scholarly journals Relative Interfering Effects of In Vivo Direct Oral Anticoagulants on Routine Coagulation Tests

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4238-4238
Author(s):  
Jinju Kim ◽  
Yejin Song ◽  
Hyun-Jeong Kim ◽  
Mi-Sook Yang ◽  
Jaewoo Song
Keyword(s):  
Conflicts Of Interest ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Regression Line ◽  
Anticoagulation Therapy ◽  
Blood Samples ◽  
Coagulation Tests ◽  
Anticoagulated Patients

Abstract Background: The interfering effects of DOACs on the screening coagulation tests, such as prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen assay, have been shown mainly by in vitro spiking experiments. However, the effects of DOACs on coagulation tests in real-world samples from anticoagulated patients are unknown because of the difficulty in selectively eliminating DOAC from blood samples already containing DOACs. Method: Citrated blood samples were drawn from patients on anticoagulation therapy (rivaroxaban and edoxaban). In addition, blood samples from patients not on anticoagulation were collected. PT INR and APTT were measured from those samples by coagulometers from two manufacturers (Roche t711, Swiss and ACL-TOP, USA). We also measured DOAC levels from the same samples by anti-FXa activity (Hyphen Biomed, France). Then, we compared the test results in relation to the DOAC levels. Results: The PT INR, APTT, and fibrinogen assay results from non-anticoagulated patients measured by the two coagulometers were comparable (PT INR: y = -3.353 + 1.029 x; APTT: y = -6.276 + 1.101x; fibrinogen: y = -3.353 + 1.029 x; Passing Bablok). We included blood samples from 61 patients on rivaroxaban and 75 patients on edoxaban. From the rivaroxaban samples we observed the regression line change for PT INR (y = 0.6303 + 0.3712x) and for APTT (y = -10.71+1.358x). The comparability of fibrinogen assay was not affected significantly (y = -17.39+1.01x). From the edoxaban samples we also observed the similar change of the regression line (PT INR: y = 0.4728 + 0.5661x; APTT: y = -133.07+2.014x). Fibrinogen levels were comparable (y = -28.95+1.082x). Conclusion: The susceptibility of screening coagulation tests to the interfering effects of in vivo DOAC is dependent on the reagents and coagulometers. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Efficacy and Safety of Direct Oral Anticoagulants in Extremes Weights

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Julie Huang ◽  
Jamie Chin ◽  
Alexander Hindenburg ◽  
Lilia Davenport ◽  
Debra Willner
Keyword(s):  
Atrial Fibrillation ◽  
Atrial Flutter ◽  
Conflicts Of Interest ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Primary Endpoints ◽  
Design And Methods ◽  
Anticoagulated Patients

Background: The clinical use of Direct oral anticoagulants (DOACs), as opposed to warfarin, has become more prevalent in patients with extremes in body weight. However, both the International Society on Thrombosis and Haemostasis' (ISTH) and anti-thrombotic therapy guidelines state that DOACs should be avoided in patients with a body mass index (BMI) >40 kg/m2, weight >120 kg, or weight < 50 kg. The purpose of this study was to analyze the efficacy and safety of DOACs in extremes of weight compared to patients treated with warfarin. Warfarin may be a safer and more effective oral anticoagulant for patients in extremes of weight, due to the availability of dosing based on INR. DOAC standard dosing may either overdose/underdose in patients with low/high BMI respectively. Study Design and Methods: A retrospective, single-institution study evaluated patients with extreme weights receiving a DOAC or warfarin for either venous thromboembolism (VTE) or atrial fibrillation/atrial flutter between October 2016 and October 2020. Inclusion criteria consisted of patients admitted to NYU Langone Hospitals continued on a DOAC or warfarin for VTE or atrial fibrillation/atrial flutter with BMI < 18 kg/m2 or BMI > 30 kg/m2. Patients newly initiated on oral anticoagulation or received anticoagulation other than atrial fibrillation/atrial flutter or VTE were excluded. Primary endpoints include incidence of VTE or bleeding events in anticoagulated patients who meet extreme weight criteria. Disclosures No relevant conflicts of interest to declare.

scholarly journals FXa-α2-Macroglobulin Complex Neutralizes Direct Oral Anticoagulants Targeting FXa In Vitro and In Vivo

2018 ◽  
Vol 118 (09) ◽  
pp. 1535-1544 ◽  
Author(s):  
Georges Jourdi ◽  
Isabelle Gouin-Thibault ◽  
Virginie Siguret ◽  
Sophie Gandrille ◽  
Pascale Gaussem ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Rotational Thromboelastometry ◽  
Α2 Macroglobulin ◽  
Number Of Patients ◽  
Attractive Candidate

Increasing number of patients are treated with direct oral anticoagulants (DOAC). An antidote for dabigatran inhibiting thrombin (idarucizumab) is available but no antidote is yet approved for the factor Xa (FXa) inhibitors (xabans). We hypothesized that a complex between Gla-domainless FXa and α2-macroglobulin (GDFXa-α2M) may neutralize the xabans without interfering with normal blood coagulation.Purified α2M was incubated with GDFXa to form GDFXa-α2M. Affinity of apixaban and rivaroxaban for GDFXa-α2M was only slightly decreased compared to FXa. Efficacy and harmlessness of GDFXa-α2M were tested in vitro and in vivo. Stoichiometric excess of GDFXa-α2M neutralized rivaroxaban and apixaban as attested by clot waveform assay and rotational thromboelastometry, whereas GDFXa-α2M alone had no effect on these assays. Efficacy and pro-thrombotic potential of GDFXa-α2M were also assessed in vivo. Half-life of GDFXa-α2M in C57BL6 mice was 4.9 ± 1.1 minutes, but a 0.5 mg/mouse dose resulted in uptake saturation such that 50% persistence was still observed after 170 minutes. Single administration of GDFXa-α2M significantly decreased the rivaroxaban-induced bleeding time (p < 0.001) and blood loss (p < 0.01). GDFXa-α2M did not increase D-dimer or thrombin–antithrombin complex formation, suggesting a lack of pro-thrombotic potential.GDFXa-α2M is therefore an attractive candidate for xaban neutralization neither pro- nor anticoagulant in vitro as well as in vivo.

The effect of DOAC-Stop on lupus anticoagulant testing in plasma samples of venous thromboembolism patients receiving direct oral anticoagulants

2019 ◽  
Vol 57 (9) ◽  
pp. 1374-1381 ◽  
Author(s):  
Michał Ząbczyk ◽  
Magdalena Kopytek ◽  
Joanna Natorska ◽  
Anetta Undas
Keyword(s):  
Venous Thromboembolism ◽  
Screening Test ◽  
Lupus Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Activated Partial Thromboplastin Time ◽  
Clotting Time ◽  
The Impact ◽  
Anticoagulated Patients

Abstract Background Direct oral anticoagulants (DOACs) cause false positive lupus anticoagulant (LA) results. We assessed the impact of DOAC-Stop, reversing in vitro effects of DOACs, on LA testing in anticoagulated patients. Methods We assessed 75 venous thromboembolism patients aged 44.5±14.6 years. Blood samples were collected 2–28 h since intake of DOACs, including 50 patients on rivaroxaban, 20 on dabigatran and five on apixaban. LA testing was performed at baseline and after DOAC-Stop treatment. Positive LA was defined as the normalized (patient/standard plasma clotting time) LA screening and screening (LA1)/confirmation (LA2) ratios exceeding 1.2. Results LA diluted Russell’s viper venom time (dRVVT) normalized screening test revealed abnormal results in 73 (97.3%) and activated partial thromboplastin time (APTT)-LA in 49 (65.3%) patients. In six (8%) patients, antiphospholipid syndrome (APS) was diagnosed. dRVVT LA1/LA2 was abnormal in 35 (50.7%) patients taking DOACs. The APTT ratio was normal in all studied subjects. DOAC-Stop completely removed dabigatran and reduced by 98% rivaroxaban and by 92.3% apixaban concentrations (all p<0.05). After DOAC-Stop screening dRVVT remained prolonged in 34 (49.3%) patients (p<0.001), while dRVVT LA1/LA2 was abnormal in six (8.7%) subjects, with no association with DOAC concentrations at baseline and after DOAC-Stop. The APTT-LA screening test remained prolonged in five (7.2%) patients, while the APTT LA1/LA2 ratio was normal in those subjects. DOAC-Stop did not influence LA testing in APS patients. Conclusions Application of DOAC-Stop effectively reduced plasma DOAC concentrations leading to appropriate dRVVT results in up to 97% of VTE patients.

A Novel Polymer Based Antidote for Reversing the Anticoagulation Effect of Clinically Used Heparins,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3359-3359
Author(s):  
Rajesh A Shenoi ◽  
Benjamin F L Lai ◽  
Dirk Lange ◽  
Donald E Brooks ◽  
Ben Chew ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Complement Activation ◽  
Conflicts Of Interest ◽  
Dose Range ◽  
Anticoagulation Therapy ◽  
The Body ◽  
Bleeding Complications ◽  
Clinical Practices

Abstract Abstract 3359 Introduction Anticoagulation is one of the most widely used and essential clinical practices in modern medicine. Heparins are universally used for the prevention of blood coagulation in surgical procedures and for the treatment of diseases such as venous thromboembolism (VTE). Unfractionated heparin (UFH), low and ultra-low molecular weight heparins (LMWHs&ULMWHs) and synthetic pentasaccharides such as fondaparinux and idraparinux are the most commonly used clinical anticoagulants. Heparin is the second most widely used drug after insulin. However, it is associated with bleeding complications and heparin induced thrombocytopenia. Hence a careful monitoring and neutralization of heparins is essential. Protamine is the only clinically approved antidote to UFH, but it has several side effects and is not effective against LMWHs and synthetic pentasaccharides. Hence there is an unmet clinical need to develop safer and more efficient antidotes for all these anticoagulants. Here, we report a novel polymer based antidote, heparin binding synthetic polyvalent cationic macromolecule (HBSPCM), that completely neutralizes UFH and LMWHs in vitro and in vivo and is highly biocompatible and non-toxic in the required therapeutic dose range. Experimental HBSPCMs were synthesized by the polymerization of glycidol and methoxy polyethylene glycol and functionalized with multifunctional tertiary amines as binding groups. Blood compatibility of HBSPCM was evaluated by activated partial thromboplastin time (APTT), prothrombin time (PT), thromboelastography (TEG), platelet and complement activation assays. Cell viability of HBSPCM was evaluated in human umbilical vein endothelial cells and fibroblast cells. Single dose tolerability in mice was studied by injecting escalating doses of HBSPCM and monitoring the body weights over a period of 29 days. HBSPCMs were tested for in vitro heparin neutralization by measuring the APTT in human plasma. An anti-fXa assay was used to study the in vivo neutralization of heparins by HBSPCM in a rat model. Pharmacokinetics and biodistribution of 3H-labeled HBSPCM was studied by bolus i.v. injection in female Balb/c mice and measuring the radioactivity in major organs at different time points. Results and Discussion The newly designed antidotes, HBSPCMs, alone do not show any adverse effect on blood coagulation, platelet and complement activation and cytotoxicity that reveal their excellent blood and cell compatibilities. When injected in mice, HBSPCMs were well-tolerated up to the maximum injected dose of 200 mg/kg, which is ten-fold higher than the maximum tolerated dose of protamine (20 mg/kg) (Figure 1). HBSPCMs were 20-times more efficient than protamine for neutralizing heparins in vitro, and unlike protamine they do not show anticoagulant effect at higher concentrations. In vivo studies in rats revealed complete neutralization of both UFH and LMWHs by HBSPCMs, and the neutralization activities for LMWHs were significantly higher than that of protamine (Figure 2). HBSPCMs and their heparin complexes showed rapid clearance through urine, without significant accumulation in major organs. Conclusions and Significance In order to overcome the challenges associated with heparin based anticoagulation therapy, there is an increasing demand to develop safer, stable, effective, economical and universal antidotes which could neutralize all the available heparin anticoagulants. The developed polymer based antidote, HBSPCM, represents a major breakthrough towards this goal and could be a potential replacement for protamine. This polymer based therapeutic agent opens the scope for the development of non-toxic antidotes for all heparin based drugs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials

2019 ◽  
Vol 45 (05) ◽  
pp. 502-508 ◽  
Author(s):  
Emma P. DeLoughery ◽  
Sven R. Olson ◽  
Cristina Puy ◽  
Owen J. T. McCarty ◽  
Joseph J. Shatzel
Keyword(s):  
Monoclonal Antibody ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Coagulation Factor ◽  
Selective Inhibition ◽  
Factor Xii ◽  
Preclinical Data ◽  
Contact Pathway

AbstractAlthough anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

Anticoagulant Properties of Three Mucopolysaccharides Used in Rheumatology

1983 ◽  
Vol 50 (03) ◽  
pp. 652-655 ◽  
Author(s):  
F Bauer ◽  
P Schulz ◽  
G Reber ◽  
C A Bouvier
Keyword(s):  
Factor Xa ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Thrombin Time ◽  
Coagulation Tests ◽  
Amplification System ◽  
Relative Potencies ◽  
In Vivo Administration

SummaryThree mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor X a activity and the dilute thrombin time. One of the compounds, Arteparon®, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon® acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon® confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.

scholarly journals Development of a blood sample detector for multi-tracer positron emission tomography using gamma spectroscopy

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Carlos Velasco ◽  
Adriana Mota-Cobián ◽  
Jesús Mateo ◽  
Samuel España
Keyword(s):  
Positron Emission Tomography ◽  
Blood Sample ◽  
Pet Imaging ◽  
Spectroscopic Analysis ◽  
Gamma Spectroscopy ◽  
Emission Tomography ◽  
Blood Samples ◽  
Positron Emission

Abstract Background Multi-tracer positron emission tomography (PET) imaging can be accomplished by applying multi-tracer compartment modeling. Recently, a method has been proposed in which the arterial input functions (AIFs) of the multi-tracer PET scan are explicitly derived. For that purpose, a gamma spectroscopic analysis is performed on blood samples manually withdrawn from the patient when at least one of the co-injected tracers is based on a non-pure positron emitter. Alternatively, these blood samples required for the spectroscopic analysis may be obtained and analyzed on site by an automated detection device, thus minimizing analysis time and radiation exposure of the operating personnel. In this work, a new automated blood sample detector based on silicon photomultipliers (SiPMs) for single- and multi-tracer PET imaging is presented, characterized, and tested in vitro and in vivo. Results The detector presented in this work stores and analyzes on-the-fly single and coincidence detected events. A sensitivity of 22.6 cps/(kBq/mL) and 1.7 cps/(kBq/mL) was obtained for single and coincidence events respectively. An energy resolution of 35% full-width-half-maximum (FWHM) at 511 keV and a minimum detectable activity of 0.30 ± 0.08 kBq/mL in single mode were obtained. The in vivo AIFs obtained with the detector show an excellent Pearson’s correlation (r = 0.996, p < 0.0001) with the ones obtained from well counter analysis of discrete blood samples. Moreover, in vitro experiments demonstrate the capability of the detector to apply the gamma spectroscopic analysis on a mixture of 68Ga and 18F and separate the individual signal emitted from each one. Conclusions Characterization and in vivo evaluation under realistic experimental conditions showed that the detector proposed in this work offers excellent sensibility and stability. The device also showed to successfully separate individual signals emitted from a mixture of radioisotopes. Therefore, the blood sample detector presented in this study allows fully automatic AIFs measurements during single- and multi-tracer PET studies.

scholarly journals A Systematic Review of the Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation Patients with Diabetes Using a Risk Index

2021 ◽  
Vol 10 (13) ◽  
pp. 2924
Author(s):  
Domenico Acanfora ◽  
Marco Matteo Ciccone ◽  
Valentina Carlomagno ◽  
Pietro Scicchitano ◽  
Chiara Acanfora ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Risk Index ◽  
Direct Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Efficacy Rate ◽  
Cochrane Central Register ◽  
Efficacy And Safety

Diabetes mellitus (DM) represents an independent risk factor for chronic AF and is associated with unfavorable outcomes. We aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF), with and without diabetes mellitus (DM), using a new risk index (RI) defined as: RI =Rate of EventsRate of Patients at Risk. In particular, an RI lower than 1 suggests a favorable treatment effect. We searched MEDLINE, MEDLINE In-Process, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The risk index (RI) was calculated in terms of efficacy (rate of stroke/systemic embolism (stroke SEE)/rate of patients with and without DM; rate of cardiovascular death/rate of patients with and without DM) and safety (rate of major bleeding/rate of patients with and without DM) outcomes. AF patients with DM (n = 22,057) and 49,596 without DM were considered from pivotal trials. DM doubles the risk index for stroke/SEE, major bleeding (MB), and cardiovascular (CV) death. The RI for stroke/SEE, MB, and CV death was comparable in patients treated with warfarin or DOACs. The lowest RI was in DM patients treated with Rivaroxaban (stroke/SEE, RI = 0.08; CV death, RI = 0.13). The RIs for bleeding were higher in DM patients treated with Dabigatran (RI110 = 0.32; RI150 = 0.40). Our study is the first to use RI to homogenize the efficacy and safety data reported in the DOACs pivotal studies against warfarin in patients with and without DM. Anticoagulation therapy is effective and safe in DM patients. DOACs appear to have a better efficacy and safety profile than warfarin. The use of DOACs is a reasonable alternative to vitamin-K antagonists in AF patients with DM. The RI can be a reasonable tool to help clinicians choose between DOACs or warfarin in the peculiar set of AF patients with DM.

Research Trends in Anticoagulation Therapy over the Last 25 Years

2020 ◽  
Vol 46 (08) ◽  
pp. 919-931
Author(s):  
Mustafa K. Mian ◽  
Subhashaan Sreedharan ◽  
Neeraj S. Limaye ◽  
Chris Hogan ◽  
Jai N. Darvall
Keyword(s):  
Conflicts Of Interest ◽  
Relative Rate ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Citation Count ◽  
Anticoagulation Therapy ◽  
Journal Title ◽  
Common Source ◽  
Level I ◽  
High Level

AbstractA large volume of literature has become available to practitioners prescribing anticoagulants. The aim of this study was to analyze the bibliometric characteristics of the top 100 most cited articles related to anticoagulation over the past 25 years, with special consideration to impact of direct or “nonvitamin K antagonist” oral anticoagulants (NOACs) compared with vitamin K antagonists. A bibliometric analysis of the 100 most cited journal articles related to anticoagulants published between 1994 and 2019 was performed in April 2019. The top 100 articles by citation count were analyzed to extract bibliometric data related to journal title, impact factor, year of publication, place of publication, anticoagulant studied, indication for anticoagulation, study design, and conflicts of interest. The median (interquartile range) number of citations per article was 806 (621–1,085). The anticoagulant most frequently researched was warfarin (37%). NOAC publications (21%) grew at a relative rate of 3.4 times faster compared with all publications. The indication most commonly researched was venous thromboembolism (26%). Eighty articles constituted level I or II evidence, with randomized controlled trials the most common type of study (74). A financial conflict of interest was declared in 87% of articles with private, for-profit organizations the most common source of funding (26%). In summary, top research related to anticoagulation is highly impactful but may be at risk of sponsorship bias. High-level evidence for NOACs continues to expand across a range of indications with citation metrics likely to soon approach or surpass that of older drugs.

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