Administration Of Fondaparinux Research Articles

Incidences of deep vein thrombosis and major bleeding under the administration of fondaparinux for thromboprophylaxis after periacetabular osteotomy: a retrospective observational study

ABSTRACTPeriacetabular osteotomy (PAO) is an effective joint-preserving procedure for patients with developmental dysplasia of the hip. Although deep vein thrombosis (DVT) is considered a serious complication of orthopaedic surgery, there is no consensus regarding a thromboprophylaxis strategy after PAO. We have routinely administered fondaparinux for DVT prophylaxis in adult patients undergoing PAO. The aim of this study was to investigate the incidences of DVT and major bleeding under the administration of fondaparinux for thromboprophylaxis after PAO. A total of 95 patients (100 hips) who underwent PAO with post-operative administration of fondaparinux for thromboprophylaxis were retrospectively enrolled. The incidences of DVT on ultrasound, major bleeding, and administration cessation were evaluated. Asymptomatic DVT occurred in one patient, major bleeding occurred in 14 hips and the administration of fondaparinux was stopped in 17 hips. Given the observed incidence of major bleeding, safer DVT prophylaxis modalities should be considered during PAO.

Assessment of endogenous fibrinolysis using a point-of-care assay to identify increased cardiovascular risk in patients with diabetes and ACS

Abstract Introduction Patients with diabetes mellitus (DM) are increased risk of myocardial infarction (MI) and following a MI, patients with DM have an increased risk of recurrent MI and cardiovascular (CV) death. Plasma turbidimetry studies show that hypofibrinolysis is a key abnormality in DM that may drive increased ischaemic risk. Such assays are cumbersome, require specialist expertise and do not provide information in a clinically-relevant timeframe. Assessment of fibrinolysis in whole blood, using a point-of-care assay, has revealed that in ACS patients, impaired fibrinolysis is predictive of adverse CV events. Whether this technique can identify residual risk in patients with DM, is unclear. Purpose It was our aim to compare thrombotic and endogenous fibrinolytic status between patients with and without DM, presenting with ACS. Methods We conducted a prospective, observational study of consecutive patients admitted with ACS. Venous blood was taken to assess thrombotic and thrombolytic status using the point-of-care Global Thrombosis Test, assessing time to occlusive thrombus formation under high shear (occlusion time, OT) and time taken for spontaneous lysis of the thrombus (lysis yime, LT). Blood was taken after dual antiplatelet therapy (DAPT) loading, but before administration of fondaparinux or low molecular weight heparin. Patients with renal or hepatic impairment, known bleeding diathesis, thrombocytopenia and those taking anticoagulation were excluded. Results A total of 775 patients were included, of whom 158 (20%) had DM. Patients with DM, compared to those without DM, more frequently had hypertension (70% vs. 39%, p<0.001), hyperlipidaemia (65% vs. 29%, p<0.001), higher BMI (28.6 [25.3–32.0] vs. 26.6 [23.7–29.8] kg/m2, p<0.001) and prior MI (28% vs 9%, p<0.001), but were less often smokers (23% vs. 34% p=0.007). In all other clinical characteristics DM and non-DM patients were matched. Time to occlusive thrombus formation was similar in patients with and without DM (OT 401 (284–519) s vs. 391 (289–514) s, p=0.603). There was a trend for longer LT in patients with DM compared to those without DM (LT 1634 (130–2321) s vs. 1562 (1247–2147) s, p=0.080). After propensity score matching to adjust for baseline differences in clinical characteristics, we observed a highly significant difference in LT between DM and non-DM patients (LT 1634 [1306–2321] s vs. 1387 [1109–1740] s, p<0.001). Patients with DM also had higher fibrinogen level (4.4 [3.5–5.4] vs. 4.1 [3.5–4.8] g/l, p=0.012) and higher C-reactive protein (5 [2–12] vs. 3 [1–8] mg/l, p=0.002). CRP correlated with LT (r=0.2, p=0.016), but no correlation was observed between fibrinogen and LT (r=0.069, p=0.424). Conclusions Amongst patients with ACS, those with DM exhibit markedly impaired endogenous fibrinolysis compared to those without DM, and this can be detected with a bedside assay using whole blood. This may explain the increased risk of secondary events in patients with ACS and DM. Funding Acknowledgement Type of funding source: None

Population pharmacokinetics and pharmacodynamics of fondaparinux inJapanese patients after artificial total kneereplacement .

This study was designed to clarify the factors affecting the efficacy, adverse events, and pharmacokinetics of fondaparinux in Japanese patients undergoing artificial knee replacement surgery. Fondaparinux (1.5mg/d) was administered subcutaneously to patients (n=30) at 24hours after surgery, and blood samples were taken at various time points thereafter. Venous thromboembolism (VTE), presence of bleeding, and pharmacokinetics were evaluated. Multivariate analysis and population pharmacokinetic analysis were performed to detect factors that necessitated withdrawal of fondaparinux and individual differences in its pharmacokinetics. VTE was observed in 9 patients (3 for whom administration was continued and 6 for whom withdrawal was necessary). The maximum plasma concentration of fondaparinux was found to be a significant factor determining withdrawal of the drug. Population pharmacokinetic analysis demonstrated that individual renal function and body weight were significant factors associated with apparent clearance and volume of distribution, respectively. A high maximum plasma concentration of fondaparinux may result in subcutaneous hemorrhage, necessitating withdrawal of fondaparinux administration. The patient's kidney function and body weight also contribute to individual differences in pharmacokinetics. We recommend considering an adjustment to the dose of fondaparinux based on body weight in patients undergoing artificial knee replacement surgery. .

Assessment of a topical product based on polysulfated galactosaminoglycan as an adjuvant in the treatment of acute STP and stasis dermo-hypodermitis.

Superficial thrombophlebitis (STP) is a relatively frequent pathology characterized by possible extension to the deep venous circulation, with notable local inflammatory reaction which is treated by subcutaneous administration of Fondaparinux. Stasis dermo-hypodermitis is characterized by cutaneous hyperpigmentation and eczema, treatment for which consists of the use of drugs targeting endothelial cells (mesoglycan, FFPM, sulodexide). In this study we evaluated the impact of local application of a mixture of semi-synthetic polysulfated galactosaminoglycans on the regression rate of STP and dermo-hypodermitis in patients treated with best medical therapy (BMT). Thirty patients (20 F and 10 M) were enrolled from May to December 2017, 20 with dermo-hypodermitis due to stasis secondary to post-thrombotic syndrome (PTS) and 10 with acute STP of the great saphenous vein or its collaterals. Topical administration of the galactosaminoglycan-based product was added to the BMT of 10 pts with PTS and 5 pts with STP for 45-60 days. In all patients a Visual Analogical Scale (VAS) was used to assess the intensity of spontaneous and induced pain at 0, 15, 30, 45 and 60 days. With regard to PTS, VAS values at time 0 were comparable between the two groups, while at later times there was a progressive reduction in the score, with values of ≤2 at 30 days for patients treated with the topical product based on galactosaminoglycans vs. 60 days for the other control subjects. With regard to STP, the values of VAS at time 0 between the two groups were comparable, while at time 15 the VAS value was lower in subjects treated with the topical product. This pilot study on the efficacy of a local formulation of a mixture of semi-synthetic polysulfated galactosaminoglycans highlighted the role of this product in accelerating the recovery of patients at the most advanced stages of chronic venous disease (CVD) and in the management of its complications. In the future, studies of larger series will be needed with the use of placebo to substantiate their effectiveness in these conditions and in other classes of CVD.

A treatment strategy using subcutaneous fondaparinux followed by oral rivaroxaban is effective for treating acute venous thromboembolism

BackgroundThe factor Xa inhibitors have been widely used for the treatment and prevention of venous thromboembolism (VTE). However, the efficacy of factor Xa inhibitors in Japanese patients with VTE has not been well examined. In this study, we investigated the effect of the sequential use of two factor Xa inhibitors in patients with acute VTE. MethodsWe conducted an observational study of 87 consecutive patients diagnosed with VTE. As an initial treatment, we administered subcutaneous fondaparinux to the patients for 7–10 days, and then switched to oral rivaroxaban. The symptoms and findings were assessed after the initial treatment and after using rivaroxaban for 7–14 days. We evaluated the deep vein thrombosis (DVT) in the legs using our own scoring system [quantitative ultrasound thrombosis (QUT) score]. ResultsOf the 87 patients, 33% had symptoms, half had pulmonary embolism (PE), and 95% had DVT of the legs. Out of the 87 patients, VTE worsened during the administration of fondaparinux in 4 patients. All of them had experienced malignancy, and died within 6 months. Of two patients developing bleeding, one patient required a transfusion. Eventually, this strategy was effective in 80 patients and had no change in one. The D-dimer level was significantly reduced by fondaparinux (17.8μg/ml±16.0μg/ml vs. 8.3μg/ml±7.2μg/ml, p<0.0001), followed by rivaroxaban (8.3μg/ml±7.2μg/ml vs. 5.5μg/ml±4.9μg/ml, p<0.0001). Similarly, the QUT score was improved by fondaparinux (4.7±2.6 vs. 2.5±2.5, p<0.0001), and further reduced by rivaroxaban (2.5±2.5 vs. 1.9±1.8, p<0.0001). ConclusionsA treatment strategy using subcutaneous fondaparinux followed by oral rivaroxaban is effective for treating acute VTE in Japanese patients.

Incidence of Venous Thromboembolism Following Laparoscopic Surgery for Gastrointestinal Cancer: A Single-Center, Prospective Cohort Study.

The occurrence of venous thromboembolism (VTE), manifesting as deep vein thrombosis or pulmonary embolism, after gastric and colorectal cancer surgery remains poorly characterized. The purpose of this study was to investigate the incidence of VTE following laparoscopic surgery in Japanese patients with gastric and colorectal cancer and identify the associated risk factors. We prospectively analyzed VTE events after laparoscopic surgery for gastric and colorectal cancer from April 2012 to March 2013 in our institute. Deep vein thrombosis was diagnosed with Doppler ultrasound sonography of the lower limb. Thromboprophylaxis, graduated compression stockings, and intermittent pneumatic compression were used in all patients. Fondaparinux sodium was used in several patients. We examined all patients' plasma D-dimer levels throughout the perioperative period. In total, 101 patients were enrolled in this study; 71 who underwent laparoscopic surgery for gastrointestinal cancer were finally analyzed. Thirteen patients (18.3 %) developed asymptomatic VTE. There were no relationships between the development of VTE and perioperative factors such as cardiovascular disease, operation time, blood loss, postoperative complications, and fondaparinux administration. Neoadjuvant treatment (chemotherapy or chemoradiotherapy) was significantly associated with VTE (p < 0.05). Plasma D-dimer levels were higher 7 days after surgery in patients with than without VTE, although the levels remained high after surgery in all patients. The incidence of VTE among Japanese patients who underwent laparoscopic surgery for gastrointestinal cancer was not low. In particular, clinicians should consider the higher risk of VTE in patients undergoing neoadjuvant therapy.

Novel self assembling nanoparticles for the oral administration of fondaparinux: synthesis, characterization and in vivo evaluation.

Fondaparinux (Fpx) is the anticoagulant of choice in the treatment of short- and medium-term thromboembolic disease. To overcome the low oral bioavailability of Fpx, a new nanoparticulate carrier has been developed. The nanoparticles (NPs) contain squalenyl derivatives, known for their excellent oral bioavailability. They spontaneously self-assemble upon both electrostatic and hydrophobic interactions between the polyanionic Fpx and cationic squalenyl (CSq) derivatives. The preparation conditions were optimized to obtain monodisperse, stable NPs with a mean diameter in the range of 150–200 nm. The encapsulation efficiencies were around 80%. Fpx loadings reached 39 wt.%. According to structural and morphological analysis, Fpx and CSq organized in spherical multilamellar (“onion-type”) nanoparticles. Furthermore, in vivo studies in rats suggested that Fpx was well absorbed from the orally administered NPs, which totally dissociated when reaching the blood stream, leading to the release of free Fpx. The Fpx:CSq NPs improved the plasmatic concentration of Fpx in a dose-dependent manner. However, the oral bioavailability of these new NPs remained low (around 0.3%) but of note, the Cmax obtained after oral administration of 50 mg/kg NPs was close to the prophylactic plasma concentration needed to treat venous thromboembolism. Moreover, the oral bioavailability of Fpx could be dramatically increased up to 9% by including the nanoparticles into gastroresistant capsules. This study opens up new perspectives for the oral administration of Fpx and paves the way towards elaborating squalene-based NPs which self assemble without the need of covalently grafting the drug to Sq.

Spinal Epidural Hematoma during Anticoagulant Therapy for Pulmonary Embolism: Postoperative Complications in a Patient with Lung Cancer

Spinal epidural hematoma (SEH) is rare but causes neurological disorders. Rapid diagnosis and treatment maximize neurological recovery. We present the case of SEH after lung cancer surgery under epidural and general anesthesia. A 64-year-old man underwent right upper lobectomy. Pulmonary embolism occurred on postoperative day 2. Anticoagulant therapy with fondaparinux and warfarin was started 2 hours after epidural catheter removal and he gradually recovered. On postoperative day 13, the level of prothrombin time-international normalized ratio reached 1.47 and fondaparinux administration was stopped. The next day, he developed back pain and paraplegia, and magnetic resonance imaging revealed a mass between Th4 and Th7 compressing the spinal cord. Emergency decompression laminectomy and hematoma evacuation were performed. After 2.5 months of rehabilitation, he regained almost all motor function and sensation. Late after epidural anesthesia, attention should be paid to possible SEH even though appropriate anticoagulant therapy had been initiated after epidural catheter removal.

Three Elderly Patients with Deep Vein Thrombosis Who Responded to Subcutaneous Administration of Fondaparinux

Three Elderly Patients with Deep Vein Thrombosis Who Responded to Subcutaneous Administration of Fondaparinux

New Options for Anticoagulation Following Total Hip Arthroplasty and Total Knee Arthroplasty: New Oral Agents on the Horizon

Patients undergoing surgery for total hip arthroplasty (THA) or total knee arthroplasty (TKA) are at particularly high risk for developing venous thromboembolism (VTE). Despite the existence of effective therapies for VTE prevention, THA/TKA patients remain at risk for developing thrombi. Furthermore, the incidence of VTE is predicted to increase as an aging and increasingly obese population experiences joint damage necessitating THA and TKA. Current guidelines recommend the use of a wide range of antithrombotic agents in patients undergoing THA and TKA. These agents include vitamin K antagonists, low-molecular-weight heparins, fondaparinux, and the new oral anticoagulants. However, adherence to guidelines in clinical practice is disappointingly low. The limitations of traditional anticoagulants present management challenges following orthopedic surgery. Vitamin K antagonists present a number of drawbacks, including a narrow therapeutic window and unpredictable pharmacokinetics and pharmacodynamics. The subcutaneous route of administration of fondaparinux and low-molecular-weight heparins may make them unacceptable to patients in the outpatient setting. The introduction of a new generation of anticoagulants promises to address many of the drawbacks associated with the traditional agents. Clinical studies have shown the new oral anticoagulants to be as effective as traditional thromboprophylaxis, with good tolerability profiles. Clinical knowledge of these new agents will be essential to ensure that patients receive appropriate care following orthopedic surgery. This article will discuss the prevention of VTE after THA and TKA based on current evidence-based practice guidelines, the limitations of conventional anticoagulants, and the promise of new therapeutics.

Bivalirudin versus unfractionated heparin in percutaneous coronary interventions of patients having received initial fondaparinux treatment: a propensity matched study

Fondaparinux is an indirect, Factor Xa inhibitor that requires co-administration of another anticoagulant with anti-Factor IIa activity for percutaneous coronary intervention (PCI) per guideline recommendations. In this setting, the use of bivalirudin, a direct Factor IIa inhibitor, is not well established. Using the Premier hospital database, we identified 971 patients who underwent elective or urgent PCI after receiving fondaparinux as the initial anticoagulant. They were treated with either bivalirudin ± glycoprotein IIb/IIIa inhibitor (GPI) (Group A=618) or unfractionated heparin (UFH) ± GPI (Group B=353) during PCI. A 2:1 propensity score matching (PSM) process was performed to control for patient and hospital level characteristics. The primary endpoints were to determine in-hospital death, bleeding and post-PCI length of stay (LOS) between treatment groups. After PSM, 512 matched patients were analysed (Group A=348 and Group B=174). In-hospital death was 1.4% in Group A vs. 2.9% in Group B (p=0.26). Clinically apparent bleeding occurred in 4.0% of Group A vs. 9.2% of Group B patients (p<0.02). Clinically apparent bleeding requiring transfusion was lower in Group A patients (0.6% vs. 2.9%; p=0.04). Post-PCI LOS was 1.9 ± 3.8 days for Group A and 2.4 ± 5.8 days for Group B (p=0.36). GPI use during PCI occurred in 9.2% of Group A vs. 44.8% of Group B patients (p<0.0001). After initial administration of fondaparinux, a bivalirudin-based strategy for PCI is associated with significantly reduced bleeding, with similar mortality and post-PCI LOS when compared with an UFH-based strategy.

Risk Factor for a Residual Deep Vein Thrombosis after Fondaparinux Administration in Patient with Postoperative Replacement Arthroplasty

Deep venous thrombosis (DVT) is a life-threatening postoperative complication and occurs frequently after total-knee-replacement arthroplasty (TKA) and total-hip-replacement arthroplasty (THA). Fondaparinux (FPX) has been used to treat and prevent DVT, however interindividual difference of the drug efficacy exists. Therefore, this chart review was retrospectively conducted to research risk factors for a residual DVT after FPX treatment. Total of 112 patients undergone TKA or THA were treated with 2.5 mg FPX once a day between postoperative day (POD) 1 and 14 from July 2007 through December 2008. Among these patients, 30 patients who were detected DVT on POD 4 were enrolled in this study. Thirty patients were divided into two groups according to the presence (n=11) or absence (n=19) of DVT on POD14. The DVT (-) group had a significantly longer activated partial thromboplastin time (APTT, median 31.4 s) on POD 1 than the DVT (+) group (28.5 s) (p<0.02). Multivariate logistic regression analysis revealed that APTT lower than 28.5 seconds on POD1 was considered to be independent risk factor significantly contributing to residual DVT (odds ratio 17.5, 95% confidential interval 2.0-295.4, p=0.02). These findings should provide useful information for understanding the interindividual difference of the efficacy of FPX after TKA or THA.

Postoperative prophylactic effect of fondaparinux for prevention of deep venous thrombosis after cemented total hip replacement: a comparative study

The aim of this study was to estimate the effective administration procedure of fondaparinux for prevention of venous thromboembolism after cemented total hip replacement (THR) in Japanese patients. The study included 471 Japanese patients. The dose regimens were 2.5 mg daily for 14 days (2.5 mg/14 day group) or 10 days (2.5 mg/10 day group), 1.5 mg daily for 10 days (1.5 mg group), 2.5 mg daily for the first 3 postoperative days and 1.5 mg daily for the subsequent 7 days (Mixed group), and no administration of fondaparinux (Control group). Deep venous thrombosis (DVT) was diagnosed by ultrasonography on postoperative day 3 or 4 and day 14. The 2.5 mg/14 day, 2.5 mg/10 day and Mixed groups were regarded as one group in the assessment on postoperative day 3 or 4, and denoted as the 2.5 mg group. The incidence of DVT on postoperative day 3 or 4 in the 2.5 mg group was significantly lower than that in the Control and 1.5 mg groups. On postoperative day 14, the incidence of DVT in the 1.5 mg and Mixed groups was significantly lower than that in the Control group in both the intention-to-treat and per-protocol analyses. The incidence in the 2.5 mg/10 day and 2.5 mg/14 day groups was significantly lower than that in the Control group in only the per-protocol analysis. The results suggest that the administration protocol of the Mixed group is effective in preventing DVT in Japanese patients undergoing cemented THR.

Dose determination of fondaparinux in healthy cats

To establish practical doses and administration frequencies of fondaparinux for cats that would approximate human therapeutic peak and trough plasma anti-factor Xa activities for thromboprophylaxis (TP) and thrombosis treatment (TT) protocols. 6 healthy adult purpose-bred cats. Dosage protocols for TP and TT were selected on the basis of a single compartment pharmacokinetic model incorporating data from humans but modified to account for the higher body weight-normalized cardiac output of cats. Fondaparinux was administered at 0.06 mg/kg, SC, every 12 hours (TP) for 7 days in one session, and 0.20 mg/kg, SC, every 12 hours (TT) for 7 days in another, with a minimum of 1 week separating the sessions. Plasma anti-factor Xa activity was measured before fondaparinux administration (day 1) and at 2 (peak) and 12 (trough) hours after drug administration on days 1 and 7. Platelet aggregation and thromobelastographic (TEG) parameters were also measured 2 hours after drug administration on day 7. Peak plasma anti-factor Xa activities on day 7 for TP (median, 0.59 mg/L; range, 0.36 to 0.77 mg/L) and TT (median, 1.66 mg/L; range, 1.52 to 2.00 mg/L) protocols were within therapeutic ranges for humans. However, only the TP protocol achieved trough anti-factor Xa activity considered therapeutic in humans (median, 0.19 mg/L; range, 0.00 to 0.37 mg/L) on day 7. There were significant changes in the TEG parameters at peak for the TT protocol, suggesting a hypocoagulable state. No significant changes in platelet aggregation were evident for either protocol. A fondaparinux dosage of 0.06 or 0.20 mg/kg, SC, every 12 hours, was sufficient to achieve a peak plasma anti-factor Xa activity in cats that has been deemed therapeutic in humans. This study provided preliminary data necessary to perform fondaparinux dose-determination and clinical efficacy studies.

Association between venous thromboembolism and plasma levels of both soluble fibrin and plasminogen-activator inhibitor 1 in 170 patients undergoing total hip arthroplasty

Background and purpose Markers of coagulation and fibrinolysis, such as soluble fibrin (SF), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), have been developed in order to determine thrombotic tendency. We investigated whether these markers could be used to diagnose venous thromboembolism (VTE) in the early phase after primary total hip arthroplasty (THA).Methods This prospective study involved 2 groups: an intermittent pneumatic compression (IPC) group (67 patients who underwent IPC only as prophylaxis for VTE) and a fondaparinux (FPX) group (103 patients who received IPC and FPX postoperatively). Plasma levels of SF and PAI-1 were measured on postoperative day 1. To diagnose postoperative VTE, multi-detector row computed tomography (MDCT) and duplex ultrasonography (US) were performed on postoperative day 7.Results VTE was detected postoperatively in 17 cases in the IPC group (25%) and in 8 cases in the FPX group (6%). In the IPC group, plasma levels of SF and PAI-1 were higher in patients with VTE (p < 0.01) than in those without VTE. On the other hand, in the FPX group there were no differences in the levels of SF or PAI-1 measured before administration of FPX on postoperative day 1. The diagnostic criterion of an increase in SF or PAI-1 above the cutoff level (19.8 µg/mL and 53.5 ng/mL, respectively) provided a sensitivity of 100% and a specificity of 67% in the IPC group. In addition, when this criterion was applied to FPX patients, 7 of the 8 patients with VTE met the criterion, and there was a negative agreement rate of 48/49.Interpretation Screening using the cutoff levels of SF and PAI-1 may be useful and shows high sensitivity in predicting postoperative VTE in the early phase after THA.

The influence of fondaparinux on the diagnosis of postoperative deep vein thrombosis by soluble fibrin and D-dimer

IntroductionThere are many reports concerning the fondaparinux prophylaxis of deep vein thrombosis (DVT) after surgery, but little is known about the usefulness of diagnosing DVT by the thrombotic markers such as soluble fibrin (SF) and D-dimer in patients treated with fondaparinux. The main purpose of this study was to evaluate the accuracy of SF and D-dimer tests for DVT screening in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) treated with fondaparinux. Materials and methodsA total of 519 patients who underwent THA or TKA were evaluated. SF and D-dimer levels were evaluated on postoperative days 1, 4, 7, 14 and 21. DVT was confirmed by ultrasonography 4days after surgery. ResultsThe incidence of DVT in patients treated with fondaparinux was significantly lower than in patients without fondaparinux. The SF test on postoperative day 1, and the D-dimer test on postoperative days 1, 4, and 7 were useful in untreated patients. However, in the patients treated with fondaparinux, the D-dimer test on postoperative day 7 only was useful for DVT screening. ConclusionThe accuracy of SF and D-dimer test for the diagnosis of DVT was decreased by administration of fondaparinux. A new strategy for diagnosing DVT might be required for patients receiving fondaparinux.

Exploring the Impact of Clinical Anticoagulants on Venous Thrombosis Stability Using a Novel Intravital Murine Model

Abstract 1246 Background:Thrombus stability influences the progression of deep vein thrombosis to a potentially fatal pulmonary embolism (PE) event. Anticoagulants are clinically administered to treat venous thrombosis. However, the effect of anticoagulants on thrombus stability remains unknown. Objective:We developed a novel intravital mouse model to explore the hypothesis that administration of clinical anticoagulants would decrease early thrombus stability, thereby potentially increasing PE risk. Methods:The trachea and jugular vein were cannulated, and the femoral vein isolated, in wild type C57/Bl6 female mice. Platelets were labeled in vivo using anti-mouse CD41 Fab fragments conjugated to Alexa Fluor-488. A 1 × 2 mm filter paper strip, saturated in 4% ferric chloride, was applied to the femoral vein for 5 minutes to induce thrombus formation. Wide-field fluorescent microscopy was used to quantify thrombus stability. Stability was related to the number of embolic events and loss of platelet intensity captured downstream of the thrombus at 5, 15, 30, 45, and 60 minutes post thrombus formation. Results:The mean number of embolic events and loss of platelet intensity decreased over time in wild type mice (n = 12). This suggested that thrombus stability increases over time. Anticoagulants were administered via a jugular vein catheter, at 12 minutes post thrombus formation, to assess impact on embolization. The anticoagulants examined were hirudin (8U/g mouse body weight), unfractionated heparin (UFH) (0.1U/g), a covalent antithrombin-heparin complex (ATH) (0.08U/g), and fondaparinux (0.1μg/g). We observed an overall a) increase in the number of embolic events and b) increase in platelet intensity lost over time in mice injected with hirudin (n = 12) and UFH (n = 12) when compared to untreated wild type control mice. The total number of embolic events occurring over one hour substantially increased in the hirudin-treated group (p = 0.09), which was also associated with an overall increase in total platelet intensity (p = 0.08), compared to untreated control mice. In addition, there was an increase in the total number of embolic events compared to the UFH-treated group (p = 0.09). Administration of hirudin, a direct thrombin inhibitor (DTI), and UFH, an indirect thrombin inhibitor, could result in decreased venous thrombus stability. However, it appears that the DTI is associated with greater thrombus instability. In the ATH-treated group (n = 12), an increase in embolic events at 15 minutes was observed, followed by a decrease in embolization. ATH could initially disrupt thrombus stability through inhibition of fibrin-bound thrombin, before acting in a stabilizing manner. Administration of fondaparinux (n = 6), an indirect factor-Xa inhibitor, demonstrated an overall decrease in embolic events and platelet intensity lost over time. When compared to control groups, there was a significant decrease in total number of embolic events and total amount of platelet intensity lost in the fondaparinux group (p < 0.05). Use of a factor-Xa inhibitor appears to enhance thrombus stability more effectively in comparison to direct and indirect thrombin inhibitors. Conclusion:Use of anticoagulants that inhibit thrombin predominantly could decrease early thrombus stability and potentially increase the likelihood of a PE event. Disclosures:No relevant conflicts of interest to declare.

Monitoring for anti-Xa activity for prophylactic administration of Fondaparinux in patients with artificial joint replacement

The efficacy of measuring anti-Xa activity was evaluated in major orthopedic surgery patients receiving thrombo-prophylaxis with Fondaparinux. Although 98 orthopedic patients including those receiving total hip replacement (THR) and total knee replacement (TKR) were treated with 1.5mg of Fondaparinux for prophylaxis of deep vein thrombosis (DVT). Sixteen patients developed DVT, but none was associated with a fatal pulmonary embolism. There was a wide range of anti-Xa activity, but there were no patients with less than 0.15mg/l or more than 0.90mg/l. Anti-Xa activity gradually increased from days 1 to 8 and showed no significant difference between patients with and without DVT. Anti-Xa activity was correlated with weight, height, body mass index, and antithrombin activity. Postoperative plasma levels of D: -dimer and soluble fibrin (SF) were markedly high, and those were significantly reduced at days 1 and 4 of treatment with Fondaparinux. Plasma levels of SF were significantly reduced at days 8 and 15, but D: -dimer was not. These findings suggested that there was continued thrombin generation after the injection of Fondaparinux until day 8 and secondary fibrinolysis occurred on day 8. In conclusion, 1.5mg of Fondaparinux may not be sufficient for the prophylaxis of silent DVT, but it was found to be useful for that of fatal pulmonary embolism. Consequently, monitoring anti-Xa activity may be unnecessary for the administration of Fondaparinux at such doses.

Postoperative prophylactic effect of fondaparinux for prevention of deep venous thrombosis after cemented total hip replacement: a comparative study

The aim of this study was to estimate the effective administration procedure of fondaparinux for prevention of venous thromboembolism after cemented total hip replacement (THR) in Japanese patients. The study included 471 Japanese patients. The dose regimens were 2.5 mg daily for 14 days (2.5 mg/14 day group) or 10 days (2.5 mg/10 day group), 1.5 mg daily for 10 days (1.5 mg group), 2.5 mg daily for the first 3 postoperative days and 1.5 mg daily for the subsequent 7 days (Mixed group), and no administration of fondaparinux (Control group). Deep venous thrombosis (DVT) was diagnosed by ultrasonography on postoperative day 3 or 4 and day 14. The 2.5 mg/14 day, 2.5 mg/10 day and Mixed groups were regarded as one group in the assessment on postoperative day 3 or 4, and denoted as the 2.5 mg group. The incidence of DVT on postoperative day 3 or 4 in the 2.5 mg group was significantly lower than that in the Control and 1.5 mg groups. On postoperative day 14, the incidence of DVT in the 1.5 mg and Mixed groups was significantly lower than that in the Control group in both the intention-to-treat and per-protocol analyses. The incidence in the 2.5 mg/10 day and 2.5 mg/14 day groups was significantly lower than that in the Control group in only the per-protocol analysis. The results suggest that the administration protocol of the Mixed group is effective in preventing DVT in Japanese patients undergoing cemented THR.

Early Postoperative Bleeding in Polytrauma Patients Treated with Fondaparinux: Literature Review and Institutional Experience

Surgery for pelvic or acetabular fractures carries a high risk of deep-vein thrombosis (DVT). Reports indicate that fondaparinux is a more effective thromboprophylactic agent than low molecular weight heparin (LMWH) after major orthopaedic surgery. The safety and efficacy of fondaparinux was evaluated in a new protocol used for DVT prophylaxis. One hundred and twenty seven patients with pelvic or acetabular fractures received either fondaparinux or enoxaparin and were analysed in a historical non-concurrent study. Specific review points included clinical deep-vein thrombosis (DVT) or pulmonary embolism (PE) and evidence of adverse effects such as bleeding or allergic reactions. Two patients that received enoxaparin were found to have a DVT and one patient had a PE. There was no documented DVT or PE in patients that received fondaparinux. The mean number of units of blood transfused postoperatively was higher in the enoxaparin group; however, multivariate regression modelling demonstrated no significant difference between the groups. The most current large randomised controlled studies investigating the administration of fondaparinux following joint arthroplasty or hip fracture surgery, have demonstrated a slight increase or a similar number of bleeding events in patients treated with fondaparinux when compared to those treated with enoxaparin. The current report supports that fondaparinux, in patients with pelvic and acetabular fractures, can be equally effective as enoxaparin and not associated with adverse bleeding events.