Pentasaccharide Fondaparinux Research Articles

Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis

No data about the use of the pentasaccharide fondaparinux, a highly selective indirect inhibitor of factor Xa, in patients treated with haemodialysis are available. Therefore, we investigated the pharmacokinetics and -dynamics of fondaparinux in 12 patients during haemodialysis. The anti-Xa activity (expressed as fondaparinux equivalent) was monitored, a semiquantitative clotting scale (SQCS) ranging from 0 (no visible traces of coagula) to 3 (complete clotting of the dialysis circuit) was applied, and the digital compression time necessary to achieve haemostasis at the puncture site was determined. After an initial period, when the regular heparin dose was replaced once weekly by fondaparinux, 0.05 mg/kg, the pentasaccharide was administered for nine consecutive haemodialysis sessions. Peak anti-Xa activity increased from 0.61 +/- 0.14 microg/l after the first dose to 0.89 +/- 0.24 microg/l after dose 9 (P < 0.001), whereas predialysis anti-Xa activity steadily rose to 0.32 +/- 0.09 microg/l (P < 0.001). A sufficient but slightly less effective anticoagulation with a mean SQCS of 1.19 +/- 0.71 (n = 121) was obtained by fondaparinux as compared with 0.65 +/- 0.58 (n = 60, P < 0.005) by 4,825 +/- 1,703 U of unfractionated heparin. Mean digital compression time rose slightly during fondaparinux from 23.7 +/- 7.4 minutes to 24.8 +/- 7.5 minutes (P < 0.05) and, more important, six of the 12 patients reported minor bleeding problems during the interdialytic interval. Thus, fondaparinux can be used to prevent circuit clotting during haemodialysis; however, accumulation results in an interdialytic increase of anti-Xa activity. Therefore, fondaparinux should be reserved for patients requiring systemic anticoagulation on the days off dialysis.

Diagnostik und Management der akuten Lungenembolie

Only in one fourth to one third of patients admitted for suspected acute pulmonary embolism (PE) is PE objectively confirmed, implying that symptoms and clinical findings of acute PE are nonspecific. Clinical pretest probability for PE may be estimated on the basis of validated clinical scores. A low clinical pretest probability and a negative D-dimer value allow exclusion of PE without further imaging procedure. Among imaging techniques, multislice CT scanning has become the preferred method to visualize PE. Alternatively, a combination of clinical pretest probability, D-dimer value and a perfusion/ventilation scan may be performed. The majority of patients presenting with acute segmental or subsegmental PE are hemodynamically stable. Right ventricular function may, however, be disturbed, and an echocardiography should be performed, therefore. Anticoagulation initiated with unfractionated or low-molecular-weight heparins or with the pentasaccharide fondaparinux overlapping with oral anticoagulation using vitamin K antagonists is the standard therapy for hemodynamically stable patients without major right ventricular dysfunction. A transthoracic echocardiography should be performed without delay in patients with suspected central PE and a positive shock index of > or = 1.0 to determine right ventricular function. When major right ventricular dysfunction is found due to central massive PE, immediate performance of surgical or catheter-guided embolectomy or thrombolysis should be considered.

Venous Thromboembolism Prophylaxis in High Risk Medically Ill Patients; a Meta Analysis.

Medically-ill patients are at increased risk for developing venous thromboembolism (VTE) due to multiple risk factors. Evidence-based practice guidelines recommend pharmacologic modalities such as unfractionated heparin (UFH), low molecular weight heparins (LMWH; i.e.enoxaparin, dalteparin, nadroparin) and pentasaccharide fondaparinux for the prevention of VTE. We conducted systematic review and meta-analysis to evaluate the role of different interventions in prevention of VTE in medically-ill patients. We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from 1981–2006 for randomized controlled trials reflecting contemporary antithrombin strategies against in-hospital VTE. Search terms included heparin, enoxaparin, dalteparin, nadroparin, and fondaparinux. Eligible studies included medically-ill patients with risk factors for VTE followed for 7–21 days. We constructed a meta-analysis using Comprehensive Meta Analysis, version 2.0 using the Der-Simonian-Laird random effects model as a sensitivity analysis. Primary end points included the incidence of DVT or PE. Secondary end points included minor and major bleeding, and death from VTE. Eight trials representing 9914 patients were selected for analysis. Four trials compared a LMWH to placebo and four trials compared a LMWH to UFH. Fondaparinux was considered an ultra LMWH. The mean age of represented patients was 72.7±4.89 years, with a mean weight of 68±2.57 kg. The results of primary end points are; 1. DVT-LMWH compared to placebo reduced the odds of DVT by 42% (OR=0.58, 95% CI [0.45–0.75], p≤0.001) with an absolute risk reduction (ARR) of 2.21% and number needed to treat (NNT) of 46. Compared to either placebo or UFH, LMWH reduced the odds of DVT by 37% (OR=0.63, 95% CI [0.50–0.79], p≤0.001) with an ARR of 1.28% and NNT of 78. 2. PE-There was no difference in the incidence of PE with either LMWH, placebo (p=0.16) or UFH (p=0.73). A 36% reduction in the odds PE or DVT (OR=0.64, 95% CI [0.49–0.82], p≤0.01, ARR=1.44%, NNT=70) was observed using a LWMH instead of UFH or placebo. The latter results were driven by the PRIME and PREVENT studies using enoxaparin and dalteparin respectively. The results of secondary end points; 1. Minor bleeding-LMWH use was associated with an increased risk of minor bleeding (OR=1.64, 95% CI [1.18–2.29], p=0.003) compared to placebo with an absolute risk increase (ARI) of 2.24% and a number needed to harm (NNH) of 45; where MEDNOX (enoxaparin study) was responsible for this difference. 2. Major bleeding-There was no difference in major bleeding with LMWH compared to placebo (p=0.18) or UFH (p=0.42). 3. VTE mortality-LMWH was similar to placebo (p=0.63) and UFH (p=0.47) for the reduction of VTE related death. LMWH also increased the risk of any bleeding or VTE-related death (OR=1.57, 95% CI [1.17–2.10], p=0.003, ARI=2.45%, NNH=41) compared to placebo which also was driven by an increase in minor bleeding from enoxaparin use. In conclusion, although there is a significant reduction in DVT when utilizing a LMWH rather than UFH or placebo, there is however, no difference in PE events. Furthermore, it is important to consider the increased incidence of minor bleeding with LMWH (NNH 43) which may offset the reduction in DVT (NNT 45). The objective of future studies should focus on the identification of potential subgroups of patients with higher risk of VTE and lower risk of bleeding to improve outcomes and optimize safety.

Cost–effectiveness of extended venous thromboembolism prophylaxis with fondaparinux in hip surgery patients

In the Penthifra Plus trial, extended prophylaxis with the synthetic pentasaccharide fondaparinux for 1 month versus 1 week in hip fracture surgery has been shown to reduce the risk of venous thromboembolic events by 96%. The cost–effectiveness of extended prophylaxis with fondaparinux still remains to be determined. The authors developed a decision analytic cost–effectiveness model comparing the use of fondaparinux for 4 weeks with 1 week from a healthcare perspective. The analyses were performed for patients undergoing hip fracture surgery and total hip replacement (THR). Efficacy data were extracted from published randomized controlled trials and natural history data after venous thromboembolic events from observational studies. Cost data were derived from the literature and other published sources. Costs were expressed in 2004 Swiss Francs (CHF) and effects as life-years gained (LYG). In patients undergoing hip fracture surgery, the incremental cost–effectiveness ratio of extended 4-week fondaparinux prophylaxis versus a 1-week regimen was CHF 2801/LYG after 30 days, with cost-savings after 5 years. In patients undergoing THR, the respective incremental cost–effectiveness ratio of extended fondaparninux prophylaxis was CHF 20,294/LYG after 30 days, with cost-savings after 5 years. In the authors’ model, the substantial clinical benefit of extended thromboembolism prophylaxis with fondaparinux in major orthopedic surgery translates into favorable cost–effectiveness figures in the short term and cost savings when a 5-year time horizon is used.

The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo

Ample evidence suggests that many of the in vivo anti-metastatic effects by heparins reflect their actions on P-selectin-mediated binding. We hypothesized that the ability of widely used heparins and derivatives to interfere with P-selectin-dependent tumour cell interactions under flow in vitro could be used to identify anticoagulants with advanced inhibitory functions on experimental blood-borne metastasis in vivo. To test this assumption, the impact of unfractionated heparin, the low-molecular-weight heparins (LMWH) nadroparin and enoxaparin, and the synthetic pentasaccharide fondaparinux on P-selectin-dependent tumour interactions in vitro and metastasis formation in vivo were evaluated. Our data revealed that these commonly used anticoagulants widely differ in their potential to interfere with P-selectinmediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition may constitute a valuable feature to identify anticoagulants that are suitable for anticancer therapy.

Management von Patienten mit heparininduzierter Thrombozytopenie

Heparin-induced thrombocytopenia is a strong risk factor for the development of arterial and venous thromboembolic events. In patients clinically suspected for HIT, immediate cessation of heparin treatment and continuation of anticoagulant treatment using alternative anticoagulants is mandatory in order to minimize the risk of thrombotic events. Alternative anticoagulants that have been successfully used in HIT include the direct acting thrombin inhibitors hirudin, bivalirudin and argatroban, and the heparinoid orgaran. In addition, there is growing evidence that the synthetic pentasaccharide fondaparinux is usable for the treatment of HIT patients. This short review summarizes the strategies of alternate anticoagulant treatment in HIT patients and also describes long-term treatment of HIT patients.

Heterogeneity of Synthetic Factor Xa Inhibitors

Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

Treating Patients with Venous Thromboembolism: Initial Strategies and Long-Term Secondary Prevention

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 months of treatment. Even though these elevations usually abated without clinical sequelae whether or not treatment was continued, their clinical relevance remains unclear. In addition, locally reported coronary events occurred more frequently in ximelagatran-treated patients during the initial 6 months of treatment, the reason for which is yet unclear. The consistent anticoagulant response and fixed oral dosing without coagulation monitoring allows ximelagatran to overcome many of the limitations inherent to current treatment options for VTE treatment and secondary prevention, provided the problem of liver enzyme elevation and coronary events is resolved.

Prophylaxis, Diagnosis and Therapy of Surgery-Related Complications in Orthopedic and Trauma Surgery

Selective factor Xa inhibition by the synthetic pentasaccharide fondaparinux is an efficient way of preventing venous thrombosis. Fondaparinux has been shown to reduce the incidence of venous thromboembolism (VTE) by 50% compared with the low-molecular-weight heparin enoxaparin. The aim of the CHANGE study was to evaluate the management of thrombosis prevention with fondaparinux, and the diagnosis and treatment of complications following major orthopedic surgery. Nationwide observational study (“CHANGE”) in 111 centers in Germany. Patients underwent elective knee or hip replacement surgery or surgery on account of fractures of the hip or lower limb. In total, 8,331 patients were documented, of which 7,787 were suitable for analysis. The mean age was 68.5 years; for 50.8% of the patients additional risk factors for VTE were reported. The most frequent main diagnoses by ICD10 were coxarthrosis (41.8%), gonarthrosis (32.8%), and fracture of femur (16.7%). 52.6% of the patients underwent hip surgery, 35.3% knee surgery, and 11.5% surgery for fractures. The mean hospital stay lasted 18 days, with only small differences between the different types of surgery. The overall complication rate was 1.68% (n = 131, 95% confidence interval [CI]: 1.42/1.99) with 0.47% VTE (n = 37, 95% CI: 0.34/0.65, 31 deep vein thromboses, five pulmonary embolisms, one not specified) and 1.2% bleedings (n = 94, 95% CI: 0.99/1.47). Most of the bleedings occurred in the surgical field. The bleeding rate was highest in the knee surgery group, and also VTE occurred more frequently following knee surgery. During the whole study, no heparin-induced thrombocytopenia was observed. The observational study CHANGE confirms the results of the published preauthorization studies with fondaparinux, with a complication rate nearly half that previously reported. Using fondaparinux for the prevention of VTE leads to improved quality of care in orthopedic patients.

Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunsorbent assay (ELISA) test for the heparin–P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.

The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia–reperfusion injury

Ischemia-reperfusion (I/R) injury is associated with activation of coagulation and inflammation. Interestingly, various anticoagulants have been shown to reduce both coagulation and inflammation in animal models of kidney I/R injury. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in the coagulation cascade. The aim of this study was to investigate the effect of fondaparinux in a lethal murine model of kidney I/R injury. A murine model of kidney I/R was established. In this model, we measured activation of the coagulation cascade and induction of inflammation. Administration of fondaparinux to I/R-injured mice reduced fibrin deposition in the kidney, reduced serum creatinine levels and increased survival from 0 to 44% compared with saline-treated control mice. Fondaparinux also reduced interleukin-6 and macrophage inflammatory protein-2 expression and decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced thioglycollate-induced recruitment of neutrophils into the peritoneum and inhibited the binding of U937 cells to P-selectin in vitro. Our data suggest that fondaparinux reduces kidney I/R injury primarily by inhibiting the recruitment of neutrophils.

Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides

Eczematous lesions, resulting from type IV sensitizations are well-known and relatively frequent cutaneous adverse effects of s.c. heparin therapy. If anticoagulation is further required intravenous heparin, heparinoids or lepirudin may be used as a substitute. However, these alternatives are not optimal in terms of practicability and/or safety-profiles. As molecular weight of different heparin preparations has repetitively been implied to determine the frequency of sensitization, we hypothesized, that due to its low molecular weight the pentasaccharide fondaparinux may provide a practicable and safe anticoagulant therapy in patients with delayed type hypersensitivity reactions (DTH) to heparin and other oligosaccharides. To test this concept, patients referred for diagnosis of cutaneous reactions after s.c. anticoagulant treatment underwent a series of in vivo skin allergy- and challenge-tests with unfractionated heparin, a series of low molecular weight heparins (nadroparin, dalteparin, tinzaparin, enoxaparin and certoparin), the heparinoid danaparoid and the synthetic pentasaccharide fondaparinux. In total, data from twelve patients was evaluated. In accordance with previously published data, we report a high crossreactivity among heparins and heparinoids. In contrast--and in support of our initial hypothesis--sensitization towards the synthetic pentasaccharide fondaparinux was rarely observed. Plotting the cumulative incidence against the determined molecular weight of the individual anticoagulant preparations, shows that molecular weight generally is a key determinant of sensitization towards heparins and other oligosaccharides (r2 = 0.842, p = 0.009). Hence, fondaparinux may be used as a therapeutic alternative in patients with cutaneous DTH relations towards heparin and other polysaccharides.

Hypersensitivity to the pentasaccharide fondaparinux in patients with delayed-type heparin allergy

Hypersensitivity to the pentasaccharide fondaparinux in patients with delayed-type heparin allergy

New Ways to Prevent Venous Thromboembolism-the Pentasaccharide Fondaparinux and the Thrombin Inhibitor Ximelagatran-a Review

During the last decade low molecular weight heparins have been the dominating methodology to prevent postoperative venous thromboembolism. They are effective and safe but in high risk surgery (major orthopaedic and abdominal/pelvic cancer) there is still a significant thrombotic problem. Recently two new thromboprophylactic principles have appeared-one Xa inhibitor in the form of the pentasaccharide fondaparinux and one direct thrombin inhibitor in the form of melagatran with an orally absorbable prodrug-ximelagatran. Both have been evaluated in extensive research programmes and both have been approved for use in major orthopaedic surgery by the European health care authorities.

Hypersensitivity to the pentasaccharide fondaparinux in patients with delayed-type heparin allergy

Hypersensitivity to the pentasaccharide fondaparinux in patients with delayed-type heparin allergy -

Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia

AbstractHeparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication of heparin therapy caused by antibodies to complexes between unfractionated heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of reactants and initiate antibody-induced platelet activation. We observed that UFH and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. These ULCs were stable and visible by electron microscopy, but they could be dissociated into smaller complexes upon addition of heparin. ULCs formed inefficiently when PF4 was incubated with low-molecular-weight heparin, and none formed with the pentasaccharide fondaparinux sodium. In addition, mutation studies showed that formation of ULCs depended on the presence of PF4 tetramers. The ULCs were more reactive as determined by their capacity to bind to a HITT-like monoclonal antibody and showed greater capacity to promote platelet activation in an antibody- and FcγRIIA-dependent manner than were the smaller complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH may play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with HITT.

Pharmcokinetics of Fondaparinux by Anti-Xa Levels and Clinical Response to Anticoagulation in a 4-Month Old Congenital Cardiac Patient with Heparin-Induced Thrombocytopenia (HIT) and Established Venous Thrombosis Transitioned from Argatroban to Fondaparinux.

Our group has recently reported on heparin-induced thrombocytopenia (HIT) as an emerging cause of morbidity and mortality in pediatric cardiac surgery patients (Alsoufi, Ped Card Surg Ann of Sem Thorac Cardiovasc Surg 2004: 7: 155). This has included our experience with the off-label use of the antithrombin argatroban as an initial alternative anticoagulant to heparin in neonates and young children with HIT. Our findings indicate the incidence of HIT in pediatric patients undergoing congenital cardiac surgery to be 1–2% with a thrombotic rate of 50–60%. As with adults, children > 1 year with HIT-related thrombosis needing intermediate-to-longterm anticoagulation can be transitioned to warfarin. However stable warfarinization of children < 1 year is difficult, particularly given the feeding difficulties seen in sick congenital cardiac patients. In one such 4 month old, reported here, we successfully used the pentasaccharide fondaparinux, verifying dosage according to fondaparinux levels as measured by a specific fondaparinux curve. A 3 month old 3 kg girl with Down's syndrome underwent cardiac surgery with cardiopulmonary bypass at our institution (complete atrio-ventricular canal repair, closure of patent ductus arteriosus and patent foramen ovale). Platelets did not rise to baseline levels post-operatively and functional HIT assay was positive on postoperative day (POD) 8. All heparin was stopped and anticoagulation with argatroban initiated after obtaining parental informed consent. Due to IV access issues and necessity for pacemaker insertion argatroban was administered with interruptions. On POD 11 the patient thrombosed a PICC line in her left thigh. The line was surgically removed, but residual non-occulsive thrombus was noted by vascular ultrasound in the left common and proximal femoral veins, which persisted on reimaging 1 week later despite sustained therapeutic argatroban infusion. To facilitate outpatient management a decision was made to attempt transition to fondaparinux. Renal function was normal. After obtaining parental informed consent therapy with fondaparinux ( t 1/2 =17−l20 hr) was initiated at 0.15 mg/kg q 24 hrs on POD 23. Anti-Xa levels were drawn at 2, 4, 8 hr post injection and then at intervals on days 2, 3, 4 and 7 of fondaparinux therapy (see table). Values were referenced against both a fondaparinux and a low molecular weight heparin (lovenox) curve. Coefficient of correlation between curves: r = 0.939. The patient did well clinically on fondaparinux with no evidence of bleeding and was discharged on POD 30. Vascular ultrasound showed complete resolution of thrombus at the time of discharge. Platelets remained stable. The patient continued on outpatient fondaparinux therapy for 3 months with stable platelet counts and no clinical evidence of bleeding or rethrombosis.Response to fondaparinux by anti-Xa levelsDay of therapyHour post injectionFondaparinux Level (fondaparinux curve)Corresponding level on LMWH curveDay 120.330.4140.470.5080.60.60Day 220.70.7340.660.6980.510.51Day 3pre0.180.1950.670.60Day 4pre0.180.3320.710.72Day 520.77not done

Fondaparinux in the Treatment of Heparin-Induced Thrombocytopenia.

The development of new non-heparin anticoagulant therapies has increased interest in the treatment of type II heparin-induced thrombocytopenia (HIT). Standard therapy involves administration of an intravenous direct thrombin inhibitor (DTI), either argatroban or lepirudin. Due to a lack of cross-reactivity to HIT antibodies in vitro, the synthetic pentasaccharide fondaparinux sodium is an appealing alternative, but its use in this disorder has not been comprehensively examined. Here, we report our experience with fondaparinux in HIT and an analysis of safety and efficacy in this setting. We reviewed all in-patient cases of HIT at the Massachusetts General Hospital that were confirmed by the heparin-platelet factor 4 antibody test and were treated with fondaparinux. Twenty patients satisfied diagnostic criteria for HIT. Each patient studied lacked another competing, compelling etiology for thrombocytopenia and was treated with fondaparinux for more than five days within one month of diagnosis. The average duration of therapy was 17 days and 16 patients (80%) were treated within two weeks of diagnosis. Patients were grouped according to whether they received fondaparinux after initial therapy with a DTI (n=10) or as initial treatment following the diagnosis of HIT (n=10). The initial dose of fondaparinux administered was 2.5 mg in 18 patients. Neither absolute nor relative thrombocytopenia was identified in either group following treatment. Patients with HIT treated with fondaparinux while thrombocytopenic experienced platelet recovery on average in 3.7 days, as represented in Figure 1. In addition, there were no observed thrombotic complications among patients treated with fondaparinux. In this analysis of a high-risk group of inpatients with type-II HIT, fondaparinux was tolerated without the continuation or recurrence of thrombocytopenia. This suggests that cross-reactivity between the heparin-PF4 antibody and fondaparinux is not likely to be clinically significant. Additionally, the absence of thrombotic sequelae among fondaparinux-treated patients argues that fondaparinux may be a well-tolerated, effective treatment for this morbid, prothrombotic disorder. A prospective trial of fondaparinux in the treatment of type-II HIT is planned. [Display omitted]

Novel antithrombotic agents: indirect synthetic inhibitors of factor Xa and direct thrombin inhibitors. Evidences from clinical studies.

The optimal drugs employed in the antithrombotic treatment and prophylaxis have ideally been suggested to have high efficacy and safety and to be easy to use as regards the administration route and the fashion of monitoring the anticoagulant effect. A number of agents are under development in order to improve such requirements. Among them, the present review is focussed on a selective factor Xa inhibitor (pentasaccharide fondaparinux) and the direct thrombin inhibitors now available on a clinical ground. Fondaparinux is the first of a new class of selective antithrombin-dependent factor Xa inhibitors; it does not interact with plasma proteins other than antithrombin, leading to a predictable pharmacokinetics, which renders monitoring and dose adjustment unnecessary. The efficacy and safety of fondaparinux has been assessed in a number of clinical trials. In patients undergoing major orthopaedic surgery, a 2.5 mg s.c administration once daily induced a 50% average relative risk reduction for overall venous thromboembolism in comparison with enoxaparin but also an increased rate of major bleeding. Parenteral direct thrombin inhibitors include hirudin, bivalirudin and argatroban. these inhibitors have been studied in patients with coronary heart disease. In particular, in patients undergoing percutaneous coronary interventions, bivalirudin showed equivalent or higher efficacy but lower bleeding in comparison with unfractionated heparin. Another series of molecules capable of inhibiting thrombin is derived from the site of fibrinogen to which thrombin binds. Inogatran and melagatran have a low bioavailability when given orally, whereas the chemically modified prodrug ximelagatran has a higher bioavailability. Ximelagatran is safe and effective at least as low molecular weight heparin in patients undergoing major orthopaedic surgery and is safe and effective also in prevention of recurrence in patients with venous thromboembolism or myocardial infarction; ximelagatran is more effective than oral anticoagulants in prevention of arterial embolism due to atrial fibrillation, with comparable safety.

Pentasaccharides in the prophylaxis and treatment of venous thromboembolism: a systematic review.

The aim of this review is to perform a critical analysis of all completed studies evaluating pentasaccharides-synthetically derived, selective inhibitors of activated factor X-in prophylaxis in major orthopedic surgery and the treatment of venous thromboembolism. Venous thromboembolism is a disorder with considerable morbidity when left untreated. New antithrombotic agents have been developed that selectively inhibit components of the coagulation system, thereby avoiding the difficulties associated with current anticoagulants. The pentasaccharides fondaparinux and idraparinux are the first of a new class of synthetic selective inhibitors of activated factor X. Fondaparinux has been extensively investigated in two areas: orthopedic surgery and venous thromboembolism. It is clear from four thromboprophylaxis studies in major orthopedic surgery that fondaparinux is 50% more effective in reducing venous thromboembolism than enoxaparin. This superior efficacy led to an overall increase in major bleeding, which was however primarily due to more fondaparinux-treated patients with bleeding indexes of 2 or greater. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two groups. In the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, fondaparinux was equally effective as low molecular weight heparins and unfractionated heparin, respectively, without a different incidence in major bleeding in fondaparinux and comparator heparin groups. Fondaparinux, one of the first of a new class of synthetic selective factor Xa inhibitors, is overall 50% more effective in reducing venous thromboembolism than enoxaparin in major orthopedic surgery, with an overall 1% increased rate of major bleeding, when compared with enoxaparin. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two treatment groups. Fondaparinux is equally effective as low molecular weight heparins and unfractionated heparin in the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, respectively. Finally, as with any new drug, fondaparinux should be used cautiously and only in patients who reflect the population of the clinical trials in which the drug was evaluated.