Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban, and Apixaban Therapy by Novel Automated Thrombelastography.

Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, ( n = 50) on apixaban, ( n = 62) on rivaroxaban, ( n = 53) on dabigatran, and ( n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the antifactor Xa (AFXa) channel, R-time demonstrated strong nonlinear correlation with rivaroxaban and apixaban levels ( r s = 0.92 and 0.84, respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers.

BACKGROUND: The ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new-generation fully automated thrombelastograph TEG 6s using resonance-frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. METHODS: A single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG _6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. RESULTS: The reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r = 0.94, P < 0.0001). Using the anti-factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r = 0.93 and r = 0.83, respectively; P < 0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. CONCLUSION: We have demonstrated that TEG _6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.

Assessment of the effect of direct oral anticoagulants dabigatran, rivaroxaban, and apixaban in healthy male volunteers using a thrombin generation assay.

BACKGROUND: There are clinical situations where monitoring direct oral anticoagulants (DOACs) may be useful. The clinical application of thrombin generation assay (TGA) in monitoring the effect of DOACs has not been well established. An ex vivo study was performed to systematically evaluate the anticoagulant effect of dabigatran, rivaroxaban and apixaban on each individual TGA parameter through serial measurements over time to assess suitability of these parameters for monitoring the anticoagulant effect of DOACs. METHODS: Ten healthy volunteers were given oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 10 mg once. TGA parameters lag time, endogenous Thrombin potential (ETP), and thrombin peak height, time to peak, and velocity index were measured at times 0, 2, 4, and 24 hours after intake of DOAC. TGA parameters and DOAC concentrations were correlated. RESULTS: The lag time was significantly correlated with all DOAC concentrations (r ≥ .81, P < .0001 for all). Thrombin peak height best correlated with direct Factor Xa inhibitor (FXa) concentrations in nonlinear fashion (R² ≥ .87). ETP was weakly correlated with DOAC levels (r ≤ .68). Besides lag time, the other TGA parameters were not significantly altered over time by dabigatran. CONCLUSION: Lag time was the only sensitive TGA parameter across the different classes of DOACs evaluated. Thrombin peak height was strongly correlated to FXa inhibitor concentrations and potentially a useful parameter to monitor FXa inhibitors at low concentrations. ETP had a weak correlation with achieved DOAC concentrations and is likely less suitable for assessment of DOAC effect as a stand-alone parameter.

In-vitro comparison of free oscillation rheometry (ReoRox) and rotational thromboelastometry (ROTEM) in trauma patients upon hospital admission.

Plasma-based assays do not provide accurate information on haemostatic resuscitation hence viscoelastic point-of-care haemostatic assays such as rotational thromboelastometry (ROTEM Delta, Pentapharm) are used to monitor coagulopathy in trauma patients. Free oscillation rheometry (FOR) is a new whole blood haemostatic assay that measures not only the clot-forming process but also the initial viscous phase; this could potentially be of value when assessing traumatic coagulopathy. A comparative analysis between FOR and ROTEM was therefore performed. This is a prospective observational study of 40 adult trauma patients admitted to a level 1 trauma centre. Citrated whole blood was analysed with ROTEM EXTEM and FIBTEM assays and FOR Fibscreen1 and Fibscreen2 assays. Predefined variables of ROTEM and FOR were compared using Spearman's ρ. ROTEM maximum clot function (MCF) in both EXTEM and FIBTEM correlated (P < 0.0001 for both) with FOR maximum elasticity Fibscreen1 and Fibscreen2, respectively. Interestingly, ROTEM EXTEM clotting time did not correlate with any of the FOR clot initiation parameters COT1, COT2 or COT2-1 of Fibscreen1. A correlation between ROTEM EXTEM and FIBTEM and FOR Fibscreen1 and Fibscreen2 clot formation and clot strength was found as was a significant correlation between lysis index after 60 min and ClotSR30. ROTEM EXTEM did not correlate with COT1, COT2 or COT2-1 of Fibscreen1 and this warrants further investigation.

Reduced clot-stability during the first 6 hours after aneurysmal subarachnoid haemorrhage--a prospective case-control study.

INTRODUCTION: Early rebleeding is an important cause of death and disability following aneurysmal subarachnoid haemorrhage (SAH). Recent studies have shown that 50-90% of the rebleedings occurred within the first 6 hours after the primary bleeding. The mechanism leading to rebleeding remains to be established. In the present prospective case-control study we hypothesize that patients with SAH develop a coagulopathy characterized by reduced clot stability during the early period after the initial bleeding. METHODS: Patients with aneurysmal SAH was studied with a dynamic clot lysis assay and markers of fibrinolysis and clot stabilizers in blood samples taken within and after 6 hours after onset of bleeding. Results were compared with blood samples from age and gender matched healthy controls. RESULTS: 36 patients were enrolled, 26 patients had blood samples collected within 6 hours after the initial bleeding whereas 10 patients had blood samples taken later than 6 hours after the initial bleeding. Patients demonstrated significantly reduced clot stability during the first 6 hours after initial bleeding. Fibrinolytic activity was increased during the first 6 hours along with the inhibitors of fibrinolysis whereas the modulators of fibrinolysis were reduced or inactivated. CONCLUSION: During the first 6 hours after SAH patients exhibit reduced clot-stability. Probably a consequence of activated fibrinolysis in combination with reduced or inactivated factor XIII and thrombin-activable fibrinolysis inhibitor.

Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy - a European Perspective.

Argatroban has been introduced as an alternative parenteral anticoagulant for HIT-patients in several European countries in 2005. In 2009 a panel of experts discussed their clinical experience with argatroban balancing risks and benefits of argatroban treatment in managing the highly procoagulant status of HIT-patients. This article summarizes the main conclusions of this round table discussion. An ongoing issue is the appropriate dosing of argatroban in special patient groups. Therefore, dosing recommendations for different HIT-patient groups (ICU patients; non-ICU patients, paediatric patients, and for patients undergoing renal replacement therapies) are summarized in this consensus statement. Because of the strong correlation between argatroban dosing requirements and scores used to characterize the severity of illness (APACHE; SAPS, SOFA) suitable dosing nomograms are given. This consensus statement contributes to clinically relevant information on the appropriate use and monitoring of argatroban based on the current literature, and provides additional information from clinical experience. As the two other approved drugs for HIT, danaparoid and lepirudin are either currently not available due to manufacturing problems (danaparoid) or will be withdrawn from the market in 2012 (lepirudin), this report should guide physicians who have limited experience with argatroban how to use this drug safely in patients with HIT.

Blood coagulation and fibrinolysis after experimental subarachnoid hemorrhage.

BACKGROUND: Aneurysmal rebleeding poses a serious risk in patients with subarachnoid hemorrhage (SAH). Studies have shown that antifibrinolytic therapy with tranexamic acid has a dramatic effect on the rate of rebleeding. Therefore, changes in the fibrinolytic system could be hypothesized. METHODS: We have used an experimental SAH rat model to demonstrate serial changes in the haemostatic system as evaluated by Thromboelastography (TEG). RESULTS: In the SAH group, a shorter reaction time (R-time) and higher maximum amplitude (MA) were observed. In the saline group, only a shorter R-time was observed. CONCLUSIONS: The study has shown that a hypercoagulable state is present immediately after experimental SAH is induced as determined by TEG. The reduction in R-time and rise in MA observed in the SAH group indicate that blood in the subarachnoid space is necessary to accomplish a full systemic coagulation response. This abnormality in coagulation profile seems to be a response to the acute traumatic event caused by induction of SAH.