Synthetic Anti-Xa Drugs Can Be Used for Parenteral Anticoagulation but Not Fondaparinux.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4088-4088
Author(s):  
Omer Iqbal ◽  
Debra Hoppensteadt ◽  
Daniel Fareed ◽  
Jawed Fareed
Keyword(s):  
Large Scale ◽  
Factor Xa ◽  
The United States ◽  
Final Concentration ◽  
Anticoagulant Effect ◽  
Factor Xa Inhibitors ◽  
Vein Thrombosis ◽  
Prothrombinase Complex ◽  
United States Food ◽  
Important Approach

Abstract Targeting at the level of factor Xa and/or prothrombinase complex by synthetic anti-Xa agents such as JTV-803 (Akros Pharma, Princeton, NJ), DX-9065a (Daiichi Pharmaceuticals, Tokyo, Japan), and Fondaparinux (Sanofi-Synthelabo, Toulouse, France) represents an important approach in anticoagulant therapy. Factor Xa is an essential component of the prothrombinase complex and leads to the generation of thrombin. Synthetic heparin pentasaccharide, Fondaparinux (Arixtra®) has been approved by the United States Food and Drug Administration for the prophylaxis of deep vein thrombosis in patients undergoing hip and knee replacement surgeries. There is a rapid stride in the development of newer synthetic inhibitors of factor Xa such as DX-9065a, and JTV-803 in various thrombotic indications. In order to evaluate the parenteral anticoagulant potential of these synthetic factor Xa inhibitors, we used the Hemochron (celite) activated clotting time (ACT) assay. DX-9065a at a final concentration of 5 and 10 μg/ml increased the ACTs to 250 and 300 seconds, respectively. Similar anticoagulant potential was noticed with JTV-803. These findings suggest that these agents may be useful as parenteral anticoagulants during interventional cardiologic procedures, surgical anticoagulation and for the prevention of vascular access occlusion. Fondaparinux requiring antithrombin (AT) for its anticoagulant effect does not increase the celite ACT to the extent as other synthetic factor Xa inhibitors. Fondaparinux even at a final concentration of 100 μg/ml increase the ACT to about 200 seconds and hence are not suitable to be used as parenteral anticoagulants. The concentrations of JTV-803, DX-9065a and fondaparinux required to increase the ACT to near 250 seconds are 6.2, 5 and 125 μg/ml, respectively. While fondaparinux is AT-dependent, the synthetic anti-Xa agents are AT-independent in their actions. The antithrombin sparing effect of direct anti-Xa agents may contribute to an additional anticoagulant effect as reflected by increased ACT levels. Furthermore, there are some other advantages of direct anti-Xa agents when compared to fondaparinux. While direct anti-Xa agents may be used for patients with AT deficiency, fondaparinux being AT-dependent, may not. The inhibition of the clot-bound and prothrombinase-bound factor Xa are additional advantages of direct Xa inhibitors when compared to fondaparinux. Fondaparinux being AT-dependent and upon complexation with AT is not capable of inhibiting the clot-bound factor Xa. Oral Xa inhibitors are being developed and when available patients may have an ideal transition from a parenteral anti-Xa agent to an oral Xa inhibitor. The results clearly suggest that synthetic factor Xa inhibitors except fondaparinux may be used as parenteral anticoagulants. Large-scale clinical studies are warranted to evaluate these findings.

scholarly journals Difficult Intraoperative Heparinization Following Andexanet Alfa Administration

2019 ◽  
Vol 3 (4) ◽  
pp. 390-394 ◽  
Author(s):  
C. James Watson ◽  
Sara Zettervall ◽  
Matthew Hall ◽  
Michael Ganetsky
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Hemodynamic Instability ◽  
The United States ◽  
Major Hemorrhage ◽  
Reversal Agents ◽  
Abdominal Aortic ◽  
United States Food ◽  
Andexanet Alfa

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement. Consideration should be given to the risks and benefits of AnXa administration in patients who require anticoagulation after hemorrhage has been controlled.

Factor Xa Inhibitors Can Be Differentiated in Xa, IIa and Microparticle Generation and Other Whole Blood Based Assays.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 931-931 ◽  
Author(s):  
Omer Iqbal ◽  
Cafer Adiguzel ◽  
Debra Hoppensteadt ◽  
Josephine Cunannan ◽  
Jawed Fareed
Keyword(s):  
Tissue Factor ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Final Concentration ◽  
Factor Xa Inhibitors ◽  
Saline Control ◽  
Functional Assay ◽  
Control Value ◽  
Anticoagulant Agents

Abstract Currently used oral anticoagulants such as Vitamin K antagonists have drawbacks, which reportedly limit their safety and efficacy. Oral Factor Xa and IIa inhibitors are claimed to overcome these limitations. Factor Xa inhibitors provide more complete suppression of thrombin generation than Factor IIa inhibitors. Four Factor Xa anticoagulant agents, both direct and indirect, namely A,B,C and D with Ki values 6–200 nM, were studied in various assays at equigravimetric final concentration of 10 ug/ml to determine their relative potencies. Apparent differences in their biochemical profiles were noted in thrombin generation, Factor Xa generation and microparticle generation inhibition assays. Furthermore, the anticoagulant potential of these Xa inhibitors was studied in celite activated clotting time (ACT) and modified celite ACT system using different concentrations of tissue factor. Microparticle generation was performed using agent- supplemented whole blood that was incubated for three minutes with varying concentrations of tissue factor. Following three minutes the reaction was stopped using EDTA stop solution. The functional assay for the determination of microparticle procoagulant activity in the plasma was performed using Zymuphen MP-Activity assay kit from Hyphen BioMed (Neuville-sur-Oise, France). While three of the Xa inhibitors studied showed microparticle generation inhibition levels of 31.37 nM, one agent provided a level of 17.87 nM compared to a saline control value of 39.28nM. Supplementation studies were also carried out in whole blood PT, APTT and Heptest assays in the concentration range of 0 to 10 ug/ml. The whole blood prothrombin time assay showed a maximum of 208.8, 61.3, 77.8 and 15.9 seconds at a final concentration of 10 ug/ml for the respective anticoagulant agents when compared to a normal value of 12.3 seconds. Similarly the whole blood APTT assay showed a maximum of 267.9, 161.8, >300 and 71.9 seconds respectively when compared to a control value of 46.8 seconds. The whole blood Heptest assay showed a varying maximum anticoagulant effect from >300, 42.7, >300 and >300 seconds respectively when compared to a control value of 13.8 seconds. In each of these assays Factor Xa inhibitors showed concentration-dependent effects and had varying potencies. In TF-mediated platelet activation assays the different Xa agents produced varying effects which were not proportionate to their Ki values. Differentiation of Factor Xa inhibitors have a clinical impact in dosage selection, dosage adjustment and their monitoring when given in large dosages. Synthetic factor Xa agents exhibit Ki values of 20–200 nM, while pentasaccharide -AT complex has a Ki value of 60 nM. However, these results do not translate into proportionate anticoagulant effects to their Ki values. Large-scale clinical studies are necessary to validate these preliminary results.

Prothrombin Complex Concentrate Reverses the Anticoagulant Effect of Rivaroxaban In Healthy Volunteers.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1094-1094 ◽  
Author(s):  
Elise S Eerenberg ◽  
Meertien K Sijpkens ◽  
Pieter W Kamphuisen ◽  
Joost CM Meijers ◽  
Marcel Levi
Keyword(s):  
Research Funding ◽  
Prothrombin Complex Concentrate ◽  
Controlled Trial ◽  
Factor Xa ◽  
Anticoagulant Effect ◽  
Factor Xa Inhibitors ◽  
Specific Factor ◽  
Antithrombotic Agent ◽  
Double Blind ◽  
Pharmacodynamic Profile

Abstract Abstract 1094 Background: Rivaroxaban is a novel oral antithrombotic agent in the class of specific factor Xa inhibitors, and is licensed in Europe and Canada for the prevention of venous thromboembolism after elective orthopedic surgery. Despite its stable pharmacokinetic and pharmacodynamic profile, immediate reversal may be required in case of a major bleeding or emergency surgery. No specific antidote is currently available, although Prothrombin Complex Concentrate (PCC) seems effective in animal studies. This study is the first to investigate the ability of PCC to reverse the antithrombotic effect of Rivaroxaban in humans. Methods: In a randomized, double-blind, placebo-controlled trial, twelve healthy male subjects received Rivaroxaban 20mg twice daily for two and a half days. One group (n=6) was then randomized to receive a single bolus of 50 IU/kg PCC (Co-fact®, Sanquin, the Netherlands) while the other group (n=6) was given a similar volume of saline. Results: The prothrombin time (PT) was significantly prolonged by Rivaroxaban (15.8 sec ± 1.3 versus 12.3 ± 0.7 at baseline; p< 0.001). Immediately after the infusion of PCC, the PT normalised almost completely (12.8 ± 1.0; p< 0.001), which was sustained for 24 hours. Saline did not reverse the PT prolongation (16.2 ± 0.8; p= 0.4). Furthermore, Rivaroxaban inhibited the endogenous thrombin potential (ETP) (51% ± 22, baseline 92 ± 22; p= 0.002), with normalisation after administration of PCC (114 ± 26; p< 0.001), but not after saline (41 ± 6; p= 0.2). Conclusions: This study provides the first data that Prothrombin Complex Concentrate reverses the anticoagulant effect of Rivaroxaban in humans and may serve as an antidote for the new oral factor Xa inhibitors. Disclosures: Eerenberg: Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Kamphuisen:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Levi:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study.

Management consensus guidance for the use of rivaroxaban – an oral, direct factor Xa inhibitor

2012 ◽  
Vol 108 (11) ◽  
pp. 876-886 ◽  
Author(s):  
Reinhold Kreutz ◽  
Juan Llau ◽  
Bo Norrving ◽  
Sylvia Haas ◽  
Alexander Turpie
Keyword(s):  
Venous Thromboembolism ◽  
Large Scale ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Clinical Trial Data ◽  
Thrombin Inhibitor ◽  
Direct Factor ◽  
Replacement Surgery ◽  
Vein Thrombosis

SummaryA number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate (a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors’ experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors’ clinical experience.

Inhibition of Prothrombinase and Not Soluble Factor Xa (fXa) Predicts Efficacy of fXa Inhibitors in an In Vivo Model of Deep Vein Thrombosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 902-902
Author(s):  
Suzanne Delaney ◽  
Ann Arfsten ◽  
Sherin Halfon ◽  
Gail Siu ◽  
John Malinowski ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Vein Thrombosis ◽  
Prothrombinase Complex ◽  
Antithrombotic Efficacy ◽  
Deep Vein

Abstract Factor Xa (fXa) inhibitors are being tested in the clinic for the prevention and treatment of deep vein thrombosis (DVT) following orthopedic surgery. The antithrombotic efficacy of these drug candidates has traditionally been established in animal models as it is not known whether fXa amidolytic activity, activated partial thromboplastin time (aPTT) or prothrombin time (PT) predict efficacious doses. The present study was designed to test the hypothesis that the potency of fXa inhibitors against fXa incorporated into the prothrombinase complex would predict in vivo antithrombotic efficacy. Eight fXa inhibitors from four structurally distinct chemical series with a range of activities against fXa were tested for their ability to inhibit the prothrombinase complex in human plasma. Thrombin generation and subsequent cleavage of a specific thrombin substrate was used as a measure of prothrombinase activity, inhibitory activity being defined by the concentration of inhibitor required to produce a 2-fold extension in the time to maximal thrombin production (2x lag). In vitro rabbit PTs were also determined. Inhibition in the rabbit DVT model was assessed as previously described (Thromb Haemost1994; 71:357) and related to plasma concentrations of drug. Agent fXa IC50 (nM) Prothrombinase 2x lag (μM) Plasma concentration in DVT (μM) Thrombosis inhibition (%) Rabbit PT 2x change (μM) PRT50034 0.5 0.18 0.06 94 7.0 PRT54681 1.3 0.22 1.14 37 2.7 PRT54676 0.7 0.24 1.65 47 1.7 PRT54004 0.4 0.25 1.04 47 1.0 PRT54456 0.8 0.34 3.39 41 1.5 PRT56848 4.4 0.92 5.2 11 4.7 PRT54955 3.5 1.35 4.6 19 8.8 PRT57106 8.2 1.66 9.2 0 64 All compounds inhibited soluble fXa by 50 % at concentrations less than 10 nM. However, the rank order of potencies for inhibition of soluble fXa differed from that required to inhibit the prothrombinase complex. There was also poor correlation between the 2x lag value for prothrombinase inhibition and the concentration required to achieve a 2x change in rabbit PT (r2 = 0.57). Neither the activities of fXa inhibition nor the change in rabbit PT predicted activity in the DVT model. In contrast, compounds could be broadly divided into 3 levels of efficacy for inhibition of in vivo thrombus growth depending on their potency in the in vitro prothrombinase assay. PRT50034 had the lowest 2x lag value of 0.18 μM and was the most potent inhibitor of in vivo thrombosis with 94 % inhibition at a plasma concentration of 65 nM. The second group of compounds, with 2x lag values in the prothrombinase assay ranging from 0.22 to 0.34 μM, inhibited in vivo thrombus formation by 37 to 47 % at plasma concentrations ranging from 1.04 to 3.39 μM. Compounds in the third category were the least potent prothrombinase inhibitors (2x lag values greater than 0.92 μM) and were unable to significantly inhibit in vivo thrombosis even at plasma concentrations of 9.2 μM. These data show that the 2x lag value obtained in the prothrombinase assay, and not inhibition of soluble fXa or extension of rabbit PT, is capable of predicting fXa inhibitor efficacy in the in vivo rabbit DVT model.

National Healthcare Utilization Trends for Deep Vein Thrombosis in the United States.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3183-3183
Author(s):  
Prabhu Viswanathan ◽  
Upasna Goswami ◽  
Lakshmanan Krishnamurti
Keyword(s):  
Large Scale ◽  
The United States ◽  
Primary Diagnosis ◽  
Care Utilization ◽  
P Value ◽  
Upward Trend ◽  
Low Molecular Weight Heparins ◽  
Vein Thrombosis ◽  
Rate Of Increase ◽  
Deep Vein

Abstract Abstract 3183 Poster Board III-120 Background Over the past 15 years, increased awareness and advances in management such as the widespread adoption of low molecular weight heparins and new anticoagulants have had a dramatic impact on practice; there are no large scale studies to determine the impact of these changes on the health care utilization and outcomes of DVT. We examined national statistics of the trends in hospital utilization for Deep Vein Thrombosis in the United States. Methods The Nationwide Inpatient Sample (NIS) is one in a family of databases and software tools developed as part of the Healthcare Cost and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality. For 2007 NIS contains all discharge data from 1,044 hospitals located in 40 States, approximating a 20-percent stratified sample of U.S. community hospitals. We examined trends for hospital utilization available through the NIS dataset. All descriptive statistics have been reported for DVT as ‘primary discharge diagnosis’ as well as ‘All discharge diagnoses’. Presence of ICD-9-CM diagnosis codes 453.0-453.9 were used to define DVT related hospitalizations. Results From 1993 to 2007 the number of annual diagnosis of DVT as one of “All Diagnoses' of DVT annually increased from 224,739 to 526,105 while the number of DVT as ‘Principal Diagnosis’ increased from 110,445 to 146,612. The average length of hospital stay has decreased from 7.6 days to 5 days (p-value <0.01). The average annual proportion of in-hospital deaths from DVT decreased during his period from 1.6% vs. 0.8% (p-value <0.01). FIG 1 For DVT as one of all diagnoses, the trends show a polynomial upward trend and the rate of increase is increasing every year (p value using T Test: 0.007). For annual number of discharges with DVT as primary diagnosis, there is a polynomial upward trend, with an index less than 1 and the curve is flattening out and the rate of increase is decreasing year over year (p value using T Test=0.0028). These findings suggest that the increase in DVT as primary diagnosis is not keeping pace with rapid increase in DVT as one of all diagnosis. For DVT as primary diagnosis, mortality rate was 1.6% and 0.3% respectively among those who underwent a procedure vs. those who did not undergo a procedure. Mortality for DVT as one of all diagnoses was 8.9% and 3.3% respectively among those who underwent a procedure vs. those did not undergo a procedure. Notably, a death in patients with DVT as one of all diagnosis was attributed to a variety of diagnoses, such as malignancies, infections and complications of implantation device. Rate of postoperative pulmonary embolism or thrombosis per 1000 surgical patients age 18 and over as a marker of Hospital-level Patient Safety Indicators age 18 and over adjusted for age, gender, comorbidities and DRG clusters, has increased from 6.3 in 1994 to 11.2 in 2006 FIG 2. From 1997 to 2006, the proportion of male patients increased from 43.1% to 45% while female patients decreased from 57% to 54.9%. (p-value <0.01) For the year 2007, with DVT as the primary or one of all diagnoses, OR procedures on vessels other than head and neck is the main principal procedure. DVT of extremities as primary diagnosis is associated with hypertension and hyperlipidemia as most important secondary diagnoses and for all DVT of the extremities as secondary diagnosis the most common primary diagnosis is pulmonary heart disease. Conclusions Survival for patients with DVT has improved and patients are likely to be discharged from acute care hospital earlier. We speculate that this could be the result of improved diagnosis and management including the use of low molecular weight heparins. Some of the changes in annual incidence may be attributed to earlier diagnosis and changes in ICD coding. However, the sustained increase in annual incidences of DVT as a secondary diagnosis and that of postoperative pulmonary embolism and thrombosis is a cause for concern and should prompt a review of strategies to prevent DVT among sick hospitalized patients. These data are subject to the well known limitations of administrative datasets, and underscore the need for large scale prospective study of the factors contributing to health care utilization and outcomes of DVT. Disclosures No relevant conflicts of interest to declare.

Laboratory assessment of the compliance to direct oral anticoagulants

2021 ◽  
Author(s):  
Н.А. Воробьева ◽  
Е.Ю. Мельничук ◽  
А.И. Воробьева
Keyword(s):  
Antithrombotic Therapy ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Direct Factor ◽  
Laboratory Assessment ◽  
Vein Thrombosis ◽  
Direct Factor Xa Inhibitors ◽  
Deep Vein

Введение. Для пролонгированной профилактики тромбозов после операций, при фибрилляции предсердий, терапии тромбозов глубоких вен и/или тромбоэмболии легочной артерии широко используются прямые пероральные антикоагулянтные препараты (ПОАК). Считается, что ПОАК лишены недостатков, присущих антагонистам витамина К (АВК) и обладают предсказуемыми фармакокинетическими и фармакодинамическими эффектами и следовательно не требуют рутинного лабораторного контроля для коррекции и подбора дозы препарата. Отдельного внимания, на наш взгляд, заслуживает вопрос приверженности к терапии ПОАК. Цель исследования: оценка приверженности к терапии прямыми пероральными ингибиторами фактора Ха путем определения концентрации ПОАК в плазме крови пациентов. Материалы и методы. Выполнено проспективное клинико-лабораторное исследование, включены 50 пациентов с продленной антитромботической терапией ПОАК. Для оценки приверженности к терапии проведено определение пиковой концентрации прямых ингибиторов фактора Ха хромогенным методом. Результаты. До 10% пациентов в реальной клинической практике не принимали назначенную антитромботическую терапию и скрыли этот факт от врача. Таким образом, с помощью определения концентрации прямых ингибиторов фактора Ха хромогенным методом можно выявить отсутствие приверженности к терапии ПОАК. Заключение. Для определения приверженности к антикоагулянтной терапии прямыми ингибиторами фактора Ха возможно использование метода оценки концентрации ПОАК в плазме крови, что позволяет оценить приверженность пациента к данному виду терапии и, как следствие, эффективность и безопасность продленной антитромботической терапии. Background. For prolonged prophylaxis of thrombosis after surgery, of atrial fibrillation, therapy of deep vein thrombosis and/or pulmonary embolism, direct oral anticoagulants (DOACs) are widely used. It is believed that DOACs lack the deficiencies inherent in antagonists of vitamin K (AVK), have predictable pharmacokinetic and pharmacodynamic effects, and therefore do notrequire routine laboratory monitoring to adjust and select the dose of the drug. We pay special attention to the issue of adherence to DOACs therapy. Objectives: to assess compliance to therapy with direct oral factor Xa inhibitors by determining plasma DOACs concentration. Patients/Methods. A prospective clinical and laboratory study was performed, 50 patients with prolonged antithrombotic therapy by DOACs were included. To assess compliance to therapy, the peak concentration of direct factor Xa inhibitors was determined by the chromogenic method. Results. In real clinical practice up to 10% of patients did not take the prescribed antithrombotic therapy and hid this fact from the doctor. Thus, by determining the concentration of direct factor Xa inhibitors by the chromogenic method, it is possible to identify a lack of compliance to therapy. Conclusions. Determination of plasma DOACs concentration allows assessing the patient’s adherence to anticoagulant therapy with direct factor Xa inhibitors and the efficacy and safety of prolonged antithrombotic therapy.

Different Characteristics of Direct Factor Xa Inhibitors: In Vitro Comparative Studies of Rivaroxaban and Apixaban.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4170-4170 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Adrian Tersteegen ◽  
Michaela Harwardt ◽  
Uwe Lange
Keyword(s):  
Platelet Aggregation ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Direct Factor ◽  
Clotting Time ◽  
Prothrombinase Complex ◽  
Direct Factor Xa Inhibitors ◽  
Ic50 Values ◽  
Antithrombotic Efficacy

Abstract Abstract 4170 Introduction Rivaroxaban and apixaban are selective, reversible but structurally different direct Factor Xa inhibitors that are in late-stage clinical development for the prevention and treatment of venous and arterial thrombosis. Studies in animal models demonstrated antithrombotic efficacy with these new agents (Perzborn E et al. J Thromb Haemost 2005;3:514–521; Wong PC et al. J Thromb Haemost 2008;6:820–829). The objective of this study was to characterize and compare in vitro rivaroxaban and apixaban in functional assays. Methods Factor Xa activity, rate constants (kon/koff), and prothrombinase activity were measured using purified Factor Xa and measuring the cleavage of chromogenic (Factor Xa), fluorogenic substrates (kon/koff), or using prothrombin as a substrate in a reconstituted prothrombinase complex and measuring the activity of the generated thrombin in the presence of a thrombin-specific chromogenic substrate. Clotting times and thrombin generation (TG) were measured using commercially available kits. Tissue factor (TF)-mediated platelet aggregation was measured in defibrinated plasma. Results Rivaroxaban and apixaban showed similar affinity for free Factor Xa (Ki 0.4 and 0.6 nM, respectively), comparable association (kon 1.7 × 107 M–1 s–1 and 0.88 × 107 M–1 s–1, respectively) and dissociation (koff 5 × 10–3 s–1 and 2.4 × 10–3 s–1, respectively) rates, and inhibition of prothrombinase-bound Factor Xa (2.1 nM and 2.7 nM, respectively; Table). However, in human plasma-based systems, the 2 agents showed different potency. Despite the reported comparable plasma protein binding for apixaban and rivaroxaban (87% and 92–95%, respectively), higher concentrations of apixaban were needed to inhibit TG and TF-mediated platelet aggregation, and to prolong clotting time, compared with rivaroxaban. The concentrations needed to double clotting times, such as prothrombin time, activated partial thromboplastin time, clotting times in thromboelastometric measurements triggered either by the extrinsic (ex-TEM®) or intrinsic (in-TEM®) coagulation pathway, and prothrombinase-induced clotting time, were 3- to 8-fold higher for apixaban than for rivaroxaban (Table). The IC50 values for reducing the peak TG and endogenous thrombin potential in the TG assay were 3-fold higher for apixaban (0.20 and 4.96 μM, respectively) compared with rivaroxaban (0.06 and 1.48 μM, respectively; Table). The IC50 values for inhibiting TF-mediated platelet aggregation were 8-fold higher for apixaban (0.51 μM) versus rivaroxaban (0.06 μM; Table). Conclusions These results demonstrate that structurally different Factor Xa inhibitors may differ in their antihemostatic potency in spite of comparable affinity to Factor Xa, and suggest that rivaroxaban may be a more potent anticoagulant and indirect inhibitor of platelet aggregation than apixaban. Disclosures: Perzborn: Bayer Schering Pharma AG: Employment. Tersteegen:Bayer Schering Pharma AG: Employment. Harwardt:Bayer Schering Pharma AG: Employment. Lange:Bayer Schering Pharma AG: Employment.

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