Redefining haemostasis: Role of rotational thromboelastometry in critical care settings

Abstract

Management of patients with acute hemorrhage requires addressing the source of bleeding, replenishing blood volume, and addressing any coagulopathy that may be present. Assessing coagulopathy and predicting blood requirements in real-time in patients experiencing ongoing bleeding can pose substantial challenges. In these patients, transfusion concepts based on ratios do not effectively address coagulopathy or reduce mortality. Moreover, ratio-based concepts do not stop bleeding; instead, they just give physicians more time to identify the bleeding source and plan management strategies. In clinical practice, standard laboratory coagulation tests (SLCT) are frequently used to assess various aspects of blood clotting. However, these tests may not always offer a comprehensive understanding of clinically significant coagulopathy and the severity of blood loss. Furthermore, the SLCT have a considerable turnaround time, which may not be ideal for making prompt clinical decisions. In recent years, there has been a growing interest in point-of-care viscoelastic assays like rotational thromboelastometry, which provide real-time, dynamic information about clot formation and dissolution.

Key Words: Bleeding; Critical care; Haemorrhage; Intensive care unit; Rotational thromboelastometry; Viscoelastic tests

Core Tip: Point of care viscoelastic tests like rotational thromboelastometry (ROTEM) can provide real-time, dynamic information about clot formation and dissolution and prove to be a valuable tool for assessing coagulation in numerous critical care settings. Unlike traditional coagulation tests, ROTEM can provide whole-blood evaluations which may aid the physicians to quickly identify coagulation issues and administer targeted treatments. With emerging technology and increasing clinical experience, new applications may emerge, and ROTEM may become an integral part of modern haemostatic management.

INTRODUCTION

Acute haemorrhage is a critical medical condition that demands rapid and effective management to prevent life-threatening complications. The primary goals in treating patients with significant bleeding include identifying and controlling the source of hemorrhage, restoring blood volume, and addressing any underlying coagulopathy. However, evaluating and managing coagulopathy during active bleeding presents considerable challenges. Traditional approaches to bleeding control, such as ratio-based transfusion strategies, often fall short of effectively managing coagulopathy or reducing mortality[1,2]. While these strategies may offer temporary support, they do not directly stop the bleeding. Instead, they buy time for clinicians to locate the bleeding source and initiate definitive treatment. Additionally, standard laboratory coagulation tests (SLCT), including prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count, are limited in their ability to provide a timely and comprehensive assessment of bleeding risk and coagulopathy severity, as they often require 30 to 90 minutes for results and are not designed to guide transfusion decisions in acute settings[3,4].

In this context, point-of-care viscoelastic assays, such as rotational thromboelastometry (ROTEM), have become valuable tools for evaluating real-time coagulation status. Unlike traditional tests that assess individual components of the clotting cascade, ROTEM provides a dynamic, whole-blood assessment of the clotting process, capturing the interactions between clotting factors, platelets, and fibrinogen. This real-time analysis of clot formation, stabilization, and lysis enables clinicians to rapidly identify specific coagulation abnormalities, such as hyperfibrinolysis or thrombocytopenia, and tailor treatments accordingly[5]. For instance, administering fresh frozen plasma (FFP) to a patient experiencing bleeding due to thrombocytopenia or hyperfibrinolysis may be of limited benefit and could expose the patient to unnecessary risks, such as infections or alloimmunization[6,7].

The use of ROTEM in clinical practice offers several advantages over SLCT, providing immediate and actionable insights that can significantly improve the management of patients experiencing acute bleeding. This article delves into the principles of ROTEM, its clinical applications across various medical scenarios, and practical approaches to interpreting its results. By integrating ROTEM into acute hemorrhage management protocols, healthcare professionals can enhance their ability to make informed decisions quickly, ultimately improving patient outcomes in critical bleeding situations.

OVERVIEW OF THROMBOELASTOMETRY: ROTEM

Viscoelastic testing facilitates the assessment and graphical depiction of the dynamic viscoelastic characteristics of whole blood during the coagulation process. Thromboelastography (TEG), initially introduced by Professor Hartert[8] in 1948, is a comprehensive technique for assessing the complete blood coagulation process, represented graphically from the onset of clot formation to fibrinolysis. The ROTEM system represents an advancement over TEG, developed in Munich between 1995 and 1997. In contrast to conventional laboratory coagulation tests conducted on centrifuged plasma fractions, viscoelastic assays that utilize whole blood, offer the benefit of a more comprehensive assessment of the interactions between cellular and plasma components (Table 1).

Table 1 Advantages of viscoelastic testing over traditional laboratory conventional coagulation testing.

	Viscoelastic assays	Standard laboratory conventional coagulation test
Specimen type	Whole blood sample	Platelet-poor plasma
Result turnaround	Rapid results in minutes	Extended turnaround time
Testing site	Assessable and analysable at point of care	Conducted in a central laboratory
Clotting system assessment	Offers a comprehensive view of ex-vivo clotting	Indicates adequacy of thrombin generation, without insights beyond that
Validation for acute bleeding	Efficacy proven in multiple randomized controlled trials for improving patient safety and outcomes	Not validated for predicting bleeding risk or guiding transfusion

Principle for ROTEM

A blood clot can be characterized as a Maxwell body, demonstrating both viscous and elastic characteristics. Viscoelastic assays assess the clot’s “shear modulus”, reflecting its propensity to deform when subjected to opposing forces. Each material possesses a distinct shear modulus; however, in the case of blood, this property undergoes alterations throughout the clotting process.

In conventional TEG, a cuvette containing whole blood is utilized, and a pin connected to a torsion wire is submerged within the sample. The cup undergoes a rotational movement of 4.45° over a duration of 5 seconds, incorporating a 1-second pause at both the beginning and the conclusion of the motion. The pin exhibits unrestricted movement when the blood is in a liquid state. The formation of blood clots and fibrin strands between the cup and the pin restricts the pin’s movement. This restriction is subsequently transformed into an electrical signal, a TEG tracing[9].

ROTEM functions with distinct operational principles. The pin traverses an arc measuring 4.75°, with the cup remaining stationary. As coagulation initiates and fibrin strands develop, the rotation of the pin becomes progressively limited (Figure 1). The observed decrease in movement is captured through optical detection, subsequently transformed into an electrical signal, processed using specialized software, and ultimately depicted in a graphical format. ROTEM enhances TEG by providing four channels for concurrent sample or diagnostic analyses, in contrast to the two channels available with TEG. Furthermore, ROTEM exhibits reduced sensitivity to mechanical stress and vibration compared to TEG[10].

Figure 1  Fundamental concept of rotational thromboelastometry.

While TEG and ROTEM function based on similar principles, the results obtained from each are not interchangeable. This variation is attributed to the mechanical differences inherent in the instruments and the unique mechanisms of action associated with their respective reagents[11]. ROTEM employs more potent activators than traditional TEG, which utilizes kaolin. ROTEM utilizes ellagic acid (INTEM) and tissue factor (EXTEM) as activators, demonstrating greater efficacy in initiating the coagulation process than kaolin. As a result, ROTEM tracing may exhibit reduced sensitivity to the impacts of low molecular weight heparins and various other anticoagulants. TEG functional fibrinogen values have the potential to overestimate fibrinogen levels in comparison to fibrinogen thromboelastometry (FIBTEM) maximum clot firmness (MCF), attributable to the varying capacities of the reagents to inhibit platelet function[12]. As a digitized point-of-care system, ROTEM presents numerous benefits for routine clinical application, including standardized measurement methodologies, pathway sub-analysis capabilities, and the provision of rapid, replicable digital signatures.

Comprehending ROTEM parameters

Historically, the curve has been plotted on both sides and measured in millimetres. The comprehensive tracing offers valuable information regarding the ex-vivo clot formation status of an individual’s whole blood. The elastic time points are categorized into the coagulation and clot lysis phases[10]. These can be further examined through clot initiation, kinetics, and clot strength (Figure 2 and Table 2).

Figure 2 Rotational thromboelastometry tracing. CT: Clotting time; CFT: Clot formation time; MCF: Maximum clot firmness; LI 30%: The proportion of clot stability retained 30 minutes after clotting time, relative to the maximum clot firmness value; ML: Maximum lysis.

Table 2 Rotational thromboelastometry parameters and their clinical significance.

ROTEM parameters	Clinical significance
Clot initiation: Clotting time	The time from the beginning of the test until a significant increase in resistance is observed, marking the onset of initial fibrin formation
Clot kinetics: Clot formation time	The duration from CT to reaching a clot firmness of 20 mm, reflecting fibrin polymerization and clot stabilization with the involvement of activated platelets and fibrin-stabilizing factor XIII
Clot kinetics: Alpha angle	The slope during the early phase of clot development, represented by the angle between the tangent line from the baseline to a 20 mm amplitude, indicates the rate of fibrin accumulation and cross-linking
Clot strength: Maximum clot firmness	The highest resistance recorded, due to enhanced clot stabilization by polymerized fibrin, activated platelets, and factor XIII, represents the maximum strength of the clot
Clot strength: Maximum lysis	The percentage decrease in MCF at specific intervals of 30 and 60 minutes, indicating clot stability and breakdown

CT: Clotting time; MCF: Maximum clot firmness; ROTEM: Rotational thromboelastometry.

ROTEM apparatus and associated reagents

The ROTEM device comprises several essential components, including the measurement system, disposable test kits, and software designed for data analysis. Ensuring an appropriate setup and calibration is essential for achieving precise results. A blood sample may be analyzed in its native state without adding any reagents, or it may undergo recalcification if collected in a citrate tube. The presence of citrate may affect the outcomes; however, it remains the preferred method in situations where immediate processing is unfeasible[13]. The storage of citrate tubes ensures the stability of samples for a minimum duration of 2 hours. Repeated sampling from the same tube should be avoided, as this practice may lead to the activation of platelets and coagulation factors[14]. Different activators or inhibitors can be introduced to the sample to illustrate various facets of haemostasis, accelerate the initiation of coagulation, or target specific elements such as fibrinogen or platelets (Table 3)[12,15]. The ROTEM system employs three distinct categories of reagents[15]: (1) The ROTEM delta system uses polybrene to neutralize up to 5 IU/mL of heparin, ensuring accuracy in high-heparin settings like a cardiopulmonary bypass; (2) The ROTEM sigma system automates tests with cartridge-based assays, categorizing results as EXTEM C, FIBTEM C, and APTEM C; and (3) ROTEM delta and platelet single-use reagents lack heparin inhibitors, which are unsuitable for unfractionated heparin (UFH) patients. Clotting issues are assessable via INTEM (S) and HEPTEM (S).

Table 3 Rotational thromboelastometry delta/sigma and rotational thromboelastometry platelet assays.

Assay	Activators and additives	Clinical significance
ROTEM delta/sigma
EXTEM	Calcium chloride + recombinant tissue factor + polybrene	Allow fast assessment of clot formation
		Explores the extrinsic coagulation pathway; VKAs; DOACs
		Increased values indicate need of PCC or FFP
		Not affected by aprotinin
		Sensitive to heparin
FIBTEM	Calcium chloride + recombinant tissue factor + polybrene + platelet inhibitor (cytochalasin D)	Depicts fibrin polymerization
		Assesses the contribution of fibrinogen to clot strength independent of platelets
		May also indicate XIII deficiency
		Used to calculate dose of fibrinogen concentrate or cryoprecipitate
APTEM	Calcium chloride + recombinant tissue factor + polybrene + aprotinin/tranexamic acid	Inhibition of premature lysis by addition of aprotinin/tranexamic acid
		In combination with EXTEM: (1) Rapid confirmation of fibrinolysis; (2) Verifying the effect of antifibrinolytic effect; and (3) Differential diagnosis of clot retraction and XIII deficiency
INTEM	Calcium chloride + ellagic acid	Assessment of clot formation and fibrin polymerization
		Explores the intrinsic coagulation pathway
		Increased values indicate need of FFP
HEPTEM	Calcium chloride + ellagic acid + heparinase	Testing in patients with very high heparin plasma concentrations
		In combination with INTEM
		To see UFH and protamine effects
NATEM	Calcium chloride	Expression of tissue factor on circulating cells, such as monocytes or cancerous cells
ECATEM	Calcium chloride + ecarin	Is sensitive for direct thrombin inhibitors (e.g., hirudin, argatroban, bivalirudin, dabigatran)
		Not sensitive to heparin
ROTEM platelet assays: These tests are used in patients treated with antiplatelet drugs or other medications that may affect platelet function, as well as in patients with suspected platelet dysfunction due to extracorporeal circulation, trauma, sepsis, or other reasons
ARATEM	Arachidonic acid	The platelets are activated with arachidonic acid to assess platelet function, particularly in patients treated with cyclooxygenase inhibitors such as acetylsalicylic acid
		Effects of CPB, trauma and sepsis on platelet function
ADPTEM	Adenosine di-phosphate	Platelets are activated using ADP to assess platelet function in patients treated with ADP receptor antagonists such as clopidogrel
		Effects of CPB, trauma and sepsis on platelet function
TRAPTEM	Thrombin receptor activating peptide-6	Platelets are activated using thrombin receptor activating peptide to evaluate platelet function in patients treated with PAR-1 receptor antagonists like vorapaxar or GP IIb/IIIa receptor antagonists such as abciximab
		Effects of CPB, trauma and sepsis on platelet function

ROTEM: Rotational thromboelastometry; DOACs: Direct oral anticoagulants; VKAs: Vitamin K antagonist; PCC: Prothrombin complex concentrate; FFP: Fresh frozen plasma; UFH: Unfractionated heparin; CPB: Cardiopulmonary bypass; ADP: Adenosine di-phosphate; PAR-1: Protease-activated receptor-1.

Analysis of ROTEM

ROTEM reference ranges have been determined for various populations, including healthy individuals, across different age groups, such as neonates, infants, children, adolescents, adults, and pregnant women during the first to third trimester and peri-partum periods[16-18]. Understanding the influence of age, gender, and pregnancy on ROTEM parameters is essential for making precise clinical decisions. Elderly patients frequently demonstrate a reduction in clotting time (CT) alongside an increase in amplitude MCF. Throughout pregnancy, the alterations in haemostasis can be effectively demonstrated using TEG and ROTEM, which indicate a “prothrombotic phenotype” marked by reduced CT and an increase in MCF, primarily due to heightened fibrinogen concentrations.

The ROTEM analysis is evaluated along the temporal axis from left to right (Figure 2). As functional assays, ROTEM demonstrates sensitivity to quantitative and qualitative changes in factors and substrates. Colloids have been shown to disrupt the initiation of coagulation and the polymerization of fibrinogen, resulting in a prolonged CT and a reduction in MCF, even following minor haemodilution[19,20]. ROTEM results offer valuable information regarding the underlying causes of a patient’s bleeding; however, they cannot predict subsequent bleeding events. Therefore, the initial step must involve assessing the presence or absence of clinically significant bleeding and determining the potential requirement for blood transfusion. This evaluation should consider the plausibility of the findings, the patient’s medical history, existing comorbidities, and the anticipated surgical source of the bleeding. If both point-of-care viscoelastic testing (ROTEM delta or ROTEM sigma) and platelet function assessment (ROTEM platelet) yield normal results, it is essential to evaluate and address the possibility of surgical bleeding. Therefore, it is advisable to refrain from acting on pathologic laboratory results (numbers) when there is no evidence of bleeding, given the low positive predictive values of specific tests such as SLCTs (14%-24%), viscoelastic assessments (15%-24%), and platelet function evaluations (27%-50%)[21,22]. This approach is crucial to prevent potential overtreatment, which could lead to thromboembolic complications and escalate healthcare expenditures.

Typically, an extension of the CT is attributed to a defect in the initiation of coagulation, whereas a diminished MCF results from a deficiency in substrates such as fibrinogen, platelets, or factor XIII. Conversely, a shortened CT or elevated MCF results from an enhanced initiation of coagulation or increased substrate levels, respectively. Clot formation time (CFT) reflects the kinetics of clot formation and is fundamentally dependent on substrates, primarily fibrinogen and platelets.

ROTEM results must be interpreted in a defined sequence, commencing with A5_FIB/A10_FIB (amplitude of clot firmness 5 and 10 minutes after clotting time in FIBTEM, respectively), prior to CT EXTEM (CT_EX), rather than relying on their availability. In severe haemorrhage, fibrinogen levels may decrease to critical thresholds (< 1 g/L), potentially leading to an extended CT_EX. This phenomenon is not observed in cases of bleeding attributable to anticoagulants or haemophilia. Consequently, the accurate interpretation of CT_EX values is contingent upon the adequacy of the FIBTEM clot amplitude measured at 5 and 10 minutes (A5_FIB/A10_FIB, respectively)[15]. Furthermore, elevated thrombin generation correlates with an increased risk of thromboembolic complications compared to substituting substrates, especially fibrinogen. The administration of FFP in response to prolonged CT_EX values may pose increased risks. Therefore, prioritizing the management of clot firmness, as evidenced by a decreased A5_FIB/A10_FIB and A5 in the EXTEM assay (A5_EX), is essential over the management of thrombin generation [FFP or prothrombin complex concentrate (PCC) administration], which is indicated by prolonged CT_EX and CT in the INTEM assay[15,23].

In cases where there is a suspicion of a “heparin effect”, a dual testing approach is employed utilizing ROTEM, specifically the INTEM and HEPTEM assays. A prolonged CT in INTEM compared to HEPTEM suggests a heparin effect. If no distinction is observed, it can be inferred that a heparin effect is absent. Consideration of the specific reagents employed in ROTEM testing is crucial, as some reagents may exhibit a greater susceptibility to interference from heparin than others. Given their sensitivity to heparin, it is essential to remove or mitigate the effects of heparin before performing tests with single-use reagents such as EXTEM and FIBTEM.

Clot analysis represents a standard physiological mechanism; however, when it transpires at heightened levels, it can considerably compromise clot stability and the overall haemostatic function, a condition referred to as hyperfibrinolysis. In ROTEM analysis, hyperfibrinolysis is characterized by ML_EX (maximum lysis in EXTEM) values of ≥ 7.5% at 30 minutes or ≥ 15% at 60 minutes[15,23]. FIBTEM serves as the most sensitive and specific assay for the identification of hyperfibrinolysis, indicated by ML_FIB (maximum lysis in EXTEM) values equal to or exceeding 10%. In contrast, APTEM is employed to validate the presence of hyperfibrinolysis and to assess the efficacy of antifibrinolytic treatment. It is essential to recognize that ROTEM is limited to the detection of systemic hyperfibrinolysis and does not have the capability to identify local hyperfibrinolysis.

CLINICAL APPLICATIONS OF ROTEM

ROTEM is utilized in various clinical scenarios, especially in environments where swift and thorough evaluation of coagulation is essential.

Trauma-induced coagulopathy

Uncontrolled hemorrhage is a leading cause of death in trauma, often linked to trauma-induced coagulopathy (TIC), a multifactorial failure of the coagulation system. TIC has a mortality rate of nearly 50%, requiring increased blood transfusions and causing higher morbidity[24]. This condition is driven by factors such as protein C activation, endothelial disruption, fibrinogen depletion, and platelet dysfunction[25,26].

Standard coagulation tests have limitations in directing transfusion strategies and detecting hyperfibrinolysis in trauma patients. Studies show that ROTEM is more effective than SLCT in assessing and managing TIC[27,28]. The ITACTIC trial, involving 396 trauma patients, compared viscoelastic haemostatic assays like ROTEM with SLCT[29]. While no significant difference in mortality or transfusion requirements was observed at 24 hours, viscoelastic assays showed better guidance for transfusions in cases of traumatic brain injury with international normalized ratio (INR) > 1.2.

ROTEM can quickly identify TIC, with A5_EX < 35 mm and A5_FIB < 9 mm, indicating hypofibrinogenemia and CT_EX > 80 seconds, suggesting impaired thrombin generation[15]. Hyperfibrinolysis, present in severe trauma cases, can be detected using ROTEM parameters (A5_EX < 35 mm or CT_FIB (clotting time in FIBTEM) > 600 s or EXTEM or FIBTEM maximum lysis (ML) ≥ 5% within 60 minutes)[30], with early tranexamic acid (TA) treatment reducing mortality, as demonstrated in the CRASH-2 trial[31].

In trauma patients, ROTEM offers essential insights for managing haemorrhage, as supported by a variety of clinical guidelines[32,33]. ROTEM provides real-time insights into the clotting process, enabling clinicians to customize interventions more precisely. This capability is crucial for effective haemorrhage management and optimizing blood product utilization (Figure 3A)[15].

Figure 3 Rotational thromboelastometry-guided management with acute bleeding and an indication for blood transfusion. A: In trauma; B: In post-partum haemorrhage; C: In liver transplantation; D: In cardiac surgery. ACT: Activated clotting time; A5_EX: Amplitude of clot firmness 5 minutes after clotting time in EXTEM; A5_FIB: Amplitude of clot firmness 5 minutes after clotting time in fibrinogen thromboelastometry; BE: Base excess; CT_FIB: Clotting time in fibrinogen thromboelastometry; CT_IN: Clotting time in INTEM; CT_HEP: Clotting time in HEPTEM; FFP: Fresh frozen plasma; Hb: Hemoglobin; ISS: Injury severity score; LI30_EX: Lysis index at 30 minutes in EXTEM; LI60_EX: Lysis index at 60 minutes in EXTEM; ML: Maximum lysis; TASH: Trauma associated severe hemorrhage; PCC: Prothrombin complex concentrate; PPH: Post-partum hemorrhage.

Post partum haemorrhage

ROTEM is utilized in obstetric care to address bleeding complications, especially postpartum haemorrhage (PPH), recognized as the primary cause of significant maternal morbidity and mortality globally. Timely diagnosis and prompt intervention are critical for achieving positive outcomes. Management strategies for PPH encompass laboratory-driven, formula-driven, and goal-directed approaches that utilize viscoelastic coagulation monitoring techniques such as ROTEM. Several recent algorithms for managing PPH have integrated ROTEM-guided strategies to optimize treatment.

In 2014, Mallaiah et al[34] conducted a study at the Liverpool Women’s Hospital comparing traditional transfusion protocols with a fibrinogen-centered approach. Guided by ROTEM, they administered fibrinogen concentrate based on specific thresholds, resulting in reduced blood product use and fewer complications associated with transfusions. Girard and colleagues from Austria, Germany, and Switzerland proposed a four-step PPH management algorithm in the same year[35]. It involves: Recognizing PPH and increasing uterine tone within 30 minutes; Interdisciplinary management with coagulation monitoring (ROTEM/TEG) and administration of TA and fibrinogen; Maintaining hemodynamic stability; and using invasive measures if bleeding persists. Similarly, the Share Network Group introduced a five-step approach tailored to specific coagulopathies during PPH, addressing hyperfibrinolysis, fibrinogen deficiency, thrombocytopenia, other clotting factor deficits, and factor XIII deficiency[36]. ROTEM was used to guide fibrinogen supplementation, with a trigger set at FIBTEM MCF < 18 mm. In Cardiff, Collis et al[37] introduced a protocol activated for bleeding over 1000 mL, using ROTEM to guide fibrinogen administration when FIBTEM is below 7 mm, ensuring timely and targeted management (Figure 3B).

Sepsis

In sepsis, early procoagulant states may progress to disseminated intravascular coagulation (DIC), consuming platelets and clotting factors and shifting from hypercoagulability to hypocoagulability, increasing bleeding risk[38]. ROTEM helps detect coagulopathy early in critically ill patients, differentiating between normal, hypercoagulable, and hypocoagulable states, which are linked to mortality[39]. ROTEM also identifies patients without DIC who remain hypercoagulable, guiding the initiation of prophylactic anticoagulation. Sequential ROTEM measurements provide a dynamic picture of sepsis-induced coagulopathy as it evolves from hypercoagulability to DIC. ROTEM correlates with the Japanese Association for Acute Medicine DIC score and outperforms SLCTs in predicting DIC[40].

Research indicates that specific thromboelastometry parameters, including the lysis index, demonstrate superior accuracy in the diagnosis severe sepsis when compared to conventional biomarkers such as procalcitonin, interleukin-6, or C-reactive protein[41,42]. Furthermore, abnormal thromboelastometry values have been associated with improved predictive capability for 30-day survival rates in sepsis compared to conventional scoring systems such as the sequential organ failure assessment or simplified acute physiology score II[43].

Thus, integrating serial ROTEM with conventional tests could improve the diagnosis and management of DIC, enhancing outcomes for sepsis patients. Further studies are required to standardize ROTEM use for detecting coagulation changes in sepsis.

Acute liver disease

In acute liver injury and acute liver failure (ALF), elevated INR often gives a false impression of increased bleeding risk, leading to cautious use of anticoagulation[44]. ROTEM, which assesses whole-blood coagulation, may offer better predictions for bleeding in ALF than traditional tests like INR. A study of 200 ALF patients found ROTEM abnormalities correlated with disease severity, and platelet count proved a stronger bleeding risk indicator than INR, suggesting platelet transfusions may be more effective than plasma[45]. The data suggests a significant prevalence of haemostatic disruption in severe cases; however, further investigation is required to confirm the efficacy of ROTEM in directing treatment strategies and mitigating bleeding risk in ALF.

Chronic liver disease

Cirrhosis disrupts haemostasis and creates a delicate balance, further affected by conditions like sepsis or acute kidney injury[9]. SLCTs are poor predictors of bleeding risk and transfusion needs in cirrhotic patients[46]. Thrombocytopenia is common, with a platelet count of 50 × 10⁹/L to 55 × 10⁹/L often used as a threshold for procedures, though the benefit of prophylactic transfusions is unclear[47,48]. Similarly, fibrinogen levels, rather than INR, guide bleeding risk, with a target of 120 mg/dL during active bleeding[47,48]. Viscoelastic tests like ROTEM and TEG better predict bleeding by assessing clot strength and hyperfibrinolysis, which is common in cirrhosis.

ROTEM helps distinguish coagulation deficiencies from heparin-like effects caused by glycosaminoglycans and detects hyperfibrinolysis[49]. The HEPTEM test can confirm heparin-like activity, offering insights beyond standard tests. Current guidelines recommend using viscoelastic tests selectively, particularly in high-risk cirrhotic cases, to assess INR and platelet abnormalities[50]. The findings from the RECIPE trial will shed light on the effectiveness of a ROTEM-based algorithm for guiding prophylactic blood component administration in cirrhotic patients, potentially enhancing clinical outcomes and minimizing unnecessary transfusions[51].

Liver transplantation

Significant haemorrhage during liver transplantation is challenging due to cirrhosis, blood loss, and clotting factor changes. Despite abnormal clotting profiles like thrombocytopenia and elevated INR, bleeding risk isn’t always higher due to a rebalanced haemostatic state[52]. ROTEM is highly effective in managing haemorrhage during liver transplants, offering superior guidance over SLCTs. It can reduce red blood cell transfusions by 62%, FFP by 95%, and platelet use by 66%, leading to fewer massive transfusions and more targeted use of fibrinogen concentrate and PCC[53,54].

Key ROTEM indicators like A5 help detect low platelet and fibrinogen levels. EXTEM CT over 80 seconds suggests PCC may be needed, while prolonged INTEM CT points to FFP transfusion. If EXTEM MCF is below 35 mm and FIBTEM MCF is above 6 mm, platelet transfusion is recommended, and fibrinogen concentrate is used when both EXTEM and FIBTEM MCF are low. ROTEM also detects fibrinolysis (ML > 15% of MCF), and if present, TA can be used to control bleeding, particularly during or after the anhepatic phase (Figure 3C)[55].

Cardiac surgery

Cardiopulmonary bypass frequently leads to a propensity for bleeding, attributable to various factors, including the effects of heparin, inadequate protamine dosing, hypothermia, haemodilution, heightened fibrinolysis, depletion of coagulation factors, diminished platelet counts and function. In the context of cardiac surgery, a crucial timeframe of 30 to 45 minutes is established for implementing haemostatic interventions following the reversal of heparin with protamine prior to the transfer of the patient to the intensive care unit. Implementing rapid point-of-care testing and facilitating prompt treatment decisions are critical during this time frame. The European Association for Cardio-Thoracic Surgery advocates using TEG/ROTEM in cardiac surgery to minimize the requirement for blood transfusions and enhance the management of blood product administration[56].

In complex cardiac surgeries, using heparin-neutralizing reagents in ROTEM delta and sigma enables effective ROTEM analysis despite elevated heparin levels after bypass. This capability supports the prompt ordering of blood products such as cryoprecipitate and platelet concentrates (Figure 3D)[57,58]. It is essential to identify any residual heparin or protamine overdose prior to implementing additional haemostatic interventions. It is essential to recognize that an extended activated CT (ACT) does not necessarily signify the presence of residual heparin. Furthermore, employing a 1:1 heparin-to-protamine reversal ratio may result in protamine overdose, subsequently leading to increased ACT[59,60].

Myocardial infarction

Myocardial infarction (MI) is a critical emergency that requires swift intervention to restore blood flow using medications, surgical techniques, or non-surgical methods. Managing MI involves not only reestablishing blood supply but also carefully monitoring coagulation to reduce bleeding and thrombotic complications[61]. Viscoelastic assays like ROTEM and TEG have become valuable tools for assessing coagulation in MI patients and guiding treatment decisions.

Despite standard antiplatelet therapy, such as aspirin and clopidogrel, some MI patients remain in a hypercoagulable state, increasing their risk of recurrent ischemic events. In a study by Zhao et al[62], MI patients undergoing percutaneous coronary intervention showed enhanced clot strength and faster clot formation, even while on antiplatelet therapy. Approximately 50% of these patients remained hypercoagulable. Additionally, those with low responsiveness to antiplatelet therapy experienced significantly more ischemic events within three months. These findings emphasize the utility of TEG in identifying patients who may need adjustments in their treatment.

Similarly, other studies have shown that patients with high platelet reactivity before cardiac stenting face a higher risk of adverse events. Viscoelastic testing can be used to tailor antiplatelet therapy by switching to stronger agents like ticagrelor or prasugrel to improve outcomes[63,64]. ROTEM also plays a role in assessing bleeding risks, helping clinicians decide whether to adjust antithrombotic therapy.

Overall, integrating ROTEM and TEG in managing MI allows for more personalized treatment, enhancing safety by balancing the risks of bleeding and thrombosis. Although more research is needed to standardize protocols, current evidence supports using viscoelastic testing to improve outcomes in MI patients.

Cardiac arrest

Following resuscitation from cardiac arrest, individuals frequently encounter post-cardiac arrest syndrome (PCAS), which arises from various factors, including reperfusion failure, ischemia-reperfusion injury, and cerebral damage[65,66]. PCAS has the potential to initiate a systemic inflammatory response and activate coagulation, which may result in organ dysfunction[66]. TEG and ROTEM have been utilized to evaluate coagulation abnormalities after spontaneous circulation (ROSC) return, with findings indicating their possible role as prognostic instruments.

A study involving 75 patients with out-of-hospital cardiac arrest demonstrated that increased clot firmness, measured by A30 of EXTEM, correlated with a successful ROSC. Specifically, an A30 value of ≥ 48.0 mm, with a lactate level of < 12.0 mmol/L, exhibited a high specificity of 94.7% for predicting ROSC[67]. ROTEM has indicated that hyperfibrinolysis may elevate the risk of bleeding following cardiac arrest, thereby suggesting the potential utility of antifibrinolytics such as TA in therapeutic interventions. In light of the current discourse surrounding the efficacy of targeted temperature management, the utilization of viscoelastic assays may assist in pinpointing patients who are most likely to benefit from this therapeutic approach.

Stroke

ROTEM provides valuable real-time insights into coagulation processes in both ischemic and haemorrhagic strokes, guiding treatment decisions. In acute ischemic stroke, it assesses hypercoagulability and monitors fibrinolysis during thrombolytic therapy[68]. Studies show hypercoagulable states in stroke patients, with reduced R and K times, even before receiving recombinant tissue plasminogen activator (rtPA). However, responses to rtPA vary, suggesting that standard dosing may not suit all patients[69]. ROTEM can also help identify individuals at higher risk of haemorrhagic transformation after thrombolysis, characterized by a rapid clotting response, potentially reflecting compensatory mechanisms to mitigate bleeding risks[70]. Similarly, in haemorrhagic stroke, ROTEM detects early hypercoagulability, potentially reflecting a compensatory mechanism to manage bleeding. Faster clot formation is linked to hematoma expansion, providing insights into which patients may benefit from earlier surgical intervention[71]. ROTEM is also effective in evaluating anticoagulation status, particularly with direct oral anticoagulants (DOACs), offering guidance on whether to withhold rtPA or initiate reversal therapy.

Integrating ROTEM into stroke management allows for more personalized treatment, improving safety during thrombolysis and optimizing surgical decisions. Further research is needed to establish standardized parameters for using ROTEM in clinical practice.

Chronic kidney disease

Patients with chronic kidney disease (CKD) experience both hyper- and hypo-coagulability, as identified through advanced haemostasis assessments[72]. ROTEM analysis in CKD patients indicated a prothrombotic state characterized by reduced CFT, increased MCF, and hypofibrinolysis[73]. This prothrombotic tendency is thought to stem from chronic inflammation, reduced clearance of pro-inflammatory substances like advanced glycation end-products, oxidative stress, and dialysis-related complications such as vascular access infections. These factors can activate the endothelium and platelets, increasing liver production of coagulation factors and further promoting a prothrombotic state.

Platelet dysfunction in CKD, a key factor in primary haemostasis, likely contributes to the increased bleeding risk. Multiple electrode aggregometry (MEA) testing has revealed platelet aggregation defects in end stage renal disease patients, with epidermal growth factor receptor significantly affecting ROTEM and platelet aggregation results[74]. MEA provides a rapid assessment of platelet function before procedures like renal biopsies or vascular line insertions and may help predict bleeding risk. It can also guide the safe use of antiplatelet medications like aspirin and clopidogrel, commonly used in uremic CKD patients. However, some studies suggest that MEA only evaluates platelet aggregation and that increased levels of von Willebrand factor in CKD may compensate for this defect[75,76].

While ROTEM may not be effective in predicting bleeding risk in CKD patients, its potential to assess arterial and venous thromboembolic events warrants further investigation. MEA could complement standard coagulation tests by providing more detailed insights into platelet function and bleeding risk in CKD patients, but further prospective studies are needed to confirm its clinical utility.

Monitoring anticoagulants

Anticoagulants are essential for preventing venous thromboembolism in high-risk patients and treating conditions like nonvalvular atrial fibrillation and acute MI[77,78]. They are also widely used to prevent clotting during dialysis and other clinical procedures. ROTEM is highly effective in monitoring various anticoagulants, including UFH, low-molecular-weight heparin (LMWH), and DOACs (Table 4)[5]. It offers real-time insights into clotting dynamics and can help tailor anticoagulant management, especially during bleeding emergencies or invasive procedures.

Table 4 Monitoring anticoagulant effects using rotational thromboelastometry.

Anticoagulant type	ROTEM parameters	Details
Parenteral anticoagulants
UFH	INTEM-CT	Prolonged CT correlates to aPTT levels
	HEPTEM-CT	Normalized if prolonged CT was due to UFH/LMWH
	INTEM/HEPTEM CT-ratio	Correlation with anti-FXa activity > 0.1 IU/mL
LMWH	INTEM-CT	Low sensitivity, but prolonged only if anti-FXa activity is > 0.4 IU/mL
	NATEM/NAHEPTEM CT-ratio	Correlates with anti-FXa activity > 0.1 IU/mL
	TFTEM	Correlates anti-FXa activity
	PiCT	Correlates anti-FXa activity
Fondaparinux	INTEM-CT	Only prolonged in case of supratherapeutic plasma concentrations
Direct thrombin inhibitors	EXTEM-CT	Correlation with plasma concentrations of argatroban and bivalirudin
	ECATEM-CT	Prolongation specific for direct thrombin inhibitors
Oral anticoagulants
VKAs	EXTEM-CT	Correlates with PT-INR
	INTEM and HEPTEM-CT	INTEM and HEPTEM CT values typically remain normal
Dabigatran (correlates with plasma concentration)	ECATEM-CT	Prolonged, specific for direct thrombin inhibitors
	TFTEM/ECATEM CT-ratio < 2	Detects dabigatran effects
	EXTEM and FIBTEM-CT	Prolongation of CT in EXTEM and FIBTEM due to dabigatran
	INTEM and HEPTEM-CT	Prolonged clotting times
Rivaroxaban, edoxaban (correlates with plasma concentration)	TFTEM and EXTEM-CT	Prolongation of CT with rivaroxaban and edoxaban
	TFTEM/ECATEM CT-ratio > 2	Detects rivaroxaban and edoxaban
	INTEM and HEPTEM-CT	Less sensitive to rivaroxaban/edoxaban
	ECATEM-CT	Normal, specific for DTIs
Apixaban (correlates with plasma concentration)	EXTEM and INTEM-CT	Less sensitive to low concentrations of apixaban
	TFTEM/ECATEM CT-ratio > 2	Detects apixaban effects
	TFTEM CT	Sensitive to low concentrations of apixaban
	ECATEM-CT	Normal, specific for DTIs

CT: Clotting time; ROTEM: Rotational thromboelastometry; NATEM: Nonactivated thromboelastometry; TFTEM: Low tissue factor thromboelastometry; PiCT: Prothrombinase-induced clotting time; LMWH: Low-molecular-weight heparin; UFH: Unfractionated heparin; VKAs: Antivitamin K antagonists; ECATEM: Ecarin-activated assay; aPTT: Activated partial thromboplastin time; anti-FXa: Anti-factor X activated; INR: International normalized ratio; PT: Prothrombin time; DTI: Direct thrombin inhibitor.

UFH: While aPTT, ACT, and anti-FXa assays are commonly used to monitor UFH, aPTT often does not correlate well with UFH levels[79,80]. ROTEM is more sensitive in detecting small amounts of UFH, with CT and CFT prolonged at concentrations as low as 0.1 IU/mL[81]. The HEPTEM assay helps neutralize heparin’s effect, improving diagnostic accuracy for detecting heparin rebound compared to ACT or aPTT[15].

LMWHs: Routine monitoring of LMWH is generally not required, but in high-risk cases ROTEM can be useful as aPTT is not useful for monitoring LMWH[82]. LMWH primarily affects clot initiation rather than propagation or strength, with MCF influenced more by fibrinogen levels, platelet count, and platelet function. Studies show that LMWH causes dose-dependent prolongation of CT and CFT and a reduction in MCF[83]. Studies show mixed results on how LMWHs affect clot strength. While enoxaparin and tinzaparin did not impact ROTEM’s MCF or CFT in some research, other studies found that high, but not therapeutic, doses of dalteparin reduced MCF[84].

There is no standardized ROTEM protocol for monitoring LMWH therapy. However, using minimal tissue factor-triggered ROTEM provides more accurate insights into LMWH effects. Newer tests, like PiCT-ROTEM, offer the potential for better dose adjustments and monitoring in critically ill patients. Further research is needed to establish clear guidelines for ROTEM use in LMWH therapy[82].

DOACs: DOACs, such as dabigatran and rivaroxaban, typically don’t require routine monitoring, but in emergencies or when the patient’s drug history is unknown, ROTEM can assess anticoagulation effects. While SLCTs are unreliable for DOACs, ROTEM detects prolonged CT in INTEM and EXTEM assays. Modified ROTEM triggers, like low tissue factor or ecarin, enhance accuracy[82]. Schäfer et al’s team developed an advanced algorithm combining standard and modified thromboelastometry tests to detect and differentiate between various anticoagulants, including direct factor Xa inhibitors, direct thrombin inhibitors, and vitamin K antagonists[85]. Machine learning and decision-tree analysis improved detection accuracy from 94% to 98%, though further validation in a multicentre study is needed.

Anticoagulation reversal with ROTEM: ROTEM is valuable in guiding anticoagulant reversal, particularly for agents like dabigatran. It offers real-time monitoring and supports the use of reversal agents like idarucizumab (for dabigatran) or PCC for other anticoagulants[82,86].

LIMITATIONS

ROTEM is important for evaluating coagulation status across diverse clinical environments. Nevertheless, it presents multiple constraints:

It is essential to recognize that the cup and pin mechanism employed in ROTEM does not faithfully mimic in vivo vascular mechanics, and neither of these techniques can identify primary haemostasis defects. The reagents employed in these assays induce a notable elevation in thrombin synthesis, activating platelets through the protease-activated receptors 1 and 4. This process may have the capacity to overshadow and obscure any inhibition of platelet activity. Consequently, ROTEM exhibits limited sensitivity regarding the impact of platelet inhibitors such as aspirin and clopidogrel and in identifying von Willebrand disease[10,15].

ROTEM is typically performed at a standard temperature of 37 °C, simulating normal physiological conditions. However, this approach may not accurately reflect the coagulation dynamics in patients experiencing acidosis or hypothermia common clinical scenarios in trauma, sepsis, or during surgeries. These conditions significantly alter coagulation processes, with hypothermia causing a proportional prolongation of CT as temperature decreases. Similarly, acidosis, while having a minimal independent effect on coagulation, can exacerbate hypocoagulability when combined with hypothermia, as reflected in ROTEM parameters, emphasizing the compounded impact of these conditions rather than acidosis alone[87,88].

The role of red blood cells in the clot formation process must be considered while evaulating whole blood samples. A variety of studies have investigated the influence of haematocrit on viscoelastic parameters. Haematocrit levels demonstrate an inverse correlation with ROTEM MCF in individuals diagnosed with iron deficiency anaemia. Nonetheless, this may present an advantage rather than a limitation, particularly in utilizing FIBTEM as an alternative to plasma fibrinogen concentration. In diluted conditions, frequently observed in patients experiencing bleeding, the influence of haematocrit seems minimal[89].

ROTEM’s visual processes are intricate and require specialized training for precise interpretation. The intricacies involved may result in user variability, especially in individuals needing sufficient training. Furthermore, the absence of level 1 evidence derived from high-quality randomized controlled trials hinders these methods’ clinical application and acceptance.

Furthermore, the presence of alcohol in the bloodstream may influence the precision of results, which could result in an erroneous assessment of coagulation status. The uncertainty surrounding the impaired clot formation observed raises questions about whether it is an artefact or a true physiological response. Additional investigation is warranted to elucidate these findings. Consequently, it is imperative to exercise caution when interpreting results in patients presenting with elevated blood alcohol levels[90].

While ROTEM offers advanced and dynamic insights into coagulation processes, its high initial and operational costs present a significant challenge, particularly for smaller healthcare facilities or those in resource-limited environments. The financial investment required to acquire the device, procure reagents, and train specialized personnel can be substantial. Moreover, ongoing expenses for maintenance and consumables can strain budgets, especially in institutions with a lower patient volume or infrequent use of ROTEM, making it harder to justify its cost relative to its benefits. Additionally, lack of standardization may diminish the perceived utility of ROTEM and impact its cost-effectiveness. Consequently, conventional coagulation tests such as PT/INR and aPTT remain more cost-effective and readily accessible, making them the preferred option in many healthcare settings despite their inability to provide comprehensive and dynamic assessments of coagulation profiles[15].

CONCLUSION

ROTEM is a pivotal tool for evaluating coagulation across various clinical scenarios, offering real-time and detailed insights into clot dynamics, including formation, strength, and stability. Unlike conventional coagulation tests which provide limited and static snapshots, ROTEM delivers dynamic whole-blood analyses that capture the intricate interplay of cellular and plasma components in haemostasis. This enables healthcare professionals to accurately identify coagulation abnormalities and implement targeted interventions with precision. ROTEM’s personalized nature further enhances its utility. Generating patient-specific coagulation profiles allows clinicians to tailor therapies, reducing unnecessary blood product usage and associated risks such as transfusion reactions, fluid overload, and immunosuppression. This not only improves patient outcomes but also optimizes healthcare resource utilization. As medical technologies advance, the potential applications of ROTEM are set to expand significantly. Innovations such as machine learning and decision-support systems promise to enhance its accuracy and predictive capabilities. In contrast, developing new reagents tailored to specific clinical needs, such as dual-pathway activators and DOAC-specific assays will refine its precision and broaden its scope. These advancements are poised to elevate ROTEM’s utility in managing complex haemostatic disorders, enabling more precise, individualized care and improving patient outcomes. Ongoing research and multicentre trials are expected to establish standardized protocols, ensuring their reliability and effectiveness across diverse patient populations and clinical settings.