Anti-factor Xa Assay Research Articles

From Activated Partial Thromboplastin Time to Antifactor Xa and Back Again.

Monitoring is essential to safe anticoagulation prescribing and requires close collaboration among pathologists, clinicians, and pharmacists. We describe our experience in the evolving strategy for laboratory testing of unfractionated heparin (UFH). An intrainstitutional investigation revealed significant discordance between activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) assays, prompting a transition from the former to the latter in 2013. With the increasing use of oral factor Xa inhibitors (eg, apixaban, rivaroxaban, edoxaban, betrixaban), which interfere with the anti-Xa assay, we adapted our protocol again to incorporate aPTT in patients admitted on oral Xa inhibitors who require transition to UFH. Our experience demonstrates key challenges in anticoagulation and highlights the importance of clinical pathologists in helping health systems adapt to the changing anticoagulation landscape.

Assessing Anticoagulation in Neonates With Congenital Diaphragmatic Hernia During Extracorporeal Membrane Oxygenation: Does Anti-Factor Xa or Thromboelastometry Provide Additional Benefit?

Objective: The optimal management of anticoagulation in neonatal/pediatric patients during extracorporeal membrane oxygenation (ECMO) has not been established yet and varies greatly among ECMO centers worldwide. Therefore, we aimed to assess whether the use of anti-factor Xa assay and/or thromboelastometry correlate better than activated clotting time with heparin dose in newborns with congenital diaphragmatic hernia during ECMO. We also examined whether these coagulation assays correlate with thrombotic and/or hemorrhagic complications, when the management of anticoagulation is based only on activated clotting time values.Methods: A prospective observational study in a neonatal ECMO center was conducted. We included all neonates with congenital diaphragmatic hernia born in our institution between March 2018 and January 2019 and requiring support with venoarterial ECMO. A total of 26 ECMO runs were analyzed. During the study, the heparin dose was still adjusted according to activated clotting time values. Measurements of anti-factor Xa assay, activated partial thromboplastin time, and a thromboelastometry from the same blood specimen were performed twice a day.Results: Anti-factor Xa levels showed a moderate correlation with heparin dose, whereas the other tests showed a weak correlation. Four patients (17.4%) had thrombotic complications, 2 patients (8.7%) experienced life-threatening bleeding, and in 11 patients (47.8%) disseminated intravascular coagulation (DIC) occurred. Anti-factor Xa levels were lower in the group with thrombotic complications (0.23 vs. 0.27 IU/ml; p = 0.002), while activated partial thromboplastin time was higher in the group with hemorrhagic complications (69.4 s vs. 59.8 s; p = 0.01). In patients experiencing DIC, heparin dose and anti-factor Xa levels were lower, while no difference in activated clotting time and clotting time in INTEM and INTEM-HEPTEM were shown.Conclusions: Anti-factor Xa levels correlate better to heparin dose than activated clotting time. The use of anti-factor Xa assay instead of activated clotting time for dosing of unfractionated heparin could reduce thrombotic complications in neonates with congenital diaphragmatic hernia on ECMO support. The thromboelastometry showed no additional benefit for this purpose.

Using a low-molecular weight heparin-calibrated anti-factor Xa assay to assess the concentration of apixaban and rivaroxaban.

Direct oral anticoagulant (DOAC)-inhibiting factor Xa (FXa-DOAC) are being increasingly used as prophylaxis of venous thromboembolism and for prevention of stroke in patients with atrial fibrillation. In contrast to vitamin K antagonists, DOACs do not require monitoring in general. However, it is sometimes of value in the acute setting, for instance when considering a reversal agent in uncontrolled bleeding in patients on DOAC. We evaluated if a low-molecular weight heparin (LMWH)-calibrated anti-factor Xa assay could be used to estimate FXa-DOAC concentration in the concentration range <100ng/mL by spiking known concentrations of FXa-DOAC and from those result calculate the FXa-DOAC concentration from the response of the LMWH assay. This procedure was then evaluated by comparing the result with a drug-calibrated chromogenic assay and liquid chromatography tandem mass spectrometry (LC-MS/MS) on clinical plasma samples from patients treated with apixaban or rivaroxaban. Although the measuring range was narrower for the LMWH-calibrated assay, concentrations recalculated from the LMWH assay was comparable with those measured by the drug-calibrated method when compared with LC-MS/MS. We suggest that an LMWH-calibrated anti-factor Xa assay can be used after characterization of the response of FXa-DOACs to give guidance on the concentration of apixaban and rivaroxaban. Shorter turnaround time than LC-MS/MS and the greater availability than drug-calibrated chromogenic assays could make this a valuable option in the acute setting.

Two Cases of Acute Direct Oral Anticoagulant Overdose Without Adverse Effect.

We report 2 pediatric patients who had acute overdoses of the direct oral anticoagulants medications. Both patients were managed conservatively; neither required reversal agents or blood products nor had any major or minor bleeding events. With therapeutic usage of direct oral anticoagulants, routine coagulation studies typically are considered insufficient measures of anticoagulation and the preferred chromogenic anti-Factor Xa assay is recommended but not widely available. Using a routine hybrid heparin anti-Factor Xa assay, 1 patient demonstrated a strong linear correlation up to a serum rivaroxaban concentration of 940 ng/mL.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

The Use of Antifactor Xa Assays in a Comprehensive Pediatric Extracorporeal Membrane Oxygenation Anticoagulation Protocol is Associated with Increased Survival and Significant Blood Product Cost-Savings.

We augmented our standard extracorporeal membrane oxygenation laboratory protocol to include antifactor Xa assays, thromboelastography, and antithrombin measurements. We performed a retrospective chart review to determine outcomes for patients placed on extracorporeal membrane oxygenation (ECMO) prior to and after the initiation of our anticoagulation laboratory protocol. A total of 663 consecutive ECMO runs were evaluated from January 1, 2007 to June 30, 2018. Of these patients, 252 were on ECMO prior to initiation of the anticoagulation laboratory protocol on September 1, 2011, and 411 patients were on ECMO after initiation of the protocol. There were no major changes to our extracorporeal membrane oxygenation circuit or changes to our transfusion threshold during this continuous study period. Transfusion utilization data revealed statistically significant decreases in almost all blood components, and a savings in blood component inflation-adjusted acquisition costs of 31% bringing total blood product cost-savings to $309,905 per year. In addition, there was an increase in survival to hospital discharge from 45 to 56% associated with the initiation of the protocol ( p = 0.004). Our data indicate that implementation of a standardized ECMO anticoagulation protocol, which titrates unfractionated heparin infusions based on antifactor Xa assays, is associated with reduced blood product utilization, significant blood product cost savings, and increased patient survival. Future prospective evaluation is needed to establish an antifactor Xa assay-driven ECMO anticoagulation strategy as both clinically superior and cost-effective.

Anticoagulation and Transfusion Management During Neonatal and Pediatric Extracorporeal Membrane Oxygenation: A Survey of Medical Directors in the United States.

To compare current practices within the United States of anticoagulation management and blood transfusion in neonatal and pediatric extracorporeal membrane oxygenation patients with a 2013 international report. Cross-sectional survey distributed between August and December 2019. Extracorporeal Life Support Organization-registered neonatal and pediatric extracorporeal membrane oxygenation centers in the United States. Extracorporeal membrane oxygenation medical directors. None. Eighty-three medical directors at 108 centers responded. After removing four duplicate responses, 79 surveys were analyzed. Seventy-nine percent (n = 62) report a written extracorporeal membrane oxygenation protocol for both anticoagulation and blood product management. Ninety-four percent (n = 74) report unfractionated heparin as their primary anticoagulant; the remaining use the direct thrombin inhibitor, bivalirudin. Ninety percent (n = 71) report measuring antifactor Xa levels. Most centers report using a combination of assays to monitor heparin therapy, either antifactor Xa and activated partial thromboplastin time (54%) or more commonly antifactor Xa and activated clotting time (68%). Forty-one percent use viscoelastic tests to aid management. Goal monitoring levels and interventions generated by out of range values are variable. Fifty-one percent will replace antithrombin. Platelet transfusion thresholds vary by age and center with ranges from 50,000 to 100,000 cells/µL. Eighty-two percent of respondents are willing to participate in a randomized controlled trial comparing anticoagulation strategies for patients receiving extracorporeal membrane oxygenation. Compared with the 2013 pediatric population, extracorporeal membrane oxygenation center anticoagulation and blood transfusion approaches continue to vary widely. Most report continued use of heparin as their primary anticoagulant and follow a combination of monitoring assays with the majority using the antifactor Xa assay in their practices, a significant shift from prior results. Antithrombin activity levels and viscoelastic tests are followed by a growing number of centers. Platelet transfusion thresholds continue to vary widely. Future research is needed to establish optimal anticoagulation and blood transfusion management.

Performance Assessment of a Multifaceted Unfractionated Heparin Dosing Protocol in Adult Patients on Extracorporeal Membrane Oxygenator.

The use of extracorporeal membrane oxygenator (ECMO) support devices are associated with complications, including bleeding and thrombosis. Unfractionated heparin (UFH) is the gold standard anticoagulant in ECMO patients. Clinically, UFH is monitored through activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-factor Xa assay. It is unknown which assay best predicts anticoagulation effects in adults. To assess the correlation of UFH dosing and monitoring using an established protocol. A pilot, prospective cohort, historically controlled study was conducted at a tertiary care hospital. Patients ≥18 years-old who received ECMO on the multifaceted anticoagulation protocol were included and compared with those on the conventional method of anticoagulation. The primary end point was to assess the correlation between UFH dose and different monitoring methods throughout 72 hours using the new protocol guided by ACT and anti-factor Xa assay. In each arm, 20 patients were enrolled. The study revealed that anti-factor Xa assay had the largest number of "strong" correlations 11/20 (55%), followed by both aPTT and aPTT ratio 10/20 (50%), and, finally, ACT 2/20 (10%). Concordance between anti-factor Xa assay and the other monitoring parameters in the prospective arm was generally low: 31% with aPTT ratio, 26% with ACT, and 23% with aPTT. The adaption of a multifaceted anticoagulation protocol using anti-factor Xa assay may provide a better prediction of heparin dosing in adults ECMO patients compared with the conventional ACT-based protocol. Further studies are needed to assess the safety and different monitoring modalities.

Assessment of empiric body mass index-based thromboprophylactic dosing of enoxaparin after bariatric surgery: evidence for dosage adjustment using anti-factor Xa in high-risk patients.

Despite thromboprophylaxis, postoperative deep vein thrombosis and pulmonary embolism occur after bariatric surgery, perhaps because of failure to achieve optimal prophylactic levels in the obese population. The aim of this study was to evaluate the adequacy of prophylactic dosing of enoxaparin in patients with severe obesity by performing an antifactor Xa (AFXa) assay. An academic medical center METHODS: In this observational study, all bariatric surgery cases at an academic center between December 2016 and April 2017 who empirically received prophylactic enoxaparin (adjusted by body mass index [BMI] threshold of 50 kg/m2) were studied. The AFXa was measured 3-5 hours after the second dose of enoxaparin. A total of 105 patients were included; 85% were female with a median age of 47 years. In total, 16 patients (15.2%) had AFXa levels outside the prophylactic range: 4 (3.8%) cases were in the subprophylactic and 12 (11.4%) cases were in the supraprophylactic range. Seventy patients had a BMI <50 kg/m2 and empirically received enoxaparin 40 mg every 12 hours; AFXa was subprophylactic in 4 (5.7%) and supraprophylactic in 6 (8.6%) of these patients. Of the 35 patients with a BMI ≥50 who empirically received enoxaparin 60 mg q12h, no AFXa was subprophylactic and 6 (17.1%) were supraprophylactic. Five patients (4.8%) had major bleeding complications. One patient developed pulmonary embolism on postoperative day35. BMI-based thromboprophylactic dosing of enoxaparin after bariatric surgery could be suboptimal in 15% of patients with obesity. Overdosing of prophylactic enoxaparin can occur more commonly than underdosing. AFXa testing can be a practical way to measure adequacy of pharmacologic thromboprophylaxis, especially in patients who are at higher risk for venous thromboembolism or bleeding.

Overview and Practical Application of Coagulation Assays in Managing Anticoagulation with Direct Oral Anticoagulants (DOACs)

The introduction of newer anticoagulants requires clinicians to fully appreciate, interpret, and correctly apply the use of coagulation assays, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-factor Xa assays. For oral vitamin K antagonists, the international normalized ratio (INR) is a predictor of anticoagulation intensity. However, for direct oral anticoagulants (DOACs), the PT or INR and APTT are unable to quantify the level of anticoagulation intensity as there is a poor correlation between plasma concentration of DOAC with these routine coagulation assays and that significant anticoagulant effect may still be present despite normal or near normal results for these routine assays. In the USA, there are 5 DOACs available including dabigatran, a direct thrombin inhibitor and 4 direct factor Xa inhibitors (FXaI), each with varying indications, doses, pharmacodynamic, and pharmacokinetic characteristics. A thorough understanding of these properties aids in the management of the periprocedural or bleeding patient. In this first section of this manuscript, we will review the laboratory tests that are commonly performed for assessing a patient’s coagulation status with known DOAC exposure. The second section will describe 3 real-world challenging case studies in DOAC-treated patients, with a focus on presenting clinical queries, interpretation of baseline laboratory tests with interpretations, followed by the case discussion to combine interpretation of appropriate laboratory tests with clinical patient considerations in an effort to guide clinical decision-making.

Perils of Antithrombotic Transitions: Effect of Oral Factor Xa Inhibitors on the Heparin Antifactor Xa Assay

Oral factor Xa inhibitors (OFXais) may interfere with the heparin antifactor Xa (antiXa) assay. The best method to measure heparin activity during the transition from an OFXai to intravenous (IV) unfractionated heparin (UFH) remains unknown. This study aimed to assess the safety and effectiveness of transitioning from an OFXai to UFH. A retrospective analysis was conducted of patients with supratherapeutic antiXa levels on UFH who received either apixaban or rivaroxaban within 72 hours before UFH initiation at NYU Langone Health. The primary objective was to identify the incidence of interference on the heparin antiXa assay due to OFXai exposure in the previous 72 hours. The secondary outcomes included the indication for transition to UFH and the rate of thromboembolic and bleeding events. A total of 93 patients with supratherapeutic antiXa activity levels with prior OFXai use were reviewed. Moderate renal impairment, defined as creatinine clearance less than 49 mL/min, was present in 67 (72%) patients. The primary indication for transition from OFXai to UFH was in anticipation for a procedure, and it occurred in 37 (40%) patients. There were 3 major bleeding events and 3 clinically relevant nonmajor bleeding events. No thromboembolic events occurred. This study assessed the prevalence of supratherapeutic antiXa levels and clinical outcomes during the transition from OFXais to UFH. Health care systems should develop guidelines to assist clinicians in monitoring antiXa activity in patients undergoing a transition from an OFXai to UFH. It is also important to assess the patient's underlying thromboembolic and bleeding risks.

Early Anti-Xa Assay-Guided Low Molecular Weight Heparin Chemoprophylaxis is Safe in Adult Patients with Acute Traumatic Brain Injury

This study evaluated the safety of early anti-factor Xa assay-guided enoxaparin dosing for chemoprophylaxis in patients with TBI. We hypothesized that assay-guided chemoprophylaxis would be comparable in the risk of intracranial hemorrhage (ICH) progression to fixed dosing. An observational analysis of adult patients with blunt traumatic brain injury (TBI) was performed at a Level I trauma center from August 2016 to September 2017. Patients in the assay-guided group were treated with an initial enoxaparin dose of 0.5 mg/kg, with peak anti-factor Xa activity measured four hours after the third dose. Prophylactic range was defined as 0.2 to 0.5 IU/mL with a dose adjustment of ± 10 mg based on the assay result. The assay-guided group was compared with historical fixed-dose controls and to a TBI cohort from the most recent Trauma Quality Improvement Project dataset. Of 179 patients included in the study, 85 were in the assay-guided group and 94 were in the fixed-dose group. Compared with the fixed-dose group, the assay-guided group had a lower Glasgow Coma Score and higher Injury Severity Score. The proportion of severe (Abbreviated Injury Score, head ≥3) TBI, ICH progression, and venous thromboembolism rates were similar between all groups. The assay-guided and fixed-dose groups had chemoprophylaxis initiated earlier than the Trauma Quality Improvement Project group. The assay-guided group had the highest percentage of low molecular weight heparin use. Early initiation of enoxaparin anti-factor Xa assay-guided venous thromboembolism chemoprophylaxis has a comparable risk of ICH progression to fixed dosing in patients with TBI. These findings should be validated prospectively in a multicenter study.

Anticoagulant Heparin Mimetics via RAFT Polymerization.

Heparin, a sulfated polysaccharide derived from animal sources, is the most commonly used parenteral anticoagulant drug, but it suffers from significant safety and supply issues. Herein, we describe the preparation of heparin mimetic homo- and copolymers via the reversible addition-fragmentation chain transfer (RAFT) polymerization in water of commercially available (non-carbohydrate) sulfonated and carboxylated monomers. The anticoagulant activities of the polymers were assessed by activated partial thromboplastin time (APTT), thrombin clotting time (TCT), and for the more promising polymers, thrombin generation, antifactor Xa, and antifactor IIa assays. Sulfonated homopolymers studied herein displayed low cytotoxicity and significant anticoagulant activity in APTT, TCT, and thrombin generation assays. In addition, copolymers of sodium styrenesulfonate and acrylic acid [poly(SSS-co-AA)] displayed unprecedented antifactor IIa activity. This study demonstrates the potential of RAFT polymers as alternative anticoagulants for biomedical applications.

Anti-Factor Xa-Based Anticoagulation during Extracorporeal Membrane Oxygenation: Potential Problems and Possible Solutions.

Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Determination of the cut-off prothrombin time to estimate plasma rivaroxaban overdose status.

Laboratory monitoring of rivaroxaban (RIV) is required under certain conditions. Mass spectrometry and anti-factor Xa assays are the recommended methods, which may not be readily available. Prothrombin time (PT) is the most widely used and simple coagulation assay. To set the cutoff PT and international normalized ratio (INR) to estimate RIV overdose status. RIV-spiked pooled normal plasma was used. PT test was performed using a CA-7000 coagulometer and Thromborel S reagent. The precise measurement of RIV concentration at the cut-off PT was evaluated according to the Clinical and Laboratory Standard Institute (CLSI) EP12-A2 guideline. The RIV concentration at 275ng/mL was analyzed using 40 replicates. Receiver operating characteristic (ROC) analysis was performed to determine the cutoff value for the determination of RIV potential overdose status. An imprecision estimation of PT was conducted with 220.00ng/mL, 247.50ng/mL, 261.25ng/mL, 288.75ng/mL, 302.50ng/mL and 330.00ng/mL concentrations of RIV in 60 replicates. According to the ROC analysis, the cutoff clotting times and INR values to determine the overdose status of RIV were 13.45s and 1.39. With these values, there was a 92.6% probability that plasma samples with RIV concentration ≤ 247.50ng/mL yielded consistently negative (on-therapy dose) results, and those with ≥ 302.50ng/mL yield consistent positive (potential overdose) results using our PT assay. PT with a reliable cutoff clotting time and INR can be used to determine the potential overdose status of RIV to facilitate the diagnosis and treatment by controlling the dose.

Validation of apixaban anti-factor Xa assay and impact of body weight

BackgroundDirect oral anticoagulants (DOACs) are widely used as therapies for venous thromboembolism and other cardiovascular diseases. However, routine coagulation monitoring is not required, but may be clinically indicated in high risk populations including obese patients. ObjectivesThe aims of this study were two fold; to validate a chromogenic assay for anti-factor Xa measurement in patients taking apixaban, and correlate it with PT/INR and PTT, and to measure anti-factor Xa levels in patients who weighed >120 kg. Patients/methodsPatients who were taking apixaban had 3 blood samples drawn over a 4 h period. Apixaban levels were determined using an anti-factor Xa activity assay (STA-Liquid Anti-Xa) using STA-Apixaban Calibrator and STA-Apixaban Controls. The PT/INR was determined using standard methodology. Apix MS, using manufacturer provided apixaban standard, was performed on plasma. Results and conclusions18 normal weight patients, 39 obese patients and 14 controls were enrolled. There was a strong correlation between apixaban anti-factor Xa activity compared to plasma Apix MS (r = 0.95). In patients >120 kg, there was a statistically significant decreased rate of change in anti-factor Xa levels after ingestion. Further, the area under the curve for apixaban anti-factor Xa levels was significantly lower in patients over 120 kg. While INR correlated with apixaban MS and apixaban anti-factor Xa activity in both normal weight and obese patients, the association was not sufficiently strong to clinically manage patients, normal weight or obese. Given these findings, research is necessary to investigate the clinical utility of apixaban anti-factor Xa activity measurement in selected populations.

Discordance between aPTT and anti-factor Xa levels and implications in patients receiving intravenous unfractionated heparin therapy

Heparin, one of the world’s oldest anticoagulation medications, accelerates the rate ofinhibition of previously activated clotting factors. It is most often used in the prophylaxis andtreatment of thromboembolic disorders and complications associated with atrial fibrillation.The two most common ways to monitor plasma heparin levels and anticoagulation therapyare the activated partial thromboplastin time (aPTT) and anti-factor Xa assay (anti-Xa). Thisarticle assesses the performance of aPTT and anti-Xa monitoring protocols and analyzes thediscordance between aPTT and anti-Xa levels and its clinical implications in patients receivingintravenous heparin therapy.

Prophylactic anti-coagulation after severe burn injury in critical care settings.

Severely burnt patients are at an increased risk of thromboembolic complications, hence sufficient prophylactic anticoagulation is of paramount importance. Local guidelines at the Burns Centre in the Queen Elizabeth Hospital, Birmingham therefore advise increasing the standard dose of low molecular weight heparin in these patients. An audit was carried out to assess the current practice in burns patients to ensure adequate anticoagulation and adherence to guidelines. Retrospective data was collected on all burns patients in the Burns Centre over a two-year period. The main objectives were to assess:anticoagulation regimes prescribed to severe burns patientsmonitoring of Anti-Factor Xa levelsadjustment of dosing based on the resultsThe locally produced trust guidelines were used as the comparator. All burns patients were prescribed anticoagulation, but often the dose was not increased as suggested in the guidelines. Although most of the severely burnt patients were prescribed adjusted higher doses of anti-coagulation, only 60% of these patients were monitored with Anti-Factor Xa assays. Of these assays, 66% showed sub-prophylactic levels. The majority of results led to the adjustment of the dose of anticoagulant. However, often dose changes were made late. The audit confirmed the need for increased doses of prophylactic anticoagulation in severe burns. The better adherence to the guidelines can be achieved by additional training and implementation of decision support via electronic prescribing system.

Rapid point-of-care detection and classification of direct-acting oral anticoagulants with the TEG 6s: Implications for trauma and acute care surgery.

The trauma patient on direct oral anticoagulant (DOAC) therapy preinjury presents a challenge in trauma and acute care surgery. Our understanding of these patients is extrapolated from vitamin K antagonists. However, DOACs have different mechanisms of action, effects on laboratory coagulation assays, and reversal strategies. Rapid identification of DOACs in the blood will allow timely reversal of factor Xa inhibitors and direct thrombin inhibitors when necessary. The present study evaluated viscoelastic testing to detect and classify DOACs in patient blood samples. This observational, prospective, open-label, multicenter study used point-of-care viscoelastic testing to analyze blood samples taken from patients with and without DOAC treatment, and healthy volunteers. Antifactor Xa and direct thrombin inhibition (DTI) assays were used to establish reference ranges for viscoelastic testing parameters on the TEG 6s system. These ranges were applied to produce a DOAC identification algorithm for patient blood samples. Internal consistency of the measurements, as well as algorithm sensitivity and specificity, was evaluated. Using the TEG 6s system, the R parameter reference range was 0.6 minutes to 1.5 minutes for the Antifactor Xa assay and 1.6 minutes to 2.5 minutes for the DTI assay. Our identification algorithm using these ranges for 2.5 minutes or less has sensitives of 98.3% and 100% for factor Xa inhibitor and direct thrombin inhibitor detection, respectively. Specificity was 100%. Both classes of DOAC were detectable, even when samples were collected during the "trough" between doses of medication. Point-of-care viscoelastic testing with TEG 6s can detect and classify DOACs with high sensitivity and specificity. This tool can be used to better determine the need for reversal in trauma and acute care surgery patients and guide optimal surgical timing in the acute setting. Prognostic and epidemiological study, level II.

Pharmacokinetic and Pharmacodynamic Drug Monitoring of Direct-Acting Oral Anticoagulants: Where Do We Stand?

For decades, oral anticoagulation has been based on vitamin K antagonist such as warfarin, which requires pharmacodynamic (PD) drug monitoring to guide the therapy. The drug effect is measured by the clotting test prothrombin time and expressed as international normalized ratio. New direct oral anticoagulants are increasingly used in fixed-dose regimens but are licensed without any therapy monitoring. However, extensive clinical experiences have demonstrated that interindividual variations in the response to the therapy with direct oral anticoagulants do exist. In situations such as bleeding or thrombosis, therapeutic drug monitoring could be useful. Unfortunately, global coagulation assays such as the prothrombin time or the activated partial thrombin time are not suitable for this purpose. To measure drug concentrations, more specific coagulation test can be used if they are externally calibrated with the respective drugs. For the direct thrombin inhibitor dabigatran etexilate, a calibrated diluted thrombin time or ecarin clotting time can be used, whereas for anti-factor Xa drugs such as rivaroxaban, apixaban, edoxaban, and betrixaban, calibrated anti-factor Xa assays are appropriate. However, the gold standard to measure drug concentrations is LC-MS/MS. The variation in bleeding and thrombotic events noted with both drug classes under fixed-dose conditions suggests additional interindividual PD differences. Therefore, PD monitoring to individualize the therapy may be an option. For dabigatran, this is the inhibition of thrombin formation and for anti-factor Xa drugs, the inhibition of factor Xa activity, which can be followed using the functional assays mentioned above but without calibration. Alternatively, thrombin generation assays have been proposed for both drug classes. So far, not many clinical data have been published about the potentially beneficial effects of PD monitoring for dose individualization. The assay platforms for PD monitoring are present in many clinical laboratories, but efforts are needed to validate and standardize available assays to perform appropriate clinical trials.