scholarly journals The influence of direct oral anticoagulants on thrombin generation on Ceveron TGA

2021 ◽  
Author(s):  
Christian Pfrepper ◽  
Lisa-Charlott Behrendt ◽  
Hagen Bönigk ◽  
Thomas Siegemund ◽  
Michael Metze ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Thrombin Generation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Interindividual Variation ◽  
Test Results ◽  
Time To Peak ◽  
Automated Assay ◽  
Coagulation Status ◽  
Lower Correlation

Abstract Introduction: Monitoring of direct oral anticoagulants (DOACs) with calibrated anti-Xa assay is limited by the high intra- and interindividual variation of the test results. Thrombin generation (TG) is a global hemostatic assay that reflects the patient´s individual coagulation status. The aim of this study was to investigate the influence of DOACs on TG measured with a fully automated assay system. Methods: All consecutive patients under apixaban and rivaroxaban coming to the outpatient coagulation center MVZ Limbach, Magdeburg, Germany between October 2017 and April 2020 were included. DOAC plasma levels were correlated with TG assessed using the fully automated Ceveron TG analyser. Results: A total of 703 rivaroxaban and 252 apixaban containing plasma samples were included. There was a significant correlation between DOAC plasma levels and all TG parameters except for lag time regarding apixaban. Time to peak and peak thrombin followed an exponential regression curve, while this was linear for the endogenous thrombin potential (ETP). Apixaban showed a lower correlation coefficient for all TG parameters compared to rivaroxaban and thrombin generation was less influenced by apixaban than rivaroxaban at plasma levels > 100 ng/mL. The sensitivity and negative predictive value of normal TG parameters for the prediction of DOAC plasma levels < 30 ng/mL was > 85%. Conclusion: The present data show a moderate predominantly non-linear correlation between TG parameters and plasma levels of apixaban and rivaroxaban. Rivaroxaban has a stronger effect on TG than apixaban.

scholarly journals Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

2021 ◽  
Author(s):  
Michael Metze ◽  
Tristan Klöter ◽  
Stephan Stöbe ◽  
Björn Rechenberger ◽  
Roland Siegemund ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Thrombin Generation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants

scholarly journals Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.M Engelen ◽  
C Van Laer ◽  
M Jacquemin ◽  
C Vandenbriele ◽  
K Peerlinck ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Heart Valves ◽  
Thrombus Formation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Mechanical Heart Valves ◽  
Contact Activation

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

scholarly journals 109Accuracy of test results for Direct Oral Anticoagulants (DOACs) and Warfarin- importance of External Quality Assessment (EQA)

EP Europace ◽  
2017 ◽  
Vol 19 (suppl_1) ◽  
pp. i46-i46
Author(s):  
DP Kitchen ◽  
A W-C Chow ◽  
S Munroe-Peart ◽  
L Brown ◽  
I Jennings ◽  
...  
Keyword(s):  
Quality Assessment ◽  
External Quality Assessment ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Test Results ◽  
External Quality

Factor VIII Efficacy and Tissue Factor Levels in Hemophilia A Patients Undergoing Total Knee Replacement.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4029-4029
Author(s):  
Wolfgang Wegert ◽  
Manuela Krause ◽  
Inge Scharrer ◽  
Ulla Stumpf ◽  
Andreas Kurth ◽  
...  
Keyword(s):  
Total Knee Replacement ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Lag Time ◽  
Major Surgery ◽  
Plasma Samples ◽  
Time To Peak ◽  
Thrombin Generation Assay ◽  
Total Knee

Abstract The changes of tissue factor (TF) blood levels in patients undergoing major surgery has been reported presenting controversial data. Whether this TF is hemostatically active or if it interacts with other coagulation factors, e.g. FVIII, is still unclear, making thrombotic risk and complications assessment for even more difficult. We analyzed plasma samples from four male patients aged 27–55 with severe hemophilia A without inhibitory antibodies, undergoing total knee replacement, which all gave informed consent. Initial FVIII doses before intervention was 75–80 U/kg. Treatment following intervention was targeted at 100 % FVIII serum levels. None received heparin. No bleeding events occurred during the observation period. The samples were taken at these timepoints (TP): 1. before preoperative FVIII substitution, 2. at the time of first incision (intervention start), 3. at circulation arrest release + 90 s after prosthesis implantation, 4. final suture (intervention end), 5. 24 h and 6. 48 h after intervention to assay procedurally induced TF production. Coagulation analyses were carried out using a fluorometric thrombin generation assay (TGA) in platelet rich plasma (PRP), RoTEG (rotation thrombelastography) in whole blood and a TF ELISA for the plasma samples’ TF levels. Both clotting function tests were started using TF diluted 1:100.000 and calcium chloride 16,7 mM (final conc.). TGA parameters were ETP, PEAK (maximum thrombin generation velocity), TIME TO PEAK, LAG TIME. TGA parameters directly related to thrombin activity (ETP; PEAK) showed no change during the intervention, but a sharp decrease 24 h later with a partial recovery 48 h later. TGA time marks (TIME TO PEAK, LAG TIME) changed in an inverse way, except for the difference from LAG TIME and TIME TO PEAK, which shortened continously after circulation arrest removal. RoTEG was characterized using 4 parameters: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF) and clot formation rate (CFR). After preoperative FVIII substitution, CT decreased by 10 % and CFT by 50 % in 48 h. MCF stayed unchanged during the intervention and the following 24 h, but increased by 20 % at 48 h. CFR increased by 10 % during intervention, and by 20 % from 24 to 48 h. TF ELISA showed preoperative TF plasma levels from 11 to 271 pg/ml. After release of circulation arrest (TP 3) TF concentration increased sharply (4 times the initial value), which was not detectable in the samples taken at TPs 2 and 4. TF levels further increased at TPs 5 and 6 to 170 % and 317 % resp. Altogether, TF plasma levels elevated after major surgery seem to correspond to a potential risk factor for postoperative thrombosis, especially when elevation is induced after intervention. However, functional coagulation assays do not change uniformly, as the thrombin generation assay reflects no marked changes under intervention, but in the period after(24–48 h). Changes in the RoTEG whole blood clotting assay are not dramatic but indicate a thrombophilic shift in coagulation balance also pronouned at 24–48h, too. These results demonstrate that increased coagulability after orthopedic surgery detected using functional clotting assays correlates with increased TF levels, but further studies must be performed to prove this relation in healthy individuals.

Direct Oral Anticoagulants Plasma Levels Measurement: Clinical Usefulness from Trials and Real-World Data

2021 ◽  
Vol 47 (02) ◽  
pp. 150-160
Author(s):  
Francesca Renon ◽  
Anna Rago ◽  
Biagio Liccardo ◽  
Antonello D'Andrea ◽  
Lucia Riegler ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Plasma Levels ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Outcome Data ◽  
Bleeding Events ◽  
Real World Data ◽  
World Data ◽  
Emergency Situations

AbstractMeasurement of direct oral anticoagulants (DOACs) activity is not routinely necessary. Indeed, evaluation of DOACs plasmatic concentration is discouraged for the majority of patients, due to the lack of outcome data supporting this approach. Nevertheless, DOAC measurements may be useful in emergency situations such as serious bleeding events, need for urgent invasive procedures, and acute ischemic stroke or in managing anticoagulation in “special populations” not adequately studied in clinical trials, for example the very elderly or those at the extremes of body weight. The aim of this review is to describe and summarize the methods for DOACs activity evaluation and the settings in which their plasma level measurement may be indicated, analyzing indications from scientific societies and evidence from clinical trials, as well as real world data on the usefulness of DOACs plasma levels “monitoring.”

Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: Results observed in four anticoagulation clinics

2016 ◽  
Vol 137 ◽  
pp. 178-183 ◽  
Author(s):  
Sophie Testa ◽  
Armando Tripodi ◽  
Cristina Legnani ◽  
Vittorio Pengo ◽  
Rosanna Abbate ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Plasma Levels ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Real Life ◽  
Anticoagulation Clinics

scholarly journals Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis

2018 ◽  
Vol 2 (2) ◽  
pp. 142-145 ◽  
Author(s):  
Neethu Menon ◽  
Ravi Sarode ◽  
Ayesha Zia
Keyword(s):  
Skin Necrosis ◽  
Protein C ◽  
Dose Adjustment ◽  
Thrombin Generation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Protein C Deficiency ◽  
Thrombin Generation Assay ◽  
Key Points ◽  
Congenital Protein C Deficiency

Key Points Rivaroxaban was efficacious and safe in a child with protein C deficiency to prevent the recurrence of skin necrosis or venous thrombosis. The dosage of direct oral anticoagulants in children with thrombophilia is unclear; a thrombin generation assay may be useful to adjust it.

Direct Oral Anticoagulant Plasma Levels for the Management of Acute Ischemic Stroke

2019 ◽  
Vol 48 (1-2) ◽  
pp. 17-25 ◽  
Author(s):  
Armin Marsch ◽  
Kosmas Macha ◽  
Gabriela Siedler ◽  
Lorenz Breuer ◽  
Erwin F. Strasser ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Plasma Level ◽  
Acute Ischemic Stroke ◽  
Plasma Levels ◽  
Emergency Treatment ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Complications ◽  
Vessel Occlusion

Introduction: The management of acute ischemic stroke in patients on direct oral anticoagulants (DOACs) is challenging. However, the substance-specific plasma level could guide treatment decisions on recanalization therapies. We present a plasma-level-based protocol for emergency treatment of stroke patients on oral anticoagulants. Bleeding complications and clinical outcome for patients on DOACs are reported and compared to patients on vitamin K antagonists (VKAs). Methods: In patients with acute ischemic stroke and suspected use of DOACs within 48 h prior to hospital admission, plasma levels were measured using the calibrated Xa-activity (apixaban, edoxaban, rivaroxaban) or the Hemoclot®-assay (dabigatran). Levels <50 ng/mL were supportive for thrombolysis, while high values >100 ng/mL excluded patients from recombinant tissue plasminogen activator use. For patients on VKAs, the cutoff was set at international normalized ratio of 1.7. Endovascular thrombectomy of a large vessel occlusion was performed independently from coagulation testing. Consecutive patients were included in an observational registry. Results: Five hundred and twenty-two patients (261 on VKAs and 261 on DOACs) were included. Thirty patients (11.5%) on VKAs and 24 (9.2%) on DOACs received thrombolysis, followed by mechanical thrombectomy in 10 and 14 patients, respectively. Seventeen patients in each group received thrombectomy only. Symptomatic intracranial hemorrhage associated with thrombolysis occurred in 1 patient on VKA (3.3%) and 1 on DOAC (4.2%; p = 0.872). The turnaround time of specific assays did not show a significant delay in comparison to standard coagulation parameters. Conclusion: DOAC plasma levels could support decisions on emergency treatment of ischemic stroke. Systemic thrombolysis below suggested thresholds appears preliminary feasible and safe without an excess in bleeding complications.

scholarly journals Laboratory Assessment of the Anticoagulant Activity of Apixaban in Patients With Nonvalvular Atrial Fibrillation

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 194S-201S ◽  
Author(s):  
Elias Kyriakou ◽  
Konstantinos Katogiannis ◽  
Ignatios Ikonomidis ◽  
George Giallouros ◽  
Georgios K. Nikolopoulos ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Plasma Concentrations ◽  
Nonvalvular Atrial Fibrillation ◽  
Laboratory Assessment ◽  
Thrombin Generation Assay ◽  
Significant Difference

Our aim is to determine the most appropriate laboratory tests, besides anti-factor Xa (anti-FXa) chromogenic assays, to estimate the degree of anticoagulation with apixaban and compare it with that of rivaroxaban in real-world patients. Twenty patients with nonvalvular atrial fibrillation treated with apixaban 5 mg twice daily and 20 patients on rivaroxaban 20 mg once daily were studied. Conventional coagulation tests, thrombin generation assay (TGA), and thromboelastometry (nonactivated TEM [NATEM] assay) were performed in the 40 patients and 20 controls. The anti-FXa chromogenic assays were used to measure apixaban and rivaroxaban plasma levels. The NATEM measurements showed no significant difference between the 2 groups of patients. Concerning TGA, endogenous thrombin potential (ETP) was significantly decreased in patients on rivaroxaban as compared to those treated with apixaban ( P < .003). A statistically significant, strong inverse correlation between apixaban plasma concentrations and ETP ( P < .001) was observed. Apixaban significantly reduces ETP compared to controls, but to a lesser extent than rivaroxaban. Thrombin generation assay might provide additional information on apixaban exposure, which is required in order to individualize treatment especially for patients with a high bleeding risk. Our findings have to be further investigated in studies with larger sample sizes, in the entire range of apixaban exposure, with other direct oral anticoagulants, and in relation to clinical outcomes.

scholarly journals Detection of direct oral anticoagulants with the dilute Russels viper venom time – observations in a real life setting

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Kloeter ◽  
T Siegemund ◽  
A Siegemund ◽  
U Laufs ◽  
S Petros ◽  
...  
Keyword(s):  
Real World ◽  
Plasma Levels ◽  
Lupus Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Real Life ◽  
Public Institution ◽  
Peak Time ◽  
Real World Data ◽  
Screening Assay

Abstract Background The detection of direct oral anticoagulants (DOACs) in emergency settings still remains challenging, especially when dedicated anti-Xa or anti-IIa tests are not readily available or the specific DOAC is unknown. The dilute Russel's viper venom time (dRVVT) is widely known in lupus anticoagulant (LA) testing and may also provide helpful information regarding the residual antithrombotic activity of DOACs. Yet real world data describing the effect of DOACs on the dRVVT is scarce. Objective The study aimed to evaluate the sensitivity and specificity of dRVVT for different DOAC plasma levels. Methods A total of 80 patients were recruited – 20 patients for each approved DOAC (apixaban, edoxaban, rivaroxaban and dabigatran). Blood plasma was sampled before (baseline), 6 and 12 hours after DOAC-intake and at plasma peak time. DRVVT was measured using the LA1 screening assay for lupus anticoagulant. Plasma levels were measured by calibrated anti-Xa or anti-IIa tests. Additionally, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured. Results All DOACs significantly prolonged the dRVVT. The effects were more pronounced at higher DOAC plasma levels. The area under the receiver operating characteristic (ROC) curve regarding a plasma level cut-off of 30 ng/ml was 0.92 (95% confidence interval (CI) 0.823 to 1.00) for apixaban, 0.97 (95% CI 0.902 to 1.00) for edoxaban, 0.87 (95% CI 0.649 to 1.00) for rivaroxaban and 0.96 (95% CI 0.871 to 1.00) for dabigatran. Conclusion A dose dependent effect of all approved direct oral anticoagulants (DOACs) on the dilute Russel's viper venom time (dRVVT) was documented in our real world setting, while relevant DOAC plasma levels did not affect standard coagulation tests. The negative predictive value for the dRVVT was high even at low DOAC plasma levels. The dRVVT could therefore be helpful to rule out relevant antithrombotic plasma activity caused of DOACs in emergency situations. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Universität Leipzig Figure 1. ROC curves

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