Thromboelastometry in the perioperative setting

Transcription

1 Review Netherlands Journal of Critical Care Copyright 2010, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received July 2009; accepted October 2009 H Schöchl 1,2, MD, C Solomon 3, W Voelckel 2 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria 2 Department of Anaesthesiology and Critical Care Centre, AUVA Trauma Hospital Salzburg, Austria 3 Department of Anaesthesiology and Intensive Care, Hannover Medical School, Hannover, Germany Abstract - Coagulation disorders in the perioperative setting are complex. Appropriate procoagulant therapy requires a reliable and timely coagulation monitoring tool. Thomboelastometry/thrombelastography used as a point-of-care monitoring (POC) method allows a rapid and accurate differential diagnosis of the underlying coagulation disorder. Thomboelastometry/thrombelastography-guided algorithms may support the coagulation management of patients with acute coagulopathic bleeding. It has been shown that thomboelastometry/thrombelastography-guided coagulation therapy can reduce transfusion requirements and patients exposure to allogeneic blood products. These methods may help avoid unnecessary transfusion of blood products and coagulation factors, decrease costs, shorten surgical procedures, and lower the frequency of reoperations. Limitations of POC testing such as handling mistakes by non-laboratory personnel may be overcome by ongoing quality control, adequate training, audits, and user meetings. Randomized controlled trials are required to establish evidence-based POC-guided transfusion algorithms. Keywords - Thromboelastometry, Thrombelastography, POC, blood management, haemorrhage, coagulation monitoring Introduction Due to the complex nature of acute perioperative coagulopathy, laboratory testing should be rapid and reliable in order to support a targeted therapeutic approach based on the test results. It has been shown that blind coagulation management underestimates the real demand of coagulation factors and platelets in situations of severe bleeding [1]. Standard coagulation tests like prothrombin time (PT), activated partial thromboplastin time (aptt) and fibrinogen plasma concentration are widely used in the perioperative setting but have not been developed to assess coagulation in acute bleeding situations. PT and aptt only provide information on the initiation of clot formation and the standard methods for fibrinogen assessment do not directly measure its plasma concentration or its effect on the clotting process. Moreover, none of these tests provides information on the quality and stability of clots. Preoperative PT and aptt testing has shown little predictive value for bleeding, while the tests performed intraoperatively and postoperatively have little value for identifying the cause of coagulopathy and are bound with a time delay that makes them inapplicable for prompt coagulation assessment. Obtaining the test results, including fibrinogen concentration, is time consuming and of little use for the guidance of emergency haemostatic therapy [2,3]. Correspondence H Schöchl herbert.schoechl@auva.at In contrast, thromboelastometry/thrombelastography provi des an accu rate and timely assessment of not only the initia tion of coagulation but also the clot formation process and the clot stability. Different reagents help evaluate different as pects of coagulation, including the stability and amplitude of the fibrin-based clot (thromboelastometric FIBTEM test). Thromboelastometry/ thrombelastography can be run at the patient s bedside. The measurements are performed in whole blood, not in plasma. Without the need for centrifugation, the turnaround times are much shorter and the test results are available fairly quickly. The development of the clot can be visualized in real time [4]. Furthermore, this monitoring tool has a great educational impact regarding coagulation assessment and the guidance of haemostatic therapy. Standard coagulation tests As the measurement of coagulation factor activity is time consuming, prothrombin time (PT) and activated partial thromboplastin time (aptt) serve as surrogate parameters. However, these tests may have limited value for the perioperative assessment of coagulopathy and for the guidance of haemostatic therapy. Routine coagulation parameters fail to accurately portray the coagulopathic state for several reasons. In vivo coagulation occurs primarily on the surface of platelets and tissue factorbearing cells [5]. The activity of coagulation factors and platelets is tightly interwoven and the red blood cells also play a significant role in haemostasis [6,7]. However, these cells are removed by the centrifugation process. In addition, conventional tests stop with the formation of the first fibrin strands, when only approximately 5% of thrombin has been generated. These assays only provide information on the beginning of clotting 23

2 H Schöchl, MD, C Solomon, W Voelckel and do not assess the quality and strength of the clot itself. Furthermore, the influence of fibrinolysis or hyperfibrinolysis on clot stability cannot be evaluated by routine coagulation tests [4,8]. Another shortcoming is represented by the duration of the centrifugation process, which means that in most centres the test results are only available after minutes. Taken together, standard coagulation tests do not offer useful information on the nature of the coagulopathy. The prognostic value for a potential bleeding tendency and transfusion of allogenic blood products is poor [9,10]. These limitations apply not only to preoperative testing, but also lead to limited usefulness of standard laboratory methods for the intraoperative and ICU periods in situations that are complicated by acute bleeding. Thromboelastometry vs. Thrombelastography Thrombelastography was first described by Hartert in 1948 [11]. Thrombelastography measures the viscoelastic properties of clot formation in whole blood under low shear conditions. It provides information on the rapidity of coagulation initiation, kinetics of clot growth, clot strength and breakdown. Two different systems are currently available. The TEG (Haemonetics Corporation, Braintree, MA) uses a prewarmed, rotating cup into which 0.36 ml of whole blood is pipetted. Subsequently, a plastic pin attached to a torsion wire is immersed in the blood sample. The cup oscillates slowly (10 s) through an arch of 4 45`. At the beginning of the measurement, the movement of the cup does not affect the stability of the pin. When coagulation starts, elastic fibrin-platelet strands form which are linked between the pin and the wall of the cup. The rotating movements of the cup are gradually transmitted to the pin, producing a mechanical signal that is transduced into an electrical one and traced as a curve over time (Figure 1). The strength of the fibrin-platelet bonds affects the magnitude of the pin s motion [4,12]. The TEG is a two channel analyzer that allows the performance of two concomitant tests. Native or citrated whole blood can be used as test samples. Kaolin and kaolin + heparinase-activated assay are available. Five parameters can be determined from a TEG tracing: reaction time (r), coagulation time (k), alpha angle, maximum amplitude (MA) and clot lysis (LY) (see table 1). The normal values are shown in table 2. ROTEM (Pentapharm GmbH, Munich, Germany) uses a plastic pin that is vertically immersed into a cup containing the blood sample. In contrast to TEG, a pin supported by ball bearing rotates slowly backwards and forwards through an angle of 4.75 (Figure 2). After re-calcification of the blood sample and the addition of an activator e.g. rabbit brain tissue factor (extrinsic activation) or ellagic acid (intrinsic activation), the coagulation process in the test cup starts. Following generation of the first fibrin filaments between the pin and the wall of the test cup, the rotation range of the pin is reduced. The movement of the pin is converted into an optical signal and transferred to a graphical display, which plots the changes in the viscoelastic properties of the clot over time (Figure 3). ROTEM is a four channel system that allows the performance of four different tests simultaneously. A set of standard reagents is used to discriminate between several potential causes of bleeding. Two basic tests that use intrinsic activation (INTEM) and extrinsic activation (EXTEM) provide information on the general coagulation status (impaired, normal, and hypercoagulable) through the following parameters: clotting time (CT), clot formation time (CFT), alpha angle (α), maximum clot firmness (MCF) and clot Table 1. TEG parameters r reaction time period to 2 mm amplitude Speed of thrombin generation K coagulation time time from the end of R until the clot reaches 20 mm Speed of clot formation α Alpha angle slope between r and K Speed of clot formation MA Maximum amplitude maximum clot strength The strength of the clot is a function of platelets, fibrin net and FXIII LY30 Lysis Reduction of the MA over 30 min Abnormal breakdown of the clot Table 2. Reference values for TEG r time k time a - angle MA LY Reaction time coagulation time [ ] Maximum amplitude [mm] Lysis [min] [min] [%] Whole blood 4 8 min 1 4 min mm Citrated blood + kaolin 3 8 min 1 3 min mm Citrated blood + kaolin and heparinase Comparison with kaolin test: A shortening in CT in kaolin and heparinase indicates the presence of heparin or heparin-like substances 24

3 Netherlands Journal of Critical Care lysis (CL) (see table 3). In the FIBTEM test, platelets are inhibited by cytochalasin D, so this test provides information on the fibrin component of the clot separately. In the APTEM assay, aprotinin is added to the EXTEM assay, which has the potential to normalize a premature breakdown of the clot due to hyperfibrinolysis (Figure 4). A test containing heparinise (HEPTEM) allows detection of heparin-induced prolongation of CT in the INTEM test. Reference ranges for the different tests have been previously determined in a multi-centre trial (Table 4) [13]. The ROTEM and TEG systems are used in a variety of clinical settings. Trauma Coagulopathy represents a serious problem of major trauma patients and accounts for 40% of all trauma related deaths [14]. Massive trauma results in a profound coagulopathy consisting of coagulation factor deficiency due to blood loss and haemodilution, impaired activity of coagulation factors due to acidosis and hypothermia and occasionally hyperfibrinolysis caused by massive hypoperfusion [15]. The management of trauma inducedcoagulopathy requires an early and rapid haemostatic treatment strategy in order to prevent exsanguination [16]. In animal models as well as in human studies, TEG has been shown to be a Figure 2. Working principle of ROTEM : A rotating plastic pin supported by a ball-bearing is immersed into a cup. The movement of the pin is converted to an optical signal and transferred to a graphical display. Figure 1. Working principle of TEG : a plastic pin attached to a torsion wire is immersed in a rotating cup. After clot formation an electrical signal is traced as a curve over time. Figure 3. Parameters of the thromboelastometric analysis Figure 4. Four channel ROTEM analysis of a hyperfibrinolytic blood sample. Hyperfibrinolysis is seen in the INTEM and EXTEM analyses. Furthermore, there is no measurable fibrin generation in the FIBTEM analysis. The APTEM test shows a stable clot when the antifibrinolytic aprotinin was added to EXTEM NVIC_NJCC 01 v1.indd :01:14

4 H Schöchl, MD, C Solomon, W Voelckel reliable monitoring tool that detects clinically relevant clotting abnormalities [17,18]. ROTEM and TEG are increasingly used in the assessment and management of coagulation in major trauma patients [19-21]. In a study that included 69 trauma patients, Kaufman et al. showed that only the injury severity score and the TEG results were predictive of early transfusion requirements [22]. In addition, hyperfibrinolysis may influence the coagulation process in major trauma and is associated with a high mortality [23]. No other coagulation test is able to diagnose this disturbance in an adequate time frame [24]. Although treatment algorithms according to ROTEM test results have been published, randomized controlled trials based on such algorithms are not available at present [21,25]. In a retrospective analysis of 131 major trauma patients with a median injury severity score of 38, ROTEM guided-coagulation management with coagulation factor concentrates was associated with a significant reduction in observed mortality compared to predicted mortality according to the trauma injury severity score (TRISS) methodology [26]. Hepatic surgery and liver transplant Orthotopic liver transplantation (OTL) is associated with complex bleeding problems. Pre-existing organ dysfunction leads to a relevant decrease in the synthesis of coagulation factors and inhibitors [27]. Portal hypertension and drainage of blood flow through the spleen causes platelet sequestration and thrombocytopenia. Disturbed platelet function is not uncommon in patients with liver cirrhosis, especially in conjunction with renal insufficiency. In addition to these pre-existing coagulation disorders, massive blood loss and subsequent volume replacement during liver transplantation causes dilutional coagulopathy [27]. As a result of reduced biosynthesis of fibrinolysis inhibitors and diminished clearance by the reticuloendothelial system of the liver, hyperfibrinolysis is a common problem, especially following organ reperfusion [28]. Exogenous heparin and release of endogenous heparinoids following liver reperfusion also contributes to the coagulopathic state [29]. Beside these factors, there is a risk of thrombosis during clamping of the caval vein, vascular occlusion in the region of the anastomosis and a risk of microthrombosis of the lung by the platelet aggregates activated in the liver graft during reperfusion [30]. The complexity of coagulation disturbances has forced clinicians to optimize coagulation monitoring in OLT [31]. This was the reason for TEG being implemented early as a haemostatic monitoring tool in this clinical setting [32]. In the meanwhile, TEG - and ROTEM -based treatment algorithms for OLT have been published [27]. However, according to a national survey in the United States in 2002, only one third of all OLT programs routinely used TEG [33]. As in trauma, there are no known randomized controlled trials available that provide clear evidence that ROTEM /TEG -based treatment algorithms can reduce transfusion requirements and are cost effective in liver surgery. Table 3. ROTEM parameters CT Clotting time time to 2 mm amplitude a function of the concentration of coagulation factors/ inhibitors which shows the time to initial thrombin and fibrin formation. CFT Clot formation time time from the end of the CT until a clot firmness of 20 mm is achieved α Alpha Angle tangent between end of CT and 20mm Comparable with CFT function of the concentration of coagulation factors / inhibitors and also of the interaction of fibrinogen with platelets MCF Maximum clot firmness reflects the absolute strength of clot in mm results from firm aggregation of platelets and formation of a stable fibrin network LI30 Lysis index Reduction of the maximum clot firmness over time Fibrinolysis can be diagnosed from an abnormal reduction in the clot firmness after it has reached its maximum Table 4. Reference values for ROTEM CT CFT MCF ML Clotting time [sec] Clot formation time [sec] Maximum clot firmness [mm] Maximum lysis [% of MCF] INTEM sec sec mm < 15% EXTEM sec sec mm < 15% FIBTEM APTEM HEPTEM 9 25 mm Comparison with EXTEM: A stable MCF confirms hyperfibrinolysis Comparison with INTEM: A shortening in HEPTEM CT indicates the presence of heparin or heparin-like substances 26

5 Cardiac surgery Bleeding disorders following cardiac surgery are common. In half of the patients undergoing reoperation for bleeding, a surgical reason could be detected. For the remaining patients, coagulopathy could be identified as a cause of bleeding [34]. The pathophysiology of coagulopathy in cardiac surgery is complex. Many patients receive platelet inhibitors prior to surgery. The use of anticoagulants during extracorporeal bypass and a decrease in platelet number and function contributes to coagulopathy. In addition, hypothermia affects platelet count and function, as well as the activity of coagulation factors. Hyperfibrinolysis may also affect the coagulation rocess [35]. A predictive value of ROTEM /TEG for postoperative bleeding following low and moderate risk procedures has been reported [36,37], while a recent study has shown that thromboelastometry/ thrombelastography was not useful in identifying patients who subsequently experienced major bleeding [38]. A variety of studies have shown that the implementation of ROTEM /TEG -guided transfusion algorithms is associated with a decreased blood loss, perioperatively and overall transfusion requirement [39 44]. In the presence of microvascular bleeding, TEG was better than routine coagulation tests in defining the coagulation abnormality and in guiding treatment strategies [40]. In a prospective randomized trial, the effect of a TEG -guided transfusion algorithm was compared with routine therapy. Intraoperative transfusion rates did not differ, but there were significantly fewer postoperative and total transfusions in the TEG group. The proportion of patients receiving FFP was significantly lower in the TEG group than in the control group (4 of 53 and 16 of 52, respectively, P<0.002). Fewer patients required transfusion of platelet concentrates (7 of 52 in the TEG group compared with 15 of 52 in the control group, P<0.05) [41]. Royston and von Kier showed a threefold reduction in the use of haemostatic products using an algorithm with a heparinase-modified TEG. Twelve-hour chest tube losses after cardio-pulmonary bypass surgery were not different between groups [42]. In another retrospective study on 990 cardiac surgical patients, transfusion requirements 6 month prior to the introduction of ROTEM were compared with transfusion 6 months after. In the 6 month period prior to the introduction of ROTEM, red blood cell concentrates were transfused in 60% of all patients, while FFP and platelets were transfused in 17% and 16%, respectively. In the following 6 months, the use of red blood cell concentrates had decreased to 53%, FFP to 12% and platelet concentrates to 11% respectively (P<0.05) [43]. Rahe-Meyer et al. showed that FIBTEM-guided coagulation therapy with fibrinogen concentrate after aortic valve and ascending aorta replacement was associated with reduced transfusion requirements and 24 h postoperative bleeding [44]. Peripartal bleeding Even if pregnancy creates a hypercoagulable state which protects the parturient from haemorrhage at childbirth, severe peripartum haemorrhage contributes to maternal morbidity and mortality and is one of the most frequent emergencies in obstetrics, occurring at a prevalence of %. Preeclampsia, HELLP syndrome and hyperfibrinolysis may generate life-threatening coagulopathy. The risk of abnormal haemostasis increases with the severity of preeclampsia and is associated with thrombocytopenia, coagulation factor deficiencies, and, in severe cases, with disseminated intravascular coagulation [48]. In a prospective observational study, 37 patients with postpartum haemorrhage (study group) and 54 without abnormal bleeding (control group) were compared based on the ROTEM test results. Median CT was higher in the haemorrhage group than in the control group (P = 0.05) and MCF was significantly lower in the haemorrhage group than in controls (P < ). There was a strong correlation with fibrinogen levels in both groups (r = , P < ). A cut-off value of A5 at 5 mm and A15 at 6 mm presented an excellent sensitivity (100% for both parameters) and a good specificity (85% and 88%, respectively) for the detection of fibrinogen levels <1.5 g/l in postpartum haemorrhage [49]. Charbit et al. showed that patients with bleeding had a significantly reduced fibrinogen concentration so one may assume that ROTEM might be helpful in guiding fibrinogen replacement during postpartum haemorrhage [50]. Table 5. Current recommendations regarding the use of ROTEM /TEG for transfusion management Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, Nashef SA; EACTS Audit and Guidelines Committee. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg Jul;34(1):73-92 Craig J, Aguiar-Ibanez R, Bhattacharya S, Downie S, Duff S, Kohli H, Nimmo A, Trueman P, Wilson S, Yunni Y. The clinical and cost effectiveness of thromboelastography/thromboelastometry. Health Tech Ass 2008;11:1-70 Thromboelastography may be used to guide transfusion in the postoperative period and studies have demonstrated a reduction in blood and blood product usage if used in conjunction with a treatment algorithm. Further studies are required before thromboelastography can be recommended as the standard of care for postoperative transfusion management. (Grade B recommendation based on level 2b studies) TE, currently used in five Scottish hospitals, appears to be a cost-effective intervention. It has the potential to reduce the need for inappropriate transfusions and can decrease blood product requirements; this is likely to be welcomed by patients. Overall, TE appears to have a positive impact on patients health by reducing the number of deaths, complications and infections, and increasing the number of life years and QALYs. A further consequence observed was the reduction in the associated costs, related to the decrease in the number of transfusions, in the average usage of blood products and in the healthcare resources needed to deal with complications and infections. The results of the budget impact analysis showed that both for patients undergoing cardiac surgery and liver transplantation, savings are expected if TE, instead of SLTs, is used for their management. 27

6 H Schöchl, MD, C Solomon, W Voelckel Hyperfibrinolyis As hyperfibrinolysis is a life-threatening bleeding disorder, quick diagnosis and therapeutic intervention with antifibrinolytic agents are clearly essential. In a variety of clinical settings such as severe trauma, hypoperfusion, peripartal bleeding, liver transplantation and cardiac surgery, a premature breakdown of the clot may be observed. Hyperfibrinolysis leads to the destruction of the fibrin network and to a decrease in clot elasticity. D-dimers are often used as a surrogate parameter for hyperfibrinolysis but specificity and sensitivity are too poor to reliably diagnose a premature breakdown of the clot [45]. The euglobulin lysis time is a timeconsuming test and its reproducibility is also poor [46]. Spiel et al. found a good correlation between in vivo t-pa and maximum lysis in ROTEM [47]. Thromboelastometry/thrombelastography is currently assumed to be the gold standard for the detection of hyperfibrinolyis [4]. It allows diagnosis of the hyperfibrinolytic state within a short time period. For ROTEM, a special test (APTEM) is available to confirm hyperfibrinolysis. Predictive or not predictive? That is not the question... There is currently a debate taking place on the importance of coagulation testing for the assessment of perioperative coagulopathy. The field of diagnostics is divided into testing with inductive value, i.e. preoperative prediction of bleeding risk and transfusion, and testing with deductive value, i.e. intraoperative diagnosis of the nature of coagulopathy. Extended research has shown that preoperative coagulation testing has limited predictive value for bleeding; this finding contrasts with the common but intensively criticized practice of ordering and even administering haemostatic drugs as prophylaxis in cases of abnormal preoperative coagulation testing. This approach has crystallized because there has been a slow shift from the question of why is the patient bleeding?, to will the patient bleed? [2]. However, none of the laboratory or POC tests has been developed to answer the latter question. In contrast, as Koscielny et al. have shown, a significantly more effective and cheaper method for predicting bleeding is to use preoperatively a standardized questionnaire on the bleeding history of the patient [51]. In contrast, deductive testing is concerned with the question of why is the patient bleeding?, a question that needs to be answered properly and promptly at any time during the operation or the post-operative ICU stay. Coagulation testing needs to be reflective of coagulopathy. In some reports, this characteristic has been mistakenly defined as predictivity for bleeding; however, the term is not used correctly in the named context. Instead, reflectiveness of coagulopathy aims at identifying the cause of bleeding. Coagulation amounts to a complex cascade of events. In any type of surgery, the coagulation system reaches various degrees of activation. When relevant blood loss occurs, the coagulation status may change rapidly. Therefore, it is imperative to use a parameter or a group of laboratory parameters that quickly identify the cause of coagulopathy. The usefulness of the ROTEM /TEG measurements lies in the possibility to monitor coagulation in a timely manner and to allow a targeted and prompt haemostatic therapy. The NHS report published in 2008 recommended the use of ROTEM /TEG not only because of the cost effectiveness that derived from the reduction of inappropriate transfusion, of overall transfusion requirements and of healthcare resources needed to deal with transfusion-related infections, but also for the assessment of the intra- and post-operative coagulopathy associated with bleeding [38]. As the measurements are performed in whole blood, at the bedside or in the operating room, ROTEM and TEG currently represent fast and very useful methods to offer an assessment of perioperative coagulopathy. Table 5 presents the current recommendations regarding the use of ROTEM and TEG in the clinical setting. Further clinical research is required until evidence-based recommendations on their application as standard of care for transfusion management can be made [52]. The use of the maximum clot firmness parameter of the FIBTEM test for guiding the administration of haemostatic agents like fibrinogen concentrate has already been described in studies in cardiac and orthopaedic surgery [44,53,54]. Maximum clot firmness has even served as a primary outcome parameter in two recent randomized, placebo-controlled studies investigating the effects of fibrinogen concentrate, and factor XIII, respectively, on impaired clot in non-cardiac surgery [55, 56]. Systems and tests validation and registration Clinicians working with POC devices often require additional information on the validation and the registration of the ROTEM TEG systems. This is due, on the one hand to the fact that in many countries thromboelastometry/thrombelastography is not a well-known standard method and, on the other hand, by publications stating that neither the thromboelastometric, nor the thrombelastographic method has been validated [57]. The authors intention is, in most cases, to underline the deficit of studies on the clinical benefit obtained with these methods, but the message that reaches less experienced users is that the devices may be insufficiently validated and perhaps not even registered. The ROTEM /TEG systems belong, from a regulatory point of view, to in vitro diagnostics, a category of medical devices. The premises for registration include, among others, the evaluation of the in vitro diagnostic device, the so-called testing for performance evaluation. The performance evaluation should verify whether the device is effective for its intended use. The accuracy (unbiasedness) and the precision of the diagnostic device must be assessed in both laboratory and clinical settings. Both systems comply with the medical device laws of the country where they are produced. The ROTEM system, produced in Germany, did not require a registration process in the same way that drugs do, but did require a European Community (CE) conformity evaluation procedure. The reference method for ROTEM /TEG is thrombelastography, introduced by Hartert in 1948 [11]. Validation procedures must be performed by comparison with the Hartert method, as performed for ROTEM by Calatzis et al. [58], while the comparison with standard laboratory methods, although investigated in several reports, does not represent a validation procedure for ROTEM /TEG. 28

7 Regarding the correlation with standard laboratory coagulation measurements, it is of importance that ROTEM /TEG cannot be compared directly with standard coagulation tests [59]. ROTEM /TEG analyses are performed in whole blood and reflect overall clot elasticity while most standard coagulation tests are performed in plasma and reflect time to clotting. An increasing interest has been raised by the FIBTEM test that measures fibrin clot firmness in the presence of platelet inhibition. Although there is a good correlation between FIBTEM (MCF) and fibrinogen according to the method of Clauss [24, 60, 61] these two tests measure different aspects of coagulation. None of the methods measures fibrinogen concentration directly. The Clauss method measures the time to fibrin formation and compares it to a calibration curve. Clauss fibrinogen is therefore a clotting time that is transformed into fibrinogen plasma concentration. This clotting time depends on many factors that are independent of functional fibrinogen. FIBTEM is a test for assessing the mechanical quality of the fibrin clot, and is therefore more a measurement of fibrin strength, rather than a fibrinogen measurement Furthermore, Clauss fibrinogen is performed in plasma, therefore centrifugation of the blood sample is necessary and the time delay associated with it makes the test inappropriate for emergency perioperative bleeding management. In the perioperative setting, obtaining fast information on the quality of the clot may be preferable. More recent reports have included FIBTEM as a pivotal parameter for the management of coagulopathic bleeding [44,53,54]. Abnormal coagulation outside the detection range of ROTEM /TEG The detection range of ROTEM /TEG is conditioned by the methodology and by the type of tests/reagents currently used. Regarding the methodology, as flow dynamics do not influence thromboelastometry/thrombelastography, the deficiency of factors influenced by shear forces, like von Willebrand factor, is not reflected by the measurement. Furthermore, the influence of the endothelium on the coagulation process cannot be assessed with ROTEM /TEG. With the currently commercially available tests, the sensitivity for coagulation factor deficiencies, including those induced by oral anticoagulation, is less pronounced compared with clotting assays [45]; however, in the research activity a series of modified reagents has been developed to diagnose specific coagulation factor deficiencies or coagulopathy not covered by the standard reagents and there is ongoing research to evaluate the ROTEM / TEG methodology in new settings [62,63]. For the ROTEM standard tests performed using activators for the extrinsic or the intrinsic pathway, high thrombin generation in the test cup overcomes diminished platelet function due to platelet inhibitors. Therefore the effects of platelet inhibitors cannot be diagnosed by such tests. The effects of several platelet inhibitors may be investigated with a development of the TEG method, the PlateletMapping system [64]. Limitations of thromboelastometry/ thrombelastography monitoring Quality control of POC analyzers is still a matter of debate [4,8,13]. POC tests are usually run by physicians or non laboratory staff with limited training for laboratory diagnostics and quality control procedures. Parallel testing by the central laboratory and documentation of quality control results may help identify technical problems. Training of the personnel, supervision and regular quality control by the central laboratory may overcome these problems. However, in emergency situations the issue of quality control becomes of secondary importance, since the only alternative available is blind therapy that is based on clinical judgement as there are no laboratory assays more accurate and similarly fast in this situation. The application in the perioperative field is conditioned not only by the user s experience, but also by the degree of sensitivity of the device to mechanical disturbances and the ease of handling. By using a fixed cup and rotating pin, and by applying an automated pipetting programme, the ROTEM device offers improved stability and applicability. The device was part of a trial where it was used without any problems on a transatlantic flight [65]. The ROTEM device may be transported over rough terrain onto the battle front without interference with the overall accuracy of the instrument, [66] and the British Army is currently evaluating ROTEM in combat settings ( militarybms.com/rotem.html). Another matter of debate is represented by the costs associated with the implementation of this POC monitoring methodology. The NHS report presented by Craig et al. found that thromboelastometry/thrombelastography appears to be a cost effective intervention in cardiac surgery and liver transplantation since it was shown to reduce the need for perioperative transfusions and blood product requirements [38]. Spalding at al. also showed in a retrospective analysis that a ROTEM -based treatment algorithm not only reduced transfusion requirements, but also had a cost saving effect [67]. Conclusion Since the ROTEM /TEG systems allow a quick diagnosis of the underlying coagulopathy in acute bleeding situations, they represent a useful tool for the management of perioperative bleeding. This whole blood methodology could potentially improve therapeutic decision-making in trauma, surgery and critical care patients, as it has clear benefits compared to the standard laboratory coagulation tests. A variety of assays helps differentiate the underlying coagulation deficit. Until now, algorithms based on the ROTEM /TEG test results have been published to guide therapeutic interventions. Randomized controlled trials are required to establish evidence-based POCguided transfusion algorithms. 29

8 H Schöchl, MD, C Solomon, W Voelckel Acknowledgment The authors are indebted to Gerald Hochleitner for his excellent technical support. Conflict of interest Herbert Schöchl received a speaker s fee from CSL Behring, GlaxoSmithKline and Pentapharm. Cristina Solomon received a speaker s fee from CSL Behring and Pentapharm. References 1. Geeraedts LM, Demiral H, Schaap NP, et al. Blind transfusion of blood products in 20. Schöchl H: Coagulation management in major trauma. Hämostasiologie exsanguinating trauma patients. Resuscitation 2007;73: ;26S21-S29 2. Kitchens CS. To bleed or not to bleed? Is that the question for the PTT? J Thromb 21. Teusinger OM, Spahn D, Hofer DR, Ganter T. Transfusion in trauma: why and how Haemost. 2005;3: should we change our current practice? Curr Opin Anasthesiol 2009;22: Dzik WH Predicting hemorrhage using preoperative coagulation screening assays. 22. 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