Concentrations Of Fondaparinux Research Articles

When Will Fondaparinux Induce Thrombocytopenia?

The pentasaccharide Fondaparinux, a synthetic selective factor Xa inhibitor, is one of the safest anticoagulants in the heparin family that is recommended as an alternative drug for patients with hypersensitivity to other drugs such as heparin-induced thrombocytopenia (HIT). However, some observations of Fondaparinux-induced thrombocytopenia (FIT) have been reported while others claimed that FIT does not occur in patients with fondaparinux therapy, indicating that the mechanism of FIT remains controversial. Here, we utilized different methodologies including dynamic light scattering, immunosorbent and platelet aggregation assays, confocal laser scanning microscopy, and flow cytometry to gain insights into FIT. We found that at a certain concentration, Fondaparinux formed sufficient large and stable complexes with PF4 that facilitated binding of the HIT-like monoclonal KKO antibody and enhanced platelet aggregation and activation. We proposed a model to describe the role of Fondaparinux concentration in the formation of complexes with platelet factor 4 and how it promotes the binding of KKO. Our results clarify controversial observations of FIT in patients as each contains a dissimilar PF4:Fondaparinux concentration ratio.

Population pharmacokinetics-pharmacodynamics of fondaparinux in dialysis-dependent chronic kidney disease patients undergoing chronic renal replacement therapy.

Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71years (63-88), weight 73kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. Model-based simulations showed that standard dosing (2.5mg three times weekly before HD) results in a median anti-Xa activity of 0.55IU/mL and 0.98IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

Development of both colorimetric and fluorescence heparinase activity assays using fondaparinux as substrate

Because tumors and other diseases are characterized by increased heparanase levels, human heparanase is a promising drug target and diagnostic marker. Therefore, methods are needed to determine heparanase activity and to examine potential inhibitors. Because of substrate comparability, we used the bacterial enzyme heparinase II (heparinase) for the assay development. Usually the substrate of heparanase assays is heparan sulfate, which has several disadvantages. Because of that, we used fondaparinux, which is being cleaved by both heparanase and heparinase. Two concepts to detect its degradation were examined: measurement of anti-factor Xa activity of fondaparinux and its direct quantification with the fluorescent sensor polymer-H. Using fondaparinux as substrate, the anti-factor Xa assay was shsown to be appropriate to determine heparinase activity. The detection with polymer-H was easier and even faster to perform. Linearity was given with fondaparinux as well as heparan sulfate, and heparin as substrates, but fondaparinux turned out to be most suitable. By modifications (incubation time, fondaparinux concentration, and polymer-H concentration), the limit of quantification and the linear range can be adapted to the respective requirements. In conclusion, a simple, accurate, and robust heparinase assay was developed. It is suitable for heparinase quality control and testing heparinase inhibitors and could be adapted to heparanase.

Pharmacokinetics of fondaparinux 1.5 mg once daily in a real-world cohort of patients with renal impairment undergoing major orthopaedic surgery

Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5mg once daily) was developed for patients with renal impairment. We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption. This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6%, 13.0% and 10.3%, respectively, in patients with renal impairment treated with 1.5mg compared with patients with normal renal function treated with 2.5mg (p < 0.01). Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5mg in patients with normal renal function, fondaparinux 1.5mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding.

Functionality of fondaparinux (pentasaccharide) depends on clinical antithrombin levels

Fondaparinux (Arixtra) is an antithrombin (AT)-dependent synthetic inhibitor of factor Xa (FXa). We undertook a study to determine the ramifications of varying levels of circulating AT on the pharmacologic activity of fondaparinux. AT-deficient human plasma supplemented with 0.125-2.0 U/ml purified human AT and plasmas from liver disease patients (n = 20; 0.3 U/ml AT) were supplemented with fondaparinux (0.125-12.5 μg/ml) then assayed by an amidolytic anti-FXa assay and the clot-based Heptest. A decrease in fondaparinux activity was observed with AT levels of 0.5 U/ml that became more pronounced with decreasing AT levels. For 0.2-1.5 μg/ml fondaparinux (plasma concentrations achieved with dosages for prophylaxis and treatment of venous thromboembolism) and AT levels of 0.5 U/ml there was 20% loss of activity and with 0.25 U/ml AT there was a 45% loss of activity compared to 1 U/ml AT. Increasing AT levels to over 0.5 U/ml or increasing fondaparinux concentrations for AT levels between 0.5 and 1 U/ml achieved fondaparinux activity comparable to that obtained with 1 U/ml AT. With AT levels above 1.0 U/ml a greater inhibitory activity was achieved. The observed potency of fondaparinux in terms of anti-FXa activity was reduced approximately three-fold in patients with liver disease. These in-vitro findings were confirmed in a rabbit model of stasis thrombosis. With AT levels below 30% of normal induced by anti-AT antibodies, there was a 60% in-vivo reduction in the antithrombotic activity of fondaparinux (ED50 75 vs. 240 μg/kg). In summary, the AT level is a rate-limiting factor for the antithrombotic activity of fondaparinux.

Peak and baseline concentrations of fondaparinux during prophylactic therapy

SummaryFondaparinux is widely approved for prophylaxis and treatment of venous thromboembolic events (VTE). However, its longer half-life time compared to heparins limits its peri-procedural use. Aim: To investigate 3h peak and 24h baseline concentrations of fondaparinux when administered for prophylaxis (1 x 2.5 mg qd). Secondary outcome measures: incidences of VTE, bleedings, HIT, allergic skin reactions, 30 days mortality. Patients, methods: Between 02/2010 and 03/2011, 3h peak and 24h baseline levels of fondaparinux were measured with a chromogenic anti-FXa method in 75 consecutive patients. Medical data were obtained from patients' records. Results: The 5% and 95% percentile of the 3h peak level were 0.20 μg/ml and 0.83 μg/ml (median: 0.53 μg/ml), and of the 24h baseline level 0.08 μg/ml and 0.53 μg/ml (median 0.21 μg/ml), respectively. An inverse correlation was found between fondaparinux levels and GFRs (rho=-0.617 (3h); rho=-0.648 (24h); p=0.01). Shorter (≤5 days) or longer (≥8 days) duration of prior fondaparinux exposure showed no significantly different 3h peak/24h baseline levels (p&gt;0.6). One progressive thrombosis occurred but no major bleedings, HIT, allergic skin reactions or fatalities. Conclusions: After fondaparinux exposure, &gt;75% of the patients still had relevant prophylactic 24h baseline levels. This did not coincide with a high rate of bleeding events. Due to the low patient number in this study undergoing surgery or interventions, it remains to be investigated whether or at which concentrations the bleeding risk is increased when baseline levels are within prophylactic ranges.

Differential inhibitory effect of fondaparinux on the procoagulant potential of intact monocytes and monocyte-derived microparticles

Monocytes and monocyte-derived microparticles (MMPs) play a major role in acute coronary syndrome (ASC). Activated monocytes (ac-M) and MMPs support thrombin generation via tissue factor (TF). The aim of this study was to evaluate the inhibitory effect of fondaparinux, a selective Xa inhibitor, on thrombin generation supported by activated monocytes and MMPs. Monocytes were purified by elutriation. They were activated by LPS, allowing to obtain both ac-M and MMPs. Thrombin generation was performed using Fluoroscan(®) in these two cell models, in comparison with a cell-free model (TF 5 pM final). Two concentrations of ac-M (0.2 × 10⁶ and 1 × 10⁶/well) and four concentrations of MMPs (40,000; 80,000; 120,000 and 160,000/well) were tested. TGT was evaluated for increasing fondaparinux concentrations (0, 0.1, 0.4, 0.7 and 1.2 μg/ml). Without fondaparinux, 0.2 × 10⁶ ac-M and 160,000 MMPs induced comparable results. Fondaparinux inhibited thrombin generation in the three models. Inhibition was fondaparinux concentration dependent. Rate index was the most sensitive parameter, compared to lag-time, peak and endogenous thrombin potential. The rate index IC(50) were 0.69 ± 0.03 μg/ml for ac-M, 0.20 ± 0.03 μg/ml for MMPs, and 0.22 ± 0.02 μg/ml for cell-free model. Fondaparinux exerted an inhibitory effect at all concentrations, including the lowest (0.1 μg/ml). The extend of inhibition was similar between MMPs and cell-free models, and stronger than ac-M model. We assume that the efficacy of fondaparinux 2.5 mg once daily in ACS patients may be in part attributed to its inhibitory effect on MMPs.

Fondaparinux for the Treatment of Thrombosis in Children: A Prospective, Dose-Finding, Pharmacodynamic and Safety Study.

Abstract 3130Poster Board III-67 BackgroundFondaparinux is a synthetic, antithrombin-dependent selective inhibitor of factor Xa currently licensed for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism in adults prior to conversion to warfarin. Fondaparinux is not approved for use in children in whom description of its use are limited to a few case reports. In comparison to low molecular weight heparin, fondaparinux has several properties which make it attractive for use in children for the treatment of DVT including a longer half-life potentially allowing once-daily dosing, lack of effects on bone metabolism, reduced risk of heparin-induced thrombocytopenia (HIT), and no risk of contamination from animal sources. With this in mind, we conducted a prospective study to determine the dosing, pharmacodynamics and safety of fondaparinux in children. MethodsChildren between 1 and 18 years of age with either an objectively confirmed DVT or pulmonary embolism or confirmed HIT were eligible to participate. Patients were excluded if they had evidence of a coagulation disorder, renal dysfunction or were pregnant. After obtaining consent, patients were enrolled and received fondaparinux 0.1 mg/kg up to a maximum of 7.5 mg once daily. Plasma fondaparinux levels determined via a fondaparinux-standard anti-factor Xa assay with results expressed in mg/L were measured immediately before and 2, 4, 12, and 24 hours after the first dose. Subsequently, peak levels were drawn at 4 hours twice weekly and following dose changes until either study drug discontinuation or hospital discharge. Blood counts, renal and liver function tests, and coagulation parameters (PT, PTT, fibrinogen) were monitored. The target peak (4 hour post dose) fondaparinux level was 0.5-1 mg/L. Patients whose levels were outside this range had doses adjusted by 10% or 25% depending on the level. If the level at 12 hours was below 0.2 mg/L, the dosing interval was changed to every 12 hours. Major and minor bleeding and adverse events were recorded per pre-defined criteria. A population pharmacokinetic model was developed from the data and simulations were performed to compare observed and predicted fondaparinux concentrations achieved in children to those typically observed in adults receiving treatment of DVT and PE. ResultsA total of 24 patients from 3 age cohorts (1-5, 6-12, and 13-18 years) were enrolled with 10, 7, and 7 in each cohort, respectively. The average time on study drug was 5.8 days (range 2-19 days). Overall, 87.5% of patients achieved a therapeutic level following the first dose and no patients required twice daily dosing. Three patients (12.5%) required a dose adjustment (increased in 2 and decreased in 1). Pharmacokinetic modeling demonstrated that Cmax and Cmin concentrations at 0.1 mg/kg once-daily dosing were similar to those of previously studied adults. Two bleeding events occurred: 1) an intracranial hemorrhage which in retrospect likely occurred prior to study drug initiation (the patient had a history of hypertensive encephalopathy and a subacute parenchymal hemorrhage was noted on a follow up MRI performed 2 days after initiation of study drug), and 2) an episode of occult blood in the stool which led to temporary discontinuation of study drug (study drug was resumed after 2 days despite ongoing occult blood in the stool which subsequently resolved while still on study drug). No other adverse events were attributed to fondaparinux. ConclusionFondaparinux at once daily dosing of 0.1 mg/kg administered to children with DVT or HIT reliably led to the targeted pharmacodynamic effect with minimal adverse events. These results support such initial dosing in carefully selected pediatric patients for whom fondaparinux may provide a net benefit over other anticoagulants. Future studies should further assess the efficacy of this agent in the management of pediatric venous thromboembolism. DisclosuresYoung:GlaxoSmithKline: Royalty Fee. Off Label Use: Fondaparinux is not approved for use in children and this is the subject of the abstract. Khanna:GlaxoSmithKline: Royalty fee.

The Reduced Anticoagulant Effect of Fondaparinux at Low Antithrombin Levels

Low antithrombin levels may compromise the anticoagulant effect of heparin and heparin-related compounds, such as fondaparinux. We compared the anticoagulant effect of 10 concentrations of fondaparinux added to plasma samples with normal range (n = 25, antithrombin 95.4% +/- 9.2%) and low antithrombin (n = 22, antithrombin 45.5% +/- 13.2%) levels, using the Heptest coagulation assay. Heptest clotting time was shorter at any given fondaparinux concentration in the antithrombin-deficient samples, indicating less anticoagulant effect than in the group with normal antithrombin levels. At a high fondaparinux concentration, a saturation effect is observed with no further increase in Heptest clotting time. Addition of antithrombin concentrates results in a shift of the dose-response curve. When antithrombin concentrate was added, Heptest clotting time increased up to a fondaparinux concentration of 10 microg/mL. In the conventional prophylactic and therapeutic dose range, not only treatment with antithrombin concentrates but also an increase in fondaparinux dose normalizes the anticoagulant effect. A saturation effect is observed at high fondaparinux concentrations. Higher levels of antithrombin lead to an exaggerated effect of fondaparinux on Heptest.

Heparin-induced thrombocytopenia: A stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings

IntroductionHeparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is highly variable in different clinical settings, and is more frequent with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT antibodies activate platelets similarly well with LMWH as with UFH. An important difference between UFH, LMWH, and fondaparinux is their widely differing plasma concentrations. We aimed to provide a model that included anticoagulant concentrations and PF4 availability as risk factors influencing the anti-PF4/heparin immune response. Materials and methodsBy photon correlation spectroscopy we determined the concentrations at which UFH, LMWH, and fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and LMWH were calculated based on ex vivo pharmacokinetic data, with information on fondaparinux and PF4 concentrations taken from the literature. Results and conclusionsThe main features of our model are: optimal complex formation occurs at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH concentrations are too high for optimal complex formation; in contrast, concentrations of fondaparinux are usually below the optimal stoichiometric range. Thus, immunization should occur more often in situations with major rather than minor platelet activation, and—for a given degree of platelet activation (PF4 availability)—as: prophylactic-dose UFH>therapeutic-dose UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model provides a framework for explaining empirical observations that LMWH induces less anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies are more often found in patients undergoing major surgery than in medical patients.

Detection of surface bound complement at increasing serum anticoagulant concentrations

Surface mediated immune complement activation can be detected by a variety of antibody utilizing methods such as ELISA, fluorescence- or radiolabelling techniques, QCM, and ellipsometry. In the present work we investigated how the common anticoagulants heparin, dalteparin, fondaparinux and sodium citrate affected the binding of anti-complement factor 3c (anti-C3c) on a model complement activator surface, immobilised IgG, after incubation in human blood serum. The results show, as expected, that different anticoagulants affect the antibody binding differently. Increasing amounts of heparin, dalteparin and sodium citrate in normal serum resulted in a decreasing anti-C3c binding. The antibody deposition was not sensitive for the fondaparinux concentration. Surprisingly high concentrations of anti-coagulantia were needed to completely eradicate the antibody binding. Experiments in EGTA–serum showed that anticoagulants interfered directly with both the classical and alternative pathways. Control C3a-des arg ELISA measurements show that the lowered antibody surface binding was not a result of complement depletion in serum. Kallikrein generation by hydrophilic glass surfaces was not affected by high anticoagulant concentrations.

Monitoring fondaparinux with the Sonoclot

Fondaparinux is a new anticoagulant that interacts with antithrombin III and activated coagulation factor X resulting in an inhibition of the coagulation system. It has been successful in doses of 2.5 mg for thromboprophylaxis as well as in higher therapeutic doses of 5-7.5 mg. No optimal method for monitoring the effects of fondaparinux has been proposed. The aim of the present study was to investigate whether a viscoelastic coagulation analyzer, the Sonoclot (Sienco, Denver, Colorado, USA), could be used for in-vitro monitoring of fondaparinux. Different concentrations of fondaparinux were added in vitro to whole blood taken from eight volunteers. The blood samples mixed with the various amounts of fondaparinux were analyzed using the Sonoclot. The whole-blood activated partial thromboplastin time with the Hemochron Jr (ITC, Edison, New Jersey, USA) was used as the reference coagulation analysis. All analyses were started expeditiously, within 30 s from sampling, and were performed at 37 degrees C. The values of the Sonoclot parameter clot rate, which measures the rate of fibrin formation, fibrin polymerization and platelet-fibrin interactions, were significantly correlated to increasing concentrations of fondaparinux (R = -0.90). The Sonoclot parameters of activated coagulation time, time to peak and clot retraction had weaker, but still significant, correlations to fondaparinux concentrations. At prophylactic doses (0.38 microg/ml blood) the clot rate decreased 15% compared with the initial unanticoagulated value, whereas at therapeutic doses (1.53 microg/ml blood) there was a 27% decrease. In conclusion, the Sonoclot parameter clot rate could be of clinical value to individualize the fondaparinux dosage, especially the higher, therapeutic, dosages.

Effect of Fondaparinux on Coagulation Assays: Results of College of American Pathologists Proficiency Testing

Fondaparinux, a factor Xa inhibitor, is approved for thromboprophylaxis after orthopedic surgery and for treatment of venous thromboembolism. It may also be efficacious, safe, and cost-effective for other patients; thus, more widespread use of fondaparinux is likely. The effect of fondaparinux on coagulation testing needs to be thoroughly examined. To report the effects of fondaparinux on coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, factor VIII, thrombin time, anti-factor Xa) across diverse methodologies. Samples with different concentrations of fondaparinux (0, 0.4, 0.8, and 2.0 microg/mL) were sent to laboratories participating in the College of American Pathologists Comprehensive Coagulation proficiency survey (N = 898). Laboratory-specific methods were used to assay coagulation parameters. Prophylactic or therapeutic fondaparinux prolonged the prothrombin time by approximately 1 second and the activated partial thromboplastin time by 4 to 5 seconds, and reduced factor VIII from 119% to 107% and 102%, respectively. Supratherapeutic fondaparinux reduced factor VIII to 85%. The activated partial thromboplastin time was prolonged in 19%, 29%, and 52% of laboratories with prophylactic, therapeutic, and supratherapeutic fondaparinux levels, respectively. Fibrinogen, antithrombin, and thrombin time assays did not show clinically significant changes. When measuring fondaparinux concentration using an anti-factor Xa assay, the most accurate results were obtained when fondaparinux was used as the calibrator. Fondaparinux, even in prophylactic doses, slightly prolongs the prothrombin time and activated partial thromboplastin time and can interfere with factor VIII assays, but it has no clinically relevant effect on fibrinogen, antithrombin, or thrombin time. A fondaparinux standard curve should be used for reporting fondaparinux levels using an anti-factor Xa assay.

Development and Clinical Evaluation of Two Chromogenic Substrate Methods for Monitoring Fondaparinux Sodium

This study was designed to develop methods for monitoring of the selective factor Xa inhibitor fondaparinux sodium (ARIXTRA) based on standard laboratory methods for the chromogenic determination of the anti-factor Xa activity of low molecular weight heparin. To examine the biologic activity of fondaparinux in comparison to its plasma concentration, 2 methods were investigated: 1 working with the addition of antithrombin (AT), the other without exogenous AT. Both methods showed a linear relationship of fondaparinux concentration and OD/min on a log-lin scale in the range from 0.1 to 2 microg/mL. Inter- and intra-assay variability was <6% in all cases. The results of spiked samples from patients on vitamin K antagonists (VKA) were in good agreement with both methods, and the determination of the fondaparinux concentration was not influenced by reduced levels of factor X in plasma caused by VKA-intake. Ex vivo samples from orthopedic patients (n=18) on prophylactic treatment with fondaparinux showed concentrations between 0.2 to 0.7 microg/mL 3 hours after s.c. injection. No significant differences were detected between both methods with these samples. The presented methods are suitable tools for monitoring of fondaparinux. The linear calibration curve in the range 0.1 to 2 microg/mL is suitable for determination of prophylactic and therapeutic application of fondaparinux. Both methods, with and without addition of AT, can be performed fully automated in clinical routine on an automated coagulation analyzer (STA coagulation analyzer). No significant differences were detected between both methods with these samples.

A dose-finding study of fondaparinux in patients with non–ST-segment elevation acute coronary syndromes: The Pentasaccharide in Unstable Angina (PENTUA) study

ObjectivesIn this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS). BackgroundFondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery. MethodsFour doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation. ResultsThe rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events. ConclusionsThis dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study.

Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma

Fondaparinux, a selective antithrombin-dependent inhibitor of activated factor X (FXa), is effective in the prevention and treatment of deep vein thrombosis and seems to be superior to enoxaparin. However, the exact mechanism of fondaparinux antithrombotic action is still unclear. We compared the effect of clinically relevant concentrations of fondaparinux and enoxaparin on the initiation and propagation phase of prothrombin activation and on the endogenous thrombin potential (ETP). Coagulation was triggered either in whole blood or in platelet-rich plasma (PRP) by recalcification in the presence of diluted thromboplastin. Prothrombin activation in whole blood was assessed with an original method by measuring the kinetics of prothrombin F1+2 formation using an enzyme-linked immunosorbent assay. We also assessed the maximum concentration of thrombin (Cmax) and the ETP in PRP using the Thrombogram-Thrombinoscope assay. Concentrations of fondaparinux achieved in prophylaxis (0.11-0.28 anti-FXa IU/ml) prolonged the initiation phase and reduced the velocity of the propagation phase of F1+2 formation. Concentrations of enoxaparin achieved in prophylaxis (0.1-0.25 anti-FXa IU/ml) did not significantly modify these parameters. Concentrations of fondaparinux equal to or higher than 0.57 anti-FXa IU/ml significantly reduced the Cmax of F1+2 or thrombin as well as the ETP. At fondaparinux concentrations equal to or higher than 0.91 anti-FXa IU/ml, a maximum 60% inhibition of thrombin generation was observed. In the presence of enoxaparin concentrations equal to or higher than 0.8 anti-FXa IU/ml, the inhibition of thrombin generation was higher than 80%. Fondaparinux prolonged the initiation phase, decreased the velocity of the propagation phase of thrombin generation and partially reduced the total amount of generated thrombin. The inhibitory effect of fondaparinux on the initiation and propagation phase of thrombin generation seems to be responsible for its antithrombotic action. The more profound inhibition of thrombin generation induced by enoxaparin is due to its supplementary anti-activated factor II activity.

In vitro comparison of the effect of fondaparinux and enoxaparin on whole blood tissue factor-triggered thromboelastography profile

Fondaparinux and enoxaparin are both effective and safe in preventing post-operative venous thromboembolism. However, neither of them significantly influence the conventional clotting tests. We compared the influence of clinically relevant concentrations of fondaparinux and enoxaparin on normal whole blood (WB) thromboelastographic profiles after triggering TF-pathway with minimal amount of thromboplastin. Diluted thromboplastin was added to WB samples supplemented with buffer (control), fondaparinux (0.25; 0.5; 1 microg/ml), or enoxaparin (0.1; 0.5; 1 anti-Xa IU/ml). Four parameters were analyzed, R: clotting time, K: time required to reach an amplitude of 20 mm, alpha angle: measurement reflecting clot development kinetics and MA: maximal amplitude. At concentrations used in prophylaxis, both enoxaparin (0.1 anti-Xa IU/ml) and fondaparinux (0.25 microg/ml which correspond to 0.27 anti-Xa IU/ml) significantly prolonged the R and K times, but did not significantly modify the alpha angle as compared to the control. At concentrations observed after administration of curative doses for the treatment of DVT (> or = 0.5 anti-Xa IU/ml for enoxaparin and > or = 0.5 microg/ml for fondaparinux) both drugs induced a significant increase of R and K times, and a significant decrease of the alpha angle (p < 0.05). In contrast to fondaparinux, enoxaparin at concentrations equal to or higher than 0.5 anti-Xa IU/ml significantly reduced MA. The present study provides evidence that the whole blood TF-triggered TEG assay is sensitive to the presence of clinically relevant concentrations of enoxaparin or fondaparinux. Moreover, the angle may be used in order to distinguish the effect of prophylactic and therapeutic concentrations, since it was significantly reduced by the later ones. Further studies are needed to evaluate the clinical usefulness of whole blood TF-triggered TEG assay for the monitoring of treatment with enoxaparin or fondaparinux.