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. 2022, 11, 860

With the advent of new viscoelastometric hemostatic assay (VHA) devices, with ready-to-use cartridge reagents allowing for their use by people without special laboratory skills, the appreciation of the actual clinical value of VHAs in settings such as severe trauma, post-partum hemorrhage, cardiac surgery and liver transplantation still needs to be fully validated. While two of the newest versions remain based on a ‘cup and pin’ system (ROTEM® sigma, ClotPro®), two other new devices (TEG® 6s, Quantra®) rely on very different technologies: clotting blood is no longer in contact with the probe and challenged by oscillation of one of the components but explored with ultrasound exposure. A systematic literature search (including Sonoclot®) retrieved 20 observational studies (19 prospective). Most studies pointed to imperfect agreements, highlighting the non-interchangeability of devices. Only a few studies, often with a limited number of patients enrolled, used a clinical outcome. No study compared VHA results with conventional laboratory assays obtained through a rapid tests panel. Clinical evidence of the utility of the new VHAs largely remains to be proven through randomized clinical trials, with clinically relevant outcomes, and compared to rapid panel hemostasis testing. The availability of new, improved VHA devices provides an impetus and an opportunity to do so.

We read with much interest the review by Volod et al. on what they named viscoelastic hemostatic assays (VHAs)-the measurement of changes in mechanical (elastic) properties of a growing and evolving clot of whole blood. The authors are to be commended for the overview of the devices currently available in clinical practice [1]. We would like, however, to raise some concerns about their actual documented clinical usefulness and as a result express a less enthusiastic view.
The authors claim that VHAs have become essential in some surgical settings such as severe trauma, cardiac surgery and liver transplantation. Some others have advocated for the use of VHAs in the diagnosis [2] and the perioperative management of patients with inherited fibrinogen disorders [3]. Even though we do not deny the educational value of VHAs and their popularity, we would like to dampen the appreciation of their actual clinical value. Cardiac surgery is, indeed, one of the clinical settings where the contribution of VHAs has been the most studied and has shown a potential benefit if integrated in a transfusion algorithm, with a decrease in mortality when a VHA-guided algorithm is preferred to a lab-guided algorithm [4][5][6][7]. In severe trauma, however, only one randomized study found a positive effect on mortality of the VHA-guided transfusion algorithm [8]. Finally, in other settings such as liver transplantation or post-partum hemorrhage, the most important is to use a transfusion algorithm and to not delay antifibrinolytic administration, keeping in mind that VHAs lack sensitivity to hyperfibrinolysis [9][10][11][12].
As stated by the authors, ROTEM ® sigma and ClotPro ® remain based on a 'cup and pin' system, whereas two other new devices are based on very different technologies: the TEG ® 6s Hemostasis Analyzer (Haemonetics Corporation, Boston, MA, USA) and the Quantra ® device (HemoSonics, LLC, Charlottesville, VA, USA); clotting blood is no longer in contact with the probe and challenged by oscillation of one of the components but explored with ultrasound exposure. Although available for a while, we wish also to consider the Sonoclot ® analyzer (Sienco, Morrison, CO, USA), since it too does not rely on the 'cup and pin' system: it monitors along clotting the changes in impedance to the movement of a probe inserted in the blood sample and vibrating at an ultrasonic frequency [13]. The critical question as to whether the results of clinical studies conducted with an old generation of VHAs based on a 'cup and pin' system can be extrapolated to operating rooms or intensive care units where another device of substantially different technology is implemented is unfortunately left unaddressed by the authors. It is of interest too to look at the comparative performances of the two older versions of VHAs based on a 'cup and pin' system: ROTEM ® sigma and ClotPro ® .
We thus performed a systematic literature search in PubMed and Scopus databases, using the following keywords: "ROTEM ® sigma OR TEG ® 6s OR Quantra ® OR Sonoclot ® OR ClotPro ® " AND "trauma OR postpartum hemorrhage OR cardiac surgery OR liver transplantation", to assess the level of evidence currently available for the use of those devices in operating rooms and/or intensive care units. The last search was conducted on 12 August 2022 and included all studies published whether in English, French or Italian. Among the 20 retrieved studies, all observational, 19 were prospective, and most of them were conducted in the field of cardiac surgery (N = 13); three evaluated VHAs in the field of trauma, two studied VHAs during post-partum hemorrhage, and two during liver transplantation (Table). The comparator was variablean older VHA (of the same company (ROTEM devices, TEG devices) or not) and/or a new one as well, with sometimes standard laboratory results and/or clinical endpoints, among which was Clauss fibrinogen. Of note, we found that most studies with Sonoclot ® were performed in cardiac surgery (four out of the five retrieved studies); ROTEM ® sigma was the only one studied during post-partum hemorrhage (in total, six studies with ROTEM ® sigma); TEG ® and Quantra ® devices were studied five times (across all settings but post-partum hemorrhage and only trauma and cardiac surgery, respectively), whereas ClotPro ® was just once, and with the tPA test only (liver transplantation). The way the comparison was analyzed was variable (see Table 1); of note, only parameters dealing with the same aspect of clotting blood in response to a similar initiation (tissue factor or contact phase activator), or with fibrinogen levels, should be compared.   Overall, the studies often pointed to imperfect agreements, often only moderate, particularly when results were outside the normal ranges; thus, the devices were often deemed not interchangeable. Each device and/or clinical setting needs their own cut-off values and algorithms. It would have been more relevant to analyze the number of cases with such a disagreement that the clinical decision would have been affected based on algorithms with cut-off values. A better agreement is expected between devices of the same brand, or between devices relying on the old 'cup-and-pin' system. It should be pointed out that the conclusions of the two studies that compared the two ROTEM ® devices delta and sigma-one in trauma [15], one in PPH [16]-out of the six studies with ROTEM ® sigma, substantially differed: there was agreement that ROTEM ® -based algorithms may be transposed from a trauma center to another for the former [15], whereas for the latter, ROTEM ® -based algorithms should be based on device-specific reference values [16].
Of note, only a few studies [19,21,25,27], often with a limited number of patients enrolled, used a clinical outcome in terms of bleeding, transfusion needs, or survival. Randomized controlled trials are still needed to confirm the clinical utility of the new devices. Moreover, none of these studies compared VHA results with conventional laboratory assays obtained through a rapid tests panel. Indeed, clinically relevant and reliable results suitable for acute patient care can be obtained in 20 min through a specific and dedicated laboratory process [34,35]. Owing to the importance ascribed to rapid fibrinogen assessment, the most important point to be checked before implementing a new device is the comparison with values obtained either in the laboratory (Clauss method) and/or the hitherto used VHA device, depending on the local environment. In this regard, such testing could also be of interest to monitor fibrinogen supplementation in patients with inherited fibrinogen disorders.
Another important aspect regards whether internal quality control is provided. A noticeable asset of TEG ® 6s and Quantra ® devices, as well as of ClotPro ® (Haemonetics Corporation, Boston, MA, USA) and ROTEM ® sigma ones, is that they are fully automated, thus making their use very convenient by eliminating pipetting stages. On the other hand, research protocols to investigate what is at stake during normal and disordered changes in viscoelastic properties of a clotting blood sample are rendered more difficult, or even impossible to conduct, since it is no longer possible to vary the experimental conditions for clotting.
As discussed by the authors, VHAs present some limitations. Besides the lack of consideration of the plasma inhibitors of coagulation and of the endothelial components of the hemostatic system (collagen, thrombomodulin, and so forth) [36], one must keep in mind that VHAs lack sensitivity towards hyperfibrinolysis [10][11][12], which is a major concern in trauma, liver transplantation, cardiac surgery and post-partum hemorrhage. Moreover, the ability of those devices to fully assess platelet function is questionable (in particular, the pre-operative estimation of the residual effect of anti-platelet therapy), even with the sophisticated TEG ® Platelet Mapping approach [37].
The authors devote a large part of the discussion to the COVID-19-related so-called 'coagulopathy' (it should in fact be named disordered hemostasis, since all its components are affected). Indeed, severe COVID-19 patients can exhibit both thrombotic and hemorrhagic complications. If VHAs contributed to the study of this 'coagulopathy' to some extent (keeping in mind that VHA assays are very sensitive to high fibrinogen plasma levels), that they helped manage is in our opinion an overstatement [38]. Overall, to the best of our knowledge, no firm evidence currently exists about the diagnostic and treatment of what can be considered hypercoagulability with any VHA.
Lastly, the assessment of anticoagulant drugs is mostly restricted to the gross appreciation of residual heparinization post cardiopulmonary bypass cardiac surgery, apart from the dedicated cartridges for direct oral anticoagulants supplied with the ClotPro ® device [39].
To conclude, clinical evidence of the utility of VHAs largely remains to be proven through randomized clinical trials, with clinically relevant outcomes, and compared to rapid panel hemostasis testing. The availability of new, improved VHA devices provides an impetus and an opportunity to do so, at last.