Assays of fibrin network properties altered by VKAs in atrial fibrillation – importance of using an appropriate coagulation trigger

2015 ◽  
Vol 113 (04) ◽  
pp. 851-861 ◽  
Author(s):  
Michal Ząbczyk ◽  
Margareta Blombäck ◽  
Jacek Majewski ◽  
Grzegorz Karkowski ◽  
Hakan N. Wallen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Thrombin Generation ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Clot Lysis ◽  
Flow Measurements ◽  
Fibrin Networks ◽  
Fibrin Network ◽  
Long Term Treatment

SummaryAtrial fibrillation (AF) is a prothrombotic condition, involving increased thrombin generation and fibrinogen concentrations. Vitamin K antagonists (VKAs) prevent arterial thromboembolism if optimal anticoagulation is achieved by individualised drug doses, assessed by determining the Prothrombin time-related International Normalized Ratio (Pt-INR). There is evidence that formation of tight-laced fibrin networks is pathogenic in prothrombotic diseases. This study was performed among AF patients, to test whether long-term treatment with VKAs affects the structure of fibrin networks, and whether the effect is altered by employing different coagulation triggers: exogenous thrombin (1 IU/ml), 10 pM tissue factor (TF) or a commercial Pt-INR reagent (containing 400-fold more TF). In the thrombin-based method, fibrin network porosity (scanning electron microscopy) and liquid permeability (flow measurements) correlated inversely to fibrinogen concentrations, while positive correlations to the degree of anticoagulation were shown with the Pt-INR reagent. In the method with 10 pM TF, the two above relationships were detected, though the influence of Pt-INR was more profound than that of fibrinogen concentrations. Moreover, greater shortening of clot lysis time (CLT) arose from more permeable clots. As a coagulation trigger, 10 pM TF vs exogenous thrombin or the Pt-INR reagent is more informative in reflecting the in vivo process from thrombin generation to fibrin formation. Since fibrin network permeability rose in parallel to elevations of INR and shortening of CLT in AF patients, antithrombotic effects on prevention of thrombotic complications may be achieved from impairment of thrombin generation, resulting in formation of permeable clots susceptible to fibrinolysis.

scholarly journals The international normalized ratio (INR) as seen in a population of patients with atrial fibrillation and cerebral infarction undergoing long-term treatment with vitamin K antagonists

2015 ◽  
Vol 28 (4) ◽  
pp. 269-272
Author(s):  
Anna Szczepańska-Szerej ◽  
Magdalena Wojtan ◽  
Beata Szajnoga
Keyword(s):  
Atrial Fibrillation ◽  
Cerebral Infarction ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Blood Parameters ◽  
Term Treatment ◽  
Adequate Treatment ◽  
Long Term Treatment

Abstract It is estimated that nearly 20% of all cerebral infarctions in the total population are the result of a complication of atrial fibrillation (AF). While oral anticoagulation with vitamin K antagonists (AVKs) substantially reduces this risk, this requires regular monitoring of the international normalized ratio (INR) in order to achieve therapeutic levels (2,0-3,0). The aim of this study was to evaluate a group at high risk of cerebral infarction, among patients with AF undergoing long-term treatment with VKAs, taking into account the significance of therapeutic INR values. The analysed group consisted of 90 acute ischaemic stroke patients with paroxysmal or chronic “non-valvular” AF, receiving treatment with VKAs. As a result of the study, therapeutic INR values (≥ 2) were seen in thirty-five of these individuals (38,8%), while 55 (61,2%) showed non-therapeutic INR values. Moreover, there were no differences in demographics, vascular risk factors, biochemical and morphological blood parameters, mean CHA2DS2-VASc score and TOAST classification between either of the two groups. Furthermore, no additional factor that would increase their risk of cerebral infarction during the adequate treatment with VKAs was found. However, patients with non-therapeutic INR values had a statistically significantly higher frequency of concomitant moderate pathology of the bicuspid valve, p<0.05. Hence, a lack of proper control of INR can proved to be particularly dangerous for this subgroup of patients. Hence, this is a group with an elevated risk of cerebral infarction and therefore requires special oversight of VKA treatment or NOA treatment.

scholarly journals Thromboembolic and hemorrhagic risk stratification in patients with atrial fibrillation. Part II: hemorrhagic risk and guidelines recommendations

2015 ◽  
Vol 80 (3) ◽  
Author(s):  
Maurizio Giuseppe Abrignani ◽  
Vincenzo Abrignani
Keyword(s):  
Atrial Fibrillation ◽  
Risk Stratification ◽  
Oral Anticoagulant Therapy ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Score System ◽  
Hemorrhagic Events ◽  
Hemorrhagic Risk ◽  
Embolic Risk ◽  
Robust Evidence

Robust evidence exists on the efficacy of traditional anticoagulant oral therapy in the prevention of thrombo-embolic risk in patients with non valvular atrial fibrillation, but fears and concerns of hemorrhagic events for the physicians and logistic difficulties related to the periodic International Normalized Ratio evaluation for the patients are at the basis of a noticeable under-utilization of the therapy with vitamin K antagonists in the real world. Stratification of the hemorrhagic risk has, thus, particular importance; for this objective we may use now several score system, among whom the more suggested is the HASBLED, with the principal aim to select and trait modifiable risk factors for bleeding. These score systems have been evaluated in some recent clinical trials. During the last years, a number of national and international guidelines on the prevention of the thrombo-embolic risk in patients with non valvular atrial fibrillation have been updated. These guidelines, generally, recommend the use of the CHA2DS2VaSC score for the evaluation of the thrombo-embolick risk, and of the HAS-BLED score for the evaluation of the hemorrhagic one. The consequent risk stratification is fundamental as a clinical guide for the use of oral anticoagulant therapy.

scholarly journals New artificial intelligence prediction model using serial prothrombin time international normalized ratio measurements in atrial fibrillation patients on vitamin K antagonists: GARFIELD-AF

2019 ◽  
Vol 6 (5) ◽  
pp. 301-309 ◽  
Author(s):  
Shinichi Goto ◽  
Shinya Goto ◽  
Karen S Pieper ◽  
Jean-Pierre Bassand ◽  
Alan John Camm ◽  
...  
Keyword(s):  
Neural Network ◽  
Artificial Intelligence ◽  
Atrial Fibrillation ◽  
Prothrombin Time ◽  
Clinical Outcomes ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
One Dimensional ◽  
Major Bleed

Abstract Aims Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from Global Anticoagulant Registry in the Field (GARFIELD)-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of prothrombin time international normalized ratio (PT-INR) within 30 days of enrolment. Methods and results Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKAs) and had at least three measurements of PT-INR taken over the first 30 days after prescription were analysed. The AI model was constructed with multilayer neural network including long short-term memory and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0–30 after starting treatment and clinical outcomes over days 31–365 in a derivation cohort (cohorts 1–3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/systemic embolism (SE), and death was assessed in a validation cohort (cohorts 4–5; n = 1523). The model’s c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively. Conclusions Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analysed by computer to help predict adverse clinical outcomes.

P4765Men who live alone have poor anticoagulation control: results from Danish registries

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A N Bonde ◽  
J Bjerre ◽  
M Proietti ◽  
G Gislason ◽  
G Y H Lip ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Living Alone ◽  
Efficacy And Safety ◽  
Men And Women ◽  
Anticoagulation Control ◽  
Cohabitation Status ◽  
Multivariable Adjustment

Abstract Background Efficacy and safety of vitamin K antagonists (VKAs) depend on quality of anticoagulation control, usually measured as time in therapeutic range (TTR). Factors that predict low TTR on VKAs could be used to identify patients who might benefit from interventions, or who would be better treated with a non-VKA oral anticoagulant (NOAC). Patients living alone may have difficulties in taking their medications, managing their diets, or coming to clinic for monitoring. Purpose To assess influence of cohabitation status on TTR with VKA among men and women. Methods We identified all Danish patients with atrial fibrillation (AF) who initiated VKA between 1997 and 2012, and studied patients who had 6 months of continuous VKA use and international normalized ratio (INR) monitoring. Patients were divided according to sex and whether they lived alone or with others. We calculated TTR using the Rosendaal method, and INR variability using Fihns method. We used a linear regression model to test for associations between TTR and covariates, and adjusted for age, income, medications and comorbidities. Results We identified 4,772 AF patients with 6 months of continuous VKA use and INR monitoring. 713 (15%) were men living alone, 1,073 (23%) were women living alone, 2,164 (45%) were men not living alone and 822 (17%) were women not living alone. INR was measured a median of 11 (interquartile range 8–15) times during the 180 days of VKA use, but men who lived alone had 0.6 (95% confidence interval (CI): 0.2 to 1.2) fewer INR measurements during the period. Median TTR was lowest among men living alone (57.2%), followed by women living alone (58.8%), women not living alone (61.0%) and men not living alone (62.5%). After multivariable adjustment, men who lived alone had a 3.6% (CI −5.6 to −1.6) lower TTR compared with men not living alone, but women who lived alone did not have significantly lower TTR (P=0.80) compared with women not living alone. Living alone had significantly greater effect on TTR among men than among women (interaction P=0.02). Men living alone also had higher adjusted INR variability (0.2, CI 0.0 to 0.4) compared with men not living alone. Conclusion Living alone was significantly related to low quality of anticoagulation control among men, but not among women. Acknowledgement/Funding this study was funded by an unrestricted grant from the Capital Region of Denmark, Foundation for Health Research

scholarly journals Dynamic Hemostasis and Fibrinolysis Assays in Intensive Care COVID-19 Patients and Association with Thrombosis and Bleeding—A Systematic Review and a Cohort Study

2021 ◽  
Author(s):  
Christine Lodberg Hvas ◽  
Julie Brogaard Larsen ◽  
Kasper Adelborg ◽  
Steffen Christensen ◽  
Anne-Mette Hvas
Keyword(s):  
Intensive Care ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Clot Lysis ◽  
Healthy Controls ◽  
Rotational Thromboelastometry ◽  
Thrombin Generation Assay ◽  
Primary Hemostasis ◽  
Normal Platelet

AbstractPatients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19), the infectious pathology caused by severe acute respiratory syndrome coronavirus 2, have a high risk of thrombosis, though the precise mechanisms behind this remain unclarified. A systematic literature search in PubMed and EMBASE identified 18 prospective studies applying dynamic coagulation assays in ICU COVID-19 patients. Overall, these studies revealed normal or slightly reduced primary hemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome. We also prospectively included 51 COVID-19 patients admitted to the ICU. Blood samples were examined on day 1, 3–4, and 7–8 with platelet function tests, rotational thromboelastometry (ROTEM), in vivo and ex vivo thrombin generation, and clot lysis assay. Data on thrombosis, bleeding, and mortality were recorded during 30 days. Primary hemostasis was comparable to healthy controls, but COVID-19 patients had longer ROTEM-clotting times and higher maximum clot firmness than healthy controls. Ex vivo thrombin generation was similar to that of healthy controls while in vivo thrombin generation markers, thrombin–antithrombin (TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2) were higher in ICU COVID-19 patients than in healthy controls. Impaired fibrinolysis was present at all time points. TAT complex and F1 + 2 levels were significantly higher in patients developing thrombosis (n = 16) than in those without. In conclusion, only few previous studies employed dynamic hemostasis assays in COVID-19 ICU-patients and failed to reveal a clear association with development of thrombosis. In ICU COVID-19 patients, we confirmed normal platelet aggregation, while in vivo thrombin generation was increased and fibrinolysis decreased. Thrombosis may be driven by increased thrombin formation in vivo.

scholarly journals Periprocedural anticoagulation in the uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation (ELIMINATE-AF) trial

EP Europace ◽  
2020 ◽  
Author(s):  
Stefan H Hohnloser ◽  
A John Camm ◽  
Riccardo Cappato ◽  
Hans-Christoph Diener ◽  
Hein Heidbüchel ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Study Drug ◽  
International Normalized Ratio ◽  
P Value ◽  
Group 14 ◽  
Group 13 ◽  
Post Hoc ◽  
Higher Doses

Abstract Aims  This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy. Methods and results  Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0–3.0). Uninterrupted anticoagulation was mandated for 21–28 days’ pre-ablation and 90 days’ post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300–400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1–Q3) time from last dose to ablation procedure was 14.8 (13.3–16.5) vs. 16.5 (14.8–19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value &lt; 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU). Conclusion  The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.

Efficacy and safety of apixaban compared with warfarin regarding time within the therapeutic range

2014 ◽  
Vol 155 (5) ◽  
pp. 177-181
Author(s):  
Kálmán Havasi
Keyword(s):  
Atrial Fibrillation ◽  
Therapeutic Range ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Bleeding Risk ◽  
International Normalized Ratio ◽  
Efficacy And Safety ◽  
Nonvalvular Atrial Fibrillation ◽  
Major Drawback ◽  
Routine Monitoring

Prevention of thromboembolism by lifelong anticoagulation is an important therapeutic goal in patients with atrial fibrillation according to recent guidelines. Major drawback of vitamin K antagonists are their narrow therapeutic range and interactions with other drugs and food. These have significant impact on the pharmacokinetics and pharmacodynamics requiring regular measurements of the international normalized ratio. Efficiency of the anticoagulant therapy depends considerably on time within the therapeutic range of prothrombin international normalized ratio. Time within the therapeutic range represents the percentage of time within the required range of prothrombin international normalized ratio. Prothrombin international normalized ratio outside the therapeutic range increases the risk of thromboembolism or bleeding according to whether it falls below or above the range. New oral anticoagulants do not require routine monitoring of anticoagulation. Their efficacy and safety are shown to be at least as good as or better than those of warfarin. In patients with nonvalvular atrial fibrillation ARISTOTLE study revealed that antithrombotic effect of apixaban compared with warfarin is better and with lower bleeding risk irrespective of the quality of prothrombin international normalized ratio control. Orv. Hetil., 2014, 155(5), 177–181.

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