“TEG” talks: technology worth spreading?

Abstract

Recently, in Research and Practice in Thrombosis and Haemostasis, Hartmann and colleagues have authored a comprehensive and aesthetically pleasing illustrated review on viscoelastic testing (VET), including thromboelastography (TEG), rotational thromboelastometry (ROTEM), and newer resonance based viscoelastic technologies. They visually describe and discuss viscoelastic technology, its 70-year history and recent growth, its various applications based on existing evidence and clinical case studies, and finally, barriers to widespread adoption and possible solutions to overcome this. VET offers a complete picture of the entire genesis and breakdown of blood coagulation at the point of care [[1]Selby R. “TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry.Hematology Am Soc Hematol Educ Program. 2020; 2020: 67-75Crossref PubMed Google Scholar]. Activation of coagulation, initiation of thrombin generation, formation and stabilization of the clot, and eventual fibrinolysis are all represented, visually as a graph and quantitatively as parameters. All elements that participate in secondary hemostasis are involved: clotting factors, platelets, fibrinogen, and initiators of fibrinolysis. Various activators and inhibitors of coagulation, platelets, and fibrinolysis have allowed the development of customized assays and assay profiles that enable indication-specific management of bleeding and coagulopathy [[1]Selby R. “TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry.Hematology Am Soc Hematol Educ Program. 2020; 2020: 67-75Crossref PubMed Google Scholar,[2]Volod O. Bunch C.M. Zackariya N. Moore E.E. Moore H.B. Kwaan H.C. et al.Viscoelastic hemostatic assays: a primer on legacy and new generation devices.J Clin Med. 2022; 11: 860Crossref PubMed Scopus (15) Google Scholar]. Conventional coagulation tests (CCTs) that assess a single component of the coagulation pathway—the prothrombin time, activated partial thromboplastin time, fibrinogen quantitation, or assessment of platelet count—have known disadvantages in the assessment of bleeding and coagulopathy. Firstly, prothrombin time and activated partial thromboplastin time are insensitive as global screening tests [[3]Chornenki N.L.J. Fralick M. Sholzberg M. International normalized ratio and activated partial thromboplastin time testing.CMAJ. 2022; 194: E1135Crossref Google Scholar,[4]Hayward C.P. Moffat K.A. Laboratory testing for bleeding disorders: strategic uses of high and low-yield tests.Int J Lab Hematol. 2013; 35: 322-333Crossref PubMed Scopus (0) Google Scholar]. Secondly, no CCT can assess fibrinolysis [[4]Hayward C.P. Moffat K.A. Laboratory testing for bleeding disorders: strategic uses of high and low-yield tests.Int J Lab Hematol. 2013; 35: 322-333Crossref PubMed Scopus (0) Google Scholar], and most importantly, laboratory test results are not available fast enough to allow for immediate and goal-directed resuscitation in urgent and dynamic situations, such as the management of major bleeding in various clinical settings. Complex coagulopathies are complex, in part because hypo- and hypercoagulability can coexist in the same patient. They may present either sequentially, as in some major trauma patients [[5]Gonzalez E. Moore E.E. Moore H.B. Chapman M.P. Chin T.L. Ghasabyan A. et al.Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.Ann Surg. 2016; 263: 1051-1059Crossref PubMed Scopus (384) Google Scholar,[6]Baksaas-Aasen K. Gall L.S. Stensballe J. Juffermans N.P. Curry N. Maegele M. et al.Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.Intensive Care Med. 2021; 47: 49-59Crossref PubMed Scopus (75) Google Scholar], or simultaneously, as in patients with liver disease or those anticoagulated on extracorporeal membrane oxygenation circuits [7Mpaili E. Tsilimigras D.I. Moris D. Sigala F. Frank S.M. Hartmann J. et al.Utility of viscoelastic coagulation testing in liver surgery: a systematic review.HPB (Oxford). 2021; 23: 331-343Abstract Full Text Full Text PDF Scopus (9) Google Scholar, 8Yoon U. Bartoszko J. Bezinover D. Biancofiore G. Forkin K.T. Rahman S. et al.Intraoperative transfusion management, antifibrinolytic therapy, coagulation monitoring and the impact on short-term outcomes after liver transplantation—a systematic review of the literature and expert panel recommendations.Clin Transplant. 2022; 36e14637Crossref Scopus (7) Google Scholar, 9Jiritano F. Fina D. Lorusso R. Ten Cate H. Kowalewski M. Matteucci M. et al.Systematic review and meta-analysis of the clinical effectiveness of point-of-care testing for anticoagulation management during ECMO.J Clin Anesth. 2021; 73110330Crossref PubMed Scopus (3) Google Scholar]. Coagulopathy of sepsis or malignancy may present as end-organ dysfunction from microthromboses or bleeding due to consumptive coagulopathy, in different patients [[10]Scarlatescu E. Juffermans N.P. Thachil J. The current status of viscoelastic testing in septic coagulopathy.Thromb Res. 2019; 183: 146-152Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,[11]Walsh M. Moore E.E. Moore H. Thomas S. Lune S.V. Zimmer D. et al.Use of viscoelastography in malignancy-associated coagulopathy and thrombosis: a review.Semin Thromb Hemost. 2019; 45: 354-372Crossref Scopus (21) Google Scholar]. Given the known disadvantages of CCT discussed above, VET, in principle, with its ability to detect both hypo-and hypercoagulability (including disordered fibrinolysis), dynamically and at the bedside, represents the ideal technology to diagnose and guide the management of patients with complex coagulopathies. What then impedes the widespread adoption of this technology for all these described indications? Let us consider the major barriers. •Lack of rigorous diagnostic accuracy and interoperator precision studies. Rigorous diagnostic accuracy studies defining the sensitivity and specificity of various parameters of the viscoelastic tracing and studies evaluating the interoperator reproducibility for the different parameters are lacking. A recent quantitative meta-analysis used Cochrane methodology to assess the predictive accuracy of point-of-care, viscoelastic, and platelet function tests for bleeding after cardiac surgery [[12]Woźniak M.J. Abbasciano R. Monaghan A. Lai F.Y. Corazzari C. Tutino C. et al.Systematic review and meta-analysis of diagnostic test accuracy studies evaluating point-of-care tests of coagulopathy in cardiac surgery.Transfus Med Rev. 2021; 35: 7-15Crossref Scopus (2) Google Scholar]. Twenty-nine studies with 7440 participants were included, of which 14 studies evaluated the diagnostic accuracy of VET using the QUADAS-2 tool to assess quality. The authors found limited validity due to significant concerns about bias, applicability, and heterogeneity in all the included studies, stemming from selection bias in the cohorts studied and lack of standardization of diagnostic parameters and reference standards (clinical outcomes). GRADE assessment for the quality of evidence for VET was low. Studies evaluating diagnostic accuracy for indications other than cardiac surgery, and studies assessing the reproducibility of parameters between operators are singularly lacking [[1]Selby R. “TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry.Hematology Am Soc Hematol Educ Program. 2020; 2020: 67-75Crossref PubMed Google Scholar].•The pitfalls of observational and single-institution studies. Decades of observational and single-center randomized controlled trials (RCTs) using VET-guided resuscitation protocols to manage trauma hemorrhage and coagulopathy suggest that VET-based algorithms reduce the need for blood products with a trend toward lowering mortality [[5]Gonzalez E. Moore E.E. Moore H.B. Chapman M.P. Chin T.L. Ghasabyan A. et al.Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.Ann Surg. 2016; 263: 1051-1059Crossref PubMed Scopus (384) Google Scholar,[13]Da Luz L.T. Nascimento B. Shankarakutty A.K. Rizoli S. Adhikari N.K.J. Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review.Crit Care. 2014; 18: 518Crossref PubMed Scopus (196) Google Scholar]. Despite significant concerns about the virtual absence of evidence for the diagnostic accuracy of VET in trauma [[14]Hunt H. Stanworth S. Curry N. Woolley T. Cooper C. Ukoumunne O. et al.Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding.Cochrane Database Syst Rev. 2015; : CD010438PubMed Google Scholar], recommendations to use VET-guided protocols in trauma have found their way (with acknowledgment of the need for large RCTs) into major trauma guidelines [[15]Inaba K. Rizoli S. Veigas P.V. Callum J. Davenport R. Hess J. et al.2014 Consensus conference on viscoelastic test-based transfusion guidelines for early trauma resuscitation: report of the panel.J Trauma Acute Care Surg. 2015; 78: 1220-1229Crossref PubMed Scopus (0) Google Scholar,[16]Bugaev N. Como J.J. Golani G. Freeman J.J. Sawhney J.S. Vatsaas C.J. et al.Thromboelastography and rotational thromboelastometry in bleeding patients with coagulopathy: practice management guideline from the Eastern Association for the Surgery of Trauma.J Trauma Acute Care Surg. 2020; 89: 999-1017Crossref PubMed Scopus (38) Google Scholar]. From 2008 to 2013, Baksaas-Aasen et al. [[17]Baksaas-Aasen K. Van Dieren S. Balvers K. Juffermans N.P. Næss P.A. Rourke C. et al.Data-driven development of ROTEM and TEG algorithms for the management of trauma hemorrhage: a prospective observational multicenter study.Ann Surg. 2019; 270: 1178-1185Crossref PubMed Scopus (0) Google Scholar] collected admission data from both CCT and VET at 6 European trauma centers and identified VET parameters that had 70% sensitivity in predicting trauma-induced coagulopathy, which was defined as an international normalized ratio >1.2, fibrinogen <2 g/L, and platelet count <100 × 10/L. These validated threshold parameters for TEG, ROTEM, and CCT were then incorporated into algorithms to guide data-driven blood product administration during major hemorrhage protocols after trauma. They were also evaluated in an RCT at the same institutions [[6]Baksaas-Aasen K. Gall L.S. Stensballe J. Juffermans N.P. Curry N. Maegele M. et al.Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.Intensive Care Med. 2021; 47: 49-59Crossref PubMed Scopus (75) Google Scholar]. The primary outcome was the proportion of patients alive and free of massive transfusion (≥10 red blood cell transfusions) at 24 hours after injury. Secondary outcomes included 28-day mortality. Prespecified subgroups included patients with severe traumatic brain injury (TBI). In the 201 patients allocated to VET-assisted and 195 patients allocated to CCT-assisted hemorrhage protocols, there were no differences between the 2 groups in any outcome. The only prespecified subgroup that showed a difference in the primary outcome of massive transfusion in favor of VET was the subgroup of patients with TBI (odds ratio, 2.12; 95% CI, 0.84-5.34). Thus, VET-guided transfusion protocols did not reduce massive transfusion or mortality after trauma in the first, well-validated, multicentre RCT. Although the above example refers to the trauma population, the majority of indications for which VET is currently recommended are based on low-quality evidence from small, single-institution, heterogeneous studies with unproven generalizability [[1]Selby R. “TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry.Hematology Am Soc Hematol Educ Program. 2020; 2020: 67-75Crossref PubMed Google Scholar].•Considerations of complexity and cost. VET tracings produce sequential parameters of coagulation activation, thrombin generation, clot stabilization, and breakdown that require both visual and quantitative interpretation by the user. If several VET assays are run in parallel, such as with and without heparinase or with and without platelet agonists, they need to be interpreted together to determine the relative contribution of anticoagulation or antiplatelet effect, respectively. This inherent complexity along with the fast pace of urgent clinical situations in which VET is used and constantly changing health care providers requires a large group of users to be competent and experienced in the testing, including running regular quality control, interpreting test results, troubleshooting errors, and maintaining competency over time. Unlike CCT, in which automation and high volumes significantly reduce the cost per assay, viscoelastic assays are single-use tests. Therefore, each assay added increases the total overall cost. Given that VET technology has a significant advantage in interpreting complex and dynamic changes in coagulation, what would be the most effective strategy to increase adoption in a way that has a favorable benefit: cost ratio without causing unintended harm? First, we need to conduct large and rigorous studies in patients with complex coagulopathies, in whom VET has a unique advantage in providing information and CCT may be misleading (eg, liver disease) or cannot detect the defect (eg, hyperfibrinolysis after TBI) [5Gonzalez E. Moore E.E. Moore H.B. Chapman M.P. Chin T.L. Ghasabyan A. et al.Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.Ann Surg. 2016; 263: 1051-1059Crossref PubMed Scopus (384) Google Scholar, 6Baksaas-Aasen K. Gall L.S. Stensballe J. Juffermans N.P. Curry N. Maegele M. et al.Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.Intensive Care Med. 2021; 47: 49-59Crossref PubMed Scopus (75) Google Scholar, 7Mpaili E. Tsilimigras D.I. Moris D. Sigala F. Frank S.M. Hartmann J. et al.Utility of viscoelastic coagulation testing in liver surgery: a systematic review.HPB (Oxford). 2021; 23: 331-343Abstract Full Text Full Text PDF Scopus (9) Google Scholar, 8Yoon U. Bartoszko J. Bezinover D. Biancofiore G. Forkin K.T. Rahman S. et al.Intraoperative transfusion management, antifibrinolytic therapy, coagulation monitoring and the impact on short-term outcomes after liver transplantation—a systematic review of the literature and expert panel recommendations.Clin Transplant. 2022; 36e14637Crossref Scopus (7) Google Scholar]. Systematic study of such patient groups in a step-by-step manner involves establishing the diagnostic accuracy of standardized VET parameters, determining correlations between individual parameter thresholds and “reference standards” (standardized clinical outcomes), and assessing the independent contribution of VET-guided clinical management compared to the standard of care in pragmatically designed, multi-institution RCTs. Although seemingly daunting, such systematic studies have been conducted by 2 groups of investigators using VET during bleed management in both cardiac surgery and major trauma [[6]Baksaas-Aasen K. Gall L.S. Stensballe J. Juffermans N.P. Curry N. Maegele M. et al.Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.Intensive Care Med. 2021; 47: 49-59Crossref PubMed Scopus (75) Google Scholar,17Baksaas-Aasen K. Van Dieren S. Balvers K. Juffermans N.P. Næss P.A. Rourke C. et al.Data-driven development of ROTEM and TEG algorithms for the management of trauma hemorrhage: a prospective observational multicenter study.Ann Surg. 2019; 270: 1178-1185Crossref PubMed Scopus (0) Google Scholar, 18Mace H. Lightfoot N. McCluskey S. Selby R. Roy D. Timoumi T. et al.Validity of thromboelastometry for rapid assessment of fibrinogen levels in heparinized samples during cardiac surgery: a retrospective, single-center, observational study.J Cardiothorac Vasc Anesth. 2016; 30: 90-95Abstract Full Text Full Text PDF PubMed Google Scholar, 19Karkouti K. McCluskey S.A. Callum J. Freedman J. Selby R. Timoumi T. et al.Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis.Anesthesiology. 2015; 122: 560-570Crossref PubMed Scopus (63) Google Scholar, 20Karkouti K. Callum J. Wijeysundera D.N. Rao V. Crowther M. Grocott H.P. et al.Point-of-care hemostatic testing in cardiac surgery: a stepped-wedge clustered randomized controlled trial.Circulation. 2016; 134: 1152-1162Crossref PubMed Google Scholar]. In a series of studies, Karkouti et al. first validated ROTEM parameter thresholds for the FIBTEM assay, demonstrating its validity as a method for accurately estimating the fibrinogen concentration during cardiopulmonary bypass [[18]Mace H. Lightfoot N. McCluskey S. Selby R. Roy D. Timoumi T. et al.Validity of thromboelastometry for rapid assessment of fibrinogen levels in heparinized samples during cardiac surgery: a retrospective, single-center, observational study.J Cardiothorac Vasc Anesth. 2016; 30: 90-95Abstract Full Text Full Text PDF PubMed Google Scholar]. They then incorporated it into an institution-based, standardized algorithm that demonstrably reduced transfusions in coagulopathic bleeding after cardiac surgery [[19]Karkouti K. McCluskey S.A. Callum J. Freedman J. Selby R. Timoumi T. et al.Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis.Anesthesiology. 2015; 122: 560-570Crossref PubMed Scopus (63) Google Scholar]. Finally, they confirmed its generalizability and benefits over standard care across 12 hospitals in a cluster randomized RCT [[20]Karkouti K. Callum J. Wijeysundera D.N. Rao V. Crowther M. Grocott H.P. et al.Point-of-care hemostatic testing in cardiac surgery: a stepped-wedge clustered randomized controlled trial.Circulation. 2016; 134: 1152-1162Crossref PubMed Google Scholar]. Similarly, in trauma patients, Baksaas-Aasen et al. [[17]Baksaas-Aasen K. Van Dieren S. Balvers K. Juffermans N.P. Næss P.A. Rourke C. et al.Data-driven development of ROTEM and TEG algorithms for the management of trauma hemorrhage: a prospective observational multicenter study.Ann Surg. 2019; 270: 1178-1185Crossref PubMed Scopus (0) Google Scholar] first led a multicenter effort to define threshold parameters for ROTEM and TEG and then incorporated these parameters into algorithms to guide transfusions while resuscitating major trauma hemorrhage. They then conducted an RCT at the same institutions comparing VET to CCT-guided interventions and assessing the independent contribution of VET on standardized, clinically relevant outcomes [[6]Baksaas-Aasen K. Gall L.S. Stensballe J. Juffermans N.P. Curry N. Maegele M. et al.Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.Intensive Care Med. 2021; 47: 49-59Crossref PubMed Scopus (75) Google Scholar]. Second, once the goal of introducing VET for a specific indication after evaluating the supporting evidence is articulated, it is critical to consider several factors prior to implementation [[1]Selby R. “TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry.Hematology Am Soc Hematol Educ Program. 2020; 2020: 67-75Crossref PubMed Google Scholar]. Clinicians must ensure that best transfusion practices are being followed. It is possible that some of the benefits attributable to VET may be because VET implementation often leads to a renewed focus on standardizing transfusion practice. If the only reason for considering VET is that a faster turnaround time is needed, then this can be achieved with CCT and implementation of a “stat” protocol for specific indications. VET implementation should be an interdisciplinary effort between clinicians and laboratory to select the device and assay(s), locally verify the accuracy and precision of VET parameters, set up an ongoing quality assurance program to ensure accuracy and precision of results, result reporting according to local accreditation standards, and ongoing training and competency of operators. Finally, the significant costs of VET should be considered. It is possible that there may be downsides to scaling up, since accurate cost effectiveness estimates about real world implementation of evidence-based interventions in health care are difficult to determine [[21]Zomahoun H.T.V. Charif A.B. Freitas A. Garvelink M.M. Menear M. Dugas M. et al.The pitfalls of scaling up evidence-based interventions in health.Glob Health Action. 2019; 121670449Crossref Scopus (17) Google Scholar].