher Risk Cardiac Surgery Patients
Stephen von Kier and David Royston
Mortality Rate
With platelets
6/21 patients  28%
Without platelets
1/16 patients  6%

56. Benefit of Intraoperative TEG® Algorithm to Reduce Platelet Transfusion Associated Adverse Outcome in Higher Risk Cardiac Surgery Patients
Stephen von Kier and David Royston
Hospital Stay
With platelets
17.6  2.9 days
Without platelets
8.8  .6 days

57. [TEG® Analysis] Decreases Transfusion Requirement After Cardiac Surgery
Linda Shore-Lesserson MD et al
RBC intra
RBC post
Non-RBC intra
Non-RBC post
CTD (ml)
TEG® analysis
17/53
10/53
5/53
3/53
577 ± 412
Control
23/52
12/52
8/52
13/52**
659 ± 429
Study presented by Dr. Shore-Lesserson of Mount Sinai Medical Center in New York at the ASA conference in October, 1998; showed that monitoring by TEG®-guided therapy reduced exposure to blood products by 3/53, 6%, versus non-TEG® guided therapy using commonly-used coagulation tests 13/52, or approximately 26%.
** p < TEG® sample vs control

58. TEG® Applications Liver transplantation Cardiovascular surgery
Heart assist device
Percutaneous Transluminal Coronary Angioplasty (PTCA)
Trauma
Obstetrics
ICU
Orthopedics Ü
This slide shows TEG® applications in various medical fields.

59. TEG® System TEG® Analytical Software Software-assisted diagnosis
Early projected values
Full report capability
Automated QC management
Additional data entry
Full peer-to-peer network support
Standard Windows interface
Touch screen and barcode
Smoothing algorithm

60. Connectivity

61. TEG® Analyzer Series
The new TEG® model 5000 differs from the previous TEG® models in that it is ergonomically designed, and it is easy to use and maintain. It is covered with a well-designed, smooth plastic cover, pleasing to the eye and easy to clean. There is a temperature sensor and heating element attached to each cup carrier holding the blood sample, providing the capability of setting each blood sample to a different temperature to measure the effects of hypothermia. It provides an automatic disposable cup and pin ejection mechanism to protect the operator from blood contact.
The following slides may be presented if the lecturer deems them necessary and if time permits.