scholarly journals Effects of a Synthetic Factor Xa Inhibitor (JTV-803) on Various Laboratory Tests

2002 ◽  
Vol 8 (4) ◽  
pp. 325-336 ◽  
Author(s):  
Mahmut Tobu ◽  
Omer Iqbal ◽  
Debra A. Hoppensteadt ◽  
Christopher Shultz ◽  
Walter Jeske ◽  
...  
Keyword(s):  
Oral Anticoagulant ◽  
Laboratory Tests ◽  
Factor Xa ◽  
International Normalized Ratio ◽  
Factor Xa Inhibitors ◽  
Rabbit Brain ◽  
Factor Xa Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Direct Inhibitors

Synthetic direct inhibitors of factor Xa are capable of prolonging the global anticoagulant assay times in a concentration-dependent fashion. The relative degree of thrombin generation inhibition at an equivalent prolongation is not similar to the results observed with heparins and oral anticoagulant drugs. In addition, the direct factor Xa inhibitors prolong the Russell' viper venom test (RVVT) and Heptest clotting times. Ecarin clotting time (ECT) and thrombin time (TT) remain unaffected. The kinetics of factor Xa inhibition are markedly different than those observed with pentasac-charide and heparins. Therefore, the methods developed for heparins and pentasaccharides may not be applicable for the monitoring of factor Xa inhibitors. To test the feasibility of using the prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), Heptest, thrombin time, RVVT, ECT, and a modified anti-Xa amidolytic assay, to monitor a synthetic factor Xa inhibitor, normal human pool plasma samples were spiked with a synthetic factor Xa inhibitor in the concentration range of 0 to 1 μg/mL and 0 to 25 μg/mL. Different laboratory tests were performed and INR and other ratios were calculated. The anticoagulant effects on whole blood were measured using the activated clotting time (ACT). Further studies on the effect of factor Xa inhibitor on platelet aggregation; factor II, VII, and X functional levels; and fibrinopeptide A (FPA) generation were carried out at equivalent INR levels in comparison to oral anticoagulant and antithrombin agents. FPA generation at equivalent anticoagulant level in comparison to heparin (twice the baseline) was also carried out. Factor Xa inhibitor produced a concentration-dependent prolongation of the ACT. ACT was doubled at a concentration of 4 to 5 μg/mL. There was a marked difference in the prolongation of the PT by a synthetic factor Xa inhibitor dependent on the ISI of the PT reagent used. When the results were calculated to determine INR, marked variations were noted between the recombinant thromboplastin and rabbit brain thromboplastin. The rabbit brain thromboplastin reagent gave markedly high INR values. Similar results were observed when different aPTT reagents were studied. In the anti-Xa assay, modification of the incubation time was employed to extend the proper sensitivity range. These studies warrant further investigation to understand the mechanism of action of factor Xa inhibitors.

Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

1990 ◽  
Vol 63 (02) ◽  
pp. 220-223 ◽  
Author(s):  
J Hauptmann ◽  
B Kaiser ◽  
G Nowak ◽  
J Stürzebecher ◽  
F Markwardt
Keyword(s):  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Clotting Time ◽  
Thrombosis Model ◽  
Activity Factor ◽  
Antithrombotic Effects

SummaryThe anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosageThe results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

scholarly journals Concurrent Treatment of VEGFR Tyrosine Kinase Inhibitors (TKIs) and Factor Xa Inhibitors Is Associated with Increased Bleeding Risks

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3681-3681
Author(s):  
Sandip Patel ◽  
Tiffany George ◽  
Tzu-Fei Wang ◽  
Sherry Mori Vogt ◽  
Edmund Folefac ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Metastatic Cancer ◽  
Bleeding Event ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Factor Xa Inhibitor ◽  
Bleeding Events ◽  
Concurrent Treatment ◽  
Clinically Significant

ABSTRACT Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P < 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.

A Comparison of Anticoagulation Activity of a Potent Heparin Preparation in Different Test

1979 ◽  
Author(s):  
A.S. Bhargava ◽  
J. Heinick ◽  
Chr. Schöbel ◽  
P. Günzel
Keyword(s):  
Blood Clotting ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Thrombin Time ◽  
Beagle Dogs ◽  
Clotting Time ◽  
Relative Potencies ◽  
Heparin Preparation

The anticoagulant effect of a new potent heparin preparation was compared with a commercially available heparin in vivo after intravenous application in beagle dogs. The anticoagulant activity was determined using thrombin time, activated partial thromboplastin time and whole blood clotting time after 5, 10 and 30 minutes of application. The relative potency of the new heparin preparation (Scherinq) was found to be 1.62 to 2.52 times higher than heparin used for comparison (150 USP units/mg, Dio-synth). The anticoagulant properties of both preparations were also studied in vitro using dog and human plasma. The relative potencies in vitro correlated well with those obtained in vivo. Further characterization with amidolytic method using chromogenic substrate for factor Xa and thrombin (S-2222 and S-2238 from KABI, Stockholm) showed that heparin (Schering) contains 243 to 378 USP units/raq depending upon the test systems used to assay the anticoagulation activity and in addition, proves the validity of the amidolytic method.

Effects of the Novel, Oral, Direct Factor Xa Inhibitor Rivaroxaban on Coagulation Assays

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3028-3028
Author(s):  
Meyer Michel Samama ◽  
Lena Le Flem ◽  
Celine Guinet ◽  
Elisabeth Perzborn ◽  
Jean-Luc Martinoli ◽  
...  
Keyword(s):  
Factor Xa ◽  
International Normalized Ratio ◽  
Peak Effect ◽  
Direct Factor ◽  
Clotting Time ◽  
Paradoxical Response ◽  
Low Concentrations ◽  
One Step ◽  
Standard Calibration

Abstract Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor that has been recommended for approval by the Committee for Medicinal Products for Human Use for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for the prevention and treatment of thromboembolic disorders. There is no need for routine laboratory monitoring with rivaroxaban. However, a hemostasis assay might be valuable to measure the pharmacodynamic (PD) effects of rivaroxaban in special situations. The aim of this study was to identify a widely available assay (clotting assay, or colorimetric or fluorometric assay) that could be used in clinical practice. Increasing concentrations of rivaroxaban were spiked into citrated pooled human platelet-poor plasma. The global clotting assays prothrombin time (PT), diluted PT (dPT), and activated partial thromboplastin time (aPTT) were compared, as well as the specific clotting assays HepTest® (heparin test), prothrombinase-induced clotting time (PiCT®), and diluted Russell’s viper venom time (dRVVT). In addition, the anti-FXa activity-based colorimetric assays STA Rotachrom® and Stachrom® and thrombin generation test (TGT) were measured. A concentration-dependent prolongation of PT, dPT, and aPTT was observed with rivaroxaban, although the results varied depending on the reagents used. When testing PT over time using frozen plasma spiked with defined concentrations of rivaroxaban, PT values did not change during storage. Using a standard calibration curve, the results of the PT test can be expressed in rivaroxaban (ng/mL) rather than as PT ratio or international normalized ratio (INR). A concentration-dependent prolongation of the clotting time was also observed with dPT, a test that may be clinically more significant than conventional PT because it is closer to in vivo conditions (i.e. it uses lower tissue factor concentrations). Conventional methods for the HepTest and two-step PiCT (incubation times of 120 seconds and 180 seconds, respectively) resulted in a paradoxical response, with low concentrations of rivaroxaban reducing clotting times. This paradoxical response was not observed with shorter incubation times (0 or 30 seconds for one-step PiCT and 30 seconds for HepTest), or when antithrombin-immunodepleted plasma was used. Rivaroxaban also increased the dRVVT concentration dependently. Rivaroxaban influenced the various parameters of the TGT concentration dependently; peak effect was the most informative parameter. Rivaroxaban concentration-dependently inhibited FXa activity in both the Rotachrom and Stachrom assays– the results were expressed as anti-FXa international unit/mL. PT assays, which are widely used, appear to be valuable assays for monitoring the PD effects of rivaroxaban. One-step PiCT and HepTest with shortened incubation times or anti-FXa assays could also be useful to monitor rivaroxaban, if standardized methods were used.

Impact of Apixaban On a Large Panel of Routine or More Specific Coagulation Assays.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2275-2275
Author(s):  
Jonathan Douxfils ◽  
François Mullier ◽  
Christian Chatelain ◽  
Bernard Chatelain ◽  
Dogné Jean-Michel
Keyword(s):  
Atrial Fibrillation ◽  
Drug Concentration ◽  
Partial Thromboplastin Time ◽  
Factor Xa ◽  
Activated Partial Thromboplastin Time ◽  
Plasma Drug Concentration ◽  
Thrombin Time ◽  
Plasma Drug ◽  
Clotting Time

Abstract Abstract 2275 Introduction: Apixaban is direct factor-Xa inhibitor that reached the market for the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery. It is also being evaluated in the reduction of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome and in the prevention of stroke in patients with non-valvular atrial fibrillation. Thanks to its predictable pharmacokinetic profile, biological monitoring is not required. Nevertheless, evaluation of plasma drug concentration may be valuable in specific situations such as recurrent thrombosis, bleedings, before urgent surgery, in case of bridging and in case of at least two risk factors among the following ones: drug interactions with caution, moderate renal impairment and moderate hepatic impairment; Monitoring may also be useful in infants, pregnant women or in extreme body weights, although no relevant data on drug levels associated with approximate therapeutic and harmful ranges are currently available. Material and Methods: Apixaban was spiked at increasing concentrations (0, 5, 10, 20, 50, 100, 200 and 500 ng/mL) in pooled citrated normal human platelet poor plasma (PPP) to measure Prothrombin Time (PT) and dilute PT with different thromboplastin, Thrombin Generation Assay (TGA) with different inducers and activity on different anti-Xa chromogenic assays. Activated Partial Thromboplastin Time with different reagents, Thrombin Time (TT), Ecarin Clotting Time (ECT) and Reptilase Time (RT), measurement of fibrinogen (Clauss method and PT-derived method) and antithrombin (anti-IIa and anti-Xa based chromogenic assays) were also tested. We also evaluated the impact of apixaban on assays used for the determination of lupus anticoagulant such as the DRVV-T.. (Screen and Confirm) as well as the PTT-LA.. and the Staclot-LA.. . Results and Discussion: As mentioned in previous studies, PT showed a weak sensitivity towards apixaban in comparison with the plasma range obtained in short pharmacokinetic studies. Indeed, the concentration needed to double the clotting time was 154 ng/mL with the most sensitive reagent while the mean Cmax obtained in a short PK study after one oral intake of 5 mg apixaban (dose given in atrial fibrillation) was 96 ng/mL. Therefore, the sensitivity of PT is not strong enough to allow accurate quantitative measurement of the plasma drug concentration (Table 1). Activated Partial Thromboplastin Time presented a better sensitivity but showed a plateau after 100 ng/mL reflecting the uselessness of this test for the quantification of apixaban. Thrombin Time, ECT and RT were logically not affected while DRVV-T.. showed a sensitivity of 205 ng/mL (Screen), which is once again not enough sensitive. On the opposite, chromogenic anti-Xa assays seemed to be very sensitive (Figure 2 and Table 1). Nevertheless, the relation was not always linear and some methodologies needed to be adapted to ensure a broader range of application. TGA (Figure 1) may be useful to assess the pharmacodynamics effects of apixaban on the coagulation process. Nevertheless, the turn around time and the lack of standardisation are currently limitations that restrict the use of this method. In the case of the exploration of an haemorrhagic event, specific tests such as RT, fibrinogen (Clauss and PT-derived method (dFib)), TT and clotting factor activity may be used. Apixaban did not interfere with these tests. Antithrombin determination if also of importance and chromogenic anti-IIa based assays should be used in face of patients treated with apixaban to avoid misdiagnosis since an overvaluation of 12% by 100 ng/mL was shown using one chromogenic anti-Xa based assay. Conclusion: PT may not be used as screening test to assess the risk of bleedings. A more specific and sensitive assay such as chromogenic anti-Xa assays using calibrators should be used to correctly assess the concentration of apixaban. Determination of lupus anticoagulant using DRVV-T.. and PTT-LA.. or Staclot LA.. as well as the determination of antithrombin using factor-Xa based chromogenic assays, were influenced by apixaban. Finally, standardization of the time between the last intake of apixaban and the sampling is mandatory. Figures: Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reversal of direct oral anticoagulants: a practical approach

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 612-619 ◽  
Author(s):  
Andrew W. Shih ◽  
Mark A. Crowther
Keyword(s):  
Phase 1 ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Ancillary Benefits ◽  
Reversal Agents

Abstract Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

scholarly journals Monitoring and reversal of direct oral anticoagulants

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Adam Cuker ◽  
Deborah Siegal
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Reversal Agents ◽  
Routine Monitoring

Abstract Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Comparison of the Antithrombotic Effectiveness of the Direct Thrombin Inhibitor, Dabigatran Etexilate, and Two Factor Xa Inhibitors in an A-V Shunt Model of Thrombosis in Rabbits.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3154-3154 ◽  
Author(s):  
Joanne van Ryn ◽  
Norbert Hauel ◽  
Henning Priepke ◽  
Kai Gerlach ◽  
Annette Schuler-Metz ◽  
...  
Keyword(s):  
Dabigatran Etexilate ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Direct Thrombin Inhibitor ◽  
Factor Xa Inhibitors ◽  
Thrombin Inhibitor ◽  
Factor Xa Inhibitor ◽  
Antithrombotic Activity ◽  
Antithrombotic Efficacy ◽  
Dose Dependent

Abstract Inhibition of two key serine proteases in the coagulation cascade, thrombin (IIa) and factor Xa, are currently being exploited for direct, oral antithrombotic activity in the clinic. However, it is still unclear if one form of coagulation factor inhibition is more effective than the other. Thus, the objective of this study was to test the antithrombotic efficacy of the clinically advanced compounds, the potent direct thrombin inhibitor, dabigatran etexilate and rivaroxaban, a potent direct factor Xa inhibitor in the rabbit A-V shunt model of thrombosis. In addition, another internally developed factor Xa inhibitor, BI42551, with properties similar to those in clinical development was tested. All three compounds have affinities (Ki) for their respective coagulation factor in the low nM range, i.e. human thrombin with dabigatran or human factor Xa with rivaroxaban or BI42551. In addition, each is at least >700-fold selective for its human coagulation factor, dabigatran etexilate for IIa vs Xa and the factor Xa inhibitors for Xa vs IIa. These compounds are highly selective inhibitors not only of the human enzyme, but also have similar values for rabbit thrombin and Xa, respectively. All experiments were performed according to German animal ethics guidelines. The femoral artery and vein of anesthetised rabbits were connected with polyethylene tubing containing a fixed length of suture, pre-soaked in tissue factor. Blood flow through the shunt was maintained over 40 min, after which the suture with any thrombus was removed from the shunt and weighed. The prodrug dabigatran etexilate and the factor Xa inhibitors were given in doses of 3 and 10 mg/kg orally and the rabbits were anesthetised either 90 min or at the highest dose, also 6.5 hrs after drug administration. There was a dose-dependent reduction of thrombus formation with all three compounds as compared to control. Antithrombotic efficacy at 3 and 10 mg/kg is shown as % inhibition of control measured 2 hrs after drug administration (table, columns 2&3). These effects were long-lasting, as significant antithrombotic activity was also measured 7 hrs post administration (last column). Plasma levels of all compounds were dose-dependent and clotting tests correlated well with dose. 3 mg/kg–2 hrs 10 mg/kg–2 hrs 10 mg/kg–7 hrs Dabigatran etexilate 61.7 ± 8.7 82.1 ± 5.5 59.5 ± 17.6 Rivaroxaban 43.2 ± 7.7 64.5 ± 8.1 41.0 ± 8.4 BI42551 31.1 ± 10.7 70.3 ± 3.3 39.9 ± 14.7 These results show that both thrombin and factor Xa inhibition are effective methods of inhibiting thrombosis in a rabbit AV shunt model. All drugs had potent and long-lasting effects after a single oral administration in this model, though dabigatran showed a trend to elevated antithrombotic efficacy at both 2 and 7 hrs. However, in the clinical setting differences in antithrombotic treatment may also be related to differences in pharmacokinetic profiles, drug interactions or metabolism, or the individual side effect profiles of each compound.

Monitoring and reversal of direct oral anticoagulants

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Adam Cuker ◽  
Deborah Siegal
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Reversal Agents ◽  
Routine Monitoring

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Effect of Factor Xa Inhibitors on the Platelet-derived Microparticles Procoagulant Activity In Vitro> and In Vivo in Rats

2000 ◽  
Vol 84 (10) ◽  
pp. 668-674 ◽  
Author(s):  
J. P. Hérault ◽  
B. Perrin ◽  
C. Jongbloet ◽  
A. M. Pflieger ◽  
A. Bernat ◽  
...  
Keyword(s):  
Factor Xa ◽  
Procoagulant Activity ◽  
Factor Xa Inhibitors ◽  
Gel Chromatography ◽  
Factor Xa Inhibitor ◽  
Dependent Manner ◽  
Platelet Surface ◽  
Prothrombinase Activity

SummaryThe aim of this study was to investigate the effect of factor Xa inhibitors on the prothrombinase activity of platelet-derived microparticles in vitro and in vivo. The factor Xa inhibitors studied were DX9065A (a direct factor Xa inhibitor) and Sanorg34006 (an antithrombin (AT)-mediated factor Xa inhibitor). Microparticles formed from the platelet surface following activation were isolated by size exclusion gel chromatography. After purification, their presence was detected by their procoagulant activity and by flow cytometry. Our results show that factor Xa and/or factor Va were present at the surface of the platelet-derived microparticles. Prothrombinase formed on the microparticles was inhibited by factor Xa inhibitors at IC50 values of 0.45 ± 0.05 and 0.045 ± 0.005 µM for DX9065A and AT-Sanorg34006 respectively. In an experiment aimed at determining the kinetics of microparticles formation we demonstrated that thrombin traces were sufficient to induce the formation of a significant quantity of microparticles. Both factor Xa inhibitors delayed the formation of microparticles by delaying thrombin generation. The thrombogenic effect of the microparticles were studied in vivo in a modified arterio-venous shunt model in the rat. In this model, the increase in the thrombus weigh due to microparticles or phospholipids did not differ significantly (33% and 23% respectively). In these conditions, prothrombinase activity seemed to play a lesser role in the thrombogenic effect than phospholipids. Nevertheless, factor Xa inhibitors were efficient and inhibited thrombus formation in a dose-dependent manner.These results demonstrate that platelet-derived microparticles display a potent prothrombotic effect in vivo and show that factor Xa inhibitors are potent antithrombotic compounds when thrombosis was induced by microparticles.

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