Non-trauma uses of viscoelastic hemostatic assays in critical care: A narrative review and primer for pharmacists

Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are point-of-care viscoelastic tests of whole blood that provide real-time analyses of coagulation. TEG and ROTEM are often used to guide blood product administration in the trauma and surgical settings. These tests are increasingly being explored for their use in other disease states encountered in critically ill patients and in the management of antithrombotic medications. As the medication experts, pharmacists should be familiar with how to interpret and apply viscoelastic tests to disease state and medication management. The purpose of this narrative review is to provide a primer for pharmacists on viscoelastic tests and their interpretation and to explore non-trauma indications for viscoelastic testing in critical care. Literature evaluating the use of TEG and ROTEM for patients with acute and chronic liver disease, ischemic and hemorrhagic stroke, myocardial infarction, cardiac arrest, coronavirus disease 2019, and extracorporeal membrane oxygenation are described. Current applications of viscoelastic tests by pharmacists and potential future roles of critical care pharmacists in expanding the use of viscoelastic tests are summarized.


| INTRODUCTION
Coagulopathies and thrombotic states are both common in critically ill patients and can even exist at the same time. 1Given the adverse patient outcomes associated with both bleeding and thromboses, adequate monitoring and assessment of coagulation parameters are essential to the care of a critically ill patient.Platelet count, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) are all used to assess coagulation status and anticoagulant therapy.The utility of these tests in an emergency setting, however, is limited by their turnaround time and the breadth of information provided.Some traditional anticoagulation assays, such as INR, can be performed via point-of-care testing, but provide data limited to one coagulation parameter. 2Some newer assays, however, can assess both fibrinolysis and thrombosis. 3scoelastic point-of-care coagulation testing devices offer a realtime hemostatic analysis by assessing physical clot properties such as clot strength, fibrinolysis, and clot initiation.Current technologies of viscoelastic devices include thromboelastography (TEG) and rotational thromboelastometry (ROTEM). 4Currently, one of the most common uses of ROTEM and TEG is in trauma-induced coagulopathy to guide hemostatic resuscitation of bleeding patients. 5Both TEG and ROTEM-based algorithms for blood product administration have resulted in decreased overall usage of blood products with noninferior patient outcomes in the settings of trauma resuscitation and high blood loss surgery. 6In addition to reducing blood product requirements, viscoelastic tests have also been associated with decreased acute kidney injury, thromboembolic events, surgical reexploration, and mortality in cardiac surgery patients. 7,8While viscoelastic devices have primarily been used in the trauma and surgical settings to guide blood product administration, there are emerging applications for their use in other disease states commonly managed in the intensive care setting and in the management of antithrombotic medications.As the medication experts on the interprofessional critical care team, pharmacists are positioned to also serve as experts in the interpretation and application of viscoelastic tests of hemostasis.
It is, therefore, important for pharmacists to gain an understanding of the tests available, how to interpret them, and their potential application to managing both disease states and medications.
The purpose of this narrative review is two-fold: first, to provide a primer for pharmacists on viscoelastic tests and their interpretation, and second, to explore emerging indications for viscoelastic devices in critical care.Specifically, this review will summarize the literature on the use of TEG and ROTEM for patients with acute and chronic liver disease, ischemic and hemorrhagic stroke, myocardial infarction (MI), cardiac arrest, coronavirus disease 2019 (COVID- 19), and use of extracorporeal membrane oxygenation (ECMO).Literature included in this review was identified through searches of the PubMed database conducted in August through December 2022 using combinations of the following terms: "TEG," "ROTEM," "viscoelastic tests," "pharmacists," "acute liver disease," "cirrhosis," "ischemic stroke," "hemorrhagic stroke," "cerebrovascular accident," "MI," "cardiac arrest," "COVID-19," and "extracorporeal member oxygenation."Manuscripts written in languages other than English were excluded.Reference lists from relevant manuscripts were reviewed to identify additional texts of interest.

| OVERVIEW OF VISCOELASTIC TESTS FOR PHARMACISTS
Viscoelastic tests non-invasively evaluate whole blood samples for the quality of the clot that forms in vitro in response to low shear stress.
Normally, the hemostatic response of the body to tissue injury results in thrombosis at the site of injury that is balanced by thrombolysis to assure adequate blood flow to the rest of the body.Viscoelastic tests provide a nearly real-time assessment of the dynamics of clot development, stabilization, and dissolution, which can guide the assessment and therapeutic management of several disorders of hemostasis. 3Viscoelastic tests should always be interpreted in the context of the clinical scenario and are often used as a supplement to conventional coagulation measurements like aPTT, PT, and INR; however, evidence in nearly 2000 patients suggests that viscoelastic tests correlate with conventional tests and may even be used to replace conventional tests in the emergency department. 9G is performed by placing a citrated sample of 340 μL of whole blood into a sample cup heated to 37 C. Calcium chloride is added to overcome the effects of citrate, kaolin to activate the intrinsic coagulation pathway, and phospholipids to optimize functioning of the extrinsic coagulation pathway.A pin from the sample cup is suspended from a torsion wire.As the sample cup oscillates, the blood clots and platelets and fibrin adhere to the pin, which generates rotational forces that are measured by the torsion wire.These forces are then transmitted to an electrical transducer that graphically displays the characteristic TEG waveform in real-time (Figure 1). 10 The entire process takes about 30-60 min. 11Rapid TEG can be performed within 15 min and is performed with citrated or non-citrated whole blood samples.Unlike conventional TEG, tissue factor is added to the sample to activate the extrinsic pathway, resulting in faster results because the extrinsic pathway involves a smaller number of clotting factors. 9TEM is another type of noninvasive viscoelastic test that evolved from TEG technology.ROTEM is unique in that it utilizes a combination of activators and inhibitors to identify coagulation pathway-specific deficiencies. 3For example, the INTEM assay evaluates the intrinsic pathway of the coagulation cascade, while the EXTEM assay evaluates the enzymatic factors of the extrinsic pathway.Therefore, while the parameters measured by ROTEM are similar to that of TEG, they are not interchangeable and the pathway for initiating clotting should be specified when interpreting results.
ROTEM is performed in a similar manner to TEG.In ROTEM, 300 μL of whole blood is placed into a cylindrical cup with 20 μL of calcium chloride and 20 μL of an activator.Unlike TEG, the cup in ROTEM remains fixed while a pin suspended on a ball-bearing device oscillates.The rotation of the pin is inhibited as clot formation occurs.
Changes in the rotation of the pin are detected through a chargecoupled device image sensor system and are displayed as a ROTEM waveform (Figure 1). 10 The rotation of the cup (TEG) or pin (ROTEM) corresponds to the amplitude on the resulting waveform, where free rotation is represented by an amplitude of 0 mm and no rotation is represented by an amplitude of 100 mm.Similarities and differences between TEG and ROTEM measurements, their reference ranges, and their significance are summarized in Table 1.In addition to these parameters measured through TEG, the manufacturer of TEG also suggests assessment of overall coagulation status through a calculated coagulation index (CI) which is based on Reaction time (R), kinetics time (K), maximum amplitude (MA), and alpha angle (α), with values less than À3.0 representing coagulopathy, values between À3.0 and + 3.0 representing the normal reference range, and values greater than +3.0 representing a hypercoagulable state. 12While not widely adopted in practice, pharmacists should be aware of the CI and its interpretation.Another notable comparison between ROTEM and TEG is the operational technology.For example, ROTEM can analyze four samples simultaneously, while TEG can analyze two samples.These operational differences are summarized in Table 2. 13 Both TEG and ROTEM have technical limitations that should be noted.For patients receiving heparin, TEG with heparinase must be performed in addition to the traditional TEG assay to assess whether a prolonged R time on standard TEG is due to circulating heparin. 14There is, additionally, a growing body of evidence that the temperature at which viscoelastic tests are performed can influence the results as can the time between blood sample collection and analysis. 15,16G and ROTEM may be performed at different times in the care of a critically ill patient including upon presentation after traumatic or non-traumatic hemorrhage, in the intra-or post-operative setting, or to assess recent or current use of antithrombotic medications.As the clinical utility of TEG continues to expand, so too will the role of the pharmacist.As medication experts, it is critical for pharmacists to understand how to interpret viscoelastic tests.Specifically, pharmacists should understand how prior receipt of medications may affect TEG and ROTEM readings, and how these tracings may be used to guide initiation and/or modification of antithrombotic therapy.
Figure 2 summarizes recommendations for blood product and medication administration in response to alterations in TEG parameters, and Figure 3 provides a visualization of the effects of medications on TEG and ROTEM waveforms.Both can be used as a guide for pharmacists to aid in their interpretation of viscoelastic tests (Table 3).It is important to note that many applications of viscoelastic tests have only been studied with one assay (i.e., TEG or ROTEM, but not both) and that most institutions have only a single test available.In the event that the viscoelastic test evaluated in the literature for a specific application is unavailable in practice, pharmacists should use their clinical judgment in determining whether and how to extrapolate the findings; a practice that is employed often for emerging and understudied areas of patient care.

| ACUTE AND CHRONIC LIVER DISEASE
Patients with cirrhosis may have an increased risk of bleeding due to decreased production of clotting factors and presence of thrombocytopenia, but may also be hypercoagulable due to lack of production of endogenous anticoagulants. 17,18Typically, these clinical symptoms are measured by INR, PT, and fibrinogen levels.Alterations in these parameters make it difficult to determine when blood product transfusions are indicated in non-bleeding patients and which specific blood products may be most advantageous.This may lead to increased blood product administration, which could contribute to longer hospital stays, higher costs, and adverse transfusion-related reactions, such as transfusion-related acute lung injury, transfusion-associated circulatory overload, or cerebral edema.Viscoelastic tests present an attractive alternative for guiding blood product transfusion in patients with cirrhosis.TEG has been studied as a guide for blood product administration in patients with cirrhosis and gastrointestinal bleeding.In a study of  19 The TEG group received fresh frozen plasma (FFP) when R time was greater than 10 min, platelets when MA was less than 55 mm, and cryoprecipitate when alpha was less than 45 , while the standard-of-care group received FFP when INR was greater than 1.8, platelets when platelet count was less than 50 Â 10 9 /L, and cryoprecipitate when fibrinogen was less than 80 mg/dL.TEG-guided transfusion of blood products resulted in a decreased transfusion volume of FFP (TEG 440 [0-1320] vs. standard-of-care 880 [0-1640] mL, apheresis units, p < 0.001), and total amount of cryoprecipitate infused (4 [0-24] vs. 16 [4-36] units, p < 0.001).However, the decreased need for blood product transfusions was not associated with significant differences in 5 or 42-day mortality.
The value of TEG-guided blood transfusions in patients with cirrhosis has also been evaluated in the perioperative setting.A total of  21 Viscoelastic tests of hemostasis may be beneficial for predicting bleeding in ALF because they assess different aspects of the coagulation process and are performed in a more physiologically similar environment (i.e., whole blood).In a study of 200 patients with ALF, ROTEM parameters were assessed daily for up to 5 days. 22evations in clotting time, clot formation time, maximum clot firmness, and alpha angle were associated with an increased number of bleeding events within the first 7 days of admission.The degree of derangement in ROTEM parameters correlated with the severity of liver injury, systemic complications, incidence of bleeding events, and poor 21-day outcomes.At day 21, ROTEM parameters indicated a more hypocoagulable state in patients that had expired or undergone liver transplantation compared with patients that survived or did not require a transplant. 22Premkumar et al. similarly found that a hypocoagulable state at baseline (at least three of the following: R > 5.5 min, K > 8 min, alpha angle <35 , and MA < 40 mm) was associated with an increased risk of bleeding (hazard ratio [HR] 2.1, p = 0.050) and mortality (HR 1.9, p = 0.043) in critically ill patients with acute-on-chronic liver failure. 23This was exacerbated in patients with acute-on-chronic liver failure and sepsis who had a prolonged Reduced synthetic function and resulting elevation in INR in liver failure create a perception of increased bleeding risk, although patients with liver failure actually have a higher incidence of thrombotic events compared with general hospitalized patients. 18This common misconception may result in withholding or under-dosing of

| ISCHEMIC AND HEMORRHAGIC STROKE
Ischemic stroke is the result of a blood clot occluding vessels within the brain.The cornerstone therapy for ischemic stroke management is centered on the timely assessment and administration of thrombolytic agents such as alteplase (rtPA).Response to this therapy is patientspecific and unpredictable and there are limited data evaluating the hemostatic response to these agents. 26Thromboelastography and ROTEM offer promising techniques for assessing clot lysis and predicting the response to thrombolytic therapy in patients presenting with acute ischemic stroke (AIS). 26liott et al. characterized the TEG profile in patients with AIS before (n = 49) and 10 min after (n = 30) rtPA bolus administration and from healthy volunteer controls (n = 49). 27 The authors concluded that the weight-based standardized dosing of rtPA does not produce the same hemostatic effect in all patients.
Bleeding risk is also important to consider in relation to rtPA administration.Yu et al. investigated the utility of TEG for predicting hemorrhagic transformation following rtPA administration in patients with AIS. 28In this observational study of 205 patients with AIS, 28 (13.7%)experienced hemorrhagic transformation.Patients that experienced hemorrhagic transformation were more likely to have a baseline pre-rtPA R time of less than 5 min on TEG (81.1% vs. 60.5%,p = 0.027).Furthermore, R time less than 5 min remained an independent predictor of hemorrhagic transformation in multivariate regression controlling for comorbidities, receipt of antithrombotic therapy, and standard indices of hemostasis (i.e., PT, aPTT, and d-dimer) (odds ratio 3.215, 95% confidence interval 1.153-8.969).This finding of decreased R time (suggesting a hypercoagulable state) in the presence of intracranial bleeding seems antithetical but has been observed in other cases of intracranial hemorrhage and is hypothesized to be due to accelerated clot formation as a compensatory response to bleeding. 29,30Together, these findings suggest that TEG may have a role in predicting the degree of fibrinolysis that will be achieved by rtPA as well as the risk of hemorrhagic conversion in patients presenting with AIS.
TEG has also been evaluated in patients with nontraumatic intracerebral hemorrhage (ICH).In a prospective, observational study of 64 patients with spontaneous ICH and 57 controls, patients with ICH had faster and stronger clot formation, as indicated by shorter R (4.7 ± 1.7 vs. 6.1 ± 1.8 min, p < 0.0001) and delta (time to a maximum speed of initial clot formation; 0.6 ± 0.3 vs. 0.9 ± 0.4 min, p < 0.0001) within 6 h of symptom onset and higher MA (70.7 ± 4.8 vs. 64.4± 5.8 , p < 0.0001) and G (12.5 ± 2.9 vs. 9.3 ± 2.0 dynes/cm 2 , p < 0.0001) at 36 h. 29This finding suggests that clotting may be accelerated during the early phase of ICH as a compensatory response.
Eleven (17%) patients had hematoma expansion at 36 h.Baseline tor treatment and may be a helpful marker for deciding when to withhold thrombolytic therapy in AIS or when to initiate anticoagulant reversal therapy in acute hemorrhagic stroke. 31Pharmacists have a primary role in this decision-making.

| MYOCARDIAL INFARCTION
MI is a life-threatening condition that requires prompt intervention to restore blood flow to the myocardium.Intervention strategies for MI may involve pharmacotherapy with surgical or nonsurgical procedures.Regardless of the treatment choice, the monitoring of hemostasis is crucial to reduce the risk of complications and adverse events, such as bleeding and thrombosis. 32TEG has been evaluated for its use in assessing hemostasis and antiplatelet therapy in patients with MI.

Zhao et al. performed a retrospective analysis of patients who
underwent percutaneous coronary intervention (PCI) to determine the value of TEG in detecting indexes of antiplatelet therapy. 33In  34 In addition to guiding the choice of antiplatelet medication, TEG can also help determine the appropriate dose.A recent study utilized TEG to analyze 100 patients receiving chronic antiplatelet therapy with aspirin and clopidogrel before undergoing non-emergent cardiac stenting.The objective of the study was to determine whether patients on chronic therapy with high on-treatment pre-procedural platelet aggregation will be at increased risk for post-procedural ischemic events.were followed for 1 year post-stenting for the occurrence of MI, stent thrombosis, stroke, or death.Eighty-seven percent of patients who experienced ischemic events within 1 year had high on-treatment platelet reactivity prior to stenting as measured by TEG.Additionally, all patients were responsive to aspirin but showed variable response to clopidogrel, further supporting the use of TEG to assess antiplatelet therapy in MI. 35 Future studies are warranted to examine the use of TEG in guiding changes in antiplatelet use for select patients who show variability in response to antiplatelet agents.This could include glycoprotein IIb/IIIa inhibitors in the periprocedural or post-PCI setting or an alternative to clopidogrel, such as ticagrelor or prasugrel.
Antiplatelet therapy following MI poses a great opportunity for the benefits of TEG in balancing the risk of thrombosis versus bleeding.Viscoelastic tests may be used to help select patient-specific antiplatelet regimens that may have increased efficacy and decreased risk of bleeding.For example, if a patient is found to have a post-MI TEG profile suggesting a higher risk of bleeding, single anti-platelet therapy instead of dual antiplatelet therapy could be considered.As health care moves towards precision medicine, pharmacists are primed to play an important role as increased utilization in these viscoelastic tests assists in selecting optimal antiplatelet therapies.

| CARDIAC ARREST
In patients successfully resuscitated from cardiac arrest, post-cardiac arrest syndrome (PCAS) often occurs following return of spontaneous circulation (ROSC) due to reperfusion failure, ischemia-reperfusion injury, and/or cerebral injury. 36,37PCAS can lead to an overwhelming systemic inflammatory response and activation of the coagulation cascade, both of which can contribute to organ dysfunction. 37TEG has been used to characterize coagulopathies following ROSC in cardiac arrest.TEG could thus potentially be used as an important clinical predictor of mortality and help identify patients more at risk for thromboses or bleeding.
9 In the PoHCAR study, 30 patients post-ROSC with a likely cardiac cause of out-of-hospital cardiac arrest (OHCA) were compared with 30 patients admitted with STEMI without cardiac arrest.ROTEM and platelet function assessments were performed at hospital admission and at several time points following PCI. 40While small differences were seen between the two groups (i.e., reduced platelet activation and prolonged maximum clot firmness with OHCA), it was concluded that there was no gross coagulopathy in patients with OHCA compared to those with STEMI without arrest. 41Hyperfibrinolysis, however, was common in patients with both OHCA and STEMI and could be a target for clinical intervention to prevent and/or treat bleeding (e.g., with tranexamic acid).
TEG has also been used to characterize post-arrest coagulopathy in the setting of induced hypothermia.In 21 OHCA survivors undergoing PCI, TEG revealed a reduced rate of clot formation, reduced clot strength, and reduced fibrinolysis in patients undergoing mild hypothermia (target temperature 32 C). 42In a separate observation of 18 patients post-ROSC, however, ROTEM was assessed before initiation of mild hypothermia therapy and at several time points after hypothermia onset.It was observed that mild hypothermia had only minor effects on coagulation parameters according to ROTEM, specifically a slight prolongation of clotting time. 43en using TEG to assess coagulation profiles in patients receiving targeted temperature management following cardiac arrest, the effect of temperature on whole blood coagulation tests should be noted.In two studies examining this phenomenon, ROTEM results were independent of the patient's body temperature when the blood sample was drawn (33 C vs. 37 C), but were dependent on the temperature used in the analyses. 15The authors conclude that the temperature used for TEG analyses should be kept at 37 C regardless of body temperature. 42romboelastography has also been evaluated for its utility in predicting outcomes of cardiac arrest, namely ROSC and neurologic recovery.Thromboelastography was evaluated during the initial, target, and rewarming phases of targeted temperature management in 125 consecutive non-trauma cases of OHCA who were treated with therapeutic hypothermia.In both univariate and multivariate analyses, TEG parameters of R less than 5 min and LY30 less than 7.5 min were independently associated with favorable neurologic function at day 28. 44These findings suggest that TEG may be used as an early prognostic tool post-cardiac arrest.In a similar study of 75 consecutive patients with non-trauma OHCA whom had ROTEM assessed during cardiopulmonary resuscitation, ROTEM parameters for patients who achieved ROSC were compared with those with unsuccessful resuscitation. 45It was found that clot firmness (A30 of EXTEM test) was higher in patients who achieved ROSC and was an independent risk factor for ROSC (OR 1.039, 95% CI 1.010-1.070).A lower lactate level (<12.0 mmol/L) and higher A30 of EXTEM (≥48.0 mm) had 94.7% specificity and 75.0%accuracy for predicting ROSC.
For patients with cardiac arrest, ROTEM analyses suggested that increased bleeding was associated with hyperfibrinolysis, a finding that could help pharmacists tailor treatment during post-arrest care, for example through the administration of tranexamic acid to prevent and/or treat bleeding.It was also observed through ROTEM analyses that hypothermia may play a role in maintaining normal coagulation dynamics in patients following ROSC.TEG and/or ROTEM analyses may have a role in prognostication following cardiac arrest.With newer studies failing to demonstrate the benefit of targeted temperature management post-cardiac arrest, the role for this intervention is increasingly controversial with some clinicians postulating that patient-specific factors may be important in determining who may benefit. 46The association between TEG parameters and neurologic recovery in patients undergoing TTM provides initial evidence that TEG could play a role in identifying patients most likely to benefit from this therapy.Pharmacists may play an active role in interpreting viscoelastic test results to determine patients likely to benefit from TTM and assess the risk of bleeding during this therapy.

| CORONAVIRUS DISEASE-2019
Coronavirus disease-2019 (COVID-19) is associated with an increased frequency of thromboembolic events, which leads to an increased mortality risk. 47There is currently a lack of clear data to guide anticoagulation for the prevention of thromboembolism in critically ill patients with COVID-19, which has resulted in variable practices regarding selection of an anticoagulant agent (i.e., unfractionated heparin or low molecular weight heparin) and intensity (i.e., prophylactic, intermediate, or therapeutic dosing). 48 Furthermore, in a multivariate analysis, fibrin clot strength greater than 40 mm was independently associated with the composite primary endpoint of in-hospital mortality and thrombotic event.
These findings also suggest that increasing anticoagulant intensity may be better guided by viscoelastic assay metrics such as fibrin clot strength versus other markers like D-dimer that have been used in practice at different stages of the pandemic. 53rther derangements in thrombogenicity have been observed in critically ill patients with COVID-19.In an observational study of 40 consecutive patients with COVID-19 and ARDS admitted to an intensive care unit in Italy, baseline assessments of rTEG revealed elevated fibrinogen activity as indicated by rTEG-Ang and TEG-ACT as well as an increase in MA and absent LY30. 55Despite these alterations in TEG parameters, standard coagulation parameters of INR, aPTT, and antithrombin were all within the normal physiologic range while plasma fibrinogen and D-dimer were elevated.After 7 days of enoxaparin 0.5 mg/kg twice daily, UFH 7500 units three times daily, or low-intensity heparin infusion, rTEG was assessed again and revealed persistent alterations in thrombogenicity despite anticoagulation therapy.
TEG can be used to predict the rates of thrombotic events and bleeding in critically ill patients with COVID-19.These predictions can help pharmacists tailor treatment (i.e., using prophylactic or therapeutic doses of anticoagulants) to each particular patient.Viscoelastic tests of hemostasis can also be used to predict mortality in patients with COVID-19, which may prompt earlier initiation of specific therapies and/or transfer to a higher level of care.

| EXTRACORPOREAL MEMBRANE OXYGENATION
The incidence of ECMO for cardiac and pulmonary support has increased markedly in recent decades, especially during the COVID-19 pandemic. 56,57This intervention is reserved for critically ill patients who fail to respond to conventional forms of rescue therapy; however, complications including both thromboses and bleeding are common. 58During ECMO, anticoagulation is necessary to prevent thrombi formation as the vascular system comes in direct contact with the ECMO circuit.Unfractionated heparin is often used as the anticoagulant of choice, but there is no well-established standard for anticoagulant agents or therapeutic monitoring during ECMO. 59andard tests of aPTT and anti-Xa are commonly used, but both have limitations. 59Viscoelastic tests present an alternative to standard tests for anticoagulation management during ECMO.
Several studies have explored the use of a TEG-based approach to anticoagulation monitoring in patients receiving ECMO.In a population of 49 pediatric patients receiving ECMO, it was determined that targeting a TEG R time greater than 17.85 min may reduce the risk of thrombosis, establishing TEG as a potential target for determining the therapeutic range of anticoagulants. 60 ence in thrombotic events (four in each group) and there was a trend toward a decrease in bleeding events (48% vs. 71%, p = 0.21). 61A larger study that is powered to detect differences in safety and efficacy is needed.
Bivalirudin is a direct thrombin inhibitor that is a common alternative to heparin for anticoagulation during ECMO and is routinely monitored by aPTT. 62

| MEDICATION MANAGEMENT
In addition to their potential role for managing anticoagulant therapy during ECMO, other roles for viscoelastic tests in medication management have been described.The ALicia trial (argatroban vs. lepirudin in critically ill patients) randomized 66 critically ill surgical patients with suspected heparin-induced thrombocytopenia to receive double-blind argatroban or lepirudin for anticoagulation, both of which were titrated to achieve an aPTT of 1.5-2 times baseline. 65It has been demonstrated that aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, but the precision of aPTT for this use in critically ill patients has been questioned. 66Therefore, a pre-specified sub-study to the ALicia trial was conducted in 35 patients and evaluated ROTEM as an alternative to aPTT for monitoring anticoagulant effects. 67 In emergent situations, timely identification of oral anticoagulants is crucial but is challenging due to the inconsistent impact of the DOACs on traditional coagulation parameters.9][70] Whole blood samples from 20 healthy donors spiked in vitro with apixaban, edoxaban, rivaroxaban, or dabigatran found a linear relationship between ROTEM clotting time and plasma DOAC concentration. 69as et al. used TEG-6S in patients with and without DOAC treatment and in healthy controls to create a DOAC identification algorithm.
Using TEG-6S, an R time of 0.6-1.5 min detected anti-Xa therapy with 98.3% sensitivity and 100% specificity while an R time of 1.6-2.5 min detected direct thrombin inhibitors with 100% sensitivity and specificity. 70 addition to detecting DOACs, viscoelastic tests may also have

R
time (indicative of delayed clot formation and risk of bleeding) compared with patients with uncomplicated acute-on-chronic liver failure (5.4 ± 1.4 vs. 4.7 ± 1.0 min, p = 0.024).These studies are limited by the lack of direct comparison of viscoelastic tests to INR for assessing bleeding risk.TEG and ROTEM provide additional information and may be used in conjunction with INR to assess risk of bleeding.
prophylaxis.Viesselmann et al. report an abstract evaluating a pharmacist-driven protocol to recommend TEG in patients with liver failure to assess the need for VTE prophylaxis and increase compliance with hospital quality metrics. 24Through this program, pharmacists screened patients daily for VTE risk factors and recommended TEG in patients with liver failure who had an INR of 1.5 or higher and who qualified for pharmacologic VTE prophylaxis but did not have it ordered.TEG was recommended in 67 patients, ordered in 40 patients, and resulted in a new order for pharmacologic VTE prophylaxis in 27 patients (67.5%), thereby increasing compliance with hospital quality metrics.This report, though limited and lacking specific TEG thresholds used, provides a prime example of how pharmacists may use viscoelastic tests to optimize therapeutic recommendations in practice.Viscoelastic measures of hemostasis including both TEG and ROTEM have been effective in identifying coagulopathy in patients Compared with healthy volunteers, patients with AIS had shorter R and K times and greater alpha angles, indicating faster clotting.Administration of rtPA resulted in universally reduced clot strength, but variable responses for clot lysis.Specifically, the post-rtPA median LY30 value was significantly increased from baseline with a wide interquartile range (IQR), indicating that the rate of clot formation and fibrinolysis was not uniformly suppressed by the standard weight-based dosing of rtPA (pre-rtPA: 0% [IQR 0-0.4] vs. post-rtPA: 94.4% [15.2-95.3],p < 0.0001).

K
and delta were longer in these patients than in those without hematoma enlargement (K: 3.1 [95% CI 2.0-4.1] vs. 1.6 [95% CI 0.6-2.6]min, p = 0.04; delta: 0.8 [95% CI 0.6-1.0] vs. 0.5 [95% CI 0.4-0.7]min, p = 0.02), indicating slower clot formation.By detecting changes in coagulation status, TEG may help guide patient-specific therapeutic intervention in the setting of ICH.For example, if a patient's delta is longer than expected at baseline, suggesting risk of hematoma enlargement, this could theoretically prompt earlier surgical intervention for hematoma evacuation, though should also be weighed against the risk of surgical bleeding.TEG is a promising clinical tool for evaluating patients presenting with ischemic and hemorrhagic stroke.It has the potential to predict response to thrombolytic therapy and risk of hemorrhagic transformation in patients with AIS or to predict hematoma expansion in patients with ICH.Future research evaluating TEG parameters as a directive for pharmacologic and/or surgical intervention could be useful in identifying a place for viscoelastic tests in the routine assessment of patients presenting with acute stroke.For example, with more research, a threshold for R time may be established as a contraindication for rtPA in AIS, or baseline K or delta values meeting a certain threshold could become an indication for surgical intervention in patients with ICH.Pharmacists are oftentimes responsible for evaluating contraindications and risk factors for bleeding prior to the administration of thrombolytic therapy in AIS.Viscoelastic tests, when available, may serve as an additional piece of data along with patient history and traditional tests for emergency decision-making in weighing the risks versus benefits of thrombolytic therapy.In addition to predicting the risk of hemorrhagic conversion, viscoelastic tests may also be helpful in identifying patients that have received anticoagulant therapy, specifically direct-acting oral anticoagulants (DOACs) which are more difficult to detect with traditional anticoagulation tests.Prolonged R time has reliably detected anticoagulant effects of factor Xa inhibi- Viscoelastic devices have been evaluated to understand their role in stratifying thromboembolic risk and guiding anticoagulant therapy in critically ill patients with COVID-19.The hypercoagulable state of critically ill patients with COVID-19 has been confirmed through TEG, which revealed shorter R and K values consistent with hypercoagulation, a prolonged alpha angle indicating rapid clot formation, prolonged MA indicating higher clot strength, and a lower LY30 indicating rapid clot lysis.49Similar findings were seen with ROTEM analyses in a small sample of 6 critically ill patients with COVID-19-associated respiratory failure.ROTEM analyses revealed elevated clot amplitude at 10 min (A10) and maximal clot firmness, as well as decreased clot formation time and clot lysis.50It has been suggested that the initial hypercoagulable state observed in patients with COVID-19 can later progress to hypocoagulability caused by anticoagulation and/or hemostasis exhaustion.51Due to the potential risk of bleeding, Stillson et al. conducted a small study evaluating TEG parameters and standard coagulation tests in critically ill patients with COVID-19 receiving intermediate or therapeutic UFH infusion who did (n = 10) or did not (n = 21) experience a bleeding event, defined by a World Health Organization bleeding scale score of two or higher.R time, K time, alpha angle, PT, aPTT, and fibrinogen were all found to be predictive of bleeding.This led to the development of an UFH titration protocol based on a combination of TEG parameters, aPTT, and fibrinogen that is hypothesized to prevent bleeding complications in critically ill patients with COVID-19.Additional research evaluating the efficacy of this protocol is ongoing.52In a subanalysis of the TARGET-COVID study, Gurbel et al. used TEG-6S to assess change in R time between the kaolin and kaolin plus heparinase channels as an indicator of response to anticoagulant therapy in 120 hospitalized patients with COVID-19.53TEG-6S is a newer technology that measures the same physical properties as the original TEG device and offers increased coagulation information through the incorporation of resonance-frequency viscoelasticity.A change in R of 1 min or greater indicated an anticoagulant effect, while a change in R less than 1 min indicated poor anticoagulant response.Poor anticoagulant response was common in patients receiving enoxaparin prophylaxis <80 mg twice daily (n = 50%, 84%), heparin prophylaxis ≤7500 units three times daily (n = 21%, 62%), and therapeutic anticoagulation (n = 17%, 53%), but occurred at a higher incidence in patients receiving prophylactic enoxaparin compared with the other two groups ( p < 0.05 for both comparisons).This hypothesisgenerating finding suggests that a personalized approach to anticoagulation management in patients with COVID-19 may be warranted.TEG has also been studied as a predictive tool for diagnosis and prognosis in patients with COVID-19.In a prospective, observational study, Gurbel et al. evaluated standard biomarkers and TEG-6S on the day of hospital admission in 119 hospitalized patients with COVID-19 pneumonia and 15 patients hospitalized with pneumonia without COVID-19. 54Patients with COVID-19 had higher platelet-fibrin clot strength, fibrin clot strength, and functional fibrinogen levels compared to patients without COVID-19 ( p ≤ 0.003 for all).Elevations in these TEG-6S parameters were also found to discriminate COVID-19-positive and negative patients better than traditional biomarkers of procalcitonin, ferritin, D-dimer, and C-reactive protein.

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role in guiding anticoagulant reversal.Gilbert et al. describe a case report utilizing serial TEG testing to guide anticoagulant reversal in a patient presenting with acute major bleeding and acute kidney injury whose home medication regimen included clopidogrel and dabigatran.71TEG was performed on admission and showed prolonged R time and activated clotting time.Repeat TEG testing was performed 4 and 8 h after the administration of idarucizumab 5 g because of the risk of rebound hypercoagulability in the setting of acute kidney injury and both tests showed complete anticoagulant reversal.This case demonstrates a potential utility for serial TEG measurement in managing complex cases of acute bleeding involving concomitant antithrombotic agents.Viscoelastic tests may have a role in guiding anticoagulant administration and reversal as well as identifying patients who have been taking anticoagulants prior to hospital presentation.Future research should evaluate the use of viscoelastic tests to guide all aspects of anticoagulant management including medication selection and monitoring and reversal of anticoagulants with medications and/or prothrombin complex concentrate or other factor products.Pharmacists should take a primary role in evaluating viscoelastic tests in order to guide medication management.10 | CONCLUSIONSViscoelastic tests including TEG and ROTEM have been explored in a variety of disease states common in critical care including liver disease, stroke, MI, cardiac arrest, ECMO, and COVID-19.Available literature is largely limited by small sample size, observational nature, and lack of comparison to current standard-of-care.As these tests gain increased use at the bedside, pharmacists are positioned to be leading experts in their interpretation and application to pharmaceutical care.Pharmacists should be aware that viscoelastic test values associated with poor outcomes in different clinical scenarios are often within the normal reference range; therefore, knowledge of the available literature is necessary.The potential roles of pharmacists in using viscoelastic tests are plentiful and include guiding choice and dosage of anticoagulant and antiplatelet therapy, titrating antithrombotic medications based on parameters from viscoelastic tests, and initiating anticoagulant reversal.
■ Related to angle of clot ■ Describes rate of formation Time to maximum velocity No equivalent parameter Time to maximum velocity (MAXV-t) ■ Related to rate of formation ■ Describes time to achieve fastest rate of formation 96 patients with non-variceal upper gastrointestinal bleeds, Kumar et al. compared TEG to guide blood product transfusion with standard-of-care using a combination of INR, PT, and fibrinogen levels.
Reported reference ranges are derived from the Cochrane Database Systematic Review referenced below but may differ based on specific assays and/or laboratory calibrations used by your institution. a T A B L E 3 Potential role of pharmacists in the application of viscoelastic tests of hemostasis in critical care.Decreased need for blood product transfusions using TEG-guided protocols in non-variceal upper GI bleeds ■ Decreased blood product transfusions prior to invasive procedures in cirrhosis ■ Better predictor of bleeding events compared with INR ■ Elevated clotting time, clot formation time, maximum clot firmness, and alpha angle associated with increased bleeding events in first 7 days of admission ■ R > 5.5 mins, K > 8 mins, α-angle <35 , maximum amplitude <40 mm associated with increased risk of bleeding and mortality Abbreviations: aPTT, activated partial thromboplastin time; GI, gastrointestinal; ICH, intracranial hemorrhage; INR, international normalized ratio; K, kinetics time; MI, myocardial infarction; R, reaction time; ROSC, return of spontaneous circulation; rtPA, recombinant tissue plasminogen activator; TEG, thromboelastography; TTM, targeted temperature management; VV ECMO, veno-venous extracorporeal membrane oxygenation.