Thromboelastography

Pathophysiology

TEG is a noninvasive test that quantitatively measures the ability of whole blood to form a clot. The principle of this in vitro test is to detect and quantify dynamic changes in the viscoelastic properties of a blood sample during clotting under low shear stress. The test is performed in a specially designed system called a thromboelastograph. The system consists of 2 chambers simultaneously examining a blood sample in duplicate to reduce the risk of sampling and measurement errors. Each chamber consists of a platform with a disposable cup where a blood sample is placed and a detection pin suspended in its center. The cup oscillates around the detection pin in a limited arc of ±4° 45′ 5″. Induced pin movement is recorded, and changes are measured as a function of time. Initially, there is little movement of the pin since liquid blood possesses minimal viscosity, and the oscillations of the cup are not transmitted to the pin.

As the blood coagulates, it begins to adhere to both the cup and the pin, and movement of the cup induces motion on the pin. These gradually increasing viscoelastic mechanical properties of the blood reflect the developing three-dimensional fibrin mesh and platelet components of the clot. The greater the viscoelasticity of the clot, the higher the amplitude of the pin motion. As fibrinolysis starts, the fibrin-platelet structure begins to dissolve gradually, and the clot loses its contact with the detection pin, which has less induced motion. The thromboelastogram is a graphical image of the recorded amplitude of movement of the pin as a function of time. Analytical software measures and quantifies these changes (see Figure. Theombelastography Tables). Therefore, TEG measures the functional ability of the blood to make a hemostatic plug. A newer version replaces the cup rotation method with a resonance technique wherein the blood sample is subjected to vibration, and the vertical movement of the blood meniscus is measured under light-emitting diode illumination. The system uses pre-measured cartridges that do not require pipetting and allows the simultaneous performance of 4 blood tests.

Specimen Requirements and Procedure

The blood sample is collected through venipuncture in a plastic vial containing 3.2% buffered sodium citrate with a citrate-to-blood ratio of 1:9. The vial is inverted several times to mix the blood and citrate. Maintaining this citrate-blood ratio is crucial for test accuracy. Citrate binds calcium, an important cofactor of coagulation, preventing the blood from clotting before the beginning of the test. A clotted specimen, reflecting a vial overfilled with blood, cannot be used. For TEG testing, the collected non-clotted samples are considered stable and usable for up to 2 hours at room temperature. Non-citrated whole blood (native blood TEG or NATEM) can also be tested, but it must be used immediately. The test and reagents used are at room temperature. A volume of 340 uL of citrated blood is pipetted to the study cup, recalcified by adding 20 uL of 0.2 M calcium chloride and then activated with a kaolin-cephalin reagent. Cephalins or phosphatidylethanolamines, a class of phospholipids commonly present in membranes of human cells, are an essential cofactor of the coagulation cascade, enabling the assembly of tenase and prothrombinase complexes on the surface of platelets that are critical for thrombin generation. Kaolin is a mineral primarily composed of hydrated aluminum silicate, a negatively charged molecule that can initiate the intrinsic coagulation pathway by activating Factor XII. Precise proportioning of the blood and kaolin-cephalin reagent is essential for accurate and reproducible TEG results.[11] Non-activated TEG is also possible, but the lack of activators significantly prolongs clotting time and the testing process, which is undesirable in a clinical emergency.

Several modifications of the classic TEG assay have been developed to improve its diagnostic value. Rapid TEG (r-TEG) uses tissue factor instead of the kaolin-cephalin reagent to activate blood coagulation. Because the tissue factor triggers the extrinsic coagulation pathway, which involves a smaller number of coagulation factors, the test can be performed faster compared to conventional TEG. r-TEG can be completed within 15 minutes and thus helps manage massive transfusions in trauma patients.[12][13] The TEG platelet mapping assay was developed to predict the inhibitory effect of antiplatelet agents, such as aspirin and clopidogrel, by evaluating platelet aggregation in the presence of adenosine diphosphate or arachidonic acid. TEG with added heparinase measures the effect of heparin reversal on blood coagulation. Rotational thromboelastography, also known as rotational thromboelastometry (RoTEM), uses an oscillating pin that rotates ±4° 45′ 6″ while maintaining the cup in a stable position. In this assay, different activator reagents are used to investigate specific components of the coagulation pathway (Table 1).

Results, Reporting, and Critical Findings

A normal thromboelastogram is schematically represented in Figure 1. Prompt qualitative analysis of the TEG tracing can be performed during the test. The quantitative analysis of TEG includes measuring the 5 parameters listed and described in Table 1. The manufacturer has also suggested a coagulation index to assess the overall coagulation status. The coagulation index (CI) for whole blood may be calculated as follows:

• CI = −0.2454R+ 0.0184K + 0.1655MA − 0.0241a − 5.0220

Normal values of the coagulation index lie within −3.0 and +3.0, which is 3 standard deviations from the mean of zero. A hypercoagulable state is defined as a CI greater than +3.0, and coagulopathy as a CI less than −3.0. Previous studies demonstrated a significantly elevated CI in the postoperative period after general surgery and in cancer patients, suggesting a prothrombotic state.[14][15] However, this index is not widely used, and its clinical usefulness is not yet validated. Other parameters derived from the thromboelastogram include projected maximal amplitude; time to maximal amplitude; the G parameter, such as shear elastic modulus strength or clot strength; and a thrombodynamic potential index. Although these variables provide additional insights, they are rarely utilized in routine clinical practice due to their complexity and limited practical application.

Normal TEG values are summarized in Table 2, although some patient-related factors may affect these values. Elderly patients tend towards more pro-coagulable TEG results, suggesting a need to correct these reference values in older individuals.[16] In some circumstances, such as in patients undergoing cardiac surgery and liver transplantation, specific reference values are less important because the principal application of TEG is to compare the patient's baseline to changes during the intraoperative and postoperative periods. In other clinical scenarios, such as trauma or postoperative bleeding, reference values are important for interpreting the results, as no baseline data are available. There is also some variability in testing results. A study involving 118 healthy volunteers revealed at least one abnormal parameter in 19% of specimens and a coagulopathy (defined as at least 2 abnormal parameters) in 9%, leading to a calculated specificity of 81%.[17] A larger prospective trial encompassing a more diverse group of patients helps establish analyzer- and reagent-specific reference values in selected patient subgroups.

Deviation of each TEG parameter from the reference values suggests specific disturbances of hemostasis and coagulation.

• Prolonged R time suggests a quantitative or qualitative deficiency of coagulation factors that may be corrected by fresh frozen plasma transfusion, prothrombin complex, or anticoagulant reversal.
• Prolonged K time or decreased alpha-angle suggests fibrinogen deficiency, which may be corrected using cryoprecipitate or lyophilized fibrinogen concentrate.
• Low maximum amplitude indicates a quantitative or functional deficiency of platelets and could be corrected by platelet concentrate transfusion or desmopressin.
• Increased LY value implies activated fibrinolysis that may be treated by fibrinolysis inhibitors (aminocaproic or tranexamic acid).

The opposite changes in TEG parameters suggest a prothrombotic state. This interpretive approach represents a convenient but rather simplified perspective on disturbances of blood coagulation. However, it is important to remember that these TEG parameters are interrelated due to the complex nature of hemostasis.

A different nomenclature is used for RoTEM assays to define the same TEG parameters—clotting time (CT) instead of R, clot formation time (CFT) instead of K, maximum clot firmness (MCF) instead of MA, and CL instead of LY. Reference values for RoTEM have been established in a multicenter study involving 500 healthy volunteers.[18] Depending on the specific TEG analyzer (TEG versus RoTEM) and the reagents used, differing results may be obtained from the same blood sample, potentially affecting clinical decision-making.[19][20] Some of these differences remain poorly understood. For example, NATEM may be more sensitive to hyperfibrinolysis compared to INTEM and EXTEM.[21] A systematic review of 4 clinical trials comparing TEG and RoTEM found clinically significant differences between the 2 tests with a lack of comparability of the results.[22] A recent systematic review did not discover a sufficient number of well-designed studies to compare the results of TEG and RoTEM in healthy individuals.[23] Hence, the results of different modifications of TEG and RoTEM cannot be considered interchangeable until head-to-head prospective comparative studies are performed.

Clinical Significance

The main advantage of TEG testing is its potential to deliver immediate goal-oriented and individualized care to a bleeding patient:

• Global assessment of blood coagulability, including coagulation cascade, platelet function, and fibrinolysis
• Rapid real-time bedside test with a simple methodology (point-of-care testing)
• Diagnosis of coagulopathic bleeding
• Guide transfusion therapy and decrease the use of blood products
• Detect dynamic changes in blood coagulation during resuscitation
• Predict the clinical efficacy of therapeutic agents affecting blood coagulability

TEG has convincingly demonstrated its utility in improving outcomes in cardiac surgery. A meta-analysis of 17 randomized controlled trials showed that TEG decreases blood product transfusions and surgical re-exploration due to postoperative bleeding in cardiac surgery patients.[24] These effects were associated with a lower incidence of acute kidney injury and thromboembolic events. Another systematic review of 17 randomized controlled trials involving 1493 patients, mainly elective on-pump cardiac surgery, revealed that TEG/RoTEM decreases transfusion of blood components and reduces overall mortality.[25] However, the quality of the included studies was considered low.[25] A recent randomized controlled trial found that intraoperative correction of coagulopathy guided by EXTEM and FIBTEM can reduce postoperative bleeding, blood transfusions, and duration of critical care in pediatric cardiac surgery patients.[26] TEG is also a more cost-effective method compared to standard coagulation tests in diagnosing coagulopathy in cardiac surgery.[27]

There is conflicting evidence regarding the usefulness of TEGs in trauma patients. A recent Cochrane database systematic review found insufficient data to compare the accuracy of TEG and RoTEM versus PT/INR in diagnosing trauma-induced coagulopathy.[28] The review concluded that these tests are still in the clinical research phase. However, whether PT/INR can be considered a good reference standard to diagnose coagulopathy is questionable. In major trauma, r-TEG is better in predicting the need for transfusion of fresh frozen plasma, red blood cells, and platelets compared to conventional coagulation tests of PT, aPTT, INR, platelet count, and fibrinogen.[29] Based on another large systematic review, although with evidence limited to cohort studies with a moderate-to-high risk of bias, TEG/RoTEM can diagnose coagulopathy and may predict blood components transfusion and mortality in trauma patients.[30] Another review of 13 cohort studies involving only RoTEM in 2835 adult trauma patients reached similar conclusions.[31] However, there was no improvement in patient morbidity or mortality.[30] Another Cochrane database systematic review of 9 randomized controlled trials involving 776 participants, mainly cardiac surgery patients, found a decreased amount of bleeding when TEG or RoTEM was used but also without a decrease in morbidity or mortality.[22] This inability of TEG/RoTEM testing to significantly reduce mortality may become a barrier to widespread clinical use. However, it is essential to realize that overall mortality in hospitalized patients with bleeding is relatively low, necessitating large clinical trials to detect a statistically significant impact of TEG on mortality. Furthermore, these patients are often complex cases, and the overall treatment strategy, rather than diagnostic testing, plays a significant role in affecting overall morbidity and mortality.

There is expanding evidence of using different TEG and RoTEM assays in other additional clinical scenarios. A small randomized controlled trial has demonstrated the ability of TEG to better guide anticoagulation during ECMO compared to aPTT, reducing the dose of heparin.[32] TEG platelet mapping can detect platelet inhibition caused by clopidogrel and aspirin in surgical patients.[33] A novel TEG-based scoring system has been suggested to diagnose disseminated intravascular coagulation.[34] TEG may detect possible coagulopathy in patients with intracranial bleeding and hematoma enlargement.[35] TEG may also be useful for patients with liver disease, as conventional coagulation tests often show abnormalities in these individuals. At the same time, TEG/RoTEM results are normal in many patients despite an abnormal INR or platelet count due to adjustments in the hemostatic system or rebalanced hemostasis.[36] Thus, TEG/RoTEM may provide a better insight into the risk of bleeding in patients with liver disease compared to conventional coagulation tests.[37] EXTEM has been found helpful in detecting intraoperative coagulopathy in liver transplant patients.[38] There are other clinical situations when TEG has demonstrated potential benefits, but listing all of them is beyond the scope of this review.

Clinical Guidelines

The NICE guidelines recommend TEG for detecting, managing, and monitoring hemostasis in cardiac surgery patients. Other clinical guidelines do not strongly recommend TEG for use in other settings due to the lack of high-quality evidence. The recently updated guidelines from the European Society of Anesthesiology recommended viscoelastic hemostatic assays (TEG/RoTEM) to guide the management of perioperative bleeding and severe peripartum hemorrhages, albeit with a low level of evidence.[39]

Limitations

An ideal test on blood coagulation does not yet exist. TEG measures blood coagulation in vitro, with or without an additional activator. A tissue factor, an essential component of the coagulation cascade, cannot be quantified in vitro. Furthermore, blood coagulation is the only component of complex processes such as clinical thrombosis and bleeding. Blood coagulation also depends on the size of the injured vessel, blood flow characteristics, and local vessel wall biology, which determines the quantity and functional activity of the membrane-bound pro- and anticoagulation factors. In other words, there are significant aspects of coagulation that are not components of the blood. An abnormal TEG in a patient without clinically relevant bleeding does not require transfusion of blood components. A single test or patient-related factor rarely guides the decision to transfuse blood components or initiate or correct antithrombotic therapy.

TEG has a sensitivity and specificity that may vary significantly in different populations. Patients on anticoagulants and antiplatelet agents are a major concern in the trauma setting. Warfarin is a commonly prescribed medication associated with increased mortality in trauma patients.[40][41] In about half of patients on warfarin, R-time may be normal in both TEG and r-TEG tests, with a poor correlation between TEG and INR.[11] Such findings are a good example of how TEG may miss a clinically significant coagulopathic state. Hence, INR is still the gold standard for monitoring warfarin therapy. Several important blood tests also cannot be currently replaced by TEG, such as P2Y12 platelet function assay to guide clopidogrel therapy, D-Dimer to exclude venous thromboembolism in low-risk outpatients, and advanced thrombophilia diagnostic tests.

Future Directions: Guiding Anticoagulation and Antiplatelet Therapy

Anticoagulation therapy is a field where TEG may become more applicable pending future clinical studies. Up to one-third of patients on warfarin therapy may have subtherapeutic anticoagulation at some point during treatment.[42] One of the advantages of direct oral anticoagulants is that there is no requirement to monitor anticoagulation therapy. However, they may be problematic in certain groups of patients, such as those with renal failure, liver failure, pregnancy, extremes of body weight, high bleeding risk, thrombosis progression, or recurrence on anticoagulation.[43] High plasma concentration of direct oral anticoagulants has been associated with higher bleeding risk.[44][45] In these situations, TEG may provide the ability to adjust the level of anticoagulation during the same office visit. As TEG activates an intrinsic coagulation pathway with kaolin, it is sensitive to heparin and low-molecular-weight heparin therapy (R time). An interesting case of an emergent heparin reversal under TEG control in a patient with intracranial bleeding has been reported.[46]

Predicting platelet inhibition by antiplatelet agents, such as aspirin, clopidogrel, abciximab, eptifibatide, or tirofiban, is another promising avenue for TEG application. Most antiplatelet agents are used with a standard dose despite several known issues associated with this approach. For example, up to 25% of patients with ST-segment elevation myocardial infarction may be resistant to clopidogrel, increasing the risk of recurrent cardiovascular events.[47] Aspirin resistance has been associated with increased myocardial infarction, stroke, or death in patients with cardiovascular disease.[48] Hence, there is significant variability in individual response to antiplatelet therapy. Available evidence does not support the use of usual laboratory testing to guide the dose of aspirin or clopidogrel.[49] Future studies may determine whether TEG can measure the effect of antiplatelet therapy, detect hyporesponsiveness, and predict the risk of bleeding or thromboembolic complications.

A novel concept of individualized health care applies to anticoagulation and antiplatelet therapy monitoring. Using a standard dose of the same medications to treat patients with different medical conditions and comorbidities may not be ideal. The potential of TEG to improve the quality of antithrombotic therapy is a promising avenue for experimental and clinical research.

Future Directions: Prevention of Venous Thromboembolism

Another potential application of TEG is to improve the diagnosis, prevention, and treatment of patients with venous thromboembolism. The most appropriate evidence-based practice to prevent venous thromboembolism is to stratify patients based on the venous thromboembolism risk using one of the risk prediction models elaborated for surgical and medical patients. These models do not incorporate conventional blood coagulation tests, as they do not predict venous thromboembolism. Several initial reports suggest that TEG may be a useful tool to help with risk stratification. TEG may have a venous thromboembolism predictive value in critically ill patients, gynecological oncology patients, and individuals with prostate cancer.[50][51][52][53] A large prospective cohort involving adult trauma patients revealed a 2-fold higher risk of venous thromboembolism in patients with hypercoagulable TEG parameters on arrival to the trauma bay.[54] However, other reports did not find TEG valuable in predicting venous thromboembolism in selected patients, such as those undergoing orthopedic surgery.[55]

Despite appropriate prophylaxis, venous thromboembolism is still a frequent concern in hospitalized patients. In a study, the R time of TEG was significantly shorter in critically ill patients on low-molecular-weight heparin prophylaxis who develop DVT compared to patients who do not.[56] Thus, TEG may help predict venous thromboembolism that occurs despite standard pharmacological prophylaxis.

Quality Control and Lab Safety

TEG/RoTEM testing requires skilled personnel to ensure accurate results, as test precision can vary significantly depending on the operator's expertise.[57] To address this, regular external quality assessments and proficiency testing are recommended to maintain consistency and reliability.[57] For optimal utilization, users should adhere to the guidelines outlined in the manufacturer's manual.

Enhancing Healthcare Team Outcomes

A team of healthcare professionals, including clinicians, specialists, advanced practice providers, pharmacists, and other healthcare providers, collaboratively participate in patient care. These members should be well-versed in TEG and its applications in diagnosing and guiding interventions. Familiarity with TEG enables these team members to interpret its diagnostic insights effectively and contribute to therapeutic decision-making. By understanding the implications of TEG results, they can provide informed recommendations, optimize care plans, and improve overall patient outcomes.

Enhancing team collaboration around TEG usage ensures that diagnostic information is seamlessly integrated into patient care strategies. For example, clinicians can use TEG to identify coagulopathies, whereas pharmacists can guide appropriate anticoagulant or hemostatic agent selection. Nurses and advanced practice providers can assist in monitoring patient responses and adjusting interventions as needed. Such a collaborative approach reinforces the critical role of interprofessional teams in delivering goal-directed, individualized care, ultimately leading to better clinical outcomes in settings where hemostatic control is crucial.