Point-of-care viscoelastic testing

Learning objectives.

By reading this article you will be able to:

• •Describe the principles, technology, uses and advantages of viscoelastic testing (VET)
• •Interpret VET results with apply them to clinical practice
• •Recall the nuances of VET use in specific specialties

Key points.

• •Point-of-care viscoelastic testing (VET) offers near-patient, rapid, global assessment of haemostasis, which is useful in the dynamic setting of acute bleeding.
• •Viscoelastic testing evaluates clot initiation, strength, dynamics and breakdown.
• •Newer, more user-friendly devices are leading to the more widespread use of VET.
• •Viscoelastic testing is of particular benefit in certain subspecialties
• •The tailored approach that VET facilitates can reduce transfusion requirements

Point-of-care viscoelastic testing (VET) offers real-time rapid assessment of haemostasis. It has the advantages of a faster turnaround time and global evaluation of haemostatic function compared with conventional coagulation tests (CCTs). The focus is not only on the initiation of coagulation, but also assessment of clot strength, dynamics and breakdown, reflecting the complexities of the now widely accepted cell-based model of coagulation. This allows for a more targeted and rationalised approach to perioperative transfusion. Inappropriate transfusion of blood products not only wastes a scarce resource but has been shown to have a negative association with patients' outcomes. The development of new VET technology is enhancing their ease of use, allowing for their more widespread incorporation into clinical practice.

This review outlines the principles and technology used in VET, describes its clinical applicability, focuses on the nuances of its use in subspecialties and highlights limitations for consideration.

The cell-based model of coagulation

The cell-based model is a key advancement in the understanding of haemostasis and acknowledges the vital role of cellular components of blood. Activation of coagulation in vivo occurs on cells that express tissue factor and involves a dynamic, interactive network of processes. This model has four stages; initiation, amplification, propagation and stabilisation. Clinically relevant deviations of ‘normal clotting’ can affect the time taken to form a clot, the dynamics and maximal strength of the clot, and finally its appropriate and controlled dissolution.

Key steps in coagulation involve the activation of platelets and the generation of thrombin. Thrombin cleaves fibrinogen to form insoluble fibrin monomers that spontaneously polymerise to form an insoluble fibrin clot. Subsequently, factor XIII, after activation by thrombin, crosslinks fibrin molecules to reinforce the fibrin network protecting it from premature breakdown.

Limitations of CCTs

Conventional coagulation tests (prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen) measure the acellular clotting process using plasma, not whole blood, reflecting the activity and concentration of procoagulant proteins. They have an important role in the investigation and management of coagulopathy, namely for the detection and characterisation of factor deficiencies and anticoagulant therapy monitoring. However, the section of global haemostasis measured is limited, reflecting the time taken for fibrin strand formation in vitro. Furthermore, CCTs are blind to platelet, von Willebrand factor (vWF), natural anticoagulants and fibrinolytic activity, without which analysis of overall haemostasis is incomplete. Finally, an important limitation in the context of acute major haemorrhage is the length of time required to obtain results.

Viscoelastic point of care devices

Viscoelastic testing allows the measurement and visual representation of the changing viscoelastic properties of whole blood as coagulation occurs. It provides a rapid assessment of the initiation process, clot strength and stability, along with clot retraction and dissolution. Rotational thromboelastometry (ROTEM) (Tem International GmbH, Munich, Germany) and thromboelastography (TEG) (Haemonetics Corporation, Braintree, MA, USA) have been the main providers to date, although similar devices are available (e.g. Sonoclot; Sienco Inc., Morrison, CO, USA).

Original TEG and ROTEM technologies involve placing a sample of whole blood with an activator into a cup with a pin at its centre. With TEG, the cup rotates and with ROTEM, the pin – rather than the cup – rotates around a circulating axis (Fig 1). The initiation of fibrin strand formation occurs, adhering the pin to the cup wall, causing impediment to rotation as the blood clots. With TEG, the pin starts to move in concert with the cup in each direction. In contrast, with ROTEM the adherence of fibrin between the cup and pin causes a reduction in movement of the pin. The blood clotting leads to the development of the TEG/ROTEM trace (Fig 2, Table 1), the interpretations of which are similar but not identical, with different reference ranges and non-interchangeable parameters. Fibrinolysis causes a discontinuation of this coordinated pin and cup movement, seen as a narrowing of the trace.

Fig. 1.

Schematic representing technologies used in thromboelastometry (ROTEM) and thromboelastrography (TEG). ROTEM, rotational thromboelastometry.

Fig. 2.

Schematic representing normal TEG & ROTEM traces with abnormalities or deficiencies (green) in addition to corrective therapy (purple) (A). Common abnormal traces (B). CFT, clot formation time; CT, clotting time; DDVAP, desmopressin; MA, maximum amplitude; MCF, maximum clot firmness.

Table 1.

Summary of abnormalities and advisable blood products. CFT, clot formation time; FFP, fresh frozen plasma; MA, maximum amplitude; MCF, maximum clotting firmness; PCC, prothrombin complex concentrate; ROTEM, rotational thromboelastometry; TEG, thromboelastography.

Value (TEG/ROTEM)	Represents	Abnormality reflected	Products to consider
R time/CT	Speed of fibrin formation - Time taken to reach 2 mm amplitude	Prolongation -Clotting factor deficiencies -Anticoagulants -Low fibrinogen	-FFP -PCC -Heparin reversal
K time/CFT	Kinetics of fibrin binding to platelets - Time between 2 mm and 20 mm amplitude	Prolongation/decreased angle -Low fibrinogen -Low/dysfunctional platelets	-Cryoprecipitate -Fibrinogen concentrate
Alpha angle	- Angle between the baseline and a slope between the split point and 20 mm points
MA/MCF	Clot strength - Greatest vertical amplitude of trace	Low amplitude -Low fibrinogen -Low platelets -Platelet dysfunction	-Cryoprecipitate -Fibrinogen concentrate -Platelets -DDAVP
LY30/LI30	Clot stability/lysis - % reduction in amplitude 30 min after MA/MCF	Elevated -Hyperfibrinolysis	-Tranexamic acid -Aminocaproic acid

Both TEG and ROTEM have now introduced automated devices; TEG 6s and ROTEM Sigma. These produce comparable results and traces to their predecessors. Whereas the ROTEM Sigma® technology continues to use the cup and pin method, TEG 6s uses a resonance method to measure clot viscoelasticity (Fig 1). A vibration using a piezoelectric actuator is applied to the sample, exposing it to a range of frequencies (20–500 Hz). A light-emitting diode passes light through the sample and a photodetector measures the up/down motion of the blood meniscus caused by the vibrations. As a clot forms, the frequency causing the greatest sample motion will change in a reproducible way and this is used to create a TEG trace.

The newer cartridge-based devices negate the need for controlled pipetting, which is subject to user variation and error. Each cartridge has channels that are preloaded with reagents to analyse various aspects of haemostasis, as described below. These systems facilitate ease and speed of use, and are more portable with the potential for more widespread clinical use. The TEG Manager software also allows remote access, with review of the real-time results at the clinical interface, via an internet browser. Other developments include applications, such as TEM/TEG Guide, available to assist in the interpretation of VETs.

With VET, various aspects of haemostasis can be assessed as indicated clinically, depending on the activating or inhibiting agents added (Table 2). Both also have ability to perform platelet function tests, discussed below.

Table 2.

Assays commonly used in the viscoelastic assessment of haemostasis. APTEM, EXTEM test with aprotinin; EXTEM, extrinsically activated thromboelastometric test; FIBTEM, fibrin-based TEM; HEPTEM, thromboelastometry heparinase assay; INTEM, intrinsically activated thromboelastometric test; ROTEM, rotational thromboelastometry; rTEG, rapid TEG; TEG, thromboelastography.

TEG		ROTEM		Comments
Assays	Activator/inhibitor	Assays	Activator/inhibitor
K	Kaolin	INTEM	Ellagic acid + phospholipid activators	•Contact activator •Evaluation of intrinsic pathway
KH	Kaolin + lyophilised heparinase	HEPTEM	INTEM + heparinase	•Neutralisation of unfractionated heparin •Allows observation of the underlying clot function in the presence of heparin and the heparin effect
Tissue factor	Tissue factor	EXTEM	Tissue factor	•Evaluation of the extrinsic pathway •Thrombocytopenia is associated with low A5 and A10 values in various studies, e.g. EXTEM A5 <18/19 equates to platelets of <50,000 mm−3.2
rTEG	Tissue factor + kaolin			•Roughly analogous to the activated clotting time •Activates intrinsic and extrinsic pathways •The double activation of the initiation of clotting allows rapid assessment of MA and clot strength •Useful in acute haemorrhage •Not used for interpretation of R time
FF (functional fibrinogen)	Tissue factor + platelet inhibitor	FIBTEM	Tissue factor + platelet inhibitor	•Isolates the fibrinogen contribution to clot strength owing to the addition of platelet inhibitor •Useful in the discrimination of platelets vs fibrinogen as to the cause of a low MA/MCF •Comparison of FIBTEM A10 and EXTEM A10 can distinguish the need for platelets vs fibrinogen/cryoprecipitate •FIBTEM can be used in the diagnosis of hyperfibrinogenaemia
		APTEM	Tissue factor + aprotinin	•Aprotinin inhibits fibrinolysis •Allows discrimination between fibrinolysis and platelet-mediated clot retraction (in combination with EXTEM)

Viscoelastic test interpretation

Clot formation

After activation of the coagulation system, there is generation of thrombin, which activates platelets and converts fibrinogen to fibrin. The TEG/ROTEM traces demonstrate this as a straight line that subsequently splits, representing the initiation phase. When the trace reaches 2 mm amplitude, the time from test start to this point becomes the reaction time (R; TEG) or clotting time (CT; ROTEM), respectively (Table 1). These variables are useful to assess the adequacy of clotting factors and presence of clotting factor inhibitors (e.g. heparin and warfarin).

Information on clot-formation kinetics can be gained from the k time (TEG) or clot formation time (CFT; ROTEM), and the alpha angle. The former represents the time between 2 and 20 mm amplitude, and the latter the angle between the baseline and a slope between the split point and 20 mm points. These values reflect the speed of fibrin formation and how well it binds to platelets. Prolongation of the time or a decreased angle can be caused by both hypofibrinogenaemia and low/dysfunctional platelets.

Clot strength

Clot strength depends on the synergistic action of fibrinogen, platelets and to a lesser extent, factor XIII. It is represented by maximum amplitude (MA; TEG) or maximum clot firmness (MCF; ROTEM). To help distinguish between platelets or fibrinogen as the cause of a low MA/MCF, a functional fibrinogen (FF) or fibrin-based thromboelastometry (FIBTEM) assay can be performed (Table 2), in which the addition of a platelet inhibitor removes the platelet contribution. A low MA/MCF with a normal FF/FIBTEM MA suggests platelet dysfunction or thrombocytopenia. Conversely, a low MA/MCF and narrowed FF/FIBTEM MA suggests fibrinogen deficiency.

In the dynamic setting of acute major bleeding, early detection of coagulopathy aids prompt management. In ROTEM, clot amplitude at 10 min (A10) and even 5 min (A5) after CT in extrinsically activated thromboelastometric test (EXTEM), intrinsically activated thromboelastometric test (INTEM), and FIBTEM correlate well with MCF; these are useful in the rapid assessment of clot strength and prediction of platelet count and fibrinogen concentrations.¹ Similarly in TEG, the RapidTEG incorporates tissue factor to the kaolin-activated sample for a rapid assessment of clot strength.²

Clot stability

There is some degree of clot retraction and contraction of the fibrin mesh as the site heals. This normal physiological process is important in maintaining vasculature patency. Hyperfibrinolysis is a pathological overactivation of this process resulting in premature clot dissolution. There is currently no universally accepted VET definition of hyperfibrinolysis, which – when it occurs – has a markedly negative impact on morbidity and mortality.³ In TEG, commonly used definitions include a reduction in amplitude of MA >7.5% after 30 min (LY30) or >15% after 60 min (LY60) and is represented by a continuous decrease in the MA with time. In ROTEM, hyperfibrinolysis is defined as a maximum lysis >15%, in which maximum lysis is the reduction of clot firmness in relation to MCF within the complete measurement period. The synchronous use of EXTEM and APTEM with or without FIBTEM (Table 2) facilitates the diagnosis by providing evidence of the normalisation of maximum lysis on addition of an antifibrinolytic agent.

Platelet function tests

Significant interindividual variability in the response to antiplatelet drugs has been reported.⁴ Patients taking antiplatelet agents presenting for surgery may therefore pose variable risks of perioperative bleeding. Platelet function testing can be applied in both elective and emergency settings. In the former, it can aid in preoperative planning with regard to timing and suspension of antiplatelet therapy, balancing the risk of thrombosis and bleeding. In the latter, the knowledge of patient-specific inhibition may assist with timing of surgery, prediction of blood product usage and the consideration and safety of regional anaesthesia.

Standard VETs are generally insensitive to most antiplatelet drugs. However, the TEG platelet mapping (TEGPM) assay provides a method for testing the degree of platelet inhibition. It analyses the contribution to clot strength of the platelets that have remained uninhibited by the antiplatelet therapy because of interindividual variability or subtherapeutic dosing. In TEGPM, up to four separate analyses on whole blood are used (Fig 3). By comparing the relative clot strength of the assays with the knowledge of maximal potential clot strength, fibrinogen contribution and residual platelet activity, the degree of platelet inhibition in the presence of a particular antiplatelet can be determined as a percentage, for both aspirin (MA-AA) and clopidogrel (MA-ADP).

Fig. 3.

Schematic representing concept behind thromboelastrography (TEG) platelet mapping.

Rotational thromboelastometry platelet mapping is an additional module that assesses platelet aggregation via impedance aggregometry; it can be performed simultaneously to VET measurement. The effects of antiplatelet therapy can be studied, with specific nomenclature associated; ARA-TEM for cyclooxygenase inhibitors (e.g. aspirin), ADP-TEM for ADP receptor antagonists (e.g. clopidogrel) and TRAP-TEM for glycoprotein IIb/IIIa inhibitors (e.g. tirofiban).

Direct oral anticoagulants

The use of direct oral anticoagulants (DOACs) has increased significantly in recent years. The main benefits of DOACs are the absence of regular monitoring owing to predictable pharmacokinetics and an improved risk profile. However, during acute bleeding or performance of invasive procedures, rapid assessment of the presence of DOACs is still challenging.

Small-scale studies have suggested that VETs can be used to identify the presence of DOACs and guide their reversal.⁵ Findings include prolonged clot formation, with higher permeability and susceptibility to lysis.⁶ However, findings are non-specific and cannot differentiate the type of DOAC.

Recent modifications of ROTEM assays show promising developments to differentiate the presence of direct thrombin inhibitors (DTIs), for example dabigatran from Xa inhibitors (e.g. rivaroxaban). These are the ECATEM assay, using ecarin activation to detect DTIs, and the use of low tissue factor concentrations (TFTEM) to detect direct Xa inhibitors. Despite only small study evaluation thus far, results are positive and may offer timely assessment of DOAC anticoagulation.⁷ Further evaluation of VETs in assessing DOAC therapy is required to optimise clinical use.

Clinical applications in different subspecialties

The advantages of VET in the perioperative setting, when used in conjunction with the clinical picture, are particularly evident in the context of acute haemorrhage. Viscoelastic testing is increasingly being incorporated into standard practice in cardiothoracic, trauma, obstetrics and liver transplantation surgery.

Liver disease

The liver is responsible for the production of many components of normal haemostasis. Contrary to the historical assumption of hypocoagulability, we now know that , coagulation is ‘rebalanced’ in patients with chronic liver disease.⁸ The synthesis of both pro- and anticoagulant factors is diminished, which in stable patients commonly results in a ‘shifted’ equilibrium. However, with acute decompensation or surgical intervention, this fragile balance is easily disrupted resulting in either hyper- or hypocoagulable states.

Conventional coagulation tests have been found to poorly recreate in vivo coagulation, do not reliably predict bleeding and do not reflect hypercoagulability in cirrhosis.8, 9, 10 In fact, they frequently indicate hypocoagulability, which can lead to inappropriate ‘correction’ of clotting. In contrast, VETs have been found to have a better predictive value for bleeding in liver disease¹¹; they can be used to guide decisions regarding the correction of coagulopathy for surgical and other invasive procedures.^9,12 During acute bleeding, VETs can facilitate timely, individualised use of blood products; enable real-time assessment of response to therapy; differentiate between surgical bleeding and coagulopathy, most commonly hypofibrinogenaemia; and avoid overcorrection with clotting products. Many centres have incorporated VET-guided transfusion algorithms for patients with liver disease, with subsequent reductions in transfusion rates, increased incidence of transfusion-free liver transplants and high-cost effectiveness compared with CCT-guided blood management.¹³

Viscoelastic testing can also guide therapy in patients with acute liver failure, which is associated with a low incidence of spontaneous and procedural bleeding despite often markedly deranged coagulation.¹⁴ Studies have reported normal TEG values in these patients despite them having a mean international normalised ratio (INR) of >3.¹⁴ Moreover, a subset of patients with acute liver failure are hypercoagulable and at risk of thrombotic events if not managed appropriately.

Trauma

Trauma-induced coagulopathy is a prominent cause of mortality in this cohort. The most common abnormality is hypofibrinogenaemia, and the majority of studies aimed at predicting transfusion requirements have assessed clot strength in VET. Low fibrinogen, reflected by abnormal CFF or FIBTEM MCF and EXTEM FF, is associated with poorer outcomes and treatment with cryoprecipitate results in clinical improvement.¹⁵ This demonstrates that detection and correction of abnormalities is vital.

Normal VET results confer a high negative predictive value for transfusion need.¹⁶ Reduced clot strength with lysis >3% on TEG can be used as an indicator of increased risk of transfusion.¹⁷ That said, VET is relatively insensitive to mild-to-moderate fibrinolysis and so it should not be used to withhold antifibrinolytic therapy if clinically indicated.

Viscoelastic testing-guided transfusion algorithms in severe trauma have been shown to reduce mortality, change transfusion practice away from empirical treatment, reduce transfusion requirements and be more cost-effective than CCTs.¹⁸ This suggests that VETs can be used effectively in the emergency department, as well and theatres and critical care.

Obstetrics

Postpartum haemorrhage (PPH) is a leading cause of maternal mortality, particularly in low-income countries, with a multitude of causes. At term, the coagulation system is in a procoagulant state: normal ranges for TEG and ROTEM variables differ from non-pregnant values.¹⁹ Protocols developed for other settings hence may not be applicable and normal values may suggest a developing coagulopathy.

Viscoelastic testing is increasingly being used as part of the treatment algorithms for the management of PPH. Hypofibrinogenaemia is the most common abnormality, and there is evidence to suggest that a FIBTEM A5 <12 mm (ROTEM) with ongoing bleeding or FIBTEM A5 <7 mm may warrant fibrinogen replacement.²⁰ Conversely, a patient with a FIBTEM A5 >12 mm is unlikely to benefit from this therapy.²¹

Cardiothoracic surgery

Viscoelastic testing has been studied most extensively in cardiothoracic surgery where mortality has been shown to increase with major bleeding and blood transfusions.²² The coagulopathy associated with cardiac surgery is complex, and rapid differentiation from surgical bleeding is critical. Causes include exposure to the extracorporeal circuit, hypothermia, large heparin doses, antiplatelet therapy, haemodilution and factor consumption.

The routine attainment of static VET values before surgery does not reliably predict bleeding.²² Rather, it is thought that a deterioration in VET values is better able to do this.²³

Meta-analyses have suggested that VET-guided transfusion therapy is superior to CCTs in cardiac surgery²² and can reduce the use of allogenic product administration and guide replacement when indicated. There is evidence to suggest that the use of VET in this setting may result in a reduction in acute kidney injury, thromboembolic events, re-sternotomy, hospital length of stay, cost and mortality.²² Furthermore, transfusion algorithms that incorporate VET can be used postoperatively to optimise transfusion strategy and identify or exclude coagulopathy as the cause of bleeding.

Algorithms

The use of VET-guided transfusion algorithms has been shown to improve both the use of blood products and clinical outcomes such as length of stay and mortality.²⁴ They are helpful in providing transfusion prompts and physiological targets (e.g. pH, calcium), and allow for standardisation of perioperative transfusion. Furthermore, algorithms can guide clinical management in those less familiar with VET interpretation. Algorithms should be adapted and validated locally for applicability to the particular patient and local institution.

Limitations

There are several limitations to VET.

Infrastructure and equipment

• 1.Near-patient testing is often remote from the laboratory, with logistical implications for the storage and maintenance of equipment.
• 2.Initial set-up can be more expensive than CCTs. However, VETs can be more cost-effective overall because of decreased allogenic product use and associated complications.
• 3.Devices need regular quality control, as per manufacturers' guidelines.
• 4.The non-cartridge-based methods require trained staff for sample/reagent preparation.
• 5.Viscoelastic testing devices are sensitive to external vibration, with implications for storage and out-of-hospital resuscitation use.

Interpretation

• 1.Training and education are necessary to interpret the results.
• 2.Viscoelastic testing remains inferior to the gold standard test of light transmission aggregometry for platelet function analysis, and are insensitive to the nuances of platelet function defects. They are also insensitive for vWF and the anticoagulant protein C system.²⁵
• 3.Viscoelastic tests are insensitive to mild–moderate fibrinolysis; thus they should not be used to withhold antifibrinolytic therapy.²⁶
• 4.There is no published consensus for accepted normal ranges, which makes comparison across centres and patient groups challenging. Each device will incorporate the manufacturer's reported reference ranges, but in addition each institution should determine local reference ranges as with other standard laboratory tests.

Summary

Viscoelastic testing provides a real-time picture of global haemostatic function in the dynamic environment of major bleeding. With advances in technology facilitating smaller and more user-friendly devices, its use is likely to become more widespread. There is still paucity of large, high-quality evidence in its association with outcomes. However, there are convincing data to demonstrate its use in significantly reducing transfusion requirements, which has large and beneficial implications on resource utilisation, cost and transfusion-associated morbidity. Thus, many centres around the world have successfully incorporated VET into their practice. More studies are required to optimise its use, and ongoing developments in technology are needed to accommodate advances in transfusion medicine.

Declaration of interests

The authors declare that they have no conflicts of interest.

Biographies

Madeleine Wells BMedSci (Hons) MRCP FRCA is a specialty trainee in anaesthesia at the Royal London Hospital (Barts NHS Trust) and was previously a clinical research fellow in liver transplant and HPB surgery.

Meera Raja BSc (Hons) FRCA is a specialty trainee in anaesthesia at the Royal Free London NHS Foundation Trust and is a clinical research fellow in liver transplant and HPB surgery.

Suehana Rahman BSc (Hons) FRCA is a consultant anaesthetist with subspecialty interests in liver transplantation, hepatopancreatobiliary and vascular surgery. She is the anaesthesia representative on the British Liver Transplant Group and expert panel member making recommendations on the optimal transfusion policy in liver transplantation.

Matrix codes: 1A01, 2A02, 2A05, 2A07, 2B05, 3A04, 3A05, 3A10, 3B00, 3G00

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