Hematology

Evaluation of direct oral anticoagulant use on thromboelastography in an emergency department population

a b s t r a c t

Background: Direct oral anticoagulant (DOAC) use presents a challenge to all providers involved in emergency care of patients since widely accepted laboratory tests to assess the level of anticoagulation for such medications are lacking. viscoelastic tests such as Thromboelastography tests are increasingly used throughout major trauma centers to help guide resuscitation efforts in patients presenting with trauma and/or hemorrhagic shock. Objective: The primary outcome compared TEG parameters between emergency department trauma patients reporting DOAC therapy and known normal TEG parameter values. The secondary outcome evaluated patients who reported time of last known DOAC dose within a preferred time frame of <12 h for once Daily dosing DOAC therapy or < 6 h for twice daily dosing DOAC therapy.

Methods: This single-center, retrospective cohort study assessed TEG values in patients receiving DOAC therapy and compared these to institution TEG ranges considered normal. TEG values of reaction time (R time), kinetics (K), alpha angle (AA), maximum amplitude (MA), and percent lysis in 30 min (LY30) were collected for patients reporting DOAC therapy.

Results: 40 patients were included in this study. 19 patients reported apixaban therapy and 21 reported rivarox- aban therapy. 5 (12.5%) patients had an elevated R time and 1 (2.5%) patient had a reduced MA. All other TEG values did not suggest hypocoagulability. For the secondary outcome assessing patients reporting last known dose within the preferred time frame, only the R time was elevated in 2 (14.3%) patients. Lastly, in a subgroup analysis of patients with elevated low-molecular-weight heparin (LMWH) orAnti- Xa levels, the R time was the only parameter affected in 25% of patients.

Conclusion: TEG values were typically not affected by rivaroxaban or apixaban use in an emergency department trauma population suggesting that TEG is not sensitive for Xa inhibitor detection and should not be relied upon for assessing anticoagulation in such settings.

(C) 2021

  1. Introduction

Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of thrombotic events and have become welcome al- ternatives to vitamin K antagonists (i.e. warfarin), the previous stan- dard of care [1]. Over the last decade, two categories of DOACs have

Abbreviations: DOAC, direct oral anticoagulant; TEG, thromboelastography; R time, reaction time; K, kinetics; AA, alpha angle; MA, maximum amplitude; LY30, percent lysis in 30 min; LMWH, low-molecular-weight heparin.

? These results have been presented as a poster at the American College of Clinical

Pharmacy (ACCP) Annual Meeting in October of 2020.

* Corresponding author at: 12850 East Montview Blvd, Aurora, CO 80045, USA.

E-mail addresses: [email protected] (J. Jenrette), [email protected] (K. Schwarz), [email protected] (T. Trujillo), [email protected] (L. Ray).

become available for use: direct thrombin inhibitors (DTI) (i.e. dabigatran) and factor Xa inhibitors (i.e. rivaroxaban, apixaban, edoxaban and betrixaban).

The most recent international guidelines for both management of venous thromboembolism and of atrial fibrillation recommend the use of DOAC therapy over vitamin K antagonists for a vast majority of indications [2,3]. These agents provide many advantages for patients compared to Warfarin therapy. DOAC use has been shown to reduce the incidence of Intracranial bleeding and offers an oral option with no re- quired routine monitoring of anticoagulant effect due to a wide thera- peutic window [4].

Despite these advantages, DOAC use can present a challenge in the emergency department (ED) since there are no standard labora- tory tests for assessing a patient’s level of anticoagulation. Patients

https://doi.org/10.1016/j.ajem.2021.12.011

0735-6757/(C) 2021

presenting with major bleeding or need for emergency surgery may re- quire reversal of anticoagulation. While specific reversal agents are available for both direct thrombin inhibitors and factor Xa inhibitors, these agents are significantly more expensive than reversal for warfarin therapy [5,6]. In the case of apixaban and rivaroxaban, the use of drug- specific reversal is only indicated for a narrow margin of patients with Life-threatening hemorrhage [7]. Additionally, reversal agents may be unnecessary given the short half-life of DOACs and the uncertainty that a patient has been adherent. The American College of Chest Physi- cians (ACCP) currently does not suggest use of specific laboratory values to guide decisions on reversal or dosing [2,3]. The Neurocritical care Society does not recommend use of laboratory tests over physical signs of bleeding to guide initial reversal decisions or redosing [8]. Furthermore, the Anticoagulation Forum recommends reversal agents in DOAC-associated major bleeding if there “is demonstration or reasonable expectation of clinically relevant plasma DOAC levels.” [9] However, guidance is not provided on specific laboratory values to assess for determination of plasma DOAC levels.

While routine coagulation monitoring is not required for these agents, knowledge of anticoagulation status could improve timeliness of interventions and cost-effectiveness in acute situations. Routinely used coagulation assays are sensitive but non-specific for assessing Xa in- hibitor therapy, which make many of these options unreliable for deter- mining reversal need or patient course of therapy [10]. Available assays, such as activated partial thromboplastin time or prothrombin time/international normalized ratio (PT/INR) correlate poorly with DOAC concentration [10,11]. Several studies have shown good correla- tion between rivaroxaban and apixaban serum concentration and anti- Xa levels, but laboratories may not dilute the samples to the extent where the interpretation is useful [12,13]. Essentially, calibration of these tests in order to assess precise level of anticoagulation can be prob- lematic to perform and interpret. In addition, specific calibrated Xa as- says for apixaban and rivaroxaban are not routinely available at this time. As such, there has been growing interest in the use of viscoelastic as- says for analysis of anticoagulation in acute care patients [14-18]. Visco- elastic assays have been available since 1948 as a modality of assessing the viscosity of blood as it clots under physiologic stress [19]. Histori- cally these assays were primarily used intraoperatively during cardiac and liver transplant surgery. Thromboelastography is a common brand viscoelastic assay that in recent decades has gained utilization in traumatic hemorrhage in order to characterize trauma-induced coagu- lopathy and guide blood-product resuscitation efforts [20]. Since the American College of Surgeons trauma quality improvement program provides guidance in massive transfusion, TEG is one of the first labora- tory Blood draws a trauma patient will receive upon arrival to an emer-

gency department [21].

Current literature is inconclusive in determining differences in TEG parameters of patients on anticoagulant therapy compared to healthy patients not on anticoagulant therapy [14-16].’Aho and Byrne found the R time was not sensitive enough to routinely detect dabigatran [15]. However, Dias et al. found a prolonged R time, K time, and alpha angle for apixaban, dabigatran and rivaroxaban with an in-vitro study design using kaolin TEG assays [14]. An additional study by Dias et al. assessed a TEG 6s DOAC-specific cartridge and found a high sensitivity and specificity for detecting DOAC therapy and differentiating between DTI and Factor Xa inhibitors [16]. Considering the lack of sensitivity and specificity of conventional coagulation tests for DOACs, we sought to as- sess the effect of DOAC use on TEG parameters in trauma patients upon arrival to the ED.

  1. Methods

This retrospective, single-center cohort study analyzed TEG values from adult patients receiving treatment with rivaroxaban or apixaban and had a TEG documented between January 2018 and February 2020. This study was performed at UCHealth University of Colorado Hospital

in Aurora, CO, an academic medical center and level 1 trauma center with over 100,000 emergency department visits annually. Data was manually collected from electronic health records (EHR) and IRB deter- mined this study exempt. Patients who had documented Xa inhibitor therapy and a TEG assay during the two-year time frame were identified and evaluated for inclusion.

Inclusion criteria were patients between 18 and 89 years of age, re- ported current Xa inhibitor therapy documented in the EHR and a doc- umented TEG assay during the same encounter. A report was generated to identify patients receiving rivaroxaban, apixaban, dabigatran, or edoxaban. Patients were included if their last known dose was within 12 h from collection of their TEG assay for once-daily-dosing DOAC reg- imens, within 6 h from collection of their TEG assay for twice-daily- dosing DOAC regimens. If patients were prescribed rivaroxaban twice daily, they were included in the twice daily regimen population. Pa- tients were also included if they did not have a documented time of last-known-dose but verbally reported good adherence to their pre- scribed DOAC. While these four DOACs were identified for inclusion in this study, there were no identified patients on dabigatran or edoxaban who met all required inclusion criteria.

Subjects were excluded for unknown DOAC, unknown dose or regi- men, or if last-known-dose was documented as greater than 12 h for once-daily-dosing or greater than 6 h for twice-daily-dosing.

For each study participant, blood samples were analyzed using the standard institution TEG 5000 analyzer. All samples were kaolin- activated citrate assays. TEG parameters analyzed included reaction time (R time, mm), kinetics (K, mm), maximum amplitude (MA, mm), alpha angle (AA, degrees), and lysis in 30 min (LY30, %). All TEG values were compared to normal reference ranges. Normal references ranges include reaction time of 2-8 min, kinetics of 1-3 min, alpha angle of 55-78 de- grees, maximum amplitude of 50-70 mm, and lysis in 30 min of 0-7.5%.

The primary outcome was to determine whether TEG measure- ments were affected by Xa inhibitors in an acute care population. The secondary outcome was to determine whether TEG parameters were af- fected by Xa inhibitor therapy in patients with documented last- known-dose within the peak interval. A peak dose was designated as last-known-dose within previous 12 h for once-daily-dosing regimens, or within previous 6 h for twice-daily dosing regimens. Post-hoc analy- ses assessed patients with a documented low-molecular-weight hepa- rin (LMWH) level or anti-Xa level above lab detection limits (>1.70 units/mL or > 1.80 units/mL, respectively).

For the primary and secondary outcomes, TEG values were assessed compared to institution reference ranges. Results were reported as quan- tity and percentages of patients whose individual TEG values were out- side of the normal reference ranges and suggested hypocoagulability.

  1. Statistical analysis

Study data were collected and stored using REDCap (Research Elec- tronic Data Capture), a secure, web-based software platform hosted at UCHealth University of Colorado Hospital [22,23]. Descriptive summary statistics were generated in Microsoft Excel and used to report and an- alyze data. Continuous variables were described with mean values and standard deviations.

TEG values were compared to institution normal reference ranges for each parameter. Values that were outside of the normal reference range and represented hypocoagulable states were reported as numer- ical values and percentages. Eighteen patients did not have documented LMWH or Anti-Xa assays collected. There was no imputation of missing data, and these data points were omitted.

  1. Results

Four hundred and twenty patients were screened for inclusion. Forty patients met inclusion criteria. 245 patients were excluded for reporting no DOAC use during same encounter TEG was drawn, 3 were excluded

for prisoner status, 52 were excluded for their last-known-dose >12 h on a once-daily-regimen, 66 were excluded for their last-known-dose

>6 h on a twice-daily-regimen, 3 were excluded due to age, 6 were ex- cluded for confidential patient encounters, 4 were excluded for un- known DOAC dose or frequency of regimen.

Demographic characteristics are shown in Table 1. Of the 40 patients included in this study, 25 patients (63%) were male. 38 patients (95%) initially presented through the emergency department and had their TEG sample collected in this setting. 20 patients (50%) were deemed trauma patients, presenting as either an activation, alert or with a trauma acute care surgery consult.

For the primary outcome shown in Table 2, the R time was pro- longed beyond the reference range in 5/40 patients (13%), and the max- imum amplitude was reduced in 1/40 patients (3%). All other TEG parameters were either within the institution normal reference range or even suggested hypercoagulability. For the secondary outcome eval- uating TEG parameters in patients who had taken their last known dose within the desired time frame, only the R time was elevated in 2/14 pa- tients (14%). All other TEG parameters were either within the institution normal reference range or did not suggest hypocoagulability.

Fig. 1 reports results of a post-hoc analysis completed in 16 patients who had a documented low-molecular-weight heparin level and/or heparin anti-Xa level greater than our institution’s lab detection limit (> 1.70 units/mL or > 1.80 units/mL, respectively). This subgroup anal- ysis was completed to assess patients who would be deemed “on” Xa in- hibitor therapy and were likely anticoagulated. In this post-hoc analysis, the R time was elevated in 4 patients (25%). Despite elevated anti-Xa ac- tivity, all other TEG parameters were either within the institution normal reference range or did not suggest hypocoagulability in this pa- tient population.

  1. Discussion

Our study suggests TEG is not reliable for assessment of anticoagula- tion status in emergency department patients on Xa inhibitor therapy. Both the primary and secondary outcome results showed TEG values were not consistently affected by Xa inhibitor use in emergency depart- ment patients. The primary outcome assessing TEG values in patients reporting Xa inhibitor therapy resulted in a prolonged R-time in 5/40 patients, and a reduced maximum amplitude in 1/40 patients. The sec- ondary outcome assessing TEG values in patients whose last known dose was within the desired time frame resulted in a prolonged R-time in only 2/14 patients. Interestingly, our post hoc analysis assessing patients with high anti-Xa assay values (>1.70 u/mL) showed a discordance with TEG values. Only 25% of these patients had elevated R times and all other TEG values did not suggest hypocoagulability. These findings suggest that TEG analysis is not sensitive for detecting Xa inhibitor use.

Our study contributes to the growing body of literature on DOAC- TEG relationships by providing the novel but pragmatic perspective of assessing Xa inhibitor influence on TEG parameters in emergency de- partment patients currently on anticoagulation therapy who have sus- tained injury [12-16]. Trauma patients included in this study had a TEG laboratory specimen drawn as part of our institutional trauma pro- tocol within minutes of arriving to the ED. We can assume due to trauma protocol criteria that there was a concern for bleeding in these patients. To us, this reflected a real-world capture of how Xa inhibitors would influence TEG analysis in an emergent setting.

There is a paucity of literature assessing DOAC influence on TEG values in a trauma or acute care population. This patient pop- ulation would benefit from having reliable and rapid assessment of

Table 1

Patient characteristics.

Apixaban

Rivaroxaban

Total

(n = 19)

(n = 21)

(n = 40)

Age (years), mean +- SD

70 +- 14

67 +- 17

68 +- 15

Male, n (%)

Indication for DOACa prior to admission, n

  • Atrial Fibrillation

10 (53%)

13

15 (71%)

8

25 (63%)

21

  • DVTb/PEc Treatment

5

13

18

  • DVT/PE Prevention

0

2

2

  • Cardiac Structural Abnormality

1

0

1

  • Stroke/TIAd

2

1

3

Hospital admission through ED,e n (%)

19 (100%)

19 (90%)

38 (95%)

Trauma activation, Alert or Consult, n (%)

10 (53%)

10 (48%)

20 (50%)

Last dose – once daily dosing regimen

Within peak,f n (%)

0 (0%)

10 (48%)

10 (25%)

Within peakf and elevated LMWHg/Anti-Xa assay,h n (%)

0 (0%)

5 (24%)

5 (13%)

Unknown, n (%)

0 (0%)

9 (43%)

9 (23%)

Unknown and elevated LMWH/Anti-Xa assay,h n (%)

0 (0%)

3 (14%)

3 (8%)

Last dose – twice daily dosing regimen

Within peak,i n (%)

4 (21%)

0 (0%)

4 (10%)

Within peaki and elevated LMWH/Anti-Xa assay,h n (%)

3 (16%)

0 (0%)

3 (8%)

Unknown, n (%)

15 (79%)

2 (10%)

17 (43%)

Unknown and elevated LMWH/Anti-Xa assay,h n (%)

4 (21%)

1 (5%)

5 (13%)

Child Pugh Class B or C, n (%)

1 (5%)

1 (5%)

2 (5%)

creatinine clearance <60 mL/min, n (%)

7 (37%)

1 (5%)

8 (20%)

Concomitant Strong Inhibitors,j n (%)

1 (5%)

1 (5%)

2 (5%)

Antiplatelet therapy, n (%)

6 (32%)

7 (33%)

13 (33%)

Hemoglobin (g/dL), mean +- SD

12 +- 3

12 +- 3

12 +- 3

Hematocrit (%), mean +- SD

36 +- 8

37 +- 8

37 +- 8

Platelets (n), mean +- SD

227 +- 91

231 +- 128

229 +- 110

a DOAC: direct oral anticoagulant.

b DVT: deep vein thrombosis.

c PE: pulmonary embolism.

d TIA: transient ischemic attack.

e ED: emergency department.

f Peak for once daily dosing regimens: last dose within 12 h.

g LMWH: Low Molecular Weight Heparin.

h Elevated LMWH/Anti-Xa assay defined as >1.70/1.80 u/mL based on lab detection limit.

i Peak for twice daily dosing regimens: last dose within 6 h.

j Strong inhibitors were defined as CYP3A4 enzyme inhibitors resulting in major Drug interaction with k rivaroxaban or apixaban.

Table 2

Primary outcome: TEG parameters in patients on DOAC therapy compared to Upper limit of normal.

Reaction Timea (minutes)

Kineticsb (minutes)

Alpha Anglec (degrees)

Maximum Amplituded (mm)

Lysis Time at

30 Minutese (%)

<= 8

> 8f

<= 3

> 36

< 556

>= 55

<506

>=50

<=7.5

>7.56

Rivaroxaban, n (n = 21)

17

4

21

0

0

21

1

20

21

0

Apixaban, n (n = 19)

Total, n (%)

18

35

1

5

19

40 (100%)

0

0

0

0

19

40

0

1

19

39

19

40

0

0

(n = 40)

(88%)

(13%)

(0%)

(0%)

(100%)

(3%)

(98%)

(100%)

(0%)

a Reaction Time institution reference range: 2-8 min.

b Kinetics institution reference range: 1-3 min.

c Alpha Angle institution reference range: 55-78 degrees.

d Maximum Amplitude institution reference range: 50-70 mm.

e Lysis Time at 30 min institution reference range: 0-7.5%.

f Values suggest hypocoagulability.

anticoagulation status while on DOAC therapy; this knowledge could guide reversal or surgery decisions. Over the last few years more reports on this subject have surfaced. One similar in vivo analysis in real-world setting by Kopytek et al. analyzed TEG 5000 parameters in 53 patients diagnosed with a VTE and determined that higher rivaroxaban and apixaban concentrations correlated with longer R times and times to maximum amplitude. Dabigatran was shown to have the greatest effect on prolongation of R time [17]. Their findings help support our conclu- sion that TEG analysis may be unreliable in assessment of Xa inhibitors. However, Kopytek et al. analyzed patients that were otherwise stable and labs were assessed at a routine clinic visit. Furthermore, all patients in their study were prescribed DOAC therapy for the use of VTE treat- ment [17]. Our study allowed for inclusion of all patients receiving Xa inhibitor therapy regardless of indication. This difference allows our re- sults to be applicable to a greater population as many patients do receive DOAC therapy for alternate indications, such as stroke preven- tion in atrial fibrillation.

Dias et al. performed an in vitro study to assess blood samples spiked with various DOAC solutions and found kaolin tests were able to detect DOAC therapy [14]. In their kaolin assays, a statistical difference was found for both R time and kinetics parameters for all concentrations of apixaban, as well as rivaroxaban concentrations above 89 ng/mL. Based on an internal study assessing validity of LMWH assays for vari- ous DOAC concentrations, we are confident our institution’s LMWH as- says correlate with DOAC concentrations. At our institution, Beyer et al. determined LMWH assays and anti-Xa assays directly at lab detection limit (1.70/1.80 IU/mL, respectively) correlate to a rivaroxaban concen- tration of 87 ng/mL [12]. This concentration likely correlates to trough or mid-interval concentrations of rivaroxaban therapy. As our study was unable to find consistent differences in TEG values for patients on

Fig. 1. Patients with an elevated LMWH/Anti-Xa level and TEG values within insitution reference range.

DOAC therapy even at the lab detection limit cutoff, it can be deter- mined that TEG assays are likely not sensitive for moderate concentra- tions of DOAC therapy. It is still possible that TEG values are affected at peak concentrations of DOAC therapy. However, LMWH/Anti-Xa as- says at many institutions are not calibrated to report peak concentra- tions and simply report if the value is above a threshold that often correlates with mid-interval concentrations of DOAC therapy. We pur- posefully selected patients in our cohort that would have likely had peak concentrations based on their known time of last dose of Xa inhib- itor therapy.

Dias et al. found high specificity and sensitivity with the in vivo use of a TEG 6s DOAC cartridge to detect and identify DOAC therapy and class [16]. These findings were extrapolated to suggest benefit in a trauma population requiring possible anticoagulation reversal for hem- orrhage or surgery. Dias et al. evaluted a specific TEG 6s cartridge with an anti-Xa assay and DTI assay used to differentiate classes of DOAC therapy, which was not available at our institution [16]. From a case- report, Gilbert et al. describe combination use of TEG, anti-Xa assay, and radiographic imaging to guide Reversal therapy of apixaban- related subdural hemorrage [18].

With increased DOAC use over the last decade, it is vitally important to determine laboratory parameters that can accurately reflect level of anticoagulation for bedside clinicians in the acute care setting. To effec- tively guide Resuscitative efforts and the need for timely reversal strate- gies that are often expensive, we must be able to rely on rapid and accurate laboratory assessments. Available literature on DOAC analysis is contradictory, suggesting a need for an in vivo analysis to determine the clinical utility of TEG parameters in the emergency department for acute trauma patients.

Current literature varies with respect to how DOACs influence TEG parameters. Our data fail to show any correlation with TEG values. How- ever, this may be due to several limitations. The retrospective study de- sign leads to reliance on chart documentation at the time of the patient encounter in the EHR. This allows for potential of missing data points at the time of chart documentation. Additionally, our study design allowed for inclusion of patients with reported good adherence to Xa inhibitor therapy but unknown time of last known dose. These included patients composed 65% of the patient population in this study. Inclusion of these patients allows for possible inclusion of patients with their last DOAC dose outside of the desired time frame (<12 h for once daily dosing and < 6 h for twice daily dosing). However, the secondary outcome in- cluded only patients with known last doses within the preferred time frame. The inconsistent variation in TEG values in this secondary out- come suggests that timing of last Xa inhibitor dose did not result in an increased correlation of affected TEG values.

Additionally, 50% of our patient population did not present as a re- sult of general trauma based on our institution’s criteria for activation, alert, or general trauma surgery consult. TEG is primarily validated in trauma patients, and extrapolation of use outside of this population

may have affected our results. Furthermore, we did not account for the individual severity of patient trauma or amount of blood loss. How this would have affected the study is uncertain as severe bleeding may cause hyperfibrinolysis or disseminated intravascular coagulation, markedly confounding our interpretation of the effect of DOAC therapy. Alterna- tively, we did not seek to assess DOAC-TEG interaction in only severely bleeding patients, or mild or no hemorrhage. Rather our goal aimed to- ward a pragmatic approach, and we placed importance on confirming if the patient’s overall emergency department presentation was due to any trauma concern, as well as confirmation that the patient was cur- rently adherent to their Xa inhibitor therapy.

More literature is needed to determine if DOAC use consistently af- fects specific TEG values to demonstrate hypocoagulability. It would be worthwhile to design studies with larger sample sizes to allow for stronger statistical comparison of DOAC patients compared to normal reference ranges. Establishing concrete timeframes of time of last known dose would also exclude patients with trough serum DOAC con- centrations.

  1. Conclusion

The effects of Xa inhibitor use on TEG values are largely unestab- lished but appear to be imprecise at best. This study demonstrates that TEG parameters are not consistently affected by use of DOAC ther- apy in an emergency department trauma patient population. Upon fur- ther subgroup analysis, patients with elevated LMWH levels also did not have TEG values that were consistently affected. Based on our analysis, TEG analysis should not be used alone to assess a patient’s anticoagula- tion status while on apixaban or rivaroxaban therapy.

Conflicts of interest

All authors declare no conflicts of interest.

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declarations of interest

None.

References

  1. Chen A, Stecker E, Warden B. Direct oral anticoagulant use: a practical guide to com- mon clinical challenges. J Am Heart Assoc. 2020 Jul 7.;9(13). https://doi.org/10.1161/ JAHA.120.017559 e017559.
  2. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrom- botic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016 Feb 1;149(2):315-52. https://doi.org/10.1016/j.chest.2015.11.026.
  3. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, et al. 2019 AHA/ ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019 Jul 9;74(1):104-32. https://doi.org/10. 1161/CIR.0000000000000665.
  4. Rose DK, Bar B. Direct oral anticoagulant agents: pharmacologic profile, indications, coagulation monitoring, and reversal agents. J Stroke Cerebrovasc Dis. 2018 Aug 1; 27(8):2049-58. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.04.004.
  5. Pollack Jr CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015 Aug 6;373(6):511-20. https://doi.org/10.1056/NEJMoa1502000.
  6. Heo YA. andexanet alfa: first global approval. Drugs. 2018 Jul;78(10):1049-55. https://doi.org/10.1007/s40265-018-0940-4.
  7. Product Information. ANDEXXA(R) lyophilized powder for intravenous injection, co- agulation factor Xa recombinant, inactivated-zhzo lyophilized powder for intrave- nous injection. South San Francisco, CA: Portola Pharmaceuticals, Inc (per manufacturer); 2018..
  8. Frontera JA, Lewin III JJ, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage. Neurocrit Care. 2016 Feb 1;24(1):6-46. https://doi.org/10.1007/s12028-015-0222-x.
  9. Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM, et al. Reversal of di- rect oral anticoagulants: guidance from the anticoagulation forum. Am J Hematol. 2019 Jun;94(6):697-709. https://doi.org/10.1002/ajh.25475.
  10. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017 Jan 1;151(1):127-38. https://doi.org/10.1016/j.chest.2016.08.1462.
  11. Mullins B, Akehurst H, Slattery D, Chesser T. Should surgery be delayed in patients taking direct oral anticoagulants who suffer a Hip fracture? A retrospective, case- controlled observational study at a UK major trauma centre. BMJ Open. 2018 Apr
    1. ;8(4). https://doi.org/10.1136/bmjopen-2017-020625.
  12. Beyer J, Trujillo T, Fisher S, Ko A, Lind SE, Kiser TH. Evaluation of a heparin-calibrated antifactor Xa assay for measuring the anticoagulant effect of oral direct Xa inhibitors. Clin Appl Thromb Hemost. 2016 Jul;22(5):423-8. https://doi.org/10.1177/ 1076029616629759.
  13. Bookstaver DA, Sparks K, Pybus BS, Davis DK, Marcsisin SR, Sousa JC. Comparison of anti-Xa activity in patients receiving Apixaban or rivaroxaban. Ann Pharmacother. 2018 Mar;52(3):251-6. https://doi.org/10.1177/1060028017738262.
  14. Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med. 2015 May;139(5):665-73. https://doi.org/10.5858/arpa.2014-0170-OA.
  15. Aho A, Byrne K. The effect of dabigatran on the kaolin-activated whole blood thromboelastogram. Anaesth Intensive Care. 2016 Nov;44(6):729-33. https://doi. org/10.1177/0310057X1604400607.
  16. Dias JD, Lopez-Espina CG, Ippolito J, Hsiao LH, Zaman F, Muresan AA, et al. Rapid point-of-care detection and classification of direct-acting oral anticoagulants with the TEG 6s: implications for trauma and acute care surgery. J Trauma Acute Care Surg. 2019 Aug 1;87(2):364-70. https://doi.org/10.1097/TA.0000000000002357.
  17. Kopytek M, Zabczyk M, Natorska J, Malinowski KP, Undas A. Effects of direct oral an- ticoagulants on thromboelastographic parameters and fibrin clot properties in pa- tients with venous thromboembolism. J Physiol Pharmacol. 2020 Feb 1;71(1): 47-53. https://doi.org/10.26402/jpp.2020.1.03.
  18. Gilbert BW, Adams TR, Reynolds TR, Moran DA, Philip GJ. Utilization of thromboelastography and a low molecular weight heparin anti-Xa assay for guid- ance in apixaban reversal: A case report. Am J Emerg Med. 2019 Oct 1;37(10): 1991-e1. https://doi.org/10.1016/j.ajem.2019.158369.
  19. Howley IW, Haut ER, Jacobs L, Morrison JJ, Scalea TM. Is thromboelastography (TEG)-based resuscitation better than empirical 1:1 transfusion? Trauma Surg Acute Care Open. 2018 Jan 1.;3(1):e000140. https://doi.org/10.1136/tsaco-2017- 000140.
  20. Gonzalez E, Moore EE, Moore HB. Management of trauma-induced coagulopathy with thrombelastography. Crit Care Clin. 2017 Jan 1;33(1):119-34. https://doi.org/ 10.1016/j.ccc.2016.09.002.
  21. TQIP A. Massive transfusion in trauma guidelines. Chicago: ACS; 2013..
  22. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. https://doi.org/10.1016/j.jbi.2008.08.010.
  23. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap con- sortium: building an international community of software partners. J Biomed In- form. 2019 May 9.. https://doi.org/10.1016/j.jbi.2019.103208.