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Can the Viscoelastic Parameter α-Angle Distinguish Fibrinogen from Platelet Deficiency and Guide Fibrinogen Supplementation?

Solomon, Cristina MD, MBA*†‡; Schöchl, Herbert MD‡§; Ranucci, Marco MD§; Schlimp, Christoph J. MD‡∥

doi: 10.1213/ANE.0000000000000738
Cardiovascular Anesthesiology: Review Article
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Viscoelastic tests such as thrombelastography (TEG®, Haemoscope Inc., Niles, IL) and thromboelastometry (ROTEM®, Tem International GmbH, Munich, Germany), performed in whole blood, are increasingly used at the point-of-care to characterize coagulopathic states and guide hemostatic therapy. An algorithm, based on a mono-analysis (kaolin-activated assay) approach, was proposed in the TEG® patent (issued in 2004) where the α-angle and the maximum amplitude parameters are used to guide fibrinogen supplementation and platelet administration, respectively. Although multiple assays for both the TEG® and ROTEM devices are now available, algorithms based on TEG® mono-analysis are still used in many institutions. In light of more recent findings, we discuss here the limitations and inaccuracies of the mono-analysis approach. Research shows that both α-angle and maximum amplitude parameters reflect the combined contribution of fibrinogen and platelets to clot strength. Therefore, although TEG® mono-analysis is useful for identifying a coagulopathic state, it cannot be used to discriminate between fibrin/fibrinogen and/or platelet deficits, respectively. Conversely, the use of viscoelastic methods where 2 assays can be run simultaneously, one with platelet inhibitors and one without, can effectively allow for the identification of specific coagulopathic states, such as insufficient fibrin formation or an insufficient contribution of platelets to clot strength. Such information is critical for making the appropriate choice of hemostatic therapy.

From the *CSL Behring, Marburg, Germany; Department of Anesthesiology, Perioperative Care and General Intensive Care, Paracelsus Medical University, Salzburg University Hospital, Salzburg, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology and AUVA Research Centre, Vienna, Austria; §Department of Anesthesiology and Intensive Care, AUVA Trauma Hospital of Salzburg, Salzburg, Austria; and Department of Anesthesiology and Intensive Care, AUVA Trauma Hospital of Klagenfurt, Klagenfurt, Austria.

Accepted for publication December 15, 2014.

Funding: This work was not funded by the National Institutes of Health (NIH), Howard Hughes Medical Institute (HHMI), Medical Research Council (MRC), and/or Wellcome Trust. Editorial assistance with manuscript preparation was provided by medical writers at Meridian HealthComms (Plumley, UK), funded by CSL Behring.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Cristina Solomon, MD, MBA, CSL Behring GmBH, Emil-von-Behring-Strasse 76, 35041 Marburg, Germany. Address e-mail to Cristina.Solomon@cslbehring.com.

Viscoelastic point-of-care tests such as thrombelastography (TEG®, Haemoscope Inc., Niles, IL) and thromboelastometry (ROTEM®, Tem International GmbH, Munich, Germany), performed in whole blood, are increasingly used to diagnose coagulopathy and guide therapy with allogeneic hemostatic blood products, such as plasma, platelets, and cryoprecipitate, as well as coagulation factor concentrates and antifibrinolytic drugs.1 Indeed, transfusion algorithms based on point-of-care coagulation testing have been shown to reduce administration of allogeneic blood products.2 Consequently, such testing is becoming an essential tool during critical bleeding management and is recommended in guidelines for the management of severe perioperative bleeding and for the management of bleeding and coagulopathy after major trauma.3,4 These methods provide an almost real-time monitoring of the coagulation process through the measurement of various parameters, including the kinetics of the development of the clot (α-angle) and its maximal strength (maximal amplitude [MA]) (Fig. 1). Whereas standard coagulation tests are performed with platelet poor plasma, viscoelastic assays are designed to be performed with whole blood. Viscoelastic devices also offer the possibility of running multiple assays simultaneously. Similar to the standard coagulation tests, including prothrombin time (PT), activated thromboplastin time, Clauss fibrinogen assay, or PT-derived fibrinogen measurement, viscoelastic tests involve the use of activators. Furthermore, addition of platelet inhibitors to block the platelet contribution to clotting allows for the specific assessment of the fibrin-based clot strength.

Figure 1

Figure 1

A Cochrane review has concluded that viscoelastic assay–guided transfusion algorithms appear to reduce both microvascular bleeding and the number of patients who require transfusion in cardiovascular surgery.5 Despite the fact that various newer TEG® assays have recently been released,6,7 the kaolin-activated assay (later described as TEG® mono-analysis) alone is often used to guide hemostatic therapy in many institutions,8–12 even though it has been occasionally noted that a mono-analysis approach cannot distinguish platelet from fibrin/fibrinogen deficiency.5,13 Therefore, when therapies for fibrinogen supplementation are available (therapeutic plasma, cryoprecipitate, or fibrinogen concentrate), there is a likelihood that fibrin-/fibrinogen-deficient patients would not receive the most appropriate therapy if decision making is based on TEG® mono-analysis alone.

Here we review the current literature on the accuracy of the TEG® mono-analysis α-angle and MA parameters for guiding fibrinogen and platelet administration. We then describe how the use of viscoelastic multiple assays warrant a more accurate distinction between fibrin/fibrinogen and platelet deficiency, where platelet deficit refers to both a low platelet count and/or platelet dysfunction.

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VISCOELASTIC METHODS AND BLOOD COAGULATION MECHANISMS

Viscoelastic methods provide continuous assessment of mechanical clot strength throughout the coagulation process. Clot strength in this coagulation assay methodology is visualized as an amplitude (Fig. 1), which in return, can be used to calculate the shear modulus of the clot expressed in dyne/cm2 (with 10 dyne/cm2 equivalent to 1 Pa [SI unit of pressure]). With a viscoelastic assay, performed for example with the TEG® device, various parameters can be determined from the trace of amplitude over time, including the time to onset of clot formation (r), rate of increasing clot strength (α-angle, k), clot strength (A), or maximum clot strength (MA).

Hartert first introduced the concept of thrombelastography to study clot formation in whole blood samples.14 The use of α-angle as a parameter for investigating the properties of clot development was described only later by others, and the exact definition is currently ambiguous.15,16 While the α-angle is sometimes defined as the angle formed between the midline of the tracing and a line drawn from the 1-mm-wide point tangential to the curve,17 other publications have reported an α-angle calculated as the angle between the tangent line drawn from the horizontal base line to the beginning of the fibrin cross-linking process.18 More recently, the α-angle parameter was described as the angle created by the tangent line from the point of clot initiation and the slope of the developing curve.19 Finally, a few reviews define the α-angle as the angle formed by the midline of the tracing and the slope between the amplitude of the trace at 2 and 20 mm.1,20–22 Overall, the published descriptions offer up to 6 different potential definitions for the α-angle parameter (Fig. 2). By default, the TEG® system calculates the α-angle as the angle formed by the tangential line to the curve starting from the split point of the trace (Fig. 2D), but it also offers the possibility of calculating the α-angle using the tangential line to the curve starting from r instead (Fig. 2F).23 While this could theoretically change the calculated values of the α-angle, the clinical impact of such variations remains unclear. The current TEG® manual specifies that, although α-angle and k are closely related, the α-angle is more comprehensive, since there might be cases of hypocoagulable states in which k cannot be defined (i.e., when the final level of clot firmness might not reach an amplitude of 20 mm).

Figure 2

Figure 2

Decades after the first description of thrombelastography, the addition of activators such as “thromboplastin fractions” prepared from biological fluids were used to investigate coagulation in vitro,24 and the device itself was subjected to further improvements with the use of disposable cuvettes and the development of an electronic output, as opposed to a read-out on photographic paper.25–27 Thrombelastography was by then already considered as a novel and unique system capable of rapidly identifying hypercoagulable and fibrinolytic states.28 The concept of a “platelet inhibition assay” to distinguish strength of the fibrin-based clot from the platelet contribution was later described.29–31 Nevertheless, the TEG® patent32 (U.S. patent no. US 6,787,363 B2) describes an algorithm based on a mono-analysis approach, where the α-angle is defined as a measure of “the rapidity of fibrin build-up and cross- linking (clot kinetics)” and the MA as “a direct function of the maximum dynamic properties of fibrin and platelet bonding via GPIIb/IIIa” and representing “the ultimate strength of the clot”. In this description, fibrinogen replacement therapy with 0.6 U/kg of cryoprecipitate is recommended for an α-angle <45° and platelet transfusion or 3 μg/kg desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin) is recommended for a MA ≤45 mm or between 46 and 54 mm, respectively (Table 1). However, it is unclear which data were used to support the recommended therapy for an α-angle <45°, as there were no references provided.

Table 1

Table 1

While there is no clear evidence that MA or α-angle parameters can distinguish platelet from fibrin/fibrinogen deficiency, they have since been incorporated into further algorithms in a number of different clinical settings.6,8–12,33–36,38,40–48 In these algorithms, the threshold values of the TEG® mono-analysis α-angle and MA trigger the recommendation for the administration of different hemostatic therapies (Table 1). These thresholds, the specific therapies and the recommended doses, vary between publications, and the differences are especially pronounced for algorithms concerning the management of bleeding in trauma patients. Since most clinical transfusion-based guidelines are often adapted to meet local and institutional requirements, differences are to be expected. However, it is surprising that such algorithms rarely specify whether their threshold values used for hemostatic product administration are based on readings obtained with native or citrated whole blood samples, as the presence of citrate slightly affects both the α-angle and MA parameters (Table 2).

Table 2

Table 2

Several reports have suggested that monitoring with TEG® mono-analysis may reduce transfusion requirements during liver transplantation,34,36 trauma,9 and cardiac surgery.54 This is perhaps not surprising, given that appropriate application of any hemostatic management algorithm is generally accepted as having a beneficial effect in reducing inappropriate transfusion.2 Consequently, in institutions where therapies other than fresh frozen plasma and platelets are available (such as cryoprecipitate and coagulation factor concentrates), decision making and dosing based on TEG® mono-analysis may still lead to unnecessary exposure to the inappropriate hemostatic agents.55,56

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LIMITATIONS AND CONSEQUENCES OF TEG® MONO-ANALYSIS TO GUIDE FIBRINOGEN SUPPLEMENTATION OR PLATELET TRANSFUSION

Algorithms based on TEG® mono-analysis consider individual TEG® parameters as an isolated reflection of distinct coagulation components, but they do not recognize the fact that viscoelastic measurements in whole blood represent the interactions between parallel coagulation processes, including thrombin generation, fibrin cross-linking, and platelet aggregation.57 For example, thrombin is an essential effector in the coagulation cascade that has many functions including fibrin cross-linking via the activation of FXIII.58 While it is important to remember that the parameters reflecting the kinetic of clot formation are affected by multiple variables, a simplified approach can be applied to the perioperative setting, with the α-angle and MA parameters being influenced by only 2 major variables in isolation (i.e., platelets and fibrin). That is, a measurement parameter (such as α-angle or MA) affected by at least 2 major influencing variables (i.e., platelets and fibrin) to different extents cannot be used to calculate a value for one or the other of the 2 variables. Admittedly, in an experimental setting, where one variable can be kept constant and the second can be variably manipulated,31,59 the measurement parameter can be used to evaluate the changes of the second variable. However, outside an experimental setting, neither of the 2 dynamic influencing variables is expected to remain constant while the other changes. Consequently, the measurement parameter integrates the 2 variables but the specific contribution of either influencing variable cannot be determined. Therefore, in a clinical situation where coagulation parameters are evaluated in whole blood samples, fibrinogen and platelets influence both MA and α-angle parameters.7,17,60–66 The α-angle reflects the speed with which the strength of the clot formed by fibrin and platelets is increasing, whereas MA reflects the combined contribution of fibrin and platelets to the overall clot strength.67 These same considerations would apply for both the α-angle and maximum clot firmness (MCF) ROTEM parameters, respectively.

A number of in vitro studies, performed on samples from normal healthy volunteers, demonstrated that it is not possible to discriminate between fibrin/fibrinogen and platelet deficiency using a single kaolin-activated assay in isolation. In a recent in vitro study investigating the individual contribution of various blood components to clot formation, Sondeen and collaborators68 demonstrated that the main factor affecting both the α-angle and MA parameters was the platelet concentration. By manipulating individual blood components while keeping other components constant, the authors found that the TEG® profiles of hemodiluted samples (using lactate Ringer’s solution) were indistinguishable from those obtained with samples where only the platelet count was altered. Similarly, Larsen and collaborators13 showed that kaolin-activated TEG® profiles from blood samples diluted with hydroxyethyl starch (to induce dilutional coagulopathy) and samples manipulated to induce thrombocytopenia, were indistinguishable from each other. These data demonstrate that although a TEG® mono-analysis is useful to identify a coagulopathic state, it cannot be used to determine its cause. Further studies demonstrated that MA is affected by both fibrinogen concentration and platelet count. Harr and colleagues assessed the contribution of fibrinogen and platelets to overall clot strength using TEG® mono-analysis.7 They found that fibrinogen concentrations determined with the Clauss method correlated with MA (r2 = 0.75; P < 0.0001), whereas platelet count had only a moderate correlation to MA (r2 = 0.51; P < 0.0001). Darlington et al.61 showed that α-angle correlated better with platelet count than with fibrinogen concentration (r2 = 0.76 vs r2 = 0.57), but this study also demonstrated that platelet count correlated equally well as fibrinogen concentration with MA (r2 = 0.77 vs r2 = 0.71). These results corroborate those reported by Chandler17 who concluded that low MA may be due to low fibrinogen concentration or low platelet count, or both.

Comparable conclusions have been drawn from clinical studies describing correlations between TEG® mono-analysis parameters and variables including platelet count and plasma fibrinogen concentration. In a prospective study of 60 surgical patients, Ågren et al.60 described a stronger correlation between fibrinogen concentration and MA (r = 0.75, P < 0.0001) compared with the correlation between platelet count and MA (r = 0.61, P < 0.0001). Furthermore, in the same study, the correlation between platelet count and α-angle (r = 0.58, P < 0.0001) was found to be stronger than that between fibrinogen concentration and α-angle (r = 0.35, P < 0.001). Similarly, in a recent retrospective study of patients who underwent cardiac surgery, the α-angle parameter was found to moderately correlate with both plasma fibrinogen concentration and platelet count (r = 0.38, P < 0.0001 and r = 0.58, P < 0.0001, respectively).69 Finally, the minimum platelet count or fibrinogen concentration required for effective clot formation is widely debated; however, in vitro and in vivo studies have shown that both MA and α-angle are greatly compromised for platelet counts of <50,000/μL to 66,000/μL.63,70,71

Overall, both in vitro and in vivo data demonstrate that fibrinogen and platelets act in synergy to promote and maintain the clot, contradicting the hypothesis laid down in the TEG® patent32 and all algorithms recommending fibrinogen supplementation depending on the α-angle and platelets depending on the MA. The validity of the α-angle as a parameter to accurately assess the rate of clot formation is subject to further controversy. In a retrospective study, Ellis et al.67 demonstrated that changes in the α-angle parameter did not provide an accurate assessment of the speed of clot propagation and recommended the use of the maximum rate of thrombus generation (MRTG) parameter instead. While the MRTG cannot help to distinguish between fibrin/fibrinogen and platelet contribution to the clot, it is noteworthy that, unlike the α-angle, MRTG offers a parametric measurement of clot propagation67 and is often used in studies investigating blood clotting processes.68,72,73 Furthermore, it is important to note that while fibrinogen and platelets both affect the α-angle, other factors also influence this parameter. Nielsen and collaborators showed that fibrinogen, FII, FVII, FX, FXII, and FXIII all have a significant influence on clot strength74,75 and consequently affect viscoelastic parameters, including the α-angle.74,76 Moreover, comparing data obtained with celite and tissue factor, TEG® parameters were also shown to vary in an activation-dependent manner.74

More recently, the RapidTEG™ has been introduced to clinical practice.6 This assay is activated with both kaolin and tissue factor rather than kaolin alone as with the standard TEG® assay. The RapidTEG™, therefore, assesses both the extrinsic and intrinsic coagulation pathways and is reported to be more sensitive and specific than standard coagulation tests in predicting transfusion requirement in trauma patients.77 Lu and colleagues78 recently investigated the clinical applicability of thrombelastography in adult liver transplant. Their data, obtained with the kaolin-activated TEG® and RapidTEG™ assays, showed that both the MA and α-angle parameters significantly correlated with fibrinogen concentration and platelet count, at baseline (time of skin incision) and 30 minutes after graft reperfusion. Furthermore, the authors demonstrated that, unlike the MA parameter, the α-angle showed a weaker correlation with fibrinogen concentration using kaolin-activated TEG® (r = 0.45, P < 0.05, at baseline; r = 0.60, P < 0.05, 30 minutes after graft reperfusion) compared with RapidTEG™ (r = 0.84, P < 0.05, at baseline; r = 0.72 [r2 = 0.52], P < 0.05, 30 minutes after graft reperfusion).78 Because the RapidTEG™ and the kaolin-activated TEG® assess different coagulation pathways, the reference ranges for each assay are different. Thus, algorithms and therapeutic thresholds for the 2 assays are not interchangeable.79 However, regardless of the method of activation or the sensitivity of the assay, α-angle remains a measure of the overall rate of clot formation influenced by platelets and fibrinogen; thus, neither of these assays (kaolin-activated and RapidTEG™) is able to distinguish between a platelet deficit and a fibrin/fibrinogen deficit.

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DIFFERENTIAL DIAGNOSIS OF FIBRIN/FIBRINOGEN DEFICIT AND PLATELET DEFICIT USING MULTIPLE ASSAYS: AN ALTERNATIVE TO THE MONO-ASSAY α-ANGLE AND MA PARAMETERS

Fibrin/fibrinogen deficiency and platelet deficiency can be quickly and accurately distinguished by simultaneously performing separate assays to evaluate clotting function in the presence and in the absence of platelet inhibition. The TEG® and ROTEM devices have 2 and 4 channels, respectively, meaning that several assays can be performed in parallel without increasing the time to diagnosis. The Functional Fibrinogen assay80 determined with TEG® and the FIBTEM assay81 (Tem International GmbH, Munich, Germany) using the ROTEM device both assess fibrin-based clot formation by eliminating the contribution of platelets to clot strength.82 Abciximab (a glycoprotein IIb/IIIa receptor antagonist) is used to eliminate the platelet contribution to clot strength in the Functional Fibrinogen assay.1,29,55 In contrast, cytochalasin D (a blocker of actin filaments polymerization and elongation) is used in the FIBTEM test as an inhibitor of platelet function.1 Fibrin/fibrinogen deficiency may manifest as a low TEG® MA (or ROTEM MCF) when platelet contribution was eliminated by either abciximab or cytochalasin D (Fig. 3); this may also be the case in the absence of platelet inhibition, unless masked by a high platelet contribution to the clot. Overall, the correlation of MA (or MCF) with fibrinogen concentration is good when the contribution of platelets to clot strength has been removed.29,83 Thus, fibrin/fibrinogen deficiency should be diagnosed primarily based on Functional Fibrinogen or FIBTEM assay results.

Figure 3

Figure 3

Platelet deficiency is diagnosed when fibrin-based clot strength is normal, but overall clot strength is decreased (Fig. 3). The “platelet component”59,84,85 (contribution of platelets to clot strength) should be determined by calculating the difference between the overall clot elasticity and the fibrin-based clot elasticity. Indeed, when interpreting TEG® and ROTEM data, it is important to be aware that the clot elasticity (dimensionless parameter derived from the clot amplitude) provides a more accurate representation of the forces applied by the blood clot. With ROTEM, the platelet component can be calculated for any time point or at the point of maximal clot amplitude. The platelet contribution to clot strength can also be calculated in a similar manner with the TEG® device using overall clot elasticity and the fibrin-based clot elasticity (calculated from the clot amplitude obtained with the kaolin-activated TEG® or RapidTEG™ assays and with the Functional Fibrinogen assay, respectively). Unlike the EXTEM (Tem International GmbH, Munich, Germany) and FIBTEM assays, which are both activated by tissue factor, the Functional Fibrinogen, kaolin-TEG®, and RapidTEG™ assays use different clot activators (tissue factor, kaolin, and tissue factor plus kaolin, respectively). Therefore, calculations made with the TEG® device cannot be directly compared with those made with the ROTEM device.

The Functional Fibrinogen assay, in conjunction with kaolin-activated TEG® analysis, has been demonstrated to distinguish between platelet and fibrin/fibrinogen deficiencies and to provide insight into transfusion therapy with hemostatic agents.7 For these reasons, multiple TEG®-based assay approaches, including the Functional Fibrinogen assay, have been described for trauma resuscitation algorithms in the Copenhagen University Hospital, where platelet transfusion or fibrinogen supplementation (i.e., with fresh frozen plasma, cryoprecipitate, or fibrinogen concentrate) is recommended when Functional Fibrinogen MA >14 mm or Functional Fibrinogen MA <14 mm, respectively.12,42,86 More recently, the concomitant use of Functional Fibrinogen, RapidTEG™, and kaolin-activated TEG® assays has also been described in patients undergoing liver transplantation.78 Similarly, results from the FIBTEM assay have been used to guide fibrinogen supplementation in numerous clinical settings, including trauma,87–91 cardiac surgery,92–94 liver transplantation,95,96 and pediatric surgery.97,98 In these studies, fibrinogen supplementation was administered according to FIBTEM MCF or A10 measurements, leading to reduction of transfusion requirements and/or correction of coagulopathy. Based on such evidence, current guidelines recommend the use of FIBTEM parameters within treatment algorithm to guide hemostatic therapy, and advise for fibrinogen supplementation therapy when FIBTEM MCF <10–12 mm,99,100 FIBTEM A10 <7 mm,100–102 or FIBTEM A10 ≤10 mm.103,104

Coagulation monitoring using FIBTEM alongside other ROTEM assays such as EXTEM can be used to indicate the need for platelet transfusion when the overall clot strength is low (as indicated by the EXTEM assay) with a sufficient fibrin-based clot strength (indicated by the FIBTEM assay) (Fig. 3).95,101,103 Görlinger et al.103 showed, in a retrospective, single center, cohort study involving patients undergoing cardiovascular surgery, that fibrinogen concentrate should be administered for EXTEM A10 ≤40 mm and FIBTEM A10 ≤10 mm. However, when the EXTEM A10 was ≤40 mm and the FIBTEM A10 >10 mm, platelet transfusion should be considered (Table 3). Efforts have recently been made to standardize and simplify the interpretation of ROTEM results perioperatively and in patients with trauma.105 In their publication, Lier et al.105 summarized the various possible combinations of ROTEM results associated with pathophysiological conditions commonly found in patients with acute diffuse bleeding in a diagram and follow on with proposing a ROTEM-based checklist to guide hemostatic therapy.

Table 3

Table 3

Concerns have been raised about the effectiveness of fibrin polymerization–based assays to fully delineate the contribution of platelets to clot strength.55,106 Solomon and collaborators107 compared results obtained with the following 3 different fibrin polymerization–based viscoelastic assays using blood samples from 30 patients undergoing cardiovascular surgery: the Functional Fibrinogen assay (containing abciximab, a glycoprotein IIb/IIIa inhibitor), the FIBTEM assay (containing cytochalasin D, an inhibitor of actin polymerization), and the FIBTEM PLUS (a novel experimental assay containing cytochalasin D and the glycoprotein IIb/IIIa inhibitor, tirofiban, to achieve greater inhibition of platelet contribution to the clot strength). They observed a low but significant correlation between platelet count and the difference between FIBTEM MCF and FIBTEM PLUS MCF (r = 0.46, P < 0.001), suggesting that, in clinical situations where the platelet count is high, cytochalasin D (used in the FIBTEM assay) alone does not completely eliminate platelet contribution to clot formation. As recently demonstrated in blood samples from surgical and healthy patients, the Functional Fibrinogen assay tends to overestimate fibrinogen levels compared with laboratory-measured fibrinogen plasma concentrations.108 Lang et al.109 assessed the effect of abciximab and cytochalasin D, alone or in combination, on the TEG® MA parameter. They found that in both whole blood and platelet-rich plasma samples, MA was lower in the presence of cytochalasin D compared with abciximab-spiked samples (P < 0.001) and that it was further reduced when both inhibitors were combined (P < 0.001 compared with abciximab-spiked samples or cytochalasin D–spiked samples). These results demonstrate that, in blood samples, cytochalasin D or abciximab alone do not fully inhibit platelet function. Similar results were recently described by Schlimp et al.106 who showed, in whole blood samples, that the addition of abciximab (to levels described in the Functional Fibrinogen assay) to the EXTEM assay led to higher MCF values compared with those obtained with the FIBTEM assay. The MCF measurements were further decreased by the addition of similar amount of abciximab to the FIBTEM assay. These results indicate that cytochalasin D is more effective at blocking platelet function than abciximab in whole blood samples while neither cytochalasin D nor abciximab can achieve a full platelet function inhibition. Overall, these data suggest that abciximab has a more limited platelet function inhibition than cytochalasin D and that combining both inhibitors would achieve a stronger inhibition of the platelet contribution to clot formation and strength in whole blood samples. From an experimental perspective, this implies that the Functional Fibrinogen assay may overestimate the contribution of fibrin/fibrinogen compared with the FIBTEM assay in both whole blood or platelet-rich samples and that target values and therapeutic triggers optimized for the FIBTEM test cannot be directly applied to the Functional Fibrinogen test.

In addition to higher values of clot strength parameters reported with the Functional Fibrinogen assay compared with the FIBTEM assay regardless of the device (i.e., TEG® or ROTEM), higher values in clot strength have also been observed with the TEG® versus ROTEM devices regardless of the assay used (i.e., Functional Fibrinogen or FIBTEM assays).55 This reinforces the concept that values and treatment triggers for the Functional Fibrinogen and FIBTEM assays are not interchangeable and that further data and experience in specific clinical settings are required to integrate the TEG® Functional Fibrinogen assay parameters into therapy algorithms.

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CONCLUSIONS

When applying TEG® mono-analysis-based transfusion algorithms, it must be kept in mind that fibrinogen and platelets synergistically contribute to the formation and maintenance of clot strength. Thus, the mono-analysis α-angle and MA parameters from this assay cannot be used to accurately distinguish between the relative contribution of fibrin/fibrinogen and platelets to clot strength. Clinicians should be aware of this limitation when attempting to specifically correct a fibrinogen or platelet deficit during hemostatic therapy. In contrast, the fibrin-based tests, such as the ROTEM FIBTEM and TEG® Functional Fibrinogen, offer a better alternative to TEG® mono-analyses for identifying a deficit in platelet and/or fibrin/fibrinogen.

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DISCLOSURES

Name: Cristina Solomon, MD, MBA.

Contribution: This author helped design the study and wrote the manuscript.

Attestation: Cristina Solomon approved the final manuscript and attests to the integrity of the data presented and is also the archival author.

Conflicts of Interest: Cristina Solomon is an employee of CSL Behring and previously received speaker honoraria and research support from Tem International and CSL Behring, and travel support from Haemoscope Ltd (former manufacturer of TEG®).

Name: Herbert Schöchl, MD.

Contribution: This author helped prepare and critically revise the manuscript for important intellectual content.

Attestation: Herbert Schöchl approved the final manuscript.

Conflicts of Interest: Herbert Schöchl has received study grants and speaker fees from CSL Behring and Tem International.

Name: Marco Ranucci, MD.

Contribution: This author helped prepare and critically revise the manuscript for important intellectual content.

Attestation: Marco Ranucci approved the final manuscript.

Conflicts of Interest: Marco Ranucci received speaker honoraria and research support from CSL Behring and Grifols, speaker honoraria from Medtronic, Haemoscope, and Roche Diagnostics, research support from Tem International, and was on the Steering committee of a FXIII study (until 2010) for Novo Nordisk.

Name: Christoph J. Schlimp, MD

Contribution: This author helped in the design of the study and wrote the manuscript.

Attestation: Christoph J. Schlimp approved the final manuscript.

Conflicts of Interest: Christoph J. Schlimp has received research support and speaker fees from CSL Behring, and research support from Tem International.

This manuscript was handled by: Charles W. Hogue, Jr., MD.

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ACKNOWLEDGMENTS

Medical writing and editorial assistance with manuscript preparation was provided by Catherine Morgan, PhD, and Sandrine M. Dupré, PhD, at Meridian HealthComms (Plumley, UK), funded by CSL Behring.

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