1 Introduction

Since the first report of a successful blood transfusion in 1667 by Jean-Baptiste Denys, blood transfusion has evolved considerably saving, undoubtedly, many lives. However, administration of blood products remains associated with numerous complications and side effects [1, 2]. This is of particular interest because the need for blood in hospitals continues to exceed the volume collected by the transfusion services with a substantial cost and a burden to the transfusion services [2]. Therefore, overuse of blood products and the resulting expenditure in a time when affordable health care is needed are receiving increasing attention by regulators and clinicians. This is in the forefront as more and more data suggest that many allogenic transfusions are either not needed or result in negative outcomes while lacking any demonstrable benefit to the patient. This is one of the reasons that led to an approach to transfusion medicine that challenges the traditional attitudes providing a strategy that will result in preemptive treatments so that allogeneic blood could be avoided or the patients’ exposure to this therapy could be substantially reduced. Patient blood management (PBM) is currently defined by the Society for the Advancement of Blood Management as “the scientific use of safe and effective medical and surgical techniques designed to prevent anemia and decrease bleeding in an effort to improve patient outcome” [3]. This target is achieved by addressing the following issues: (1) prevention of present or potential coagulopathy; (2) detection, diagnosis, and proper treatment of anemia; (3) enforcement of all appropriate modalities of blood conservation; and (4) multimodal team approach including shared patient decision [4]. According to this matrix, one of the classic and simplest ways to reduce transfusion is to prevent blood loss. From this point of view, the most appropriate management of perioperative patient coagulation is of utmost importance [5]. In fact, perioperative coagulation management is a complex task that has a significant impact on the perioperative journey of patients. Anesthesia providers play a critical role in the decision-making on transfusion and/or hemostatic therapy in the surgical setting. Various tests are available in identifying coagulation abnormalities in the perioperative period. While the rapidly available bedside hemoglobin measurements can guide the transfusion of red blood cells, blood product administration is guided by many in vivo and in vitro tests. The introduction of newer anticoagulant medications and the implementation of the modified in vivo coagulation cascade have given a new dimension to the field of perioperative transfusion medicine. A proper understanding of the application and interpretation of the coagulation tests is vital for a good perioperative outcome.

The aim of this review is to report the basic principles of the current point-of-care (POC) coagulation analyzers, to outline their clinical use, and to evaluate their ability to monitor different pharmacological substances interacting with hemostasis in the perioperative setting.

2 Why POC Testing of Hemostasis Gained Interest in Recent Years?

Hemostasis is a combination of a number of events that occur in a sequence following the breach of vascular integrity. They include vasoconstriction, platelet aggregation, thrombus formation, recanalization, and healing. Conventionally, secondary hemostasis was described as intrinsic and extrinsic pathways merging at a final common pathway. This in vitro model ignores the link between primary and secondary hemostasis and is not applicable in vivo. The currently employed cell-based model of coagulation reflects the in vivo process, and it differs from the previous model in two key ways. First, the complex formed by the tissue factor and factor VII contributes in the activation of factor IX, demonstrating that the intrinsic and extrinsic coagulation pathways are interconnected almost from the beginning of the process. Second, the complete process requires three consecutive phases: an initial phase, an amplification phase, and the propagation phase. Platelets and thrombin are actively involved in the last two phases [6]. There is no universally accepted definition of hemostasis. The most simplistic definition is the “cessation of bleeding.” An alternative view is the mechanistic concept that hemostasis represents the platelet and coagulation cascades involved in the cessation of bleeding. A more refined clinical definition of hemostasis is bleeding control without the induction of pathologic thrombotic events such as myocardial infarction, stroke, arterial thrombosis, or deep vein thrombosis. Hemostasis can thus be considered as control of bleeding within the finely tuned balance of procoagulant, anticoagulant, fibrinolytic, and antifibrinolytic activities [6]. A number of coagulation tests are available in the perioperative period to assist clinicians in identifying coagulation abnormalities. In recent years, incorporation of various forms of coagulation monitoring has provided valuable information in the management of perioperative coagulopathies. The ideal laboratory test to evaluate hemostasis in the bleeding surgical or medical patient should reflect the dynamic status of bleeding and be accurate and available in real time to enable the physician to make treatment decisions rapidly. Testing should be specific for different physiologic mechanisms to target specific treatments to correct deficits in hemostasis. The test result should have meaningful clinical implications and closely reflect the patient’s hemostatic status. Other characteristics of the ideal test include reproducibility, resistance to effect of pre-analytic variables, and ease of use in point-of-care settings such as the operating room, emergency department, and intensive care unit [6].

Perioperative management of coagulopathic bleeding requires timely hemostatic intervention using allogeneic blood products, administration of coagulation factor concentrates, or both. To guide these interventions, fast laboratory workup is essential. If it comes to the question which laboratory test should be performed to assess hemostasis, current guidelines usually refer to standard plasma coagulation tests (SLTs), that is, prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time. Although the complete panel of standard coagulation testing almost always covers additional measurements of fibrinogen and platelet count, interpretation of SLTs is most frequently used to assess coagulopathy. Generally speaking, coagulopathy is presumed when SLTs are prolonged by more than 1.5-fold, although the evidence to support this degree of prolongation as diagnostic of coagulopathy is limited. However, there are major limitations to SLTs. In fact, these tests are time-consuming (with turnaround times sometimes longer than 60 min), and, as a consequence, they are often omitted in situations of severe bleeding, where prompt treatment must be ensured. Moreover, if the results of PT/aPTT are more than 1.5 times prolonged, the treatment options range from transfusion of fresh-frozen plasma (FFP) to administration of coagulation factor concentrates such as prothrombin complex concentrates (PCC) or activated recombinant factor VII. Remarkably, all these treatment options may be linked to serious side effects, and their administration should be rigorously justified. More importantly, we need to question what information we obtain from a PT or aPTT. In routine clinical practice, PT and aPTT are commonly used either for bleeding risk assessment before an invasive procedure or for the assessment of the hemostasis profile with respect to detection of underlying coagulopathy and guiding subsequent blood component therapy. In fact, PT/INR and aPTT are plasma-based coagulation tests that were basically designed to monitor vitamin k antagonists and heparin, respectively, and to assess coagulation factor deficiencies. However, it is important to outline that PT/INR and aPTT were not conceived or intended to monitor perioperative coagulation disorders, predict bleeding, or to guide bleeding therapy in the perioperative setting. All in all, there are significant shortcomings of SLTs in the perioperative and major bleeding management setting in terms of accuracy, evidence for their efficacy, valuable turnaround times in a clinical setting where a quick decision-making is mandatory [7]. Therefore, alternatives, such as the point-of-care coagulation tests (POCT), also termed as near-patient coagulation tests (NPT) that refer to measures of coagulation that can be performed at or near the patient and provide results much more quickly with a more comprehensive overview of the whole coagulation process, became very attractive for clinicians.

2.1 Viscoelastic POC Testing of Hemostasis: Terminology

Thrombelastography was first described by Hartert in 1948 as a method to assess the global hemostatic function from a single blood sample. In the earlier literature, the terms “thrombelastography,” “thrombelastograph,” and “TEG” have been used generically. However, in 1996 the term “TEG®” became a registered trademark of the Haemoscope Corporation and from that time has been used to describe the assay performed using Haemoscope instrumentation. Alternative instrumentation marketed by Pentapharm GmbH uses the terminology thromboelastometry for the process of measurement and “ROTEM®” for the instrumentation and resultant graphical output. Thromboelastography and ROTEM are viscoelastic hemostatic assays [2,3,4] that provide a graphical evaluation of the kinetics of all stages of clot formation (initiation, propagation, strength, and dissolution) in whole blood. The descriptive data associated with both the described instruments is summarized in Table 1.1.

Table 1.1 Nomenclature used for TEG® and ROTEM®
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2.2 Viscoelastic POC Testing of Hemostasis: How it Works

The TEG/ROTEM® assesses the viscoelastic properties of blood samples under low shear conditions. The TEG® measures the clot’s physical property by using a stationary cylindrical cup that holds the blood sample and oscillates through an angle of 4°45′ (Fig. 1.1a). Each rotation cycle lasts 10 s. A pin is suspended in the blood by a torsion wire and is monitored for motion (Fig. 1.2a). The torque of the rotation cup is transmitted to the immersed pin only after fibrin-platelet bonding has linked the cup and pin together. The strength of these fibrin-platelet bonds affects the magnitude of the pin motion. Thus, the output is directly related to the strength of the formed clot. As the clot retracts or lyses, these bonds are broken, and the transfer of cup motion is again diminished. The rotation movement of the pin is converted by a mechanical-electrical transducer to an electrical signal, finally being displayed as a tracing. The generated electric signal gets converted into a “bell- shaped” graphical display demonstrating the characteristic of shear elasticity against time. The shape of the graphical display aids in a quick qualitative assessment of different coagulation states (hypo, normal, hyper) representing specific abnormalities in clot formation and fibrinolysis.

Fig. 1.1
figure 1

Working principles of viscoelastic point-of-care coagulation devices. (a) TEG®: (1) rotating cup with blood sample, (2) coagulation activator, (3) pin and torsion wire, (4) electromechanical transducer, (5) data processing. (b) ROTEM®: (1) cuvette with blood, (2) activator, (3) pin and rotating axis, (4) electromechanical signal detection, (5) Print output

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Fig. 1.2
figure 2

Diagrammatic representation of a TEG®/ROTEM® trace indicating the commonly used variables

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The ROTEM® instrument (Fig. 1.1b) uses a modified technology: the signal of the pin suspended in the blood sample is transmitted via an optical detector system, not a torsion wire, and the movement is initiated from the pin, not the cup. Both the instruments are now equipped with cartridges replacing cups, pins and electronic pipettes and look simpler and more user friendly.

TEG®/ROTEM® both measure and graphically display the changes in viscoelasticity at all stages of the developing and resolving clot, i.e., the time until initial fibrin formation (TEG®, reaction time; ROTEM®, clotting time [CT]), the kinetics of fibrin formation and clot development (TEG®, kinetics, α-angle; ROTEM®, clot formation time, α angle), the ultimate strength and stability of the fibrin clot (TEG®, maximum amplitude [MA]; ROTEM®, maximum clot firmness [MCF]), and clot lysis. Although TEG® and ROTEM® tracings look similar (Fig. 1.2), the nomenclature and reference ranges are different. The differences may be explained by different components, materials, and proprietary formulas of the coagulation activators (composition, concentrations) used.

2.3 Viscoelastic POC Testing of Hemostasis: Clinical Experience

There is emerging evidence that point-of-care tests based on “goal-directed” coagulation management can modify the transfusion strategy by providing better understanding of the underlying pathology and by the targeted use of not only FFP but also fibrinogen and prothrombin complex concentrates hence reducing the need for blood products, which enables the clinician to tailor hemostasis management according to the patient’s needs. Although POC hemostasis testing may aid care of any critically ill surgical patient, it is likely to be particularly helpful in certain groups of patients who are more vulnerable to hemorrhagic complications. These include patients undergoing hepatic, cardiac, or vascular surgery and victims of polytrauma.

2.3.1 Liver Surgery

One of the first clinical applications of thrombelastography was in the hemostatic monitoring of liver transplantation. Problems associated with hepatic surgery and particularly orthotopic liver transplantation (OLT) stem from both surgery itself and preoperative coagulopathy from hepatic dysfunction. In particular, OLT was historically associated with major blood loss. However over the years, improvements in surgical and anesthetic management allowed significant improvements in the perioperative management of this class of patients with significant reduction in the transfusional needs. The same happened with liver surgery, particularly when performed in patients with liver disease. The coagulopathy of chronic liver disease is present preoperatively, and further disturbance of coagulation can occur intraoperatively, resulting in bleeding complications but also thrombotic events [8].

There is increasing evidence that the changes in coagulation factors and platelet count regularly observed in patients with liver cirrhosis cannot be interpreted as a reliable indicator of diffuse bleeding risk. Instead, a differentiated view on hemostasis has led to the concept of a rebalanced coagulation system. In fact, while it is important to recognize that procoagulant factors are reduced in liver cirrhosis, it is also evident that synthesis of anticoagulant factors and fibrinolytic proteins produced in the liver is also diminished. Similarly, the decreased platelet count may be counterbalanced by increased platelet aggregability caused by highly active von Willebrand multimers. Although “rebalanced,” hemostasis in cirrhotic patients is not as stable as in healthy subjects, and therefore, while under normal “unstressed” conditions, diffuse bleeding is rarely observed; both diffuse bleeding and thrombus formation may occur when compensation mechanisms are exhausted [9, 10].

Because TEG®/ROTEM® are global tests providing a composite analysis that reflect function of plasma, blood cells, and platelets, they are increasingly viewed as an appropriate tool to investigate the coagulopathy of cirrhotic patients. In agreement with the concept of rebalanced hemostasis, patients with cirrhosis often maintain normal global hemostasis as assessed by TEG. In a cohort of 273 patients with stable cirrhosis, it was found that mean and median TEG® parameters were all within normal limits, although the MA decreased in proportion to the severity of thrombocytopenia and severity of liver disease [11]. Theoretical benefits of the use of TEG® or ROTEM® in the hepatic surgical setting include a rationalization of blood products, a reduction in transfusion-related side effects, and an improvement in patient outcomes including mortality with a reduction in costs. A typical example is fibrinogen. Fibrinogen is the first factor to reach critical levels when hemodilution or massive bleeding occurs. Fibrinogen concentration can easily be monitored by POC viscoelastic technologies, and substitution therapy based on guidance according to the clot firmness reduced the rate of red blood cells, fresh-frozen plasma, and platelet transfusion by more than 50%. Additionally the rate of transplantation without transfusion of the above blood-related products rose from 3.5% to 20% [12]. In a recent review on fibrinogen and fresh-frozen plasma in surgery, the authors concluded that fibrinogen level was generally associated with improved outcome measures, while fresh-frozen plasma failed to show evidence for effectivity and had severe side effects [13]. Besides fibrinogen, other coagulation factors may decrease during liver surgery and transplantation resulting in a reduction of thrombin generation and prolongation of clotting time. In these cases, prothrombin complex concentrate can correct coagulopathy. Theoretically, there are four-factor PCC and three-factor PCC. Four-factor PCC contain factors II, VII, IX, and X and the anticoagulant factors protein S and protein C. Infectious risk is reduced or eliminated by virus elimination, and thromboembolic complication occurs in only 0.9%. In liver transplantation, POC-guided substitution of blood products including prothrombin complex concentrate in liver transplantation did appear safe as they did not show to increase the occurrence of thrombosis, pulmonary, and ischemic events compared to patients who did not receive these concentrates [14].

TEG®/ROTEM® are not of exclusive use for OLT patients only but also for medical cirrhotic patients. A review was recently conducted using the following key words: “cirrhosis,” “coagulation,” “bleeding,” “INR” (international normalized ratio), “aPTT” (activated partial thromboplastin time), and “thrombocytopenia.” PubMed was used as the basic database. The authors showed that although pathological values of SLT and thrombocytopenia have traditionally been regarded as indicators of a high risk for bleeding in all patients, and especially in those with cirrhosis, this approach has been challenged in recent years. The conventional approach in assessing a bleeding risk was based on pathological values of SLT. A 1.5-fold increase of INR or aPTT or platelets <50/nL is assumed as pathological. The traditional approach of reducing the risk of excessive bleeding during an invasive procedure was to transfuse FFP or PLT concentrates in order to improve hemostasis and to avoid bleeding complications. In the recent 20 years, several studies have provided us with a basis for questioning this approach. Their results indicated that SLT were not able to predict hypocoagulation and bleeding complications. Moreover, transfusion of various blood products has been associated with an increased risk for acute lung injury, transfusion-associated circulation overload, bacterial infections, and modulation of the immune system with increased numbers of nosocomial infections. Furthermore, a high-volume overload, which is required to correct a hemostasis disorder if FFP are being used in cirrhotic patients, may increase portal venous pressure. This might significantly increase bleeding in these subjects. However, some very recent studies demonstrated that the use of TEG/ROTEM for assessing the risk of bleeding avoids futile transfusion with a similar safety profile. The implementation of TEG®-/ROTEM®-based coagulation management and the use of coagulation factors (prothrombin complex, fibrinogen concentrate) have led to a highly significant reduction of FFP and red blood cell transfusions, without an increased incidence of thrombosis or bleeding [11]. In conclusion, also medical cirrhotic patients will benefit of a coagulation treatment based on TEG®/ROTEM®. Finally, a temporary hypercoagulable state is common after liver transplantation due to imbalance between the procoagulant and anticoagulant systems, as well as fibrinolytic shutdown. This may play a role in the early development of hepatic artery thrombosis. The use of TEG®/ROTEM® can accurately assess postoperative hypercoagulability and thrombosis. To this end, there is interesting evidence that this monitoring technique could demonstrate hypercoagulability in the majority of the subjects after living donor liver transplantation and general surgery and may, therefore, be used to guide antithrombotic treatment in the perioperative period [15, 16].

2.3.2 Cardiac Surgery

Postoperative bleeding is a common complication of cardiac surgery and a major cause of re-exploration. Coagulation management of patients undergoing cardiac surgery is complex because of a balance between anticoagulation for cardiopulmonary bypass (CPB) and hemostasis after CPB [17]. Furthermore, an increasing number of patients have impaired platelet function at baseline due to administration of antiplatelet drugs. During CPB, optimal anticoagulation dictates that coagulation is antagonized and platelets are prevented from activation so that clots do not form. After surgery, coagulation abnormalities, platelet dysfunction, and fibrinolysis can occur, creating a situation whereby hemostatic integrity must be restored. Heparin is used during cardiopulmonary bypass in open-heart surgery, and excessive postoperative bleeding has been attributed to the insufficient reversal of heparinization with protamine sulfate. This is partly due to the fact that conventional monitoring by means of activated clotting time may fail to differentiate between the contributions from heparinization, dilution, and platelet dysfunction [17]. Johansson et al. reviewed over 3250 cardiac patients reported in 16 studies and demonstrated superiority of TEG®/ROTEM® over SLT in predicting bleeding and the need for reoperation. The total number of blood transfusions was reduced with TEG/ROTEM-guided transfusion compared with SLT-based practices. The degree of heparinization could be evaluated with assays that neutralize the heparin (heparinase in TEG and HEPTEM in ROTEM), so that non-heparin-related hemostatic problems could be detected [18]. These findings were corroborated in a recent Cochrane analysis [19].

In a recent meta-analysis of randomized controlled trials and observational trials retrieved from a literature search in PubMed, EMBASE, and Cochrane Library, trials comparing transfusion strategy guided by TEG®/ROTEM® with a standard-of-care control group undergoing cardiac surgery were included. The literature search retrieved a total of 17 trials (9 randomized controlled trial and 8 observational trials) involving 8332 cardiac surgery patients. POCT-guided transfusion management significantly decreased the odds for patients to receive allogeneic blood products (OR 0.63, 95% CI 0.56–0.71; P < 0.00001) and the re-exploration rate due to postoperative bleeding (OR 0.56, 95% CI 0.45–0.71; P < 0.00001). Furthermore, the incidence of postoperative AKI (OR 0.77, 95% CI 0.61–0.98; P = 0.0278) and thromboembolic events (OR 0.44, 95% CI 0.28–0.70; P = 0.0006) was significantly decreased in the TEG®/ROTEM® group. No statistical differences were found with regard to in-hospital mortality, cerebrovascular accident, or length of intensive care unit and hospital stay [20]. Furthermore, it has been shown that implementation of TEG®/ROTEM®-guided coagulation management is cost-effective and resulted in a significant reduction of transfusion blood products [21, 22]. Finally, the National Institute for Health and Care Excellence (NICE) has recently reviewed the available evidence for use of viscoelastic testing in cardiac surgery and concluded that viscoelastic testing improves the use of blood products and factor concentrates, reduces red cell transfusion, and is cost effective. It also concluded that the above was true for intra- and postoperative use; however, they did not recommend any particular transfusion algorithm. For ROTEM® and TEG®, the effect on mortality, length of ICU and hospital stay, and rate of re-sternotomy was not statistically significant across all studies [23].

There remains great controversy regarding the platelet transfusion threshold to be applied in cardiac surgery, due to the platelet function defect present in all patients after CPB [24]. Numeric platelet counts from the laboratory may not be accurate due to clumping, particularly if the patient is hypothermic or if the sample was taken during or immediately after CPB, which can lead to an artifactually low platelet count. The numerical analysis of platelets in the laboratory does not take into account a variable degree of platelet dysfunction induced by CPB and potentially exacerbated by preoperative treatment with platelet antagonists and/or uremia [17]. The monitoring of platelet blockade with impedance aggregometry (Multiplate®), platelet mapping (TEG®), or latex agglutination (Verify Now®; Accumetrics, San Diego, CA, USA) remains outside what is considered the standard of care, and the clinical utility of preserved patient platelet function in vitro remains to be established. All in all, the best measure of platelet function postoperatively remains unresolved [17]. Currently, platelet function testing may be more important for preoperative risk stratification. Most measures of platelet function become invalid at platelet counts <50–100 × 109 in the test tube [25]. Enriching platelets in vitro to allow an assessment in this situation introduces significant delay, which is why platelet aggregometry, considered the gold standard of platelet function assessment, has never become standard in postoperative patients after cardiac surgery [26]. Finally, there has been a lot of interest in hyperfibrinolysis since the introduction of aprotinin. In current clinical practice, true hyperfibrinolysis apparent in vitro by TEG® is a rare occurrence. It would appear that a degree of fibrinolysis is to be expected after cardiac surgery, but the definition of systemically apparent hyperfibrinolysis is less clear [17].

Tranexamic acid (TXA), used almost ubiquitously in UK cardiac surgical practice, and epsilon aminocaproic acid (EACA) are synthetic lysine analogues that reversibly block the lysine-binding site of plasminogen which inhibits the lysis of polymerized fibrin. They have a plasma half-life of around 2 h and are excreted in the urine in high concentrations. The optimum dose of TXA is unknown despite its widespread international use, with 10 mg/kg bolus followed by 1 mg kg/h as a continuous infusion being the most commonly used regimen, with little evidence for higher doses. Both agents have been shown to reduce blood loss, when used prophylactically in cardiac surgery [17]. Tranexamic acid may be slightly more effective than EACA in reducing blood loss; however, there is little evidence to support the exceedingly high doses (up to 10 g) used in some centers [27].

2.3.3 Obstetrics

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality. In the current treatment of severe PPH, first-line therapy includes transfusion of packed cells and fresh-frozen plasma in addition to uterotonic medical management and surgical interventions. In persistent PPH, tranexamic acid, fibrinogen, and coagulation factors are often administered. Secondary coagulopathy due to PPH or its treatment is often underestimated and therefore remains untreated, potentially causing progression to even more severe PPH. In most cases, medical and transfusion therapy is not based on the actual coagulation state because conventional laboratory test results are usually not available for 45–60 min. Therefore, TEG®/ROTEM® coagulation testing comes of interest. Data on thromboelastography and thromboelastometry in pregnant women are however limited, particularly during the peripartum period and in women with PPH, so more research in this field is truly needed [28]. However, the emergency nature of PPH makes randomized controlled trials logistically difficult. Therefore, population-based observational studies should be encouraged as they can usefully strengthen the evidence base, particularly for components of PPH treatment that are difficult or impossible to assess through RCT [29]. A recent observational cross-sectional/longitudinal study aimed at demonstrating changes in clot mechanics during pregnancy and to determine the effect that delivery has on immediate postpartum thromboelastography parameters. Thromboelastography was performed on whole blood aliquots obtained from women carrying singleton pregnancies and was repeated 6 h after delivery among patients recruited in the third trimester or labor. Bleeding questionnaires were completed and routine clinical/demographic data obtained. Overall, 112 women were included. The thromboelastography parameters were significantly correlated with length of pregnancy. From the third trimester to the postpartum period, there was a significant decrease in time until fibrin formation (P = 0.036) and in time to reach a certain clot strength (amplitude of 20 mm; k value; 1.3 vs 1.1 min, P = 0.007). From established labor to after delivery, there was a significant increase in clot lysis at 60 min after the maximum amplitude of clot formation (LY60; 1.8% vs 3.1%, P = 0.001). The authors concluded that their study describes a novel finding regarding changes in clot mechanics in late pregnancy/puerperium and supports the concept of using thromboelastography as part of the routine assessments at delivery [30]. Another study aimed at comparing the use of thromboelastography and laboratory analyses to evaluate hemostasis during major obstetric hemorrhage. A secondary aim was to evaluate correlations between the results of thromboelastography, laboratory analyses, and estimated blood loss. Forty-five women with major obstetric hemorrhage and 49 women with blood loss <600 mL were included. The following thromboelastography analyses were performed: time to start of clotting (TEG-R), time to 20 mm of clot firmness (TEG-K), rate of clot growth (TEG-Angle), maximum amplitude of clot (TEG-MA), and lysis after 30 min (TEG-LY30). In addition, platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen, antithrombin, and D-dimer were measured. Thromboelastography variables reflecting clot stability and fibrinolysis were decreased in women with massive obstetric hemorrhage compared to women with normal bleeding, while clot initiation was accelerated. Laboratory analyses also showed impaired hemostasis with the most pronounced differences in platelet count, fibrinogen concentration, and antithrombin activity. The strongest correlations existed between fibrinogen and TEG-MA and between estimated blood loss and TEG-MA, fibrinogen, and antithrombin, respectively. The authors conclude that impaired hemostasis, demonstrated by thromboelastography and laboratory analyses, was found after an estimated blood loss of 2000 mL. Thromboelastography provides faster results than standard laboratory testing which is advantageous in the setting of ongoing obstetric hemorrhage. However, laboratory analyses found greater differences in coagulation variables, which correlated better with estimated blood loss [31]. In a study of nonpregnant, healthy term pregnant women, and postpartum women, it was demonstrated that a hypercoagulable state exists during pregnancy and persists through the first 24 h postdelivery. Both native TEG and celite-activated TEG were used, and it was found that r and k were decreased, while alpha angle and MA were significantly increased in the pregnant and postpartum women compared with the normal group [32]. More recently, the hypercoagulability status of women with and without gynecologic malignancies was compared using TEG. Blood specimens from 25 women with newly diagnosed gynecologic malignancies and from 21 age-matched controls were analyzed. Hypercoagulability was defined by a short r value (min), a short k value (min), an elevated maximum amplitude (MA) value (mm), and a broad alpha angle (°). A two-tailed, two-sample t-test was used for statistical analysis. When compared with specimens from age-matched controls, specimens from women with gynecologic malignancies demonstrated values consistent with hypercoagulability. The specific parameters are presented as a mean (±SD). Patients with gynecologic malignancies were found to have a short r value (7.1 ± 2.1 min vs. 11.8 ± 1.8 min; P < 0.001), a short k value (3.1 ± 0.9 min vs. 4.6 ± 0.9 min; P < 0.001), a prolonged MA value (64.7 ± 5.4 mm vs. 58.8 ± 6.1 mm; P = 0.001), and a greater alpha angle (70.6° ± 5.3° vs. 61.6° ± 4.9°; P < 0.001). The authors concluded that detection of hypercoagulability as measured by thromboelastography is statistically more common among women with gynecologic malignancies compared with age-matched controls [33]. In summary, goal-directed therapy using point-of-care testing has not been well studied in the obstetric setting but holds promise for individualizing resuscitation measures [34].

2.3.4 Trauma

Hemorrhagic shock is a leading cause of death in trauma patients. Surgical control of bleeding and fluid resuscitation with both crystalloid and blood products remain the mainstay of therapy for injured patients with bleeding. Current evidence suggests that hemodilution, hypothermia, acidemia, and the consumption of clotting factors all play roles in the pathogenesis of coagulopathy in trauma. In such a complicated panorama, there is an emerging understanding of the key role played by the management of coagulation in this particular clinical setting. In fact, restoration and subsequent maintenance of normal coagulation function is essential for survival of the severely injured bleeding patient. Furthermore, after initial stabilization, trauma patients paradoxically face the dangers of a hypercoagulable state, demanding accurate risk stratification and chemoprophylaxis for prevention of highly morbid thromboembolic events [35].

A systematic review found 55 studies of TEG®/ROTEM® examining the diagnosis of trauma coagulopathies, including hypocoagulation, hypercoagulation, platelet dysfunction, and fibrinolysis, guidance of blood product administration, and associations with mortality. To our knowledge, this review is the first to summarize the literature on the use of TEG® and ROTEM® in trauma [36]. The overall methodologic quality of included studies was moderate. No RCTs were reported; most cohort studies lacked clinically similar control groups managed without TEG®/ROTEM®, and standard measures of diagnostic accuracy were inconsistently reported. Observational data suggest that TEG® and ROTEM® may have adequate diagnostic properties for abnormalities identified by RSCTs and may identify additional coagulation disorders. However, the effect of these tests on the need for blood product transfusion and mortality is unclear. Studies also examined different patient populations, transfusion triggers, and transfusion protocols, limiting direct comparisons and generalizability. In summary, our systematic review demonstrated limited but rapidly growing observational evidence on the use of TEG® and ROTEM® in trauma. Both methods may be useful for diagnosis of early trauma coagulopathies, specifically hypocoagulability, hypercoagulability, hyperfibrinolysis, and platelet dysfunction. They may also be used to direct blood and blood product transfusion; effects on patient-important outcomes are uncertain. All in all, the existing literature helps clinicians to appreciate the potential impact of these novel methods on transfusion guidance and outcomes in trauma. However, adequately powered and methodologically sound RCTs will be required to prove positive effects on blood product transfusion and patient-important outcomes [36].

Recently, the pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma, founded in 2004 and including representatives of six relevant European professional societies, used a structured, evidence-based consensus approach to address scientific queries that served as the basis for recommendations and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomized clinical trials have not or cannot be performed. Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013 [37]. With regard to coagulation monitoring, this group of experts recommends that routine practice will include the early and repeated monitoring of coagulation, using either a traditional laboratory determination [prothrombin time (PT), activated partial thromboplastin time (APTT) platelet counts and fibrinogen] (Grade 1A), and/or a viscoelastic method (Grade 1C). The authors outline that despite the widespread use of viscoelastic methods, the usefulness has recently been questioned. In fact, In a recent systematic review Hunt et al. found no evidence of the accuracy of thrombelastography and very little evidence to support the accuracy of thromboelastometry and were therefore unable to offer any advice about the use of these methods [38]. In the above examined systematic review, Da Luz et al. concluded that only limited evidence from observational studies support the use of viscoelastic tests to diagnose early traumatic coagulopathy, but while these tests may predict blood product transfusion, mortality and other patient-important outcomes may be unaffected [36]. A number of other limitations to the use of viscoelastic methods have been described. Larsen et al. found that thrombelastography was unable to distinguish coagulopathies caused by dilution from thrombocytopenia, whereas thromboelastometry was indeed capable of distinguishing these two different types of coagulopathy and suggesting the correct treatment [39]. The use of thrombelastography may thus lead to unnecessary transfusion with platelets, whereas the application of thromboelastometry may result in goal-directed fibrinogen substitution. All in all, according to these findings, although use is rapidly increasing, controversy remains at present regarding the utility of viscoelastic methods for the detection of posttraumatic coagulopathy. Finally, according to the pan-European, multidisciplinary Task Force, the following are the leading key points regarding the use of TEG/ROTEM in trauma patients [37]:

  1. 1.

    The literature on TEG® and ROTEM® in trauma is limited by the lack of randomized controlled trials and the moderate quality of observational studies.

  2. 2.

    TEG® and ROTEM® may be superior to routine screening coagulation tests to promptly diagnose early trauma coagulopathy, including hypocoagulability, hyperfibrinolysis, hypercoagulability, and platelet dysfunction.

  3. 3.

    Many TEG® and ROTEM® abnormalities predict the need for massive transfusion and predict death, but predictive performance is not consistently superior to routine screening coagulation tests.

  4. 4.

    Limited evidence from one observational study suggests that a ROTEM®-based transfusion algorithm reduces the amount of blood and blood products transfused.

  5. 5.

    TEG® and ROTEM®-based resuscitation for bleeding trauma patients is not associated with lower mortality in most observational studies, but the question requires evaluation in randomized trials.

3 Shortcomings and Criticisms to TEG/ROTEM

Perioperative POC testing of hemostasis would be invaluable if it could identify patients at increased risk of postoperative hemorrhage. Nevertheless, it should always be considered that this technique is not without limitations. In fact, indeed the coagulation status is assessed in whole blood, allowing in vivo coagulation system interactions with platelets and red blood cells to provide useful information on the more appropriate clinical approach. However, a significant difference between in vitro and in vivo coagulation has to be considered: viscoelastic coagulation tests measure the coagulation status under static conditions (no flow) in an artificial situation (cuvette or cartridge and not an endothelialized blood vessel). Therefore, results obtained from these in vitro tests must be carefully interpreted after considering the clinical conditions (e.g., overt bleeding in the surgical site). As in any assay there are some blind spots in monitoring coagulation using the viscoelastic method. Platelet dysfunction either inherited or drug induced will not be detected. Another shortcoming is the insensitivity to detect the effects of von Willebrand factor, which is involved in the initiation of clot forming. Moreover, factor XIII, which is mainly responsible for stabilization of the fibrinogen network, is also not adequately displayed [40]. However, it must always bear in mind that thromboelastography is and remains a POC and not a traditional laboratory technology. More importantly, there are concerns about standardization of the assays [41, 42]. On an operational level, viscoelastic tests have been criticized for not having undergone the same evaluation process as conventional coagulation tests. There are wide technical variations in how TEG®/ROTEM® are performed, and the machine requires calibrations two to three times a day which causes significant inconvenience in daily point-of-care usage. While originally designed for fresh whole blood with no additional activators, subsequent modifications have included sample anticoagulation and the use of different activators to standardize the initiation of coagulation. Patients’ gender, age, and alcohol drinking may also affect the result. Moreover, the normal reference ranges for viscoelastic tests were derived from hospitalized surgical patients in 1 study, and from a small sample of 12 healthy volunteers in another [43]. Hence, it is suggested that each center is recommended to generate its own reference range by specially trained personnel according to the guidelines from the Clinical Laboratory Improvement Amendments (the federal regulatory standards that apply to all clinical laboratory testing performed on humans in the United States) [44]. All these necessitate an active and tightly controlled quality assurance program. Finally, there are conditions in which viscoelastic tests may fail to detect hemostatic dysfunction. The test setting is at 37 °C. Therefore, the effect of hypothermia, which has a well-recognized negative impact on coagulation, may not be recognized if not appropriately addressed. Lastly, the interchangeability of results between TEG® and ROTEM® has been questioned. Although they share the same fundamental principles, and similar parameters, hardware, and techniques, the results generated may not be directly comparable, possibly due to the use of different activators. Consistent correlations are limited to that between TEG-MA and ROTEM MCF measurements and that between TEG CL and ROTEM ML in diagnosing hyperfibrinolysis and predicting mortality [43].

4 Conclusions

Hemostatic function is a critical factor determining patient outcomes in emergency or elective procedures. Conventional coagulation tests have limitations in detecting hemostatic dysfunction in subgroups of patients and are largely ineffective in diagnosing hyperfibrinolysis. The viscoelastic tests are potentially useful point-of-care tools to provide information on clot formation, clot strength, and fibrinolysis, as well as to guide goal-directed transfusion and antifibrinolytic therapy. However, standardization of techniques and reference ranges is required before these tests can be widely used in different clinical settings. There is growing evidence that application of TEG®-/ROTEM®-guided transfusion strategies may reduce the need for blood products and improve morbidity in patients with bleeding. However, these results are primarily based on trials of elective cardiac surgery involving cardiopulmonary bypass, and the level of evidence remains low. Further evaluation of TEG®/ROTEM®-guided transfusion in acute settings and other patient categories in low risk of bias studies is needed.