Thromboelastography: Where Is It and Where Is It Heading? (2001)

Introduction Thromboelastography (TEG) has been in existence since 1948. However, it is only recently that it has made great strides into the clinical practice arena, where it is being used to assist in the diagnosis and management of coagulation problems during liver transplantation and cardiac surgery and in obstetrics. With the advent of computerization in the last decade, TEG has evolved from a research laboratory tool into a compact, user-friendly process, providing global information on the entire coagulation process. In fact, TEG is the only single test method that provides information on the balance between two important and opposing components of coagulation, namely thrombosis and lysis. The battery of traditional coagulation tests, which include bleeding time, prothrombin time (PT), partial thromboplastin time (PTT), thrombin time, fibrinogen and factor assays, and platelet function studies, are based on the isolated, static end points of standard laboratory tests. 1 They do not take into account the interaction of clotting cascade and platelets in the whole blood. Furthermore, some of these tests can be nonspecific. For example, bleeding time has been shown to be a nonspecific indicator of platelet function. 2 Platelet aggregation tests are expensive, laborious, and difficult to reproduce, and abnormalities cannot be used to predict risk of hemorrhage. 3 The tests that measure clot lysis, which include fibrinogen degradation products, can be elevated in renal and hepatic disease. 3 In contrast, hemostasis is an integrated, interactive, dynamic, and extremely complex process involving coagulation proteins, activators, cellular elements, and inhibitors. TEG measures this interactive dynamic coagulation process from the initial clotting cascade to platelet interaction and clot strengthening (via platelet GPIIb/IIIa receptors) to fibrinolysis. In addition, TEG can guide in therapy, by documenting changes in coagulation in vitro before a therapy is instituted. 4 Measurement Technology TEG measures the viscoelastic properties of blood in vitro. It has never been popular with hematology laboratories, because it is not capable of performing multiple-batch analyses. 5 It consists of a heated (37°C) cuvette or cup that holds the blood (0.36 mL) as it oscillates through an angle of 4°45´. Each rotation lasts 10 seconds, which includes a 1-second rest period at the end of the excursion. A pin, which is suspended freely in the blood by torsion wire, is monitored for motion (Fig. 1). The torque of the rotating cup is transmitted to the pin once the clot starts to form. Therefore, the strength and rate of these fibrin-platelet bonds affect the magnitude of pin motion. When the clot lyses, the bonds are broken and the transfer of cup motion is diminished. The rotation of the pin is converted by a mechanical-electrical transducer to an electrical signal that can be monitored and recorded by a computer. Thus, TEG documents initial fibrin formation, clot rate strengthening, and fibrin-platelet bonding via GPIIb/IIIa to eventual clot lysis (Fig. 2).Figure 1.: Thromboelastography sample cup design. Reproduced with permission from Haemoscope, Skokie, IL.Figure 2.: Thromboelastography tracing parameters. Reproduced with permission from Haemoscope, Skokie, IL.Components of a TEG R time (measured in millimeters, or minutes which equals ½ × mm) is the period of time that the blood was placed in the TEG until the initial fibrin formation. It is prolonged by anticoagulants and shortened by hypercoaguable conditions. K time (measured the same as R time) is measured from R until the level of clot firmness reaches 20 mm (divergence of the lines from 2–20 mm). Therefore, K is a measure of speed of clot strengthening. K is shortened by an increased fibrinogen level and, to a lesser extent, by increased platelet function and is prolonged by anticoagulants. Angle α is formed by the slope of the TEG tracing at R from the horizontal line. Like K, it also denotes the speed at which solid clots form. Angle α is also increased by increased fibrinogen levels and, to a lesser extent, by increased platelet function and is decreased by anticoagulants. In hypocoaguable states, in which the clot amplitude never reaches 20 mm (i.e., K is undefined), the angle is more comprehensive than K time. Maximum amplitude (MA) (measured in millimeters) is the measurement of maximum strength of the developed clot, which depends on fibrin and platelets. G is the actual measure of clot firmness (shear elastic modulus strength, or SEMS) is measured in dynes per squared centimeter. It is calculated from MA as follows:G = 5,000 MA/100 − MA. An amplitude of 50 mm (normal value for whole blood) corresponds to a SEMS of 5,000 dyne/cm2. An increase in MA from 50 to 67 mm is equivalent to a twofold increase in the SEMS. Therefore, it is more sensitive to small changes in the clot strength or clot breakdown than the amplitude is in millimeters. A coagulation index (CI) that describes patient's overall coagulation is derived from the R, K, MA, and α of native or celite-activated whole blood tracings (CI for celite-activated blood = 0.3258R − 0.1886 K + 0.1224 MA + 0.0759α − 7.7922). Normal values range from −3.0 to +3.0, which is equivalent to three standard deviations about the mean of zero. Positive values outside of this range (CI > 3) indicate that the sample is hypercoagulable, whereas negative values outside this range (CI < −3) indicate that the sample is hypocoagulable. LY30 and LY60 measure percentage of lysis at 30 minutes and 60 minutes, respectively, after MA is reached. Measurements are based on the reading of the area under the TEG tracing from the time MA is measured until 30 or 60 minutes after the MA. Therefore, when LY30 or LY60 values are high, the fibrinolytic activity is high. Types of TEG Native Nonactivated blood (native) is used to study TEG. Activated Celite (which consists of silica particles) acts as a contact surface activator, which activates factor XII, and platelets are added to reduce the running time of a whole blood (activated) by as much as half. When fresh blood is used, the sample must be placed in the cuvette within 4 minutes. Citrated Activated or Native To facilitate transport, citrated blood can be used but needs to be recalcified before performing a TEG. Twenty microliters of calcium chloride is added to 340 μL of blood to neutralize citrate and thus initiate clot formation. The normal range varies depending on type of sample, for example whether it is native or activated (Table 1).Table 1: Thromboelastography (TEG) ParametersTissue Factor Tissue factor (TF) is an enzyme that, together with factor VII, shortens coagulation time by activating factors IX and X (extrinsic pathway). Human recombinant factor (e.g., Hemoliance Ortho, Columbia Diagnostics, Carol Stream, IL) is a TF relipidated with highly purified phospholipids, calcium, and stabilizers. Heparinase The whole blood sample in vitro can be modified by the addition of heparinase when the patient is on heparin or when the presence of free circulating heparin is suspected. Heparinase I, from Flavobacterium heparinum, is an enzyme that rapidly and specifically neutralizes the anticoagulant properties of heparin. Heparinase acts by cleaving the heparin molecule into small, inactive fragments without affecting the function of other blood components involved in coagulation. This, along with a nonheparinase TEG, enables a distinction to be made as to whether heparin is the cause of coagulation abnormality resulting in bleeding, particularly after cardiopulmonary bypass. Compare the R parameter of heparinase-modified TEG samples and non-heparinase-modified samples for patients undergoing cardiopulmonary bypass. If the R parameters are the same, enough protamine was given to neutralize all administered heparin. Heparinase also eliminates any problems or concerns associated with drawing blood from a heparinized catheter. Under these circumstances, heparinase will correct in vitro a prolonged onset of clotting compared with a control sample. Platelet Blockers Because all platelet-fibrinogen interaction is mediated by the platelet integrin GPIIb/IIIa receptor, it is possible to negate the platelet contribution to TEG tracing with drugs such as c7E3 Fab (ReoPro), an antibody fragment that inhibits clot retraction and abolishes platelet aggregation by binding to fibrinogen receptors GPIIb/IIIa on platelets. The resulting MA now represents the fibrinogen component of clot strength MA(fibrinogen). If MA of whole blood [MA(whole blood)] without ReoPro is known, then platelet function (platelet contribution to clot strength) can be computed as follows:EQUATION Antifibrinolytic Drugs Antifibrinolytic drugs (ε-aminocaproic acid [EACA], tranexamic acid) identify how a previously identified fibrinolytic TEG tracing will respond to this inhibitor. Temperature Effect TEG samples are analyzed at 37°C, normal body temperature. However, under some circumstances, such as hypothermia, it might be desirable to run samples at lower temperatures, matching the lower body temperature. Because the TEG analyzer is capable of running samples over a wide range of temperatures, you can measure the effect of lower body temperature by comparing one sample run at 37°C degrees and the other at the lower body temperature. Differences in tracing would be attributable to the effect of the temperature. Data Analysis TEG tracings can be qualitatively or quantitatively analyzed. Various patterns are easily recognized (Fig. 3) as hypocoagulation, normal coagulation, hypercoagulation, and fibrinolysis. However, by using the measurements and established normal ranges and indices, the patterns can be quantified as to the degree of abnormality, which allows therapies to be judged for their effectiveness in correcting the pathological state.Figure 3.: Characteristic shapes of thromboelastograms. A: normal; B: prolonged R (anticoagulants, factor deficiency); C: decreased maximum amplitude (MA) (thrombocytopenia, platelet blockers); D: fibrinolysis; E: hypercoagulability (decreased R and K, MA and angle increased); F: disseminated intravascular coagulation (DIC) early stage (hypercoagulable with secondary fibrinolysis); G: DIC later stage (hypocoagulable).Clinical Application of TEG There is currently an enormous interest in deciphering the use of TEG in a variety of clinical circumstances. It is being used in liver transplant surgery to rapidly analyze and treat the changing coagulation profile of the patients during various phases of liver transplantation. 6,7 Studies have evaluated the utility of TEG in cardiac surgery to assess coagulopathies after cardiopulmonary bypass 8 and to assess blood product transfusion requirements. From liver and cardiac surgical operating rooms, the last few years have seen the utility of TEG extended to other clinical arenas such as obstetrics and trauma. In obstetrics, it has been used to assess coagulation during regional anesthesia with low platelet counts 9 and to guide the treatment of disseminated intravascular coagulation (DIC). 10 It has been also used to monitor the anticoagulant affect of low-molecular-weight heparin (LMWH) in the peripartum period. 3,11 In trauma patients, the utility of TEG in the assessment of coagulation is being investigated. 12 The current trend of the usefulness of TEG in these clinical circumstances is now discussed. Liver Transplantation Liver transplant surgery requires a mean of 10 units of whole or packed red blood cells, but at times up to 300 units have been used. 13 The first clinical use of TEG during liver transplantation was in 1966 by Von Kaulla and colleagues, 14 who observed a fibrinolytic pattern on TEG and treated it with EACA. Later, Howland and associates 15 demonstrated a heparin-like effect and reversed it with protamine sulfate. In the 1980s, as surgical techniques improved and as transplant surgery began to evolve, the clinical utility of TEG was readdressed by anesthesiologists at the University of Pittsburgh. 7 Liver transplantation patients have preexisting coagulopathy secondary to liver disease and factor deficiency. In addition, they have thrombocytopenia as a result of splenomegaly, shortened platelet survival caused by platelet consumption and sequestration in regenerating liver, folic acid deficiency as a result of ethyl alcohol–induced liver disease, and the toxic effects of ethanol on megakaryocytes. In addition, the levels of thromboxane A2 and adenine nucleotides are decreased in patients with liver disease. 6 Fibrinolytic activity is increased because of imbalances in the levels of tissue plasminogen activator, plasminogen, proteins C and S, and α2 antiplasmin. Rarely, these patients can be hypercoagulable because of protein C or S deficiency. During the preanhepatic phase of a liver transplantation, coagulation is complicated by the dilution of exogenous heparin added to the priming solution during venovenous bypass and fibrinolysis as a result of the reduced clearance of inhibitors and activators of coagulation. These changes worsen during the reperfusion of grafted liver; a heparin-like effect is observed in about one third of patients. 6 The newly grafted liver resumes its synthetic function, returning the coagulation to normal within 1–2 hours after reperfusion. However, in a poorly functioning graft, the coagulopathy may persist, resulting in uncontrollable blood loss. 1 Before the use of TEG, blood products and antifibrinolytics were used empirically. TEG not only gives information about the coagulopathy (e.g., factor deficiency, fibrinolysis) but also is used in vitro to assess the effect of treatments such as antifibrinolytic treatment, cryoprecipitate, fresh-frozen plasma, platelet, and protamine. After administering these corrective factors based on the in vitro TEG, the coagulation is reassessed with TEG to determine the efficacy, success, and further planning of corrective treatment. Some patients are at risk for vascular thrombosis (especially of the hepatic arterial anastomosis) as a result of protein C and antithrombin III deficiency after liver transplant. A prothrombotic state is difficult to diagnose on routine coagulation tests. TEG plays an important role in detection of such prothrombotic patients and hence decreases the incidence of thrombotic complications. Cardiac Surgery The institution of cardiopulmonary bypass has well-documented effects on the hemostatic and fibrinolytic systems, producing platelet dysfunction, coagulation factor activation and depletion, and fibrinolysis. 8 In view of this, cardiac surgical procedures consume 10–20% of the nation's supply of allogeneic blood products. 8 Spiess and colleagues 16 assessed the usefulness of TEG during cardiac surgical procedures. Thirty-nine patients were studied with activated clotting time, TEG, and coagulation profiles during three periods: before bypass, during bypass, and after protamine administration. TEG was a significantly better predictor (87% accuracy) of postoperative hemorrhage and the need for reoperation than activated clotting time (30%) or coagulation profile (51%). Tuman and coworkers 17 compared routine coagulation tests (RCTs), which included PT, PTT, platelet count, and fibrinogen levels, with TEG and sonoclot (SCT) after cardiopulmonary bypass. They found that, although RCTs were normal, TEG and SCT were abnormal, reflecting a platelet-fibrin interaction defect. The overall accuracy for predicting postoperative hemorrhage with TEG was 88% compared with 33% with RCT; the false-positive result rates were 15% with TEG and 73% with RCT. Shore-Lesserson and colleagues 8 compared transfusion requirements in a randomized, prospective trial of high-risk cardiac surgical patients. Patients were assigned randomly to TEG-guided transfusion therapy (n = 53) or standard laboratory–based transfusion therapy (n = 52). Patients in both the groups received antifibrinolytic therapy with EACA. They noted that patients in the TEG group received fewer total transfusions. Four patients in the TEG group received fresh-frozen plasma compared with 16 in the control group, and 7 patients in the TEG group received platelet transfusions compared with 15 in the control group. Even the volume of fresh-frozen plasma received in the TEG was reduced (36 ± 142 vs. 217 ± 463 mL). The authors concluded that TEG-based transfusion algorithm reduced transfusion requirements. Spiess and colleagues 18 compared transfusion requirements and reoperation for hemorrhage in cardiac surgical patients before and after instituting TEG-guided coagulation testing. They found that the TEG group had a lower incidence of transfusion (78.5% vs. 86.3%). Mediastinal reexploration for hemorrhage was 5.7% before the institution of TEG-based coagulation monitoring and 1.5% in TEG-monitored patients. The authors concluded that TEG monitoring decreased the cost and probably the potential risk from transfusions for patients undergoing cardiac surgery. Obstetrics One of the changes that occurs during pregnancy is increased coagulability. The hypercoagulability of pregnancy has been attributed to increased platelet aggregation; increased concentrations of coagulation factors; decreased concentrations of coagulation inhibitors, especially antithrombin III and proteins C and S; activated protein C resistance; and decreased fibrinolysis capacity. TEG, which can quantify hypercoagulability, has been used to determine changes in coagulation profiles during the course of a normal pregnancy. 19 Two stages of coagulation changes were noted: an initial stage, in which blood attains a certain level of hypercoagulability in the first trimester (shortened R, increased MA, and CI), and a final stage, in which degree of hypercoagulability increases further (increased MA and R). Interestingly, the final stage also is associated with an increased rate of clot strengthening for the first time in pregnancy (increased angle α and K). There were no significant changes in coagulation in the second trimester compared with the first trimester. A linear correlation between gestational age and MA exists (r = 0.72, P < .001), despite decreasing platelet number. Fibrinogen's contribution to the clot strength begins to increase in the first trimester of pregnancy and becomes significant by the second trimester. No further increases are seen in the last trimester. Platelet function (as studied using ReoPro) does not change in pregnancy except for a transient decrease in platelet function in the second trimester. During labor there is a further increase in hypercoagulability, 5 which persists through the first 24 hours after delivery. 20 Also, coagulability increases when general anesthesia is used for cesarean section compared with spinal anesthesia. 21 Preeclampsia TEG has been used to assess coagulation during preeclampsia. Preeclampsia is associated with abnormal hemostasis, most commonly as a result of thrombocytopenia and rarely because of DIC. 22 Orlikowski and coworkers studied 49 patients with preeclampsia. 23 They found no correlation between the bleeding time and platelet count but noticed a strong correlation between the platelet count and TEG MA. 3 Similar findings were noted by Sharma and others. 22 They noted that patients with mild preeclampsia were hypercoagulable, whereas patients with severe preeclampsia and platelet count <100,000/mm3 were hypocoagulable. There also was a strong correlation between low platelet count and MA from TEG. 22 It has been generally recommended that regional anesthesia be avoided if the platelet count is below 100,000/mm3, because the bleeding time may be abnormal if platelet counts are below this level. The bleeding time test is no longer considered a valid test of platelet function, however, and a vast majority of anesthesiologists has changed their view of the suitability of regional anesthesia for parturients with low platelet counts. Currently, regional are administered to patients with platelet counts after of the of regional general anesthesia. Sharma and colleagues 22 studied the between platelet count and the MA of TEG, which is a measure of platelet function. They that the MA does not decrease until the platelet count decreases below A was in study of by Orlikowski and others. 23 These two to the current practice of administering regional anesthesia to parturients with platelet counts between and the risk of a spinal or during regional anesthesia cannot be a normal TEG, despite low platelet count, assist in the and when between general anesthesia and regional anesthesia in patients. platelet also can be associated with bleeding and 24 the of for labor in a patient with platelet count in which TEG was patients are to DIC. The that may be associated with DIC include in and hemorrhage. clotting tests PTT, and measurement of plasma fibrin degradation product and concentrations are degradation product levels may be normal in 15% of patients of 3 however, and may elevated if clearance is decreased because of renal levels are elevated after surgery and trauma. TEG can be used to quantify clot lysis and DIC Sharma and colleagues the management of a patient with hemorrhage and coagulopathy using TEG are used as treatment or The activity of is attributed to Currently, the only measure of is factor activity which is a and TEG an increase in R in patients TEG has been used to determine whether coagulation has to normal after of before performing regional anesthesia. Effect of on The effect of on coagulation is Some as a whereas to be an is probably to the that the tests used are static tests. TEG has been used to study the effect of on coagulation in parturients The that does not overall coagulation after or two hours of therapy, no to the of regional anesthesia. There is a great of interest in the study of TEG in Factor levels are during the first 6 of In studies, TEG no in coagulation when compared with a hemostatic process in in than 12 clots were and developed than in the process values by 1 TEG has also been used during liver transplantation in 6 with that in coagulopathy was severe in undergoing liver transplantation, because of better hepatic of disease, or better function. 6 TEG has also been used in than 2 years undergoing cardiopulmonary bypass to guide in the blood component therapy during and Analysis of TEG during blood which was with and red blood cells, demonstrated a trend increased coagulability than TEG of coagulopathy was seen only when blood was more than of blood The increased coagulability was attributed to of clotting changes associated with and the of tissue thromboplastin from tissue trauma. and 30 using TEG, noted of blood coagulation when the dilution of blood volume to solution volume was than solution had a of an effect on blood coagulation than or had the effect on coagulation. 30 of abnormalities are for and after A normal TEG provides early of patients in the clinical course is to be = In contrast, an abnormal TEG patients in a severe clinical bleeding will TEG to be a more predictor of disease than the TEG for TEG is a monitor of coagulation, especially for fibrinolysis. TEG has early detection of fibrinolysis with significant clinical bleeding in a patient after surgery. diagnosis the institution of antifibrinolytic therapy and monitoring of a patient's and surgical and of Factor monitoring to assess the of recombinant activated factor to hemostasis in patients with inhibitors to factor or IX has to be TEG has been used as an to study the and monitoring of recombinant activated factor and TEG have been extended to study coagulation changes after decreases hemostatic function by decreasing the coagulation contribution to decrease in hemostatic function may to associated with vascular surgery. TEG to have made a in the management of coagulation abnormalities during liver transplant surgery. The of TEG in its in other For example, if further that TEG the transfusion requirements of cardiac surgical patients, then it may a in cardiac surgical would reduce and the risk of of and In anesthesia and in general operating rooms, TEG may assist in the to regional anesthesia in patients with low platelet counts and in patients If the TEG may as of a routine of coagulation in a variety of and