The introduction of new oral anticoagulants (NOACs) has. Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants

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1 Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants João D. Dias, PhD; Katherine Norem, BA; Derek D. Doorneweerd, PhD; Robert L. Thurer, MD; Mark A. Popovsky, MD; Laurel A. Omert, MD Context. The clinical introduction of new oral anticoagulants (NOACs) has stimulated the development of tests to quantify the effects of these drugs and manage complications associated with their use. Until recently, the only treatment choices for the prevention of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with atrial fibrillation, were vitamin K antagonists, antiplatelet drugs, and unfractionated and low-molecular-weight heparins. With the approval of NOACs, treatment options and consequent diagnostic challenges have expanded. Objective. To study the utility of thromboelastography (TEG) in monitoring and differentiating between 2 currently approved classes of NOACs, direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). Design. Blood samples from healthy volunteers were spiked with each NOAC in both the presence and absence of ecarin, and the effects on TEG were evaluated. Results. Both the kaolin test reaction time (R time) and the time to maximum rate of thrombus generation were prolonged versus control samples and demonstrated a dose response for apixaban (R time within the normal range) and dabigatran. The RapidTEG activated clotting time test allowed the creation of a dose-response curve for all 3 NOACs. In the presence of anti-xa inhibitors, the ecarin test promoted significant shortening of kaolin R times to the hypercoagulable range, while in the presence of the direct thrombin inhibitor only small and dose-proportional R time shortening was observed. Conclusions. The RapidTEG activated clotting time test and the kaolin test appear to be capable of detecting and monitoring NOACs. The ecarin test may be used to differentiate between Xa inhibitors and direct thrombin inhibitors. Therefore, TEG may be a valuable tool to investigate hemostasis and the effectiveness of reversal strategies for patients receiving NOACs. (Arch Pathol Lab Med. 2015;139: ; doi: / arpa oa) The introduction of new oral anticoagulants (NOACs) has changed the management of patients with venous and arterial thromboembolic diseases. Unlike traditional oral vitamin K antagonists, NOACs are given at fixed doses and have a lower potential for drug and food interactions, eliminating the requirement for routine laboratory monitoring. 1,2 These novel agents show similar or improved efficacy and safety profiles compared with vitamin K antagonists such as warfarin and established parenteral Accepted for publication July 11, From Clinical Marketing, Haemonetics SA, Signy, Switzerland (Dr Dias); Operations Department (Ms Norem) and Scientific Research & Biomedical (Dr Doorneweerd), Haemonetics Corporation, Rosemont, and Medical Affairs, Haemonetics Corporation, Chicago (Dr Omert), Illinois; Hospital Division (Dr Thurer) and Medical Affairs (Dr Popovsky), Haemonetics Corporation, Braintree, Massachusetts; and Department of Surgery, Einstein Medical Center, Philadelphia, Pennsylvania (Dr Omert). Dr Omert is now with Acquired Bleeding, CSLBehring,KingofPrussia,Pennsylvania. This work was supported by Haemonetics Corporation, Rosemont, Illinois. Drs Dias, Doorneweerd, Thurer, and Popovsky and Ms Norem are employees of Haemonetics Corporation. Dr Omert was an employee of Haemonetics Corporation at the time of the study. Reprints: João Dias, PhD, Haemonetics SA, PO Box 262, 1274 Signy-Centre, Switzerland ( agents, including unfractionated heparin and low-molecular-weight heparin. 2 Currently licensed NOACs are dabigatran (Pradaxa; Boehringer Ingelheim International GmbH, Ingelheim, Germany), rivaroxaban (Xarelto; Bayer Pharma AG, Leverkusen, Germany, and Janssen Pharmaceuticals, Inc, Titusville, New Jersey), and apixaban (Eliquis; Bristol-Myers Squibb, New York, New York, and Pfizer EEIG, Sandwich, United Kingdom). All of these agents, and others in development, are under investigation for the management of multiple thromboembolic disorders Dabigatran is an oral direct inhibitor of thrombin (factor IIa) that is not permanent, selective, and competitive. Rivaroxaban and apixaban are oral direct inhibitors of factor Xa and are also competitive, selective, and not permanent. 11 Dabigatran is the only NOAC administered as a prodrug and metabolized to the active form. All 3 agents are licensed in the European Union and the United States to reduce the risk of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Furthermore, rivaroxaban is approved in the European Union for the secondary prevention of acute coronary syndrome. Rivaroxaban can be administered in combination with acetylsalicylic acid or with acetylsalicylic acid plus clopidogrel or ticlopidine for Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al 665

2 Figure 1. Illustration of a thromboelastography tracing and accompanying parameters. A, Depiction of a thromboelastography tracing and parameters measured throughout the life span of a clot. B, Thrombus generation curve (V-curve in green) overlaying a thromboelastography tracing. A V-curve is plotted from the first derivative of changes in clot resistance, expressed as a change in clot strength per unit of time (dynes/cm 2 /s), representing the maximum velocity of clot formation. Abbreviations: ACT, activated clotting time; a, a angle; K, coagulation time; Ly30, percentage lysis 30 minutes after maximum amplitude; MA, maximum amplitude; MRTG, maximum rate of thrombus generation; R, reaction time; TMRTG, time to maximum rate of thrombus generation. the prevention of thrombotic events in adult patients with elevated cardiac biomarkers after a coronary event. 12 The NOACs present management challenges to both clinicians and laboratory personnel when patients develop bleeding diatheses. In some cases, there are no useful methods to detect and monitor these agents, and no antidotes are available to reverse their effects. Miyares and Davis 13 recently reviewed the usefulness and sensitivity of current coagulation assays for dabigatran, rivaroxaban, and apixaban. The most easily available tests for emergency situations, prothrombin time and partial thromboplastin time, were described as not ideal with the exception of the partial thromboplastin time for dabigatran. 13 Less widely available tests, including thrombin time, ecarin clotting time, Heptest (American Diagnostica, Stamford, Connecticut), prothrombinase-induced clotting time, and chromogenic factor IIa, either do not correlate well with drug levels or are cumbersome and lengthy to perform. The difficulty of managing trauma patients receiving dabigatran was highlighted by Cotton et al in an editorial in which the authors emphasized that...there is no readily available means for assessing the degree of anticoagulation with dabigatran, there is no readily available reversal strategy, and lifethreatening bleeding complications can occur after an injury in patients taking this drug. (pp ) Viscoelastic measurements of coagulation provided by tests such as thromboelastography (TEG) are increasingly being used to assess trauma patients who arrive in shock secondary to massive bleeding, as well as for acute care of surgical patients with bleeding diatheses. Thromboelastography is widely used as a management tool for cardiac surgery and transplant patients and provides information to guide the administration of blood products. 15 Thromboelastography is able to detect both low-molecularweight and unfractionated heparins and, with the use of a heparinase cup, can illustrate whether the effects of these agents have been completely reversed. Furthermore, the TEG PlateletMapping assay (Haemonetics Corporation, Braintree, Massachusetts) is used to quantify the response to antiplatelet therapies, including clopidogrel and aspirin, that can be used in combination with NOACs. Thromboelastography assays using ecarin have been used to monitor recombinant hirudin and bivalirudin during cardiac surgery. 16,17 In this study, we investigated whether TEG could detect dabigatran, rivaroxaban, and apixaban in low, normal, and high doses using spiked blood samples from healthy volunteers. In addition, we tested an assay to differentiate these agents from each other. MATERIALS AND METHODS We studied 3 NOACs, dabigatran, rivaroxaban, and apixaban, using blood from 14 healthy volunteer donors. For each NOAC tested, citrated blood from 3 donors was spiked with 3 different concentrations of the active drug. The spiked blood samples and control samples spiked with diluent were tested with the TEG 5000 Thrombelastograph hemostasis analyzer (Haemonetics Corporation) using kaolin and RapidTEG (rteg) (Haemonetics Corporation) reagents. Each sample was run in triplicate. All samples were tested with and without ecarin (Enzyme Research Laboratories, South Bend, Indiana). The work in this study was institutional review board approved, and all donors were 18 years or older and signed informed consent forms. Sample Preparation Blood was drawn using standard venipuncture technique and a Vacutainer push-button collection set (Becton, Dickinson and Company, Franklin Lakes, New Jersey) with a 21-gauge needle. Blood was spiked and tested within 2 hours of being drawn. Dabigatran stock was prepared from the active dabigatran moiety (Alsachim, Illkirch Graffenstaden, France) by dissolution in 0.1M hydrogen chloride and further dilution in 1:1 dimethyl sulfoxide and water. The final stock used to spike the blood had a concentration of 20 ng/ll in 0.1M hydrogen chloride, dimethyl sulfoxide, and water. Tubes of citrated blood were spiked with this 666 Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al

3 Table 1. Thromboelastography Kaolin Test Coagulation Parameters Sensitivity in Healthy Donor Spiked Samples With Different Doses of Apixaban, Rivaroxaban, and Dabigatran in the Presence or Absence of Ecarin a Variable R Time, min K Time, min No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value Apixaban, ng/ml *** ,**, *** , *** , ** , *** , * ,.001 Control , Rivaroxaban, ng/ml ,,*** ,**, ,** ** ** , * , *.001 Control , Dabigatran, ng/ml ,,*** ,,*** ,*** ,,*** ^^^,*** ^^^,*** ^,*** ^^,**, *** ***, ** ,.001 Control , Abbreviations: K Time, coagulation time; MRTG, maximum rate to thrombus generation; R Time, reaction time; TMRTG, time to maximum rate of thrombus generation. a Statistically significant between (higher dose and medium dose), (higher dose and lower dose), ^ (medium dose and lower dose), and * (control). Standard error of 3 independent experiments measured in triplicate. Single symbol, ^, and * indicates P,.05; 2 symbols,, ^^, and ** indicate P,.01; and 3 symbols,, ^^^, and *** indicate P,.001. Statistically significant between paired sample with or without ecarin. Table 1. Extended a Angle, 8 MRTG, mm/min TMRTG, min No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value ** , ** , ,,*** **, ** , * , *** , * , * , *** , , ** * ** ,,*** ,,***, * ***, , * **, , ,,*** ,,*** ,*** ,,** ,,*** ,,***, ^,*** ^^^,**, ^,*** ^^,*, ^^,*** ^^^,*** *** , * , *** ***, ,.001 Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al 667

4 dabigatran stock to create final concentrations of 500, 200, and 50 ng/ml of citrated whole blood. Dabigatran is approved for the prevention of venous thromboembolism following elective knee or hip replacement (220 mg/d for patients without renal impairment and 150 mg/d for patients with moderate renal impairment) and for the prevention of stroke in patients with renal impairment and atrial fibrillation in the United States (at a reduced dose of 75 mg/ d). 18,19 A 150-mg oral dose of dabigatran has a maximum plasma concentration of 110 ng/ml. 20,21 Rivaroxaban stock was prepared by agitation of a 20-mg rivaroxaban tablet in a 1:1 dimethyl sulfoxide and water solution, which was diluted to a final concentration of 20 ng/llofrivaroxaban in 1:1 dimethyl sulfoxide and water. Tubes of citrated blood were spiked with this rivaroxaban stock to create final concentrations of 500, 89, and 22 ng/ml in citrated whole blood. Rivaroxaban is approved for the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation (20 mg/d in the European Union and the United States), as well as for the treatment of deep venous thrombosis and pulmonary embolism and for the prevention of recurrent deep venous thrombosis and pulmonary embolism in adult patients (15 mg twice daily for 3 weeks, followed by 20 mg/d, in the European Union and the United States). 12,22 An oral dose of 10 mg of rivaroxaban has a maximum plasma concentration of 141 ng/ml. 21,23 Apixaban stock was prepared in a similar manner from a 2.5-mg apixaban tablet, with final concentrations of 1000, 500, and 250 ng/ml in whole blood. Apixaban is approved for the prevention of venous thromboembolism in elective hip or knee replacement surgery (2.5 mg twice daily) and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (5 mg twice daily). 24 An oral dose of 20 mg of apixaban has a maximum plasma concentration of 460 ng/ml. 21,25 Control samples were prepared for each tested drug. These included a solvent control containing only citrated blood and the diluent used to dilute the drug stock, as well as an unadulterated citrate blood tube. Thromboelastography Testing was performed on TEG 5000 analyzers (Haemonetics Corporation) using kaolin tubes, 0.2M calcium chloride, rteg vials, diluent water, and disposable clear cups and pins provided by the manufacturer (Haemonetics Corporation), as well as ecarin. All testing was performed in triplicate at each dose and allowed to continue until the maximum amplitude (MA) parameter had defined. The various components of the TEG tracing are shown in Figure 1, A. The kaolin test generates a reaction time (R time) parameter, which is measured in minutes, and is the time elapsed from the initiation of the test until the point where the onset of clotting provides enough resistance to produce a 2-mm amplitude reading on the TEG tracing. This parameter represents the initiation phase of coagulation related to the function of enzymatic clotting factors. The R time parameter has a normal range of 5 to 10 minutes. A prolonged R time indicates slower clot formation. K is a measurement of the interval from the split point to the point where fibrin cross-linking provides enough clot resistance to produce a 20-mm amplitude reading measured in minutes. The a angle is the angle formed by the slope of a tangent line traced from the R time to the coagulation time (K time) and a central line measured in degrees. The K time and the a angle denote the rate at which the clot strengthens and are representative of thrombin s cleaving of the available fibrinogen into fibrin. The MA indicates the point at which clot strength reaches its MA, measured in millimeters on the TEG tracing, and reflects the end result of maximum platelet-fibrin interaction via the glycoprotein IIb-IIIa receptors. 26 The rteg test incorporates both tissue factor and kaolin to generate the conventional kaolin parameters, as well as the TEG activated clotting time (ACT) parameter, which is measured in seconds. The TEG ACT is equivalent to the activated clotting time 27 and has a normal range of 86 to 118 seconds. A prolonged TEG ACT time indicates slower clot formation. In addition, velocity curves derived from the above-mentioned kaolin and rteg tests were plotted using TEG software (Haemonetics Corporation). These curves represent the speed of clot propagation (maximum rate of thrombus generation [MRTG] and the time to MRTG [TMRTG]) (Figure 1, B). In the kaolin test, 1 ml of citrated blood sample was mixed with kaolin, and a 340-lL aliquot of this blood was added to a TEG cup containing 20 ll of 0.2M calcium chloride for recalcification. The kaolin with ecarin test was performed in a similar fashion using 20 ll of an ecarin and calcium chloride solution (0.16M calcium chloride and 19 Endotoxin Units/mL [EU/mL] of ecarin). In the rteg test, the reagent was reconstituted with 20 ll of diluent water and allowed to stand for 5 minutes per the manufacturer s instructions. Ten microliters of this reconstituted reagent was added to the TEG cup with 20 ll of 0.2M calcium chloride for recalcification. A 360-lL aliquot of the citrated blood sample was added to the cup with these 2 reagents, and the contents of the cup were mixed 3 times by drawing the contents of the cup up into the pipette and redispensing it into the cup. The test was started immediately after mixing and allowed to run until the MA parameter had defined. The rteg with ecarin test was performed as the rteg test above using 20 ll of an ecarin and calcium chloride solution (0.16M calcium chloride and 19 EU/mL of ecarin). Statistical Analysis Statistical analyses were performed using a 2-tailed Student t test. For all analyses, P,.05 was deemed statistically significant. RESULTS Kaolin Test The R time, K time, a angle, and MRTG parameters in the kaolin test achieved statistical significance only for the higher concentrations of rivaroxaban (Table 1 and Figure 2, A) but were able to detect the presence of all tested concentrations of apixaban (P.04) (Table 1 and Figure 2, B) and dabigatran (P.04) (Table 1 and Figure 2, C). In addition, for all drugs the TMRTG parameter was statistically different between the control group and all tested concentrations. Furthermore, the R time, a angle, and TMRTG parameters for the dabigatran samples were significantly different between all concentrations, indicating an appropriate dose response (Table 1 and Figure 2, C). Finally, the MA values from the kaolin test for rivaroxaban and dabigatran did not change with the addition of the studied NOACs compared with the control, illustrating the lack of effect of these agents on platelet-fibrin contribution to clot strength. However, apixaban tracing at a concentration of 250 ng/ml demonstrated that the MA was significantly different from the control group (P,.001) but was still within the normal range (data on file). rteg Test The TEG ACT parameter for all tested drugs in the rteg test was significantly different between the control group and all tested concentrations of rivaroxaban, apixaban, and dabigatran (Table 2 and Figure 2, D through F) with the exception of the rivaroxaban concentration of 22 ng/ml (P ¼.58) (Table 2 and Figure 2, D). Furthermore, the TEG ACT parameter was able to distinguish between concentrations of rivaroxaban (Table 2 and Figure 2, D) and dabigatran (Table 2 and Figure 2, F), indicating a good dose-response curve. The K time, a angle, and MRTG parameters for both apixaban and rivaroxaban from the rteg test did not show any statistical difference between the control or between studied concentrations (Table 2). 668 Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al

5 Figure 2. The thromboelastography kaolin test reaction time (R Time) sensitivity as a function of different concentrations of rivaroxaban (A), apixaban (B), and dabigatran (C) and RapidTEG activated clotting time (ACT) test time sensitivity as a function of different concentrations of rivaroxaban (D), apixaban (E), and dabigatran (F). The R times for all doses of dabigatran, as well as the highest concentrations of apixaban and rivaroxaban, tested significantly higher than the expected normal range. The ACT times for all concentrations of dabigatran, as well as the normal and higher concentrations of apixaban and rivaroxaban, tested significantly higher than the normal range for ACT. The dotted parallel bars show the normal ranges of R times. Statistically significant between (higher dose and medium dose), (higher dose and lower dose), ^ (medium dose and lower dose), and * (control)., ^^, **P,.01 and,, ^^^, *** P,.001. Error bars represent the standard error of 3 independent experiments measured in triplicate. However, the K time for the dabigatran group was statistically different from the control for the lower tested concentrations (P ¼.003 for 200 ng/ml and P ¼.003 for 350 ng/ml) but not for the concentration of 500 mg/ml (P ¼.44), and the a angle from the dabigatran group was statistically different from the control for the concentrations of 500 ng/ml (P,.001) and 50 ng/ml (P,.001) but not for the concentration of 200 ng/ml (P ¼.38) (Table 2). In addition, both the K time and a angle were able to differentiate between the highest dabigatran concentration and the other concentrations (P ¼.002 for 500 versus 200 ng/ml and P,.001 for 500 versus 50 ng/ml) (Table 2). Furthermore, the MRTG parameter was sensitive to the 2 lowest concentrations of dabigatran (P ¼.06for500ng/mL, P ¼.002 for 200 ng/ml, and P,.001 for 50 ng/ml). The TMRTG parameter from the rteg test is sensitive to the presence of both rivaroxaban and dabigatran but not apixaban (Table 2). Furthermore, the TMRTG parameter is able to differentiate between concentrations of dabigatran (P,.001 for 500 versus 200 ng/ml and P,.001 for 200 Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al 669

6 Table 2. Rapid Thromboelastography Test Coagulation Parameters Sensitivity in Healthy Donor Spiked Samples With Different Doses of Apixaban, Rivaroxaban, and Dabigatran in the Presence or Absence of Ecarin a Variable ACT, s K Time, min No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value Apixaban, ng/ml ,,*** ,***, ,** *** *, * *** , Control , Rivaroxaban, ng/ml ,,*** **, ^^,** , *, Control , Dabigatran, ng/ml ,,*** ,,***, , , ^^^,*** ^^,***, ** ^^ *** **, ** Control , Abbreviations: ACT, activated clotting time; K Time, coagulation time; MRTG, maximum rate to thrombus generation; TMRTG, time to maximum rate of thrombus generation. a Statistically significant between: (higher dose and medium dose), (higher dose and lower dose), ^ (medium dose and lower dose), and * (control). Standard error of 3 independent experiments measured in triplicate. Single symbol, ^, and * indicates P,.05; 2 symbols,, ^^, and ** indicate P,.01; and 3 symbols,, ^^^, and *** indicate P,.001. Statistically significant between paired sample with or without ecarin. Table 2. Extended a Angle, 8 MRTG, mm/min TMRTG, min No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value No Ecarin With Ecarin P Value ** * ,*** ***, *** **, ** **, , ,,** ,* , , ,,*** ,,***, ^ ** ^,* ^^^,*** ^^,***, *** *** *** ** ***, Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al

7 versus 50 ng/ml) (Table 2). Finally, the MA values of the rteg test for rivaroxaban and apixaban did not change with the addition of the studied drug concentrations compared with the control, and only the MA values of the dabigatran 500-ng/mL concentration were significantly different from the control group (P,.001) but were still within the normal range (data on file). Ecarin Test The addition of ecarin to the kaolin test caused a significant decrease in the R time, K time, and TMRTG values for both the treated and control groups (P.003 for rivaroxaban, P.01 for apixaban, and P.004 for dabigatran) (Table 1 and Figure 3, A through C) and a significant increase in the a angle and MRTG values for both the treated and control groups (P.01 for rivaroxaban, P.04 for apixaban, and P.009 for dabigatran) (Table 1). Furthermore, the addition of ecarin to the kaolin test in the presence of anti-xa drugs severely decreases the R times to the hypercoagulable range (, 5 minutes), with no statistical difference from the control with the exception of the higher studied dosages: these values for rivaroxaban were P ¼.002 for 500 ng/ml, P ¼.08 for 89 ng/ml, and P ¼.90 for 22 ng/ ml and for apixaban were P ¼.03 for 1000 ng/ml, P ¼.76 for 500 ng/ml, and P ¼.05 for 250 ng/ml (Table 1 and Figure 3, A and B), while in the presence of dabigatran there is only a dose-related decrease in the R time (Table 1 and Figure 3, C). The addition of ecarin to the kaolin test did not change the MA values of the samples for dabigatran or rivaroxaban relative to samples run without ecarin, but in the presence of apixaban the MA values were statistically different (P ¼.02 for 1000 ng/ml, P ¼.009 for 500 ng/ml, and P,.001 for 250 ng/ml) from samples run without ecarin but were still within the normal range (data on file). The addition of ecarin to the rteg test significantly increases the TEG ACT times for both anti-xa and direct thrombin inhibitor (DTI) drugs (P,.001 for apixaban, P.001 for rivaroxaban, and P,.001 for dabigatran), as well as the TMRTG times in the presence of both rivaroxaban and dabigatran (P,.001 for rivaroxaban and P,.001 for dabigatran), increasing the hypercoagulable status (Table 2). On the other hand, the rteg a angle did not change for any of the studied concentrations when ecarin was added in the presence of rivaroxaban or apixaban. However, for the lowest concentrations of dabigatran, there was a decrease in the a angle (P ¼.047 for 200 ng/ml and P ¼.02 for 50 ng/ ml) (Table 2). The rteg K times significantly decreased for the highest and lowest concentrations of apixaban (P ¼.02 for 1000 ng/ml and P ¼.17 for 250 ng/ml) and the middle concentration of rivaroxaban (P ¼.04 for 89 ng/ ml) but increased in the middle concentration of dabigatran (P ¼.004 for 200 ng/ml) when ecarin was added. Finally, the addition of ecarin to the rteg test significantly decreased the MA value of only the 200-ng/ ml concentration of dabigatran (P ¼.02) but was still within the normal range (data on file). COMMENT The lack of a readily available method to determine the degree of anticoagulation creates a major challenge to clinicians treating bleeding patients who are potentially receiving NOACs. Moreover, the potentially irreversible coagulopathy associated with their use is of great concern to trauma and emergency physicians. Therefore, we studied the effect of the currently approved NOAC drugs (dabigatran, rivaroxaban, and apixaban) on TEG and the ability of the ecarin test to distinguish a DTI from anti-xa drugs using TEG. We observed that both R time and TMRTG parameters in the kaolin test were sensitive to apixaban and dabigatran. Furthermore, it was found that the rteg test ACT parameter is sensitive to all 3 NOACs tested. Finally, in the presence of anti-xa inhibitors, the ecarin test promoted significant shortening of kaolin R times to the hypercoagulable range, while in the presence of DTI only a small and dose-proportional R time shortening was observed, allowing to distinguish the presence of DTI from anti-xa inhibitors. Although the drugs investigated in this study are clinically effective, they present challenges in monitoring and difficulties in reversal should bleeding occur. Dabigatran has a half-life of 12 to 17 hours, which is lengthened in patients with renal dysfunction. 18 The high renal clearance of dabigatran (80%) precludes its use in the European Union for patients with severe renal insufficiency, although it is indicated for the prevention of stroke in patients with severe renal impairment experiencing atrial fibrillation in the United States (at a reduced 75-mg daily dose). 18,19 Apixaban and rivaroxaban have shorter half-lives than dabigatran. However, apixaban also has an increased half-life of up to 44% in patients with severe renal impairment compared with healthy volunteers. 28 Furthermore, the presence of moderate hepatic and renal impairment may lead to significant changes in the pharmacokinetics of rivaroxaban (mean, 2.3-fold increase in the area under the curve compared with healthy volunteers), and there are no data in patients with severe hepatic impairment. 12 Rivaroxaban and apixaban, which are eliminated in greater proportions via other nonrenal routes, may be used with caution in such patients. 12,24 For patients, part of the attractiveness of NOACs is that they do not require regular blood testing. Unlike warfarin, however, there are currently no antidotes for NOAC reversal. Dabigatran can only be partially removed from circulation by dialysis. 18,19 There is no established way to reverse the anticoagulant effect of apixaban or rivaroxaban, which can be expected to persist for at least 10 to 30 hours after the last dose (ie, for about 2 half-lives). Hemodialysis does not have a substantial impact on anti-xa drug levels. 12,22,24 Activated charcoal reduces apixaban and rivaroxaban absorption, reducing the plasma half-life; however, the reductions are limited. 12,22,24 Therefore, bleeding can be extremely resistant to known therapies. The Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY trial) reported a 1.45% per year incidence of lifethreatening bleeding or death related to bleeding complications from treatment with dabigatran, and this led to safety advisories being issued in several countries. 6,13 Agents that may be used to reverse the effects of dabigatran such as the activated prothrombin complex concentrate (FEIBA; Baxter, Deerfield, Illinois) and the recently approved 4-component prothrombin complex concentrate (Kcentra; CSL Behring, King of Prussia, Pennsylvania) may be effective, but without laboratory guidance the dosing is difficult, and thrombosis may result. 28,29 The most commonly used coagulation tests, prothrombin time and partial thromboplastin time, can detect the presence of dabigatran but are lacking in sensitivity, Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al 671

8 Figure 3. The thromboelastography kaolin test reaction time (R Time) as a function of drug concentrations in the presence or absence of ecarin for rivaroxaban (A), apixaban (B), and dabigatran (C). Rivaroxaban and apixaban both show an equivalent and significant quickening of the R time to a hypercoagulable status, despite the concentration of drug. Dabigatran has a concentration-dependent decrease in the R time. The dotted parallel bars show the normal ranges of the R times for normal donors. Statistically significant between (higher dose and medium dose), (higher dose and lower dose), ^ (medium dose and lower dose), and * (control). Statistically significant between paired sample with or without ecarin (P.001). Error bars represent the standard error of 3 independent experiments measured in triplicate. P ¼.02;,, ** P,.01; and, ^^^, *** P,.001. especially the prothrombin time, which is only increased at concentrations that are higher than therapeutic. Other assays such as ecarin clotting time and chromogenic anti factor IIa are not readily available and/or have not been specifically studied with dabigatran. For the anti-xa inhibitors rivaroxaban and apixaban, chromogenic assays against human factor Xa are preferred. 30,31 Although anti factor Xa chromogenic assays can provide accurate results over a wide range of rivaroxaban concentrations, the addition of exogenous antithrombin results in falsely elevated results, suggesting unsuitability for use with rivaroxaban. 32 Furthermore, a recent trial investigated interlaboratory variability of the measurement of rivaroxaban plasma concentrations with anti factor Xa chromogenic assays and demonstrated an interlaboratory variation greatest at lower concentrations. 33 Although the prothrombin time results are prolonged in the presence of rivaroxaban or apixaban, the results are reagent dependent, making the test unreliable for use in actively bleeding patients. 30,31 Thromboelastography can provide a quick determination of the effects of dabigatran, rivaroxaban, and apixaban using either the rteg or citrated kaolin assays. Both illustrate prolongation of the enzymatic phase of coagulation with prolonged TEG ACT in the rteg assay and a long R time in the kaolin assay. In trauma patients who may present with hemorrhagic shock and are either suspected or known to have taken NOACs, the persistence of the long R time/act following resuscitation and correction of surgical bleeding can demonstrate persistent NOAC effects. Furthermore, a universal reversal agent for anti- Xa inhibitors is currently in development (Andexanet Alfa, PRT4445; Portola Pharmaceuticals, Inc, San Francisco, California). The dosing of this drug could potentially be monitored by TEG to avoid potential adverse effects. Furthermore, patients receiving NOACs who require emergent procedures are not well served by conventional coagulation tests and can be successfully treated when TEG is used to guide therapy. 34 Some initial studies 14,34,35 have identified the TEG kaolin test as useful in monitoring the effects of dabigatran. However, in the case of rivaroxaban, both the TEG kaolin test and the ROTEM (Tem International GmbH, Munich, Germany) INTEM and EXTEM tests lacked sensitivity. 35,36 Our findings support this because we observed that a reagent that tests both intrinsic and extrinsic pathways (rteg) is more sensitive to the presence of anti-xa inhibitors than single-pathway reagents. If the specific oral anticoagulant is not known, an ecarin assay can be performed to differentiate between dabigatran and the anti-xa inhibitors rivaroxaban or apixaban. The patients on dabigatran will only have a dose-proportional shortening of the R time, while the patients on anti-xas will have a dramatic shorting of the R times back to the control level independently of the dose used. Thus, our findings support the need to develop a new reference range in healthy volunteers for the kaolin plus ecarin test to facilitate the distinction when it is not known whether the patient is receiving a DTI or an anti-xa. In conclusion, we conducted an in vitro characterization of the effects of the currently approved NOACs on clot formation using the TEG Thromboelastography is sensitive to the effects of NOACs and can potentially be used to guide NOAC reversal therapies. While the role of TEG requires additional clinical validation, it may be a valuable tool to investigate both the hemostatic derangements and the effects of reversal strategies in patients treated with NOACs. We thank Daniel P. Herbstman, BA, for his service to Haemonetics Corporation, Rosemont, Illinois. 672 Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al

9 References 1. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6)(suppl):160S 198S. 2. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2)(suppl):e44S e88s. doi: /chest Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16): Turpie AG, Eriksson BI, Lassen MR, Bauer KA. Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol. 2003;10(5): O Brien CL, Gage BF. Costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation. JAMA. 2005;293(6): Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12): Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis. 2013;2013: doi: /2013/ Ahmed S, Levin V, Malacoff R, Martinez MW. Dabigatran: a new chapter in anticoagulation. Cardiovasc Hematol Agents Med Chem. 2012;10(2): Heit JA, Colwell CW, Francis CW, et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med. 2001;161(18): Eriksson BI, Borris L, Dahl OE, et al. Oral, direct factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006;4(1): Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5): Bayer Pharma AG. XareltoW (rivaroxaban) summary of product characteristics. Product_Information/human/000944/WC pdf. Accessed June 12, Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012;69(17): Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med. 2011;365(21): Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3): Koster A, Buz S, Krabatsch T, et al. Monitoring of bivalirudin anticoagulation during and after cardiopulmonary bypass using an ecarin-activated TEG system. J Card Surg. 2008;23(4): Choi TS, Khan AI, Greilich PE, Kroll MH. Modified plasma-based ecarin clotting time assay for monitoring of recombinant hirudin during cardiac surgery. Am J Clin Pathol. 2006;125(2): Boehringer Ingelheim International GmbH. Pradaxa (dabigatran etexilate) summary of product characteristics. document_library/epar_-_product_information/human/000829/wc pdf. Accessed June 12, Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) prescribing information /022512s017lbl.pdf. Accessed June 12, Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5): Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11(1):10. doi: / Janssen Pharmaceuticals, Inc. Xarelto (rivaroxaban) prescribing information. pdf. Accessed June 12, Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4): Bristol-Myers Squibb/Pfizer EEIG. Eliquis (apixaban) summary of product characteristics. -_Product_Information/human/002148/WC pdf. Accessed June 12, Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1): Khurana S, Mattson JC, Westley S, O Neill WW, Timmis GC, Safian RD. Monitoring platelet glycoprotein IIb/IIIa fibrin interaction with tissue factor activated thromboelastography. J Lab Clin Med. 1997;130(4): Chavez JJ, Foley DE, Snider CC, et al. A novel thrombelastograph tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during cardiopulmonary bypass. Anesth Analg. 2004;99(5): Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in lifethreatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41(5):e42 e46. doi: /ccm. 0b013e31827caaa van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6): Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit. 2010; 32(6): Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013;34(7): b. doi: / eurheartj/ehs Mani H, Rohde G, Stratmann G, et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost. 2012;108(1): Samama MM, Contant G, Spiro TE, et al. Evaluation of the anti factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107(2): Neyens R, Bohm N, Cearley M, Andrews C, Chalela J. Dabigatranassociated subdural hemorrhage: using thromboelastography (TEG) to guide decision-making. J Thromb Thrombolysis. 2014;37(2): Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2013;111(5): Casutt M, Konrad C, Schuepfer G. Effect of rivaroxaban on blood coagulation using the viscoelastic coagulation test ROTEM. Anaesthesist. 2012; 61(11): Arch Pathol Lab Med Vol 139, May 2015 Use of TEG for Detection of NOACs Dias et al 673

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