Transfusion and Apheresis Science 51 (2014) 105–110

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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i

Review

What is happening? The evolving role of the blood bank in the management of the bleeding patient: The impact of TEG as an early diagnostic predictor for bleeding Aurora Espinosa a,*, Jerard Seghatchian b,** a b

Department of Immunology and Transfusion Medicine, St. Olav’s Hospital, Trondheim, Norway International Consultancy in Blood Component Quality/Safety Improvement, Audit/Inspection and DDR Strategy, London, England, UK

A R T I C L E

I N F O

A B S T R A C T

Despite recent advances in the understanding and treatment of coagulopathy, the management of the bleeding patient remains as a major challenge. Traditionally, the main task of the blood bank has been to guarantee the supply of high quality blood and blood components/products to the hospital. Decisions regarding the use of blood components have always been the clinicians’ responsibility, with little active involvement of the transfusion service. In the last years, many hospitals have implemented the use of “acute transfusion packages” for massively bleeding patients and point-of-care (POC) instruments such as TEG and RoTEM for monitoring coagulation status in this patient group. This, in addition to the implementation of patient blood management programs in the hospitals, has led to an increasing involvement of transfusion medicine specialists in transfusion decision making, especially regarding strategies for monitoring and treatment of the massively bleeding patient. This new trend may contribute to a more optimal management and monitoring of the bleeding patient, as POC testing may be used as an early predictor for blood usage. The blood bank should optimise the use of POC testing to provide accurate information in a cost-effective way. © 2014 Published by Elsevier Ltd.

Contents 1.

2.

Introduction ......................................................................................................................................................................................................................... 1.1. Optimal coagulopathy monitoring .................................................................................................................................................................. 1.2. Acute transfusion packages and goal-directed hemotherapy by POC testing in the massively bleeding patient ............... 1.3. Should TEG be used as a POC instrument? ................................................................................................................................................. 1.4. Technical pitfalls ................................................................................................................................................................................................... 1.5. Reference values for different patient settings ........................................................................................................................................... 1.6. Future directions ................................................................................................................................................................................................... Conclusions .......................................................................................................................................................................................................................... References .............................................................................................................................................................................................................................

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* Corresponding author. Department of Immunology and Transfusion Medicine, St. Olav’s Hospital, N-7001 Trondheim, Norway. Tel.:(+47) 725 73 247; fax: (+47) 725 76 420. E-mail address: [email protected] (A. Espinosa). ** Corresponding author. International Consultancy in Blood Component Quality/Safety Improvement, Audit/Inspection and DDR Strategy, London, England, UK. E-mail address: [email protected] (J. Seghatchian). http://dx.doi.org/10.1016/j.transci.2014.10.017 1473-0502/© 2014 Published by Elsevier Ltd.

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1. Introduction 1.1. Optimal coagulopathy monitoring The cell-based model of coagulation focused on the importance of the tissue factor and platelets in the coagulation process [1], and the value of routine laboratory tests such as activated partial prothrombin time (aPTT), prothrombin time (PT) and INR has therefore been questioned for monitoring coagulopathy. Being performed in plasma, these tests do not take into account the effect of cellular blood components in the coagulation process. This may explain why it has been difficult to find correlations between traditional coagulation tests and those from POC instruments, which involve blood cells. POC instruments such as TEG and RoTEM are increasingly used to monitor the coagulation status of massively bleeding patients. These instruments provide a global graphic representation of the coagulations process, based on the changes of the viscoelastic properties of the clot. The TEG curve gives information on all the steps of coagulation, from the initial thrombin formation to fibrinolysis. Optimal assessment of the massively bleeding patient requires rapid availability of test results. Depending on the assay the results may be ready in 15– 30 minutes. There are three key parameters in a TEG curve, as shown in Figs 1 and 2, and Table 1. The (R) variable, which reflects the patients’ level of coagulation factors, is available within a few minutes. A variant of the TEG analysis, rapid TEG (rTEG), uses both kaolin and tissue factor as coagulation activators, and the results are available after 15 min. Experiences with TEG and rTEG suggest that this instrument may be useful to monitor the coagulation status of the patient as well as for guiding the transfusion therapy [2,3]. Several studies have shown that the implementation of TEG based transfusion algorithms may contribute to reduce transfusion requirements in cardiac surgery [4]. As the author’s experience is mainly on TEG, this article will be focused on this instrument. Fibrinogen is a plasma protein critical to haemostasis and clot formation and the first coagulation factor to decrease below critical levels in massively bleeding patients [5]. Excessive bleeding has been reported at fibrinogen levels below 50–100 mg/dL, but there is evidence indicating that higher fibrinogen levels may be necessary for sufficient fibrin clot polymerization [6,7]. In recent years, hyperfibrinolysis has been identified as a key feature in trauma-associated coagulopathy and significantly associated to increased mortality [8]. TEG has been shown to be useful in the early detection of hyperfibrinolysis, as well as guiding therapy with fibrinogen supplements or antifibrinolytic therapy [9]. There are two informative variables in the TEG analysis regarding fibrinogen levels: Alpha angle is directly associated with fibrinogen level and many studies have shown a

Fig. 1. Graphic representation of the parameters in the TEG curve.

strong correlation between alpha angle and fibrinogen levels measured by Clauss test [10]. Ly30 may reflect increased fibrinolysis and reduced fibrinogen as a consequence. In addition, a specific TEG assay for assessing functional fibrinogen level has been available in the last years. 1.2. Acute transfusion packages and goal-directed hemotherapy by POC testing in the massively bleeding patient The prompt diagnosis and management of coagulopathy in the massively bleeding patient remains a challenge and requires the collaboration of many medical specialties. The concept of reconstitution of whole blood from blood components by “transfusion packages” has been in use for some years, based on the positive experiences with fresh whole blood transfusion in trauma patients in the Afghanistan and Iraq war [11]. A transfusion package is intended to be a rapid issuing and transfusion in parallel of packed red blood cells, platelet concentrates and plasma at fixed ratios, in an attempt to reconstitute whole blood. In non-trauma patients, common indications for activation of an acute transfusion package have been gastrointestinal bleeding, surgical complications, obstetric bleeding and ruptured aorta aneurysm [12]. Even if the use of acute transfusion packages has been increasing in the last years, there is still lack of evidence of the benefits in non-trauma patients. The literature for (1:1:1) ratio-driven blood resuscitation applied to non-trauma patients is insufficient to recommend that this transfusion support strategy be directly applied to nontrauma patients with major bleeding [13]. One possible explanation for this is that massive bleeding in non-trauma

Table 1 Variables and reference values in the TEG curve. R (Clotting time) α (Alpha angle) MA (Maximal amplitude) Ly30 (Lysis of the clot)

4–8 min. 53–67 deg 55–73 mm %

Relates to the level of coagulation factors Relates to the fibrinogen level Relates to fibrinogen level and platelet function Relates to fibrinolysis

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Fig. 2. Representation of a normal TEG curve.

patients has different physiological mechanisms that the trauma associated coagulopathy [14]. Different ratios have been proposed as the ideal for the transfusion packages. Several studies have shown that the composition of these packages is not as important as the prompt delivery of the blood units to the emergency room. The simple fact of having implemented a massive transfusion protocol in the hospital, with rapid issuing of blood components by the blood bank, may lead to improved morbidity and mortality, regardless of the composition or the ratios [15]. In recent years, the concept of goal-directed control resuscitation has been introduced, where initial treatment with acute transfusion packages is adjusted by the results from POC instruments such as TEG or RoTEM (Figs 3 and 4). It has been suggested that POC instruments might be better at assessing coagulopathy in patients requiring acute transfusion packages than routine coagulation tests [16]. Goal-directed haemostatic control has been shown to improve 30-days survival in patients with ruptured abdominal aorta aneurysm compared to a transfusion protocol based on fixed ratios [17].

1.3. Should TEG be used as a POC instrument? Even if both TEG and RoTEM are usually thought to be POC instruments, there are some technical differences between the two instruments. In the RoTEM, the torsion wire rotates into the cup. This gives a great stability to the instrument, regardless of disturbances the environment, and that makes it suitable as a POC instrument in the emergency room. In the TEG instrument the cup rotates into the torsion wire (Fig. 5), and as a consequence, vibrations and other kind of physical disturbances near the instrument may affect the results. The TEG instrument requires daily calibration and routine quality controls, as well as standardisation in its use to ensure the optimal performance and reliable results. These demands can hardly be accomplished by busy emergency room personnel. For these reasons, TEG analysis should be performed by trained laboratory technicians at the laboratory department. Other factors such as medication, age and gender, as well as underlying medical conditions may affect the TEG results [18],

Fig. 3. First TEG curve in a massively bleeding patient at arrival to the hospital (10:09 am).

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Fig. 4. TEG curve from the same patient as in Fig. 3 after the transfusion of platelet concentrates and Octaplas (03:31 pm).

and they should be taken into consideration by the clinicians when interpreting a TEG curve. To avoid delays by reporting the TEG results to the clinicians, the manufacturer offers a software solution called Remote TEG. This implies that the TEG curve is shown on data screens in real time, as the test is performed at the laboratory department. With this measure the hospital benefits from both optimal performance of the TEG analysis and rapid assessment by the clinicians by real-time TEG on the screens. In that sense, the implementation of Remote TEG may contribute to make TEG a real POC instrument. 1.4. Technical pitfalls Originally, the TEG instrument was designed to be performed in whole blood. The problem with this approach was that the test should be done within 4 minutes after the withdrawal of the blood sample. For practical reasons, and to allow an extended period for the performance of the test to up to two hours, citrate blood samples are recalcified and activated with kaolin. Laboratories should standardise the performance of the test to avoid additional variables that may affect the results. (Fig. 6a and b).

Some studies have suggested a waiting period of 30– 40 minutes before the test should be run [19], but other studies have not confirmed these findings [20]. At our institution, the TEG analysis is performed as soon as possible when the blood sample is received by the pneumatic tubes. The effect of acceleration forces through the pneumatic tubes on the blood sample should be validated as this may affect the TEG results. The laboratory technicians are responsible for the technical performance of the TEG analysis, but not for the interpretation of the curves. We believe that the global interpretation of the TEG results should be made by the attending physicians, as they have all the required information regarding medical history and medications that have to be taken into account when interpreting a TEG curve. A challenging situation for the anaesthetist is how to interpret a normal TEG curve when the patient is still bleeding. The clinician should evaluate factors that may not be reflected in the TEG curve before ruling out coagulopathy as the cause of bleeding. One of the limitations of TEG is that it does not detect the effect of oral anticoagulants (OACs). In patients on medication with clopidogrel and other OACs, the patient may have severe depletion of the platelet function without this being showed in the TEG. To solve this problem, a special TEG assay, called Platelet Mapping is available and it should be perform when history of OACs is not known or it is unavailable. The Platelet Mapping assay measures clot strength and platelet function including the contribution of adenosine phosphate and thromboxane A2 receptors to clot formation . In addition, one should bear in mind that neither POC instruments nor coagulation tests are able to detect alterations in the vascular endothelium, which is a crucial contributor to the haemostasis. 1.5. Reference values for different patient settings

Fig. 5. Key elements in the TEG instrument.

The TEG manufacturer offer limited references for proposed normal values, and these have not been sufficiently validated. In addition, these values do not take into account variables that may affect the TEG results, such as gender,

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Fig. 6. Examples of alterations in the TEG curves caused by disturbances in the surroundings of the TEG instrument or problems when adding in the blood sample to the cup.

age and medical conditions and reference values may therefore differ from those proposed by the manufacturer [7]. To solve this problem it is important to validate the TEG for different patient settings, such as paediatric patients, obstetrics, and oncology and intensive care patients. As an example, in a study performed at our institution in nonbleeding intensive care patients (data not shown), we found hypercoagulopathy in a high number of patients. We strongly recommend that institutions should elaborate local reference values for different patient groups for an optimal interpretation of the TEG curves.

endothelium plays an important role in the pathophysiology of traumatic coagulopathy. The role of the live endothelial cells can not be assessed with the current available diagnostic tools and new ways to assess the endothelial function as an early predictor of bleeding should be explored. POC instruments such as ROTEM and TEG have emerged as practical, rapid and sensitive diagnostic modalities, but their performance in different patient groups and the potential new applications needs to be validated.

1.6. Future directions

2. Conclusions

A novel application of TEG includes its use to assess quality and functionality of stored platelet concentrates. Its potential to be used as a tool to select platelet aphaeresis donors should be further investigated [21]. Vascular

In the last decade there has been a paradigm shift regarding the management of the massively bleeding patient [22]. Rapid delivery and transfusion of plasma and platelet concentrates, as well as implementation of TEG-based

Fig. 6. (continued)

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transfusion protocols have contributed to better patient blood management and probably less blood transfusion requirements. In addition, the use of fresh whole blood as a therapeutic option to treat severe hemorrhagic shock needs to be investigated [23]. Blood bank physicians should be actively involved in the optimisation of strategies for the management of massively bleeding patients, as the need for massive transfusion may have a considerable impact on the blood bank store. Measures directed to optimise the use of acute transfusion packages, coagulation monitoring and goaldirected blood component therapy in this patient group will contribute to better patient blood management. TEG may as well be used to assess quality in stored platelet concentrates, assess the haemostatic changes in sepsis and monitor treatment with OACs. Additional work including the vascular endothelial cell in new generation of diagnostic tools is warranted. At our institution we believe that the use of TEG may contribute to improve transfusion therapy in different perioperative situations. References [1] Hoffman M, Monroe D. A cell-based model of haemostasis. Thromb Haemost 2001;85:958–65. [2] MacIvor D, Rebel A, Hassan ZU. How do we integrate thromboelastography with perioperative transfusion management? Transfusion 2013;53:1386–92. [3] Luddington RJ. Thromboelastography/thromboelastometry. Clin Lab Haem 2005;27(2):81–90. [4] Westbrook AJ, Olsen J, Bailey M, Bates J, Scully M, Salamonsen RF. Protocol based on thromboelastograph (TEG) out-performs physician preference using laboratory coagulation tests to guide blood replacement during and after cardiac surgery: a pilot study. Heart Lung Circ 2009;18:277–88. [5] Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and Hemostasis: a primary hemostatic taget for the management of acquired bleeding. Anesth Analg 2012;114:261–74. [6] Lier H, Böttinger BW, Krep J, Bernhard M. Coagulation management in multiple trauma: a systematic review. Int Care Med 2011;37:572– 82. [7] da Luz LT, Nascimento B, Rizoli S. Thromboelastography (TEG®): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Emerg Med 2013;21:29. [8] Cotton BA, Harvin JA, Kostouscouv V, Minei KM, Radwan ZA, Schöchl H, et al. Hyperfibrinolysis at admission is an uncommon but

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highly lethal event associated with shock and prehospital fluid administration. J Traum Acute Surg 2012;73:365–70. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, et al. Primary fibrinolysis is integral in the pathgenesis of the acute coagulopathy in trauma. Ann Surg 2010; 252:434–44. Espinosa A, Stenseth R, Videm V, Pleym H. Comparison of three point-of-care testing devices to detect hemostatic changes in adult elective cardiac surgery: a prospective observational study. BMC Anesthesiol 2014;14:80. Spinella PC. Warm fresh whole blood transfusion for severe hemorrhage: U.S. military and potential civilian applications. Critic Care Med 2008;(7 Suppl.). McDaniel LM, Etchill EW, Raval JS, Neal MD. State of the art: massive transfusion. Trans Med 2014;24:138–44. Dzik WH, Blajchman MA, Fergusson D, Hameed M, Henry B, Kirkpatrick AW, et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products – massive transfusion consensus conference 2011: report of the panel. Crit Care 2011; 15(6):242. Allen SR, Kashuk JL. Unanswered questions in the use of blood component theapy in trauma. Scand J Trauma Emerg Med 2011;19:1– 5. Riskin DJ, Tsai TC, Riskin L, Hernandez-Boussard T, Purtill M, Maggio PM, et al. Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg 2009;209:198–205. Davenport R, Khan S. Management of trauma haemorrhage: treatment priorities and controversies. Br J Haematol 2011;155:537– 48. Johansson P. Goal-directed hemostatic resuscitation for massively bleeding patients: the Copenhagen concept. Trans Apher Sci 2010; 43:401–5. Scarpellini S, Rhind SG, Nascimento B, Tien H, Sheek PN, Peng HT, et al. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res 2009;42(12):1210–7. Vig S, Chitolie A, Bevan DH, Halliday A, Dormandy J. Thromboelastography: a reliable test? Blood Coag Fibrinolysis 2001;12:555–61. Johansson PI, Bochsen L, Andersen S, Viuff D. Investigation of the effect of kaolin and tissue factor-activated citrated whole blood, on clot formation variables, as evaluated by thromboelastography. Transfusion 2008;48:2377–83. Bontekoe IJ, van der Mier PF, de Korte D. Determination of thromboelastographic responsiveness in stored single-donor platelet concentrates. Transfusion 2013. Jakoi A, Kumar N, Vaccaro A, Radcliff K. Perioperative coagulopathy monitoring. Musculoeskeletal Surg 2014;98:1–8. Spinella PC, Strandenes G, Bekkestad ER, Seghatchian J. Symposium on fresh whole blood for severe hemorrhagic shock: from in-hospital to far forward resuscitations. Transfus Apher Sci 2012.

What is happening? The evolving role of the blood bank in the management of the bleeding patient: The impact of TEG as an early diagnostic predictor for bleeding.

Despite recent advances in the understanding and treatment of coagulopathy, the management of the bleeding patient remains as a major challenge. Tradi...
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