Dr. Hellmut Hartert invented thromboelastography (TEG), the first viscoelastic test (VET), in Germany in 1948 (1). This was even before the activated partial thromboplastin time test (aPTT), which Langdell, Wagner, and Brinkhous first described in 1953 (2). Shortly after, rotational thromboelastometry (ROTEM) evolved from TEG. Both devices provide real-time visual assessment of clot formation and dissolution under low shear rate blood flow using so called cup and pin technology.
Clinical laboratories did not adopt VET widely until the introduction of a cell-based model of hemostasis in 1994, showing the importance of platelets and tissue factor in hemostasis. Their initial applications were limited to liver transplantation and cardiac surgeries.
Relying on conventional plasma-based coagulation testing (CCT) has proven difficult in managing trauma patients. The advent of data-driven algorithms using VET emerged as a reliable way to predict need for transfusion and to guide transfusion therapy in traumatic injury (3). The COVID-19 pandemic exponentially elevated the need for rapid assessment of COVID-19 patients’ hemostasis and appropriate management of their coagulopathy, as many patients with COVID-19 have an abnormally increased risk for blood clotting.
MODERNIZATION OF VISCOELASTICITY TESTING
Over the past two decades, the TEG 5000 (Haemonetics Corporation) and ROTEM delta (Werfen) have been the principal VET technologies, or “legacy devices.” Both technologies require personnel to pipette blood and are prone to human error. Another legacy linear motion system, Sonoclot (Sienco), is not widely used in the U.S. and will not be discussed here.
To improve precision, reduce the potential for human errors, and improve ease of performing the assay, companies recently have developed several new generations of cartridge-based automated VET that have received Food and Drug Administration (FDA) clearance for specific clinical indications. Advantages and limitations of these assays and their clinical indications are reviewed below.
TEG 6S
A new generation of thromboelastography, TEG 6s (Haemonetics), assesses blood viscoelastic properties by resonance technology (4). Alteration of resonance is measured by the light-emitting diode (LED). The collected data is converted into a graph that is identical to that used in the cup and pin method. Pneumatically controlled microfluidic cartridges improve sample handling and minimizes the effect of preanalytical variables that were affecting the original TEG device. However, it still requires specimen pipetting into the cartridge.
Currently, three TEG 6s cartridges are FDA-approved in the United States for adult patients: global hemostasis (GH) for cardiovascular surgeries, global hemostasis with lysis (GHL) for trauma coagulopathies, and platelet mapping (PM).
ROTEM SIGMA
The ROTEM sigma device (Werfen) is a completely automated cartridge-based device which eliminates specimen pipetting (4). A cup and pin system is still used, but it uses freeze-dried reagents.
The ROTEM sigma has two cartridges: ROTEM sigma complete and ROTEM sigma complete + hep. The ROTEM sigma complete cartridge discriminates between hyperfibrinolysis and platelet mediated clot retraction/FXIII deficiency and provides in vitro assessment of antifibrinolytic drug effect. The ROTEM sigma complete + hep detects heparin and heparin-like substances.
Recently, FDA approved ROTEM sigma use in adult patients to assess perioperative hemorrhage and/or thrombosis in cardiovascular surgery and liver transplantation.
QUANTRA
The Quantra System (HemoSonics) is a new device that assesses blood viscoelastic properties by a unique ultrasound-based technology called sonic estimation of elasticity via resonance (SEER) sonorheometry (4). The Quantra Analyzer is a cartridge-based, fully automated four-channel device. The cartridge is the only component of the device that is in direct contact with blood. The sample is introduced by directly attaching a standard 3.2% citrated whole blood tube to the input port of the cartridge. The sample is then automatically drawn into the cartridge to initiate testing. No sample pipetting is required.
Currently, two Quantra cartridges are FDA approved in the United States for adult patients: QPlus for use in the perioperative setting of cardiac and major orthopedic surgery (no lysis assessment) and Qstat for trauma and liver transplant surgery (allows lysis assessment).
Unlike TEG and ROTEM traces, Quantra results are displayed as dials or curves on a screen, which are more intuitive and easier to interpret.
Another important Quantra distinction from classical cup and pin technologies is that SEER sonorheometry directly measures the clot’s shear modulus in rational pascal units, an objective parameter that describes the elastic properties of a solid material. In contrast, TEG and ROTEM provide a rather indirect measurement of clot stiffness: maximum amplitude in millimeters (MA, mm) in TEG, or as maximum clot firmness also in millimeters (MCF, mm) in ROTEM.
CLOTPRO
The ClotPro (enicor) is a 6-channel viscoelastic cup and pin method like the original technologies of the TEG 5000 and ROTEM delta analyzers. ClotPro uses elastic motion thrombelastography, an improved next-generation viscoelastometry technique. It also has simplified the multiple manual pipetting and reagent preparation procedures with the use of a standard pipette. The pipette contains predosed reagents that activate on contact with the blood sample.
ClotPro is used mainly in Europe and is not FDA approved in the U.S. (3). Table 1 provides additional comparison of the next-generation FDA-approved VETs.
VETS AGREEMENT AND INTERCHANGEABILITY
The TEG 5000 uses a mechanical detection system (a pin suspended in a blood sample with a torsion wire that is monitored for motion). The TEG 6s measures clot viscoelasticity by using resonance technology, exposing the blood sample to a fixed vibration frequency.
Because TEG 6s and the TEG 5000 use different methods to assess similar coagulation components, there is a difference in absolute values of respective parameters of the two devices, and they are not interchangeable. Published studies in healthy donors, simple cardiac surgeries, and critically ill patients demonstrate strong correlation between the two devices especially for the reaction time (R) and MA parameters (5, 6). There was poor concordance between devices for the LY 30 parameter assessing fibrinolysis with a correlation coefficient of 0.33 (6). TEG 5000 based algorithms may not be interchangeably used for the TEG 6s device (6, 7).
The same cup and pin technology is used in the ROTEM delta and sigma devices. This allows for the use of the same algorithms that are already established for the ROTEM delta device.
In a small sample size study, the ROTEM sigma device was found to be precise and had results comparable to the ROTEM delta device (8). In a separate study comparing the TEG 6s with the ROTEM sigma, the authors observed strong correlations for R time, kinetic time, and alpha angle. Absolute values were substantially different between the two platforms (9).
Similarly, the Quantra showed a strong correlation with the ROTEM sigma for determining clot times and clot stiffness. However, these parameters were not directly interchangeable (10).
Whether legacy or next-generation devices, none can be used in a comparative setting. Each institution must establish its own device-specific reference ranges (4, 11, 12).
VET LIMITATIONS
Since VETs assess blood flow under low shear rate, they are not sensitive to von Willebrand disease (vWD) because activation of the vW factor requires high shear rate forces and collagen.
Due to the overwhelming effect of thrombin on platelets, VETs cannot detect specific platelet receptor abnormalities without the use of specialized VET assay modification known as TEG platelet mapping.
Detecting the hemostatic competence of patients treated with direct oral anticoagulants (DOACs) or warfarin also requires specialized reagents and testing. The standard TEG/ROTEM/Quantra activators activate a blood sample with a contact phase activator such as kaolin or ellagic acid. TEG 6s global and platelet mapping cartridges, Q Plus cartridges and ROTEM sigma complete + hep cartridges do not display the lysis parameter.
VETs have been widely used in pediatric patients, but they are FDA approved only for adults
VETS EXPAND ACROSS CLINICAL SETTINGS
The rapidly evolving COVID-19 pandemic has revealed a changing landscape around the acceptance of VETs in treating COVID-19 associated coagulopathy (CAC). Conventional coagulation tests (CCT) didn’t reflect the complexity of hemostatic alterations and were not available for immediate decision-making at the point of care. Clinicians managing severe COVID-19 were interested in using tests that could help
them quickly understand whether an individual patient was hypocoagulable, hypercoagulable, or had abnormal fibrinolysis.
In January 2021, FDA issued guidance allowing hospitals to use all FDA-approved VETs for COVID-19 patients. The agency indicated that using these devices in hospitals could provide real-time assessment of whole blood viscoelastic properties and aid in patient management.
In a short time, numerous case reports, as well as prospective, retrospective, and single-center observational studies, have been published using VETs to study and manage CAC (4). This rapid expansion of the literature on VETs and CAC led to increased adoption of next-generation VET at the bedside in a variety of other clinical settings including trauma, postpartum hemorrhage, extracorporeal mechanical oxygenation, surgical, and critical care medicine (12).
Without a doubt, VET is becoming part of patient management protocols in a variety of clinical settings. According to manufacturer Haemonetics, the
company will continue to expand the utilization of the new TEG 6s analyzer and support all TEG 5000 users only until March 31, 2029. After this date, they do not intend to sell or service any TEG 5000 analyzers or disposables. Werfen likely will also follow Haemonetics in withdrawing ROTEM delta from the market.
Which of the next-generation VETs is more closely representative of true hemostatic alterations, including fibrinolysis, is a question that further research will need to elucidate.
Oksana Volod, MD, is director of coagulation consultative service and professor of pathology at Cedars-Sinai Medical Center. She is also associate professor of pathology at the David Geffen School of Medicine at the University of California, Los Angeles. +Email: [email protected]
REFERENCES
- Hartert, H. Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschr 1948; doi: 10.1007/BF01697545
- Langdell RD, Wagner RH, Brinkhous KM. Effect of anti-hemophilic factor on one-stage clotting tests: a presumptive test for hemophilia and a simple one-stage anti-hemophilic factor assay procedure. J Lab Clin Med 1953; doi: 10.5555/uri:pii:0022214353903126
- Baksaas-Aasen K, Van Dieren S, Balvers K, et al. Data-driven development of ROTEM and TEG algorithms for the management of trauma hemorrhage: a prospective observational multicenter study. Ann Surg 2019; doi: 10.1097/SLA.0000000000002825
- Volod O, Bunch CM, Zackariya N, et al. Viscoelastic hemostatic assays: a primer on legacy and new generation devices. J Clin Med 2022; doi: 10.3390/jcm11030860
- Gurbel PA, Bliden KP, Tantry US, et al. First report of the point-of-care TEG: a technical validation study of the TEG-6S system. Platelets 2016; doi: 10.3109/09537104.2016.1153617
- Lloyd-Donald P, Churilov L, Zia F, et al. Assessment of agreement and interchangeability between the TEG5000 and TEG6S thromboelastography haemostasis analysers: A prospective validation study. BMC Anesthesiol 2019; doi: 10.1186/s12871-019-0717-7
- Neal MD, Moore EE, Walsh M, et al. A comparison between the TEG 6s and TEG 5000 analyzers to assess coagulation in trauma patients. J. Trauma Acute Care Surg 2020; doi: 10.1097/TA.0000000000002545.
- Schenk B, Gorlinger K, Treml B, et al. A comparison of the new ROTEM® sigma with its predecessor, the ROTEM delta. Anaesthesia 2019; doi: 10.1111/anae.14542
- Ziegler B, Voelckel W, Zipperle J, et al. Comparison between the new fully automated viscoelastic coagulation analyzers TEG 6s and ROTEM Sigma in trauma patients: a prospective observational study. Eur J Anaesthesiol 2019; doi: 10.1097/EJA.0000000000001032
- Baulig W, Akbas S, Schütt PK, et al. Comparison of the resonance sonorheometry based Quantra® system with rotational thromboelastometry ROTEM® sigma in cardiac surgery −a prospective observational study. BMC Anesthesiol 2021; doi: 10.1186/s12871-021-01469-5
- Bareille M, Lecompte T, Mullier F, et al. Are viscoelastometric assays of old generation ready for disposal? Comment on Volod et al. Viscoelastic hemostatic assays: a primer on legacy and new generation devices." J Clin Med 2023; doi: 10.3390/jcm12020477
- Volod O, Bunch CM, Miller J, et al. Reply to Bareille et al. Are viscoelastometric assays of old generation ready for disposal? Comment on "Volod et al. Viscoelastic hemostatic assays: a primer on legacy and new generation devices." J Clin Med 2023; doi: 10.3390/jcm12020478