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.
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.
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.
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.
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.
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.
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).
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:
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 10-15 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.
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.
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.
Study by Dr. Gravlee et al: In a study conducted by Dr. Gravlee et el, Predictive Value of Blood Clotting Tests in Cardiac Surgical Patient , (Ann Thorac Surg 1994; 58:216-21) using 897 consecutive cardiac surgical patients over a period of 18 months, "(t)he tests included activated clotting time, activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, fibrin/fibrinogen degradation products, platelet count, and Duke's earlobe bleeding time." The conclusion of the study was that "(t)he best multivariate model constructed could explain only 12% of the observed variation in postoperative blood loss".
Study by Dr. Spiess et al: Dr. Spiess et al, in the study Thromboelastography as an Indicator of Post-Cardiopulmonary Bypass Coagulopathies, (Journal of Clinical Monitoring, Vol 3 No 1 January 1987) reported that "Thromboelastography was a significantly better predictor (87% accuracy) of postoperative hemorrhage and need for reoperation than was the activated clotting time (30%) or coagulation profile (51%)."
Baseline of 3-month old pediatric patient undergoing valve repair.
Coagulation profile while patient is on the pump. Clear case of platelet dysfunction. MA is almost ½ of Baseline MA.
Baseline tracing superimposed with tracing on the pump.
Two tracings post-protamine superimposed, both tracings with celite; one with heparinase, one without heparinase. The R parameter on both tracings are almost identical, indicating that enough protamine has been given. Both MAs small, indicating platelet dysfunction which is consistent with the tracings that we have seen on the pump. The pediatric patient is bleeding. The recommendation is to transfuse platelets. Note: The closing of the tracings shown on this slide is due to the technical error of turning off the TEG® unit to run a new sample before terminating the samples properly through the software.
10 minutes after transfusing one unit of platelets. Tracing is normal, almost back to the baseline tracing. The pediatric patient stopped bleeding.
Slide 20 superimposed on a tracing prior to platelet transfusion.
Standard Protocol for Cardiovascular Applications, self-explanatory.
Standard Protocol for Cardiovascular Applications, self-explanatory.
Standard Protocol for Cardiovascular Applications, self-explanatory.
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."
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%.
This study by Mayo Clinic shows that, in liver transplantation, monitoring blood coagulation using the TEG® instrument reduced the transfusion of RBC, FFP, platelets and cryoprecipitate; exposed patients to fewer blood donors; and reduced the cost of monitoring per patient compared with monitoring blood coagulation with commonly-used coagulation tests such as PT, PTT, ACT, TT, platelet count, and fibrinogen level.
This slide, from a study done by the University of Washington, shows the reduction in the rate of incidence of surgical bleeding to be between 300%-400% by monitoring blood coagulation with the TEG®-guided therapy compared with monitoring blood coagulation with commonly-used coagulation tests. These results were reported by Dr. Spiess et al, prior to the introduction of heparinase. Since the introduction of heparinase, an abnormal TEG® test can be repeated during the heparinized period to confirm coagulopathy and reduce surgical bleeding even further.
After carotid surgery; the patient has developed a carotid hematoma. The tracing without heparinase shows a typical heparin curve, with an elongated R. The heparinase tracing shows a normal curve; this indicates that more protamine is needed to reverse the remaining heparin. ACT is 150 and was considered normal.
Based on the ACT, the patient undergoes reexploration. During reexploration, oozing was found but no bleeding. Another TEG® sample was run; residual of heparin was found but the ACT was 137 and considered normal. The patient was treated with 50 mg. protamine.
After protamine was administered, the surgical field was dry; the hematoma disappeared. Both TEG® tracings became normal; ACT was 140 and considered normal. The patient could have been saved from undergoing reexploration if the TEG® instrument had been the device used for diagnosis of residual heparin, instead of the ACT. These results are consistent with the relative insensitivity of ACT and the greater sensitivity of the TEG® instrument to very low levels of heparin. This is consistent with the results published by Dr. Tuman et al in the paper, Evaluation of Coagulation During Cardiopulmonary Bypass With a Heparinase-Modified Thrombelastographic Assay, in the Journal of Cardiothoracic and Vascular Anesthesia, April 1994.
This slide shows TEG® applications in various medical fields.
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.
The following slides may be presented if the lecturer deems them necessary and if time permits. Slides 35-37: Patient: James Proctor, 92 years old, undergoing three bypasses. The protocol in this hospital for elderly patients is to administer the Hammersmith regimen, which is 3 million K.I.U., of aprotinin which is 50% of the high dose aprotinin regimen. Slide 35 shows baseline hypercoagulabilities, C.I.=+5.75. Based on the hypercoagulable baseline, it was decided to put 1 million K.I.U. aprotinin in the pump prophylactically instead of the standard protocol and monitor with the TEG® instrument and decide accordingly whether to use the rest of the standard dosage of aprotinin through I.V.
Tracing with heparinase of the patient on the pump for at least one hour. The tracing shows hypercoagulability, very similar to the baseline tracing, C.I.=+3.16, no sign of fibrinolysis or any other coagulopathy. There was no need for additional aprotinin.
Two tracings post-protamine superimposed. Both tracings with celite; one with heparinase and one without heparinase. Both Rs are almost identical and normal, which means that the patient has received enough protamine to neutralize all heparin; the tracings show no coagulopathy; if there were any bleeding, it would be surgical. The patient finished completely dry. The above example illustrates that not all elderly or redos are the same, and therefore a single protocol for all, using expensive prophylactic drugs such as aprotinin is costly and can be contraindicated in the presence of hypercoagulability. The correct way would be to measure the baseline and monitor any changes in hemostasis during surgery, then provide proper treatment accordingly.
Acute myocardial infarction (AMI) Approximately 2.5 million people in North America and Western Europe suffer AMI each year. Despite improvement in survival and myocardial salvage observed with the introduction of thrombolytic therapy, cardiovascular disease remains the leading cause of loss of potential life-years under age 75 in the Western world 44 . Current projections indicate that cardiovascular mortality will continue to increase and by the year 2020 will be the leading cause of death worldwide 45 . Hence the need to develop improved therapies to treat AMI and prevent its complications is paramount. The clinical syndrome of AMI is typically treated with thrombolytic agents that act by stimulating enzymatic dissolution of the fibrin network. This action results in clot dissolution and re-establishment of coronary artery patency. To date, however, thrombolytic agents result in normal coronary flow in only 40-60% of cases and mortality rates of 7-10%. 46 In some cases, the reason for this may be due to reocclusion of a patent coronary artery due to residual thrombus, particularly in view of the fact that thrombolytics stimulate thrombin release, which is the most potent platelet activator. Use of a GPIIb/IIIa inhibitor should help minimize the tendency for reformation of thrombus, resulting in a greater likelihood of achieving normal coronary flow after thrombolytic therapy. Therefore, combination therapies with GPIIb/IIIa inhibitor agents together with thrombolytic agents is the future treatment of patients with AMI, gradually replacing thrombolytic monotherapy.
Disseminated Intravascular Coagulation (D.I.C.) is commonly initiated through release of tissue factors that activate the extrinsic pathway, resulting in a deposition of thrombi in the microcirculation system. The D.I.C. process can be divided into two stages: Stage I — Hypercoagulable phase This is the initial stage of the D.I.C. in which activation of the coagulation system induces hypercoagulability and fibrinolytic activity as a response to the deposition of thrombi. This stage must be treated with anticoagulant drug therapy, such as LMWH, heparin/ATIII if available. Stage II — Hypocoagulable phase If Stage I is not treated, the activation of the coagulation system will result in the consumption of the coagulation factors/platelets and it will be followed by Stage II.
Placental Infarct (miscarriage) The prothrombotic state of pregnant women is attributed to high levels of fibrinogen. Therefore, a pre-condition prothrombotic state in women can be exacerbated by pregnancy and may lead to a deposition of thrombin in the developing placenta, resulting in placental infarct.
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 2
Normal Hemostasis… … is controlled activation of clot formation and clot lysis that stops hemorrhage without permitting inappropriate clotting (thrombosis). 3
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 during7 vascular recovery.
Formal Definition of TEG® Parameters R R is the time of latency from the time that the blood was placed in the TEG® analyzer until the intial fibrin formation. α The α 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. LY30 LY30 measures the rate of amplitude reduction 30 minutes after MA. This measurement gives an indication of the stability of the clot.11
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 Heparinase bonded (blue) cup and pin 3&4 10 min post protamine Split sample: •Heparinase bonded (blue) cup and pin •Plain (clear) cup and pin 5&6 Post op Split sample: •Heparinase bonded (blue) cup and pin •Plain (clear) cup and pin19
Suggested Treatment Treatment protocol TEG® value Clinical cause Suggested Treatment R between 7 - 10 min ↓ clotting factors x 1 FFP or 4 ml/kg R between 11-14 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 49 -54 mm ↓platelet function .03g/kg DDAVP MA between 41 -48 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 choice20 LY30 less than 7.5%, C.I. greater than 3.0 Prothrombotic state anticoagulant of choice
Predictive Value of Blood Clotting Tests in Cardiac Surgical Patients Glenn P. Gravlee et al • A study using 897 consecutive cardiac surgical patients over 18 months in which “(t)he tests included activated clotting time, activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, fibrin/fibrinogen degradation products, platelet count, and Duke’s earlobe bleeding time.” • “The best multivariate model constructed could explain only 12% of the observed variation in postoperative blood loss.” (Ann Thorac Surg 1994; 58:216-21)21
Thrombelastography as an Indicator of Post- Cardiopulmonary Bypass Coagulopathies Bruce D Spiess et al “Thrombelastography was a significantly better predictor (87%) accuracy) of postoperative hemorrhage and need for reoperation than was the activated clotting time (30%) or coagulation profile (51%).” (J Clin Mon, Vol 3 No 1 January 1987) 22
Standard Protocol for Cardiovascular Applications • Baseline tracing on induction – 1 sample with kaolin and heparinase (heparinase in case of heparin presence or contamination)29
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 heparinase30
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 and heparinase – 1 sample with kaolin only31
* 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 the32 pump.
Reduced Hemostatic Factor Transfusion Using Heparinase-modified Thrombelastography During Cardiopulmonary Bypass (CPB) Stephen von Kier and David Royston Actual Predicted Group C DT C DT (n=30) (n=30) (TEG®) (lab) Pts transfused 10 5 2 12 Platelets 16 5 1 22 FFP 9 1 133
Thrombelastography Decreases Transfusion Requirement After Cardiac Surgery Linda Shore-Lesserson MD et al RBC RBC Non- Non- CTD intra post RBC RBC (ml) intra post TEG 17/53 10/53 5/53 3/53 577 ± 412 Control 23/52 12/52 8/52 13/52** 659 ± 429 ** p < 0.006 TEG vs control34
Mayo Clinic Study: Blood Product Transfusion Therapy after Liver Transplantation(LT): Comparison of theThrombelastogram (TEG®) and Conventional Coagulation Studies (CCS) D. J. Plevak et al TEG® CCS TEG® reduction in % RBC 1.47 3.06 52 FFP .11 .78 86 Platelet .95 2.67 64 Cryoprecipitate 0.00 1.67 100 N of donors 2.53 8.17 69 Cost 149.60 282.00 4735
Cardiopulmonary Bypass Coagulation Management, Education and Transfusion Practice at the University of Washington* Incidence of Monitoring with: Reoperation Standard lab (units) TEG® (units) Total 28/488 9/591 5.7% 1.5%** CABG 16/355 6/443 4.5% 1.4%** Open 12/133 03/148 Ventricle 9.0% 2.0%** * ASA Scientific Exhibit, 1991, Dr. Gilles, BSA, et al, Seattle WA36 ** p<.01
Introduction Major Role of Platelets • Are activated by and attached to negatively charged surfaces of the subendothelium collagen • Provide the phospholipid surfaces to enable the hemostasis protein’s enzymatic reaction to take place • Localize the clotting process at the site of injury • Protect the enzyme complexes from inhibitors that circulate to protect against propagation of the clotting activation downstream • Fibrin bonding via platelet GPIIb/IIIa receptor to form the clot • Stabilize the three-dimensional fibrin structure by its position in the fibrin network cross point • Provide contractility forces to the clot enabling it to resist the deforming shear forces of the circulating blood 46
Introduction The Hemostasis Process • Interactive process – Multiple interactions between factors that include coagulation and fibrinolytic proteins, platelets, activators, and inhibitors • Dynamic and complex – Not static – Does not occur in isolation • All enzymatic reactions take place on platelet phospholipid surfaces 47
Haemostasis in the Old vs the New Millennium • Old: Cause and treatment of hemorrhagic state • New: Cause and treatment of prothrombotic state 48
Coagulation in the New Millenium Treatment and identification of the source of the prothrombotic state • Identification of the source of the prothrombotic state 1. Platelets 2. Enzymatic 3. Differential treatment 49
Treating the Prothrombotic State — Platelets AMI Acute myocardial infarction (AMI) • High incidence of AMI is the leading cause of death under age 75 in Western World and projected to increase, becoming leading cause of death worldwide by 2020. • Despite treatment with thrombolytic agents, only 40-60% of cases result in normal coronary flow, and 7-10% mortality rates occur. – Due to patent coronary artery reocclusion caused by residual thrombus – GPIIb/IIIa inhibitor should minimize reformation of thrombus • Future: Combination therapy of GPIIb/IIIa inhibitors with thrombolytics will replace monotherapy in AMI patients. 50
Treating the Prothrombotic State — Enzymatic D.I.C. • Disseminated Intravascular Coagulation (D.I.C.) is commonly initiated through activation of the extrinsic pathway. The D.I.C. process can be divided into three stages: – Stage I — Prothrombotic phase – Stage II — Secondary fibrinolytic phase – State III — Consumptive hemorrhagic phase • Future: Treat prothrombotic phase 51
Treating the Prothrombotic State — Enzymatic Placental Infarct Placental Infarct (miscarriage) • The prothrombotic state of pregnant women is attributed to high levels of fibrinogen. • Prothrombotic state exacerbated by pregnancy can lead to deposit of thrombin in the placenta, resulting in placental infarct. • Future: treat the prothrombotic state 52
New Millennium Monitoring of Hemostasis Including Prothrombotic State • Has been proven clinically to reduce use of blood products and predict thrombotic events • All phases of hemostasis measured with whole blood sample • Measures the net product between clot formation and clot lysis • Measures patient risk of either hemorrhagic or prothrombotic states • Differentiates between surgical and physiological bleeding • Provides results in less than 15 minutes • Has a high level of reproducibility and low coefficient of variation 53
New Millennium Monitoring of Hemostasis Including Prothrombotic State • Software that interfaces with the hospital network to allow viewing of hemostasis information anywhere • Software that interfaces with the hospital information system to merge hemostasis information with clinical variables • Software that can interpret the hemostasis results and advise therapy • Software that can check the instrument’s electronics and detect faulty user procedures 54