Dominika Woźniak, *Barbara Adamik
Department of Anaesthesiology and Intensive Therapy, Wrocław Medical University
- Fig. 1. Thromboelastogram; coagulation activation and clot polymerisation assessed based on clotting time, time of clot formation and angle of deflection α. The clot stability is evaluated using maximum clot stability and clot stability in a given time. Clot lysis is assessed based on maximum clot lysis and clot lysis in a given time
Coagulopathies of various origins have been mentioned among the leading causes of morbidity in hospitals all over the world. Time-consuming coagulation assays delay the diagnosis and response to a dynamic pathology. The need to analyse whole blood for the accurate identification of coagulopathies has led to a revival of interest in thromboelastography (TEG). This simple test can be performed at the bedside using non-anticoagulated blood, and enables complex assessment of extrinsic and intrinsic pathways of coagulation and fibrinolysis. TEG can be also used to predict postoperative bleeding and/or organ dysfunction.
TEG has been widely used in research, but poor understanding of the technique has limited its clinical use. Controversies regarding the relationship between traditional tests and TEG have made the bedside use of TEG less popular than it should be. In the review, the authors discuss details of the process and practical aspects of its use in clinical settings.
Coagulapathies cause great difficulties in the diagnosis and treatment of diseases in hospitals all over the world. The classic diagnostic methods for hyper- and hypocoagulation are often insufficient and time-consuming, particularly in cases of perioperative bleeding, clots or embolism, and haemorrhagic complications during sepsis [1, 2]. The key analytic problem is time-consumption; due to dynamic changes of the clotting system, the time-consuming procedure makes the precise monitoring of the patient’s condition impossible. Thromboelastometry is the method enabling accurate and fast analysis of haemostasis, bed-side diagnostics and monitoring of ongoing coagulation and fibrinolytic changes [3, 4, 5].
The method was first described by Hartert in 1948, which initiated further studies in this field . The principle of functioning of first thromboelestographs was based on a ballistic pendulum . Those devices were characterized by long time of measurements and low repeatability of results; the introduction of automated devices and standard activators of coagulation enabled faster readings and improved the reliability of results .
Although thromboelastometry has been widely used in scientific research, its application in routine diagnostic procedures is less common, mainly due to difficulties in interpretation of thromboelastographs and in understanding the relations between the results of thromboelastometric and conventional methods for assessment of clotting disturbances. Recently, thromboelastometry has been more widely used in clinical practice in cardiac surgery, transplantation, obstetrics and gynaecology and orthopaedics wards [8, 9]. The method enables comprehensive evaluation of intrinsic and extrinsic pathways of coagulation and fibrinolysis and estimation of risk of postoperative bleedings and organ dysfunction, which is likely to contribute to a reduction in the number of haemorrhagic complications and blood transfusions [8, 10, 2].
The thromboelastographs are bedside devices using fresh full blood or blood with anticoagulant (sodium citrate). The sample of fresh blood should be examined immediately before the clot has formed. The advantage of fresh blood is markedly shortened time of determinations yet the result may be false when the analysis is carried out with delay. Therefore, if the test is not performed immediately, it is recommended to collect the blood to the test-tube with an anticoagulant.
With the suitable stimulators of intrinsic and extrinsic coagulation pathways added, the blood sample is placed in the cylindrical cuvette in the heating chamber (37°C) to detect the forming clot. A probe with the sensor is introduced to the cuvette. The probe rotates (4.75°), and the movement resistance caused by the thrombus formation is recorded by the optical system. The more stable the thrombus becomes, the higher the resistance is. The optical system record is then processed and the coagulation time, time of clot formation, stability and time of its disintegration are presented numerically and as graphic recordings of changes occurring already 5-10 min later (Fig. 1).
The following parameters are used to assess the activation of coagulation and clot polymerisation:
- clotting time (CT) (sec) – measured from the start of assay to the onset of clot formation (probe amplitude 2 mm); enables to assess the effects of clotting factors and anticoagulants on the rate of fibrin formation. The deficiency of clotting factors and anti-thrombotic therapy may prolong CT;
- clot formation time (CFT) (sec) – enables to evaluate the effects of the number and activity of platelets, fibrinogen concentration and its polymerisation capacity on kinetics of the stable clot formation ( probe amplitude 20 mm);
- deflection angle α – between the reference line and the tangent of clotting curve; it shows the speed of clot formation and , similarly to CFT, depends on the number and activity of platelets, fibrinogen concentration and its polymerisation capacity. Lower values of α are likely to suggest reduced blood clotting whereas high values – proneness to thrombi.
To assess the stability of a clot, the following parameters are used:
- maximum clot firmness (MCF), which is the maximum amplitude during examination (mm), indicates the clot quality and depends on the number and function of platelets, fibrinogen concentration and its polymerisation capacity, concentration of factor XIII and activation of fibrinolysis. The low value of MCF is associated with the risk of bleedings.
- clot stability A (mm) achieved after a given time unit, denoted as A(x), where x is time of measurement (after 5 min, 10 min, etc.).
The clot lysis is assessed using the following parameters:
- maximum lysis (ML), defined as a decrease in clot stability (%MCF); high values of ML indicate enhanced fibrinolysis. Clot lysis examined after a given time unit (LI(x), where x is 30, 45, 60 min) may indicate early or late fibrinolysis.
The additional parameters measured by the device but not used in everyday clinical practice include:
- maximum clot firmness time (MCF-t)(sec);
- maximum clot elasticity (MCE) (mm), helpful for interpretation of big amplitudes.
Monitoring of the patient’s condition and comparison of results makes sense only if the same device and the same activators are used, as measurements with different devices may differ significantly. In Poland, two thromboelastographs are currently available – ROTEM (Pentapharm, Germany) and TEG (Haemoscope, USA).
In the ROTEM system, the diagnostic management should be started with the EXTEM pathways (activation of extrinsic clotting pathway) and INTEM pathways (stimulation of intrinsic clotting pathway) [9, 11 , 12]:
- EXTEM based on CT, CFT, α angle, MCF, A(x), LI(x) defines the clot formation after administration of thromboplastin and activation of extrinsic pathway. The test assesses the clotting factors VII, X, V, II, I, platelets and fibrinolysis;
- INTEM based on CT, CFT, α angle, MCF, A(x), LI(x) defines the clot formation after intrinsic pathway activation. The activator is ellagic acid; the test enables assessment of such clotting factors as XII, XI, IX, VIII, X, V, II, I, platelets, and fibrinolysis.
Normal values of EXTEM and INTEM indicate that the bleeding is not caused by haemostasis disturbances but discontinuity of blood vessels due to surgery. Abnormal values evidence haemostasis disturbances and increased risk of bleedings.
The further diagnostics is performed using the FIBTEM, HEPTEM and APTEM functions:
- FIBTEM – interpreted together with EXTEM after the addition of the platelet-blocking factor – cytochalasin D, enables assessment of fibrin polymerisation, fibrinogen deficiencies and platelet dysfunction;
- APTEM – interpreted together with EXTEM after addition of fibrinolysin inhibitor – aprotinin. The abnormal values indicate increased fibrinolysis;
- HEPTEM – interpreted together with INTEM after the addition of heparinase, the enzyme breaking down heparin, enables assessment of heparin-induced disturbances. Abnormal values of HEPTEM can also be caused by deficiencies of clotting factors XII, XI, IX, VIII, X, V, II, I, masked by heparin.
The TEG procedure differs from the ROTEM system. Clotting disorders and fibrinolysis are assessed based on: 1) diagnosis of coagulation processes and platelet function using the coagulation activator, i.e. kaolin, 2) determination of the effect of heparin after addition of heparinase and kaolin, 3) assessment of platelet function and results of anti-platelet therapy after administration of arachidonic acid and ADP, and 4) examination of non-activated, native blood .
USEFULNESS OF THROMBOELASTOMETRY IN INTENSIVE THERAPY
Irrespective of the system, the use of a thromboelastometre/thromboelastograph enables quick assessment of haemostasis disturbances and proper choice of therapeutic strategy. However, it should be remembered that the reference values for individual parameters of a thromboelastograph were defined based on tests in healthy individuals. The clotting parameters are individual features of the given populations; therefore, it is recommended to define characteristic parameters of a particular ward and the methodology of reference ranges used.
In ITUs, clotting and fibrinolysis disturbances manifesting in bleedings, disseminated intravascular coagulation (DIC), or multi-organ failure are common, particularly in patients with severe sepsis and septic shock. Routine diagnostic procedures in septic patients based on determinations of platelet count, prothrombin time (PT), kaolin-cephalin clotting time (APTT), concentration of fibrinogen and fibrin/fibrinogen degradation products are time-consuming and do not reflect the actual haemostasis disturbances. The examinations are performed with delay, require centrifugation of full blood to obtain plasma, thus the sample is deprived of thrombocytes, which have the crucial impact on the coagulation process. The test ends with the clot formation, therefore its stability cannot be assessed. The tests can only be used for monitoring the initial stage of blood clotting, which represent only 4% of thrombin . The study describing the usefulness of thromboelastometry for differential diagnosis in patients with severe sepsis and DIC and those with severe sepsis without DIC demonstrated that higher severity of coagulopathies in severe sepsis, which enables the assessment of the risk of bleedings and thrombi, might be fully diagnosed using thromboelastography .
Moreover, thromboelastography was shown to facilitate the diagnosis of coagulopathies in multiple traumas and peritraumatic bleedings; since the test can be performed at bedside, and blood without citrate can be used, the time to obtain results is markedly shortened .
Monitoring of haemostasis based on thromboelastograms is used during surgical procedures, in emergencies and chronic diseases. The clotting system complications, accompanied by dysfunction of blood vessels, extremely commonly affect patients with type 2 diabetes. Coagulation and fibrinolysis disturbances can enhance vascular changes in this group of patients, and abnormalities disclosed by the thromboelastogram help to diagnose such changes .
Diseases of the coagulating system caused by deficiencies in clotting factors can be monitored using thromboelestography as the procedure enables fast full assessment of intrinsic and extrinsic coagulation pathways and treatment outcomes [16, 17]. The thromboelastograph has proved helpful in monitoring the patients with acquired haemophilia treated with recombinant factor VIIa (rFVIIa) due to acute haemorrhage . In the thromboelastogram, the angle of deflection angle was bigger in patients responsive to rFVIIa treatment, so were the clotting time and time of clot formation. The changes were visible during administration of subsequent booster doses whereas the changes in thromboelastogram parameters after the first dose of rFVIIa did not correlate with the clinical response of the patient to the drug.
Thromboelastography is not free of interferences. The measurements can differ in the values obtained as well as kinetics of the reaction; therefore, monitoring of the patient’s condition and comparison of results makes sense only when the same machine and the same activators are used. The inter-measurement differences resulting from the use of blood collected to the test-tube with anti-coagulant (sodium citrate) compared to fresh blood samples were described . To standardise the results, only the blood collected for anticoagulant (which is recommended by the manufacturers of thromboelastometres/thromboelastographs) or fresh blood should be used and the analysis performed immediately. The measurement results are also likely to be affected by decreased blood pH and hypothermia. The animal studies demonstrated significantly prolonged clotting time and time of clot formation plus worse stability of thrombi in acidized blood samples . Such changes were not observed in alkalinized blood. Hypothermia can also alter the result causing marked prolongation of clotting time, time of clot formation and worse clot stability .
Thromboelastometry-thromboelastography is a modern, bedside method enabling assessment of clotting/fibrinolysis disturbances, detection of their causes and extent. To popularise its use for identification of the causes of bleedings and their effective treatment, better recognition and understanding of the individual elements of the thromboelastogram and their clinical significance is required.
1. Vorweg M, Doehn M, Kolde HJ: Rapid diagnosis & differentiation of acute haemostasis disorder with whole blood global assay. European Clinical Laboratory 2002; 8: 12-15.
2. Sivula M, Pettilä V, Niemi TT, Varpula M, Kuitunen AH: Thromboelastometry in patients with severe sepsis and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2009; 20: 419-426.
3. Collins PW, Macchiavello LI, Lewis SJ, Macartney NJ, Saayman AG, Luddington R, Baglin T, Findlay GP: Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol 2006; 135: 220-227.
4. Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM: Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study. Crit Care 2009; 13: 1-8.
5. Luddington RJ: Thromboelastography/thromboelastometry. Clin Lab Haem 2005; 27: 81-90.
6. Hartert H: Blutgerinnung Studien mit der Thromboelastographie, einen Neuen Untersuchingsverfahren. Wien Klin Wochenschr 1948; 26: 577-583.
7. Macfarlane RG, Tomlinson AH: An apparatus for measuring the tensile strength of blood clots. J Clin Pathol 1961; 14: 320-323.
8. Benedetto P, Baciarello M, Cabetti L,Martucci M, Chiaschi A, Bertini L: Thrombelastography. Present and future perspectives in clinical practice. Minerva Anesthesiol 2003; 69: 501-515.
9. Trzebicki J, Kuźmińska G, Domagała P: Tromboelastometria – nowa metoda wspomagająca decyzje terapeutyczne w zaburzeniach hemostazy, oparta na tromboelastografii Harteta. Pol Merk Lek 2009; 27: 85-91.
10. MacDonald S, Phil M, Luddington RJ: Critical factors contributing to the thromboelastography trace. Semin Thromb Hemost 2010; 36: 712-722.
11. Anderson L, Quasim I, Soutar R, Steven M, Macfie A, Korte W: An audit of red cell and blood product use after the institution of thromboelastometry in a cardiac intensive care unit. Transfus Med 2006; 16: 31–39.
12. Mazibuko AZ: Thromoelastography. http://anaesthetics.ukzn.ac.za/Libraries/FMM_R_B_2009/Thromboelastography_Dr_AZ_Mazibuko.sflb.ashx
13. Mann KG, Butenas S, Brummel K: The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23: 17-25.
14. Jeger V, Zimmermann H, Exadaktylos AK: Can rapid TEG accelerate the search for coagulopathies in the patient with multiple injuries? J Trauma 2009; 66: 1253-1257.
15. Yureklia BPS, Ozcebeb OI, Kirazlib S, Gurlek A: Global assessment of the coagulation status in type 2 diabetes mellitus using rotation thromboelastography. Blood Coagul Fibrinolysis 2006; 17: 545-549.
16. Dehmel H, Werwitzke S, Trummer A, Ganser A, Tiede A: Thrombelastographic monitoring of recombinant factor VIIa in acquired haemophilia. Haemophilia 2008; 14: 736-742.
17. Hvas AM, Sorensen HT, Norengaard L, Christiansen K, Ingerslev J, Sorensen B: Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A. J Thromb Haemost 2007; 5: 2408-2414.
18. Ramaker AJ, Meyer P, van der Meer J, Struys MM, Lisman T, van Oeveren W, Hendriks HG: Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser. Blood Coagul Fibrinolysis 2009; 20: 436-439.
Katedra i Klinika Anestezjologii i Intensywnej Terapii
Akademia Medyczna we Wrocławiu
ul. Borowska 213, 50– 556 Wrocław
tel.: +48 71 733 23 10, fax: +48 71 733 230 09
e– mail: firstname.lastname@example.org
received: 02.04.2011 r.
accepted: 25.06.2011 r.