fondaparinux and Thrombosis

The objective of this study is to comprehensively review the efficacy and safety data of low-molecular-weight heparins (LMWHs) and fondaparinux in pediatric patients with obesity.. A comprehensive literature search of PubMed, SCOPUS, CINAHL, Academic Search Complete, PsycInfo, Cochrane Library, and Web of Science databases was conducted (1900 to July 2020). Search terms utilized included. Studies that reported pediatric patients with described overweight or obesity and utilized LMWHs or fondaparinux were considered.. Of 207 studies screened, 12 were included. Average dose reductions of 12.9% to 37.3% from the starting dose were observed with treatment indications of enoxaparin and increased up to 27.3% for prophylactic indications. Trends could not be concluded in the dalteparin and fondaparinux studies. Four thrombotic and 15 bleeding events were reported in the studies.. Pediatric patients with obesity may initially be underdosed or overdosed with enoxaparin compared with children with healthy body weight, depending on the indication.. Pediatric patients with obesity may benefit from proactively adjusting enoxaparin dosing on initiation of therapy. Further studies are needed for dalteparin and fondaparinux in these populations. Clinical controversy exists with the relevance of monitoring these high-risk medications for therapeutic and prophylactic indications. Thrombotic and hemorrhagic events were similar to reported adult outcomes.

Topics: Anticoagulants; Child; Child, Preschool; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Obesity; Retrospective Studies; Thrombosis; Venous Thromboembolism

Heparin-induced thrombocytopenia (HIT) is an immunologically-mediated complication, which usually follows heparin exposition, less frequently exposition to other drugs or even occurs spontaneously. The type of heparin, its dose and mode of application as well as the exposition time, major trauma or operation, and obesity represent the main risk factors for HIT. The probability of HIT correlates with so-called 4T-score. A confirmatory laboratory diagnostic should be exclusively reserved for patients with a medium to a high probability of HIT development (more than 3 points in 4T-score). The screening method is based on serological detection of antibodies against heparin-platelet factor-4 complexes; confirmation tests aim to identify the activation of platelets. The treatment of HIT requires an immediate interruption of heparin application and rigorous antithrombotic treatment with an alternative agent. Herein authors describe a clinical case of HIT manifested as an extreme urticarial reaction in the location of nadroparin application as well as thrombosis of deep subcutaneous veins in a polymorbid obese patient with an extensive and infected burn. Due to timely diagnosis and fondaparinux treatment, no more severe thrombotic events occurred in this patient.

Topics: Anticoagulants; Fondaparinux; Heparin; Humans; Thrombocytopenia; Thrombosis

Patients with chronic kidney disease (CKD) are at increased risk for both thrombotic events and bleeding. The early stages of CKD are mainly associated with prothrombotic tendency, whereas in its more advanced stages, beside the prothrombotic state, platelets can become dysfunctional due to uremic-related toxin exposure leading to an increased bleeding tendency. Patients with CKD usually require anticoagulation therapy for treatment or prevention of thromboembolic diseases. However, this benefit could easily be offset by the risk of anticoagulant-induced bleeding. Treatment of patients with CKD should be based on evidence from randomized clinical trials, but usually CKD patients are excluded from these trials. In the past, unfractionated heparins were the anticoagulant of choice for patients with CKD because of its independence of kidney elimination. However, currently low-molecular-weight heparins have largely replaced the use of unfractionated heparins owing to fewer incidences of heparin-induced thrombocytopenia and bleeding. We undertook this review in order to explain the practical considerations for the management of anticoagulation in these high risk population.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Platelets; Drug Administration Schedule; Factor Xa; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Renal Insufficiency, Chronic; Thrombin; Thrombocytopenia; Thrombosis

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2-3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.

Topics: Administration, Oral; Anticoagulants; Asian; Black or African American; Disease Management; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Polysaccharides; Prevalence; Quality of Life; Recurrence; Risk Factors; Taiwan; Thrombosis; United States; Venous Thromboembolism; Vitamin K; Warfarin; White People

Increasing thrombotic complications in children with complex medication conditions have led to more widespread use of anticoagulants [Raffini et al. in Pediatrics 124(4):1001-8, 2009]. While current guidelines for the management of antithrombotic therapy in neonates and children exist, they are based on low- and very low-quality evidence [Monagle et al. in Chest 141(2 Suppl):e737-801S, 2012]. Despite numerous differences, current anticoagulation practice is largely extrapolated from adult studies. This is sub-optimal, particularly in neonates who have a rapidly evolving hemostatic system. The majority of pediatric patients have underlying medical conditions that may significantly influence drug choice and bleeding risk. This article reviews the use of anticoagulants in children with thrombosis, focusing on practical aspects such as dosing, monitoring, and complications. Low molecular weight heparin has become the preferred anticoagulant in children, although unfractionated heparin and warfarin remain frequently used. Other anticoagulants, including fondaparinux, direct thrombin inhibitors, and the newer target-specific oral anticoagulants are also discussed. Given the many unique challenges surrounding the use of anticoagulants in children, pediatric hospitals should have written practice guidelines as well as experienced providers to care for children with thrombosis. This is an evolving field, and further studies of the use of anticoagulants in neonates and children are greatly needed to help optimize care.

Topics: Anticoagulants; Antithrombins; Child; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Practice Guidelines as Topic; Thrombosis; Warfarin

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzamides; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostatics; Heparin; Humans; Infusions, Parenteral; Intracranial Hemorrhages; Polysaccharides; Protamines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombosis; Vitamin K

During pregnancy thrombo-prophylaxis could be required in high risk women. If a severe allergic reaction to low-molecular-weight-heparin (LMWH) or a heparin-induced-thrombocytopenia (HIT) occurs, it's mandatory to stop the drug. Fondaparinux could be an effective option. In the present review, the maternal and pregnancy outcomes of 65 pregnancies in women using Fondaparinux were reported. It was well-tolerated and rate of pregnancy complications was similar to that observed in general population. Regarding congenital malformations, further studies are necessary to investigate the safety of the drug.

Topics: Anticoagulants; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Maternal Exposure; Patient Safety; Polysaccharides; Pregnancy; Pregnancy Complications, Cardiovascular; Risk; Thrombocytopenia; Thrombosis

Thrombotic complications are increasing at a steady and significant rate in children, resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the older multitargeted agents (heparin, low-molecular-weight heparin, and warfarin) and the newer targeted agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the multitargeted and targeted anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. The various agents differ in their pharmacokinetics, requirements for therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The targeted anticoagulants have properties that may make them more attractive for use in specific clinical situations. Prospective clinical trial data are presented supporting the current and future use of these agents in children.

Topics: Adolescent; Anticoagulants; Arginine; Child; Clinical Trials as Topic; Fondaparinux; Hematology; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombosis; Treatment Outcome; Warfarin

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

The introduction of venography into patient care was a major advance because it was the first accurate method for the diagnosis of DVT. Compression ultrasound has since become the preferred test for patients with suspected DVT because, unlike venography, it is simple, non-invasive and widely available. Venography has facilitated the development and approval of new anticoagulants and remains widely used as an efficacy outcome in trials of venous thromboembolism prevention. Most thrombi detected by screening venography are, however, small and unimportant for patients. In order to calculate the trade-off between an asymptomatic thrombus and a bleed we require an estimate of the number of asymptomatic thrombi that must be prevented to avoid a patient-important thrombus. A credible estimate of this ratio is not available. Therefore when used as a measure of efficacy in trials of thromboprophylaxis, venography has limitations for comparing the relative effects of alternative antithrombotic agents on outcomes important to patients.

Topics: Anticoagulants; Cardiology; Clinical Trials as Topic; Contrast Media; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Phlebography; Polysaccharides; Reproducibility of Results; Thrombosis; Treatment Outcome; Venous Thrombosis

Fondaparinux sodium (pentasaccharide) was the first of a new class of antithrombotic agents developed for the prevention and treatment of venous thromboembolism (VTE), blocking thrombin generation by selectively inhibiting factor Xa.. This review focuses on the currently available information evaluating the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of fondaparinux in the prevention and treatment of VTE and treatment of acute coronary syndromes (ACS).. Fondaparinux is an alternative to low-molecular-weight heparins (LMWH) for thromboprophylaxis in various clinical settings (major orthopedic surgery of the lower limbs, major abdominal surgery, immobilized medical patients at high risk of VTE), as well as for the treatment of VTE (deep venous thrombosis, pulmonary embolism). It is currently challenged, in the context of both surgical thromboprophylaxis and acute VTE treatment, by the new oral anticoagulants. Fondaparinux remains the sole drug validated in patients with isolated superficial vein thrombosis of the lower limbs, and at prophylactic doses is a good alternative to LMWH at anticoagulant doses for patients with ACS, especially those ineligible for percutaneous coronary intervention.

Topics: Animals; Anticoagulants; Drug Evaluation, Preclinical; Fondaparinux; Humans; Polysaccharides; Thrombosis; Treatment Outcome

To investigate the relative benefits of unfractionated heparin, low molecular weight heparin(LMWH), fondaparinux, and bivalirudin as treatment options for patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI).. Mixed treatment comparison and direct comparison meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors.. A search of Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing unfractionated heparin plus glycoprotein IIb/IIIa inhibitor(GpIIb/IIIa inhibitor), unfractionated heparin, bivalirudin, fondaparinux, or LMWH plus GpIIb/IIIa inhibitor for patients undergoing primary PCI.. The primary efficacy outcome was short term (in hospital or within 30 days) major adverse cardiovascular event; the primary safety outcome was short term major bleeding.. We identified 22 randomized trials that enrolled 22,434 patients. In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 (95% confidence interval 1.21 to 1.84), as were bivalirudin (relative risk 1.34 (1.01 to 1.78)) and fondaparinux (1.78 (1.01 to 3.14)). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 (0.30 to 0.74)) or unfractionated heparin (0.58 (0.37 to 0.90)). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. Results were similar in direct comparison meta-analyses: bivalirudin was associated with a 39%, 44%, and 65% higher risk of myocardial infarction, urgent revascularization, and stent thrombosis respectively when compared with unfractionated heparin with or without GpIIb/IIIa inhibitor. However, bivalirudin was associated with a 48% lower risk of major bleeding compared with unfractionated heparin plus GpIIb/IIIa inhibitor and 32% lower compared with unfractionated heparin alone.. In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding. These relationships should be considered in selecting anticoagulant therapies in patients undergoing primary PCI.

Topics: Anticoagulants; Antithrombins; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Integrin beta3; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Purinergic P2Y Receptor Antagonists; Recombinant Proteins; Stents; Thrombosis; Treatment Outcome

Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents.

Topics: Anticoagulants; Child; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombosis; Vitamin K

New anticoagulants promise to have better efficacy, more safety and/or a better manageability than traditional anticoagulants. However, knowledge is limited regarding special situations such as renal insufficiency, obesity, pregnancy, long-term therapy, heparin-induced thrombocytopenia, treatment in patients with mechanical heart valves, use for children, and in patients with a high risk of thromboembolic complications. These situations have rarely or even never been the objective of randomised controlled trials. The purpose of the present article is to summarize and discuss available data on efficacy and safety in these special situations for one of the first new anticoagulants, the indirect factor-Xa inhibitor fondaparinux. Furthermore, we discuss safety in licensed indications and management of bleeding complications and comment on measuring of drug concentration in plasma.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Evidence-Based Medicine; Factor X; Female; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Pregnancy; Thrombosis

High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.. Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.. We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Topics: Administration, Oral; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Infusions, Intravenous; International Normalized Ratio; Long-Term Care; Patient Education as Topic; Polysaccharides; Randomized Controlled Trials as Topic; Self Care; Societies, Medical; Thrombosis; United States; Vitamin K

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Topics: Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Infusions, Intravenous; Peptide Fragments; Pipecolic Acids; Polysaccharides; Practice Guidelines as Topic; Recombinant Proteins; Societies, Medical; Sulfonamides; Thrombin; Thrombosis; United States

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Fondaparinux; Hemorrhage; Heparin; Humans; Polysaccharides; Practice Guidelines as Topic; Preoperative Care; Thrombosis; Warfarin

Anticoagulant prophylaxis for preventing venous thrombembolism (VTE) is a worldwide established procedure in hip (HR) and knee replacement (KR) surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Hemostasis and Thrombosis, the Italian Society of Orthopedics and Traumatology, the association of Orthopedic Traumatology of Italian Hospitals, together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care have set down easy and quick suggestions for VTE prophylaxis in HR and KR surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and thus at improving its proper application. Special focus is given to fragile patients, those with high bleeding risk, and on those receiving chronic antiplatelet and vitamin K antagonists treatment. A special chapter is dedicated to regional anesthesia and VTE prophylaxis.

Topics: Anesthesia; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Consensus; Femoral Neck Fractures; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Patient Safety; Polysaccharides; Postoperative Complications; Postoperative Hemorrhage; Risk; Stockings, Compression; Thrombosis; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Arginine; Autoantibodies; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombosis; Warfarin

The elucidation of the structure of the antithrombin binding sequence in heparin has given a large impulse to the rational design of heparin related drugs. De novo chemical synthesis of the corresponding pentasaccharide as well as simplified analogues has provided very specific, antithrombin-mediated inhibitors of factor Xa with various pharmacokinetic profiles. Fondaparinux and idraparinux are examples of such compounds that have found clinical application as antithrombotics. Because of the very specific binding to antithrombin the pharmacokinetics of pentasaccharides can be predicted and transferred to other molecules covalently bound to them. The new chemical entities thus obtained display a wide array of antithrombotic activities, giving improved heparin molecules as well as new anticoagulants, devoid of the undesired side effects of heparin and with unprecedented pharmacological profiles. In this context, a direct thrombin inhibitor was covalently coupled to a pentasaccharide by an inert spacer. This compound, EP42675 exerts antithrombin mediated anti-factor Xa activity together with direct thrombin inhibiting capacity. It displays favourable pharmacokinetics as imposed by the pentasaccharide. EP42675 was further modified by the introduction of a biotin moiety in its structure. The new entity obtained, EP217609 exerts the same pharmacological profile as EP42675 and it can be instantaneously neutralised by injection of avidin. Due to this unprecedented mechanism of anticoagulant activity and its ability to be neutralised, EP217609 deserves to be investigated in clinical settings where direct thrombin inhibition is required.

Topics: Animals; Anticoagulants; Antithrombin III; Avidin; Binding Sites; Biotin; Drug Design; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparin Antagonists; Humans; Molecular Structure; Oligosaccharides; Polysaccharides; Rabbits; Structure-Activity Relationship; Thrombosis

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of side-effects or overdose. The efficacy of idraparinux was was proven in clinical studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Atrial Fibrillation; Avidin; Biotin; Carbohydrate Conformation; Carbohydrate Sequence; Drug Design; Drug Evaluation, Preclinical; Fondaparinux; Hemorrhage; Heparin Antagonists; Humans; Molecular Sequence Data; Molecular Structure; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombosis; Treatment Outcome

Disseminated intravascular coagulation (DIC) is the physiologic result of pathologic overstimulation of the coagulation system. Despite multiple triggers, a myriad of laboratory abnormalities, and a clinical presentation ranging from gross hemostatic failure to life-threatening thrombosis, or even both simultaneously, a simplified clinical approach augmented by a few readily available tests allows prompt identification of the process and elucidation of treatment opportunities. Platelet counts in DIC may be low, especially in acute sepsis-associated DIC, yet increased in malignancy-associated chronic DIC. Thrombotic risk is not a function of the platelet count, and thrombocytopenia does not protect the patient from thrombosis. The stratification of both thrombotic risk and hemorrhagic risk will be addressed.

Topics: Adenocarcinoma; Aged; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Esophageal Neoplasms; Fatal Outcome; Fondaparinux; Foodborne Diseases; Hemorrhage; Heparin; Hepatitis C, Chronic; Humans; Male; Middle Aged; Multiple Organ Failure; Polysaccharides; Postoperative Complications; Thrombocytopenia; Thrombophlebitis; Thrombosis; Vibrio Infections; Vibrio vulnificus; Young Adult

Fondaparinux is a synthetic pentasaccharide that inhibits thrombin formation and thrombus development via selective antithrombin mediated inhibition of factor Xa. The complete bioavailability (100%) and elimination half-life of approximately 17 hours allows once-daily administration of fondaparinux. In a well designed trial (ARTEMIS) in acute medical patients aged > or = 60 years, fondaparinux was significantly more effective than placebo in terms of reducing the incidence of venous thromboembolism (VTE) up to day 15. The beneficial effect of fondaparinux therapy was observed in all subgroups of patients irrespective of underlying illness (e.g. acute heart failure or acute respiratory disease) in a predefined subgroup analysis of the ARTEMIS trial. Similarly, in a retrospective analysis of the trial, age and renal function did not appear to affect the incidence of VTE in fondaparinux and placebo recipients. Fondaparinux was generally well tolerated in this clinical trial. In patients receiving fondaparinux, the incidence of major bleeding was similar to that in patients receiving placebo and the incidence of minor bleeding was <3%.

Topics: Aged; Anticoagulants; Biological Availability; Clinical Trials as Topic; Fondaparinux; Half-Life; Humans; Middle Aged; Polysaccharides; Thrombosis

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small-scale, in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.

Topics: Anticoagulants; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombocytopenia; Thrombosis

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

Hospital-acquired deep vein thrombosis (DVT) affects 10-25% of medical patients and up to 60% of surgical patients. While thromboprophylaxis is without a doubt under utilized in the hospital setting, there is also a need for more efficacious agents. Fondaparinux, the first of a new class of agents Factor Xa inhibitiors, has recently come into clinical use. It is a synthetic pentasaccharide and indirect Factor Xa inhibitor with a predictable antithrombotic action. Being a synthetic product, there are no concerns about supply, nor viral or prion protein contamination. Initial large international trials in orthopaedic patients demonstrated its superior efficacy to standard thromboprophylaxis. Further trials confirmed its superior efficacy in venous thromboembolism (VTE) prevention, both in medical and surgical patient groups, as well as treatment of pulmonary embolism and DVT. Its use has also recently been evaluated in acute coronary syndromes and angioplasty. Fondaparinux currently has licenses in the UK for thromboprophylaxis and treatment of VTE and a license for the management of acute coronary syndrome is likely to be forthcoming. It has a favourable side effect profile and if the price is acceptable, is likely to take over from low molecular weight heparins in these indications as the drug of choice on the grounds of efficacy and safety.

Topics: Anticoagulants; Antithrombin III; Coronary Disease; Fondaparinux; Humans; Polysaccharides; Thrombosis; Venous Thrombosis

Shortcomings of the existing anticoagulants, vitamin K antagonists and heparins, have led to the development of newer anticoagulant therapies. In particular, Vitamin K antagonists' slow onset of action, numerous drug interactions, narrow therapeutic window and need for frequent monitoring make it the most obvious target for replacement. Targeting specific coagulation enzymes or steps in the coagulation pathway, new anticoagulants have been or are under evaluation in clinical trials for a number of clinical indications, namely the prevention and treatment of venous thromboembolism, the prevention of ischemic stroke in patients with atrial fibrillation, and in acute coronary syndromes. Following a brief review of pharmacological aspects, this article will summarize the results of Phase III clinical trials evaluating the novel anticoagulants fondaparinux, ximelagatran and idraparinux. At present, most attention is directed at developing an oral anticoagulant to replace vitamin K antagonists for prevention of systemic thromboembolism. A number of newer agents are in both early and advanced stages of investigation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa act

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Drug Administration Schedule; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Randomized Controlled Trials as Topic; Thrombin; Thrombosis; Warfarin

Topics: Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sensitivity and Specificity; Sulfonamides; Thrombocytopenia; Thrombosis

Venous thromboembolism (VTE) is a major problem in non-surgical patients admitted to the hospital, both during the hospitalization period and after discharge. Risk factors for VTE are well known and scoring systems have been published. Nevertheless, prophylaxis against VTE is in many hospitals used less often than ideal and also inappropriately. Electronic tools to alert the physicians to provide prophylaxis and suggest suitable measures have shown promising results with a reduction of clinically relevant VTE. Large randomized clinical trials have demonstrated efficacy of low molecular-weight heparin (LMWH), pentasaccharide(fondaparinux) and unfractionated heparin. The results were, however, driven by asymptomatic deep vein thrombosis (DVT), including distal DVT in some studies. A reduction of pulmonary embolism is achieved, but without any significant effect on the mortality. The agents are generally safe, with only a small increase of major bleeding, less with LMWH than with unfractionated heparin. The challenge is still to direct the efforts to the most appropriate patients.

Topics: Clinical Trials as Topic; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Premedication; Thromboembolism; Thrombosis; Treatment Outcome; Venous Thrombosis

During the past decade, a large number of new anticoagulant and antithrombotic drugs have been developed. These agents represent a wide variety of substances that are derived using natural sources, biotechnology-based methods, and synthetic approaches. Because of the structural and molecular characteristics, these agents exhibit physicochemical and functional diversities. Thus, each of these classes of drugs controls thrombogenesis by way of distinct mechanisms. The main classes of these new drugs include peptides, peptidomimetics, heparinomimetics, and recombinant proteins. Despite these significant developments, heparin and heparin-derived drugs have continued to play a major role in the management of thrombotic and cardiovascular disorders.

Topics: Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Oligosaccharides; Pharmacokinetics; Polysaccharides; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombosis; Warfarin

Modern approaches to prevention of venous thromboembolic complications in patients with chronic heart failure are analyzed in this review which contains results of large studies of low molecular weight heparins. In MEDENOX trial the use of enoxaparin in medical patients was associated with 63% reduction of risk of thrombosis. The authors own experience showed that 2 weeks of therapy with enoxaparin in patients with chronic stage IIB-III heart failure caused significant lowering of soluble fibrin-monomer complexes, fibrinogen, and index of turbo-dynamic potential. These changes evidenced for decreased intravascular blood coagulation. Thus enoxaparin can be effectively used for prevention of thrombosis and thromboembolism in patients with chronic heart failure. Novel antithrombotic agents fondaparinux, idraparinux, ximelagatran, recombinant thrombomodulin are perspective medications for prevention of venous thromboses and embolism in medical patients.

Topics: Anticoagulants; Azetidines; Benzylamines; Dalteparin; Double-Blind Method; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heart Failure; Humans; Multicenter Studies as Topic; Oligosaccharides; Placebos; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Thromboembolism; Thrombomodulin; Thrombosis; Time Factors; Venous Thrombosis

Antithrombotic drugs: heparins and oral vitamin K antimetabolites are connected with many side effects, which delimit their application in clinical practise. Continuous research has led to synthesis of new drugs which are safer and easier in use. Actually used antithrombotic drugs with their faults are discussed. Mechanism of action and data from trials relating to efficacy and safety of new drugs: fondaparinux, idraparinux and ximelagatran are presented.

Topics: Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thrombosis

Topics: Angina, Unstable; Animals; Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Glycine; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thrombosis

Inhibition of activated coagulation factor X (FXa) is an attractive target for antithrombotic treatment strategies, because of the central position of FXa in the coagulation cascade. Most of the now available anticoagulant drugs have inhibitory effects not only on FXa, but also on thrombin. With the development of pentasaccharides, a new class of antithrombotic agents has emerged that acts by specific inhibition of FXa and lacks activity against FIIa. Fondaparinux, the first synthetic short-acting pentasaccharide, has been evaluated, in a large phase II and III clinical programme concerning prophylaxis and treatment of venous thromboembolism and also in phase II studies in patients with acute coronary syndromes. Idraparinux, the long-acting pentasaccharide, has been studied in a dose-finding study in patients with established deep-vein thrombosis and phase III studies are now planned in patients with venous thromboembolism and in patients with atrial fibrillation.

Topics: Acute Disease; Anticoagulants; Blood Coagulation; Coronary Disease; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Fondaparinux (a synthetic heparin analogue) (Sanofi-Synthelabo; Paris, France and Organon Research; Oss, The Netherlands) is the subject of intense recent clinical evaluation for the prevention and treatment of venous and arterial thromboembolism. The drug replicates the sulphated antithrombin-binding pentasaccharide sequence in heparin and induces potent and specific antithrombin-mediated anti-Xa activity with excellent bioavailability and a long circulating half-life of 18 hours that makes it ideal for once-daily subcutaneous dosing. Its very short chain length ensures this heparin pentasaccharide (PS) is devoid of anti-factor IIa activity. No need for laboratory monitoring is anticipated. Fondaparinux does not cross-react ex vivo with the anti-platelet antibodies responsible for heparin-induced thrombocytopenia. Fondaparinux was evaluated in four large, randomized, placebo-controlled, double-blind phase III trials of deep vein thrombosis prevention after major joint surgery where the PS given after surgery was compared with a low molecular weight heparin (LMWH). LMWH was started before surgery in two comparisons and soon after surgery in the others. The trials shared the same blindly adjudicated efficacy and safety endpoints: efficacy was measured by recording subclinical deep vein thrombosis detected by screening with bilateral venography, plus clinically suspected and confirmed symptomatic thrombosis and embolism; safety was indicated by the rate of major bleeding. Bleeding was considered major if it caused death or reoperation, affected an internal organ, or was overt and associated with a bleeding index of 2 or more. By comparison with LMWH, 2.5 mg/d of the PS beginning 4 to 8 hours after wound closure reduced venous thromboembolism rates by 56% and 26% after elective hip replacement, 63% after knee replacement, and 62% after hip fracture surgery. In three studies and overall, the effect was statistically very significant and included similarly reduced rates of proximal deep vein thrombosis. In absolute terms, the DVT rates with PS are the lowest yet seen after major joint surgery. Trends toward more major bleeding with PS in three studies were statistically significant in one trial. PS did not increase risks from reoperation, internal bleeding, or death because of bleeding, because between-group differences were caused entirely by an excess of patients with a raised bleeding index. Post hoc analysis suggests this excess can be explained by too-ear

Topics: Animals; Clinical Trials as Topic; Fondaparinux; Heparin; Humans; Oligosaccharides; Orthopedic Procedures; Polysaccharides; Thrombosis

Fondaparinux (Org-31540 / SR-90107A) is a new drug chemically synthesized for treatment and prophylaxis of thromboembolic disease. Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models. Phase I trials have shown a 100% bioavailability after subcutaneous (s.c.) administration, a rapid onset of action and an approximate half-life of 13.5 h. Fondaparinux is cleared as an active substance by the kidneys. In elderly patients, renal clearance is reduced and the half-life is longer. The phase II Pentathlon trial demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism in total hip-replacement patients and the optimal dose was determined to be 2.5 mg s.c./24 h. Four phase III trials have evaluated fondaparinux starting 6 hours after surgery compared with enoxaparin for prevention of venous thromboembolism following orthopedic surgery in 7,344 patients. The risk of thrombosis was reduced by 50% with fondaparinux and no differences were observed in death or severe bleeding. In a phase II trial, similar efficacy and incidence of major bleeding were seen with fondaparinux s.c. compared with dalteparin s.c. in the treatment of deep venous thrombosis. In patients with acute myocardial infarction, the efficacy of fondaparinux during fibrinolytic therapy was assessed in 326 patients who had acute coronary syndromes of less than a 6 hour duration, showing a slight but statistically not significant advantage for fondaparinux over unfractionated heparin in the coronary angiographies. There is currently no antidote for fondaparinux.

Topics: Animals; Blood Coagulation; Fibrinolytic Agents; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism; Thrombosis; Vascular Diseases; Venous Thrombosis

Superficial-vein thrombosis can lead to deep-vein thrombosis and pulmonary embolism. Rivaroxaban, an oral factor Xa inhibitor, might simplify treatment compared with fondaparinux because it does not require daily subcutaneous injection and is cheaper. We compared efficacy outcomes in patients with superficial-vein thrombosis and additional risk factors given either rivaroxaban or fondaparinux to assess whether rivaroxaban is non-inferior to fondaparinux in the prevention of thromboembolic complications.. In this open-label, masked endpoint, randomised, non-inferiority phase 3b trial, we recruited patients aged 18 years or older with symptomatic superficial-vein thrombosis from 27 sites (academic, community hospitals, and specialist practices) in Germany. We randomly assigned patients (1:1) to receive 10 mg oral rivaroxaban or 2·5 mg subcutaneous fondaparinux once a day for 45 days. Patients were eligible if they had symptomatic thrombosis (at least 5 cm in a supragenual superficial-vein segment) and at least one additional risk factor (older than 65 years, male sex, previous venous thromboembolism, cancer, autoimmune disease, thrombosis of non-varicose veins). Main exclusion criteria were: symptoms for longer than 3 weeks, thrombus within 3 cm of the sapheno-femoral junction, indication for full-dose anticoagulation therapy, and substantial hepatic or renal impairment. Randomisation was done with a central block randomisation process. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality at 45 days in the per-protocol population (all randomly assigned patients without major protocol violations). We used a non-inferiority margin of 4·5% (absolute difference between rivaroxaban and fondaparinux). The main safety outcome was major bleeding. This study is registered with ClinicalTrials.gov, number NCT01499953.. Between April 25, 2012, and Feb 18, 2016, 485 patients were enrolled in the study and 472 were randomly assigned to the rivaroxaban group (n=236) or the fondaparinux group (n=236). In the 435 patients included in the per-protocol analysis set, the primary efficacy outcome occurred in seven (3%) of 211 patients (95% CI 1·6-6·7) in the rivaroxaban group and in four (2%) of 224 patients (0·7-4·5) in the fondaparinux group (hazard ratio [HR] 1·9, 95% CI 0·6-6·4; p=0·0025 for non-inferiority) at day 45. There were no major bleeds in either group. There was one death in the rivaroxaban group; this patient died from cardiogenic shock on day 50 after a type A aortic dissection, not related to treatment.. Rivaroxaban was non-inferior to fondaparinux for treatment of superficial-vein thrombosis in terms of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality, and was not associated with more major bleeding. Therefore, rivaroxaban could offer patients with symptomatic superficial-vein thrombosis a less burdensome and less expensive oral treatment option instead of a more expensive subcutaneous injection.. GWT-TUD and Bayer Vital.

Topics: Aged; Aged, 80 and over; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Rivaroxaban; Thrombosis; Venous Thrombosis

Activated clotting time (ACT) is widely used to guide unfractionated heparin dosing during percutaneous coronary intervention. However, its value in predicting complications is controversial in the modern era. We sought to examine the relationship between ACT and outcomes in non-ST-segment-elevation acute coronary syndrome patients.. In the Fondaparinux With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA/OASIS-8) trial, 2026 patients with non-ST-segment-elevation acute coronary syndrome treated with fondaparinux 2.5 mg/d and undergoing percutaneous coronary intervention were randomized to low-dose unfractionated heparin (50 U/kg) or standard-dose unfractionated heparin (85 U/kg or 60 U/kg with glycoprotein IIb/IIIa inhibitors, with ACT guidance). No difference was shown for major bleeding and there was a trend toward a reduction in ischemic events with standard-dose unfractionated heparin. To clarify the additional value of ACT guidance, we analyzed with logistic modeling peri-percutaneous coronary intervention outcomes according to peak ACT as a linear function. A threshold effect was then investigated. No linear correlation was found between ACT and thrombotic or bleeding events. In patients not receiving planned glycoprotein IIb/IIIa inhibitors, a significant increase in rates of death, myocardial infarction, and target vessel revascularization was identified in patients with an ACT≤300 s (4.86% versus 2.78%; adjusted odds ratio, 1.84; 95% confidence interval, 1.06-3.21; P=0.03). No threshold was found for hemorrhagic complications in patients with or without glycoprotein IIb/IIIa inhibitors.. Non-ST-segment-elevation acute coronary syndrome patients undergoing percutaneous coronary intervention with an ACT≤300 s are at increased risk of thrombotic complications. ACT, however, does not predict hemorrhagic complications.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790907.

Topics: Aged; Female; Fondaparinux; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Polysaccharides; Postoperative Hemorrhage; Predictive Value of Tests; Prognosis; Thrombosis; Treatment Outcome; Whole Blood Coagulation Time

Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 μg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 μg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 μg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 μg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 μg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.

Topics: Adolescent; Adult; Anticoagulants; Biotin; Cardiac Catheters; Enoxaparin; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Male; Middle Aged; Oligosaccharides; Polysaccharides; Prothrombin; Thrombosis

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.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Polysaccharides; Prospective Studies; Renal Dialysis; Thrombosis; Time Factors; Treatment Outcome

Topics: Antibody Formation; Autoantibodies; Fondaparinux; Humans; Orthopedic Procedures; Platelet Factor 4; Polyelectrolytes; Polymers; Polysaccharides; Thrombosis

The literature recommends against the use of fondaparinux in patients with kidney failure and dialysis as it may, with repeated dosing, accumulate and put patients at risk of bleeding. The management of patients with thrombosis in the presence of heparin-induced thrombocytopenia HIT requires the introduction of an alternative anticoagulant like bivalirudin or argatroban. When these drugs are not available, fondaparinux, remains the only alternative. In similar scenarios, there are few studies addressing how to administer it.  METHODS: We developed a protocol for fondaparinux in patients with renal failure where pharmacokinetic parameters are altered, and levels changed only after hemodialysis or in cases of residual renal activity. Patients received a full first dose except for high risk of bleeding. We targeted a peak anti-factor Xa activity level of 0.6-1.3 units/ml and changed the subsequent dose accordingly. Furthermore, we monitored the patients for signs of bleeding, a drop in hemoglobin level, or clinical signs of thrombosis.  DISCUSSION: We described 10 patients with kidney failure and suspected HIT taking fondaparinux. All the patients achieved therapeutic anti-factor Xa activity levels. However, one developed new-onset venous thromboembolism (VTE) despite therapeutic anti-factor Xa levels. Another patient experienced a bleeding episode. We believe that these two patients developed complications due to their medical conditions rather than the use of fondaparinux.. Fondaparinux can be safely used in kidney failure using our protocol. However, despite its safety profile and relative success, this case series was small. More robust studies need to be conducted prior to drawing conclusions.. New Fondaparinux Protocol to Reduce the Risk of Blood Thickening and Blood Clots Formation in Adults with Kidney Disease and Heparin-induced Thrombocytopenia (drop in platelets after the use of heparin): A Test Study.Fondaparinux is a drug used to treat patients suffering from thrombosis (clot in blood) and prevent vessels occlusions. When patients have kidney disease, the ideal treatment for thrombosis would be heparin; and, in case of Heparin Induced Thrombocytopenia (HIT), an unexpected drop in platelets after the use of heparin, the ideal treatment would be argatroban or bivalirudin. Fondaparinux can be used for HIT. However, studies recommend against its use in kidney disease as it might accumulate and cause bleeding.We were put in a challenging situation where we had patients with life-threatening thrombosis, kidney disease, HIT and unavailability of both argatroban and bivalirudin. Our only option was fondaparinux. We had to devise a safe and efficient protocol. The starting dose was the one used had the patient had a normal kidney function. Then, anti-Factor Xa activity was regularly measured with the target level 0.6-1.3units/ml 4 h after a dose. The dose was individualized, changed based on the Factor Xa activity result, the risk of bleeding or thrombosis, the overall kidney function and the need for dialysis.Our protocol was tested on 10 patients. All our patients could reach the target and safe Factor Xa activity. We had 2 exceptions. The first had a clotting event despite having therapeutic Factor Xa activity and the second was a very sick cancer patient who was bleeding despite skipping many doses of fondaparinux. We consider that these 2 cases developed complications due to their medical conditions rather than the use of fondaparinux.We concluded that fondaparinux can be safely used in patients with kidney disease, granted that Factor Xa activity is measured, the risk of bleeding is weighed to the risk of thrombosis and the dose is individualized. However, our sample size is small and further studies with a larger number of patients are needed to draw a conclusion.

Topics: Adult; Anticoagulants; Fondaparinux; Hemorrhage; Heparin; Humans; Renal Insufficiency; Retrospective Studies; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia (HIT) is a serious thrombotic disorder caused by ultralarge immune complexes (ULICs) containing platelet factor 4 (PF4) and heparin that form the HIT antigen, together with a subset of anti-PF4 antibodies. ULICs initiate prothrombotic responses by engaging Fcγ receptors on platelets, neutrophils, and monocytes. Contemporary anti-thrombotic therapy for HIT is neither entirely safe nor entirely successful and acts downstream of ULIC formation and Fcγ receptor-initiated generation of thrombin.. To determine whether HIT antigen and ULIC formation and stability could be modified favorably by inhibiting PF4-heparin interactions with fondaparinux, together with blocking formation of PF4 tetramers using a humanized monoclonal anti-PF4 antibody (hRTO).. Results: The combination of fondaparinux and hRTO inhibited HIT antigen formation, promoted antigen dissociation, inhibited ULIC formation, and promoted ULIC disassembly at concentrations below the effective concentration of either alone and blocked Fcγ receptor-dependent induction of factor Xa activity by monocytic THP1 cells and activation of human platelets in whole blood. Combined with hRTO, fondaparinux inhibited HIT antigen and immune complex formation and activation through Fcγ receptors at concentrations at or below those used clinically to inhibit FXa coagulant activity.. HIT antigen and immune complexes are dynamic and amenable to modulation. Fondaparinux can be converted from an anticoagulant that acts at a downstream amplification step into a rationale, disease-specific intervention that blocks ULIC formation. Interventions that prevent ULIC formation and stability might increase the efficacy, permit use of lower doses, shorten the duration of antithrombotic therapy, and help prevent this serious thrombotic disorder.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antigen-Antibody Complex; Fondaparinux; Heparin; Humans; Platelet Factor 4; Receptors, IgG; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Cardiology; Fondaparinux; Humans; Thrombosis; Venous Thrombosis

Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with antiphospholipid antibodies. Dysregulation of the complement pathway has been implicated in APS pathophysiology. We report the successful use of eculizumab, an anti-C5 monoclonal antibody, in controlling and preventing recurrent thrombosis in a refractory case of APS. An 18-year-old female was diagnosed with APS after developing extensive, unprovoked deep vein thrombosis (DVT) of axillary, inferior vena cava, and brachiocephalic veins. Thrombophilia evaluation revealed triple-positive lupus anticoagulant, β-2 glycoprotein IgM, IgA, and anticardiolipin antibodies (each >40 U/mL) with persistently positive titers after 12 weeks. She was refractory to multiple anticoagulants alone (enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin) with antiplatelet (aspirin and clopidogrel) and adjunctive therapies (hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis). Despite these, she continued to develop recurrent thrombosis and additionally developed hepatic infarction and pulmonary embolism with failure to decrease titers after 6 weeks of plasma exchange. Following this event, eculizumab (600 mg weekly × 4 weeks followed by 900 mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen without recurrence of thrombosis. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS.

Topics: Adolescent; Antibodies, Monoclonal, Humanized; Antiphospholipid Syndrome; Aspirin; Clopidogrel; Female; Fondaparinux; Humans; Hydroxychloroquine; Thrombosis

Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT-Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT-Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.

Topics: Anticoagulants; COVID-19 Vaccines; Fondaparinux; Heparin; Humans; Immunoglobulin G; Platelet Factor 4; Thrombocytopenia; Thrombosis

Hospital-associated venous thromboembolism (HA-VTE) is a major cause of morbidity and mortality and is internationally recognized as a significant patient safety issue. While cirrhosis was traditionally considered to predispose to bleeding, these patients are also at an increased risk of VTE, with an associated increase in mortality. Hospitalization rates of patients with cirrhosis are increasing, and decisions regarding thromboprophylaxis are complex due to the uncertain balance between thrombosis and bleeding risk. This is further accentuated by derangements of hemostasis in patients with cirrhosis that are often considered contraindications to pharmacological thromboprophylaxis. Due to the strict inclusion and exclusion criteria of seminal studies of VTE risk assessment and thromboprophylaxis, there is limited data to guide decision making in this patient group. This guidance document reviews the incidence and risk factors for HA-VTE in patients with cirrhosis, outlines evidence to inform the use of thromboprophylaxis, and provides pragmatic recommendations on VTE prevention for hospitalized patients with cirrhosis. In brief, in hospitalized patients with cirrhosis: We suggest inclusion of portal vein thrombosis as a distinct clinically important endpoint for future studies. We recommend against the use of thrombocytopenia and/or prolongation of prothrombin time/international normalized ratio as absolute contraindications to anticoagulant thromboprophylaxis. We suggest anticoagulant thromboprophylaxis in line with local protocols and suggest low molecular weight heparin (LMWH) or fondaparinux over unfractionated heparin (UFH). In renal impairment, we suggest LMWH over UFH. For critically ill patients, we suggest case-by-case consideration of thromboprophylaxis. We recommend research to refine VTE risk stratification, and to establish the optimal dosing and duration of thromboprophylaxis.

Topics: Anticoagulants; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Liver Cirrhosis; Thrombosis; Venous Thromboembolism

Limited evidence exists to guide the management of recurrent thrombosis occurring despite therapeutic anticoagulation in patients with thrombotic antiphospholipid syndrome (APS). In this case series, fondaparinux, with or without an antiplatelet agent, provided an effective and safe option in three patients with thrombotic APS, all two triple and one single positive for antiphospholipid antibodies, who had recurrent venous and/or arterial thromboembolism. Rituximab was also used in all patients. Recurrent events occurred despite therapeutic anticoagulation, including at high-intensity, with warfarin and subsequent low-molecular-weight heparin. There were no major bleeding events. Adjunctive therapies used for thrombosis included catheter-directed thrombolysis and rituximab.

Topics: Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Lupus Erythematosus, Systemic; Platelet Aggregation Inhibitors; Rituximab; Thrombosis; Warfarin

Thrombin generation (TG) with and without thrombomodulin (TM) was evaluated in COVID-19 patients with different disease severity and thromboprophylaxis regimen, in order to understand the prothrombotic profile.. We enrolled consecutive patients with confirmed diagnosis of COVID-19 admitted to Medical Departments (MD) or Intensive Care Units (ICU), and 54 healthy controls.. Eighty-nine patients were included (mean age 60.4±16.1 years, 68.5% male); 33.7% admitted to ICU. Twenty-four patients (26.9%) were enrolled before thromboprophylaxis administration; 45 patients (50.6%) received standard and 20 (22.5%) intermediate sub-therapeutic dose thromboprophylaxis. Overall, patients with COVID-19 showed a TG profile comparable to that of healthy subjects (i.e. comparable peak height, endogenous thrombin potential [ETP] with and without TM). The only exception was lag time and time to peak, prolonged in COVID-19 patients vs. controls. MD patients showed a similar TG profile to healthy controls, and ICU patients showed significantly decrease ETP (p=0.030) compared to MD. As for thromboprophylaxis, TG profile was significantly increased in COVID-19 patients without thromboprophylaxis vs. controls and vs. those with thromboprophylaxis. In this latter group, ETP inhibition was significantly decreased (p=0.0003) and positively correlated with anti-Xa activity (r=0.49, p=0.0017). However, patients with thromboprophylaxis had similar TG profile vs. controls. Intermediate dose thromboprophylaxis more effectively inhibited TG in severe COVID-19 patients by increasing ETP inhibition via ETP with TM reduction vs. standard dose.. COVID-19 patients showed increased TG at diagnosis. Standard thromboprophylaxis reduced TG to levels of healthy controls. Intermediate sub-therapeutic thromboprophylaxis more effectively inhibited TG by decreasing ETP with TM.

Topics: Adult; Aged; Anticoagulants; COVID-19; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Prospective Studies; SARS-CoV-2; Thrombin; Thrombomodulin; Thrombosis

Splanchnic vein thrombosis (SVT) is a possible complication of acute pancreatitis (AP). There are no precise guidelines on the use of anticoagulant therapy (AT) in these patients. The aim of the study was to determine the safety and the efficacy of AT in AP-associated SVT. Two hundred twenty-one patients were retrospectively and consecutively enrolled from the Pancreatic Outpatient Clinic of the "A. Gemelli" hospital. Patients had a diagnosis of AP and a diagnostic imaging to evaluate whether they had or not SVT. Twenty-seven out of 221 AP patients had SVT (12.21%) and AT therapy was administered to 16 patients (59.3%), for 5.2 ± 2.2 months. A therapeutic dose of low molecular weight heparin was administered (100 UI/kg b.i.d.) at the diagnosis, with fondaparinux 7.5 mg/day, or vitamin K antagonist, or the novel direct oral anti-coagulants, upon discharge. The presence of SVT resulted significantly associated to male sex (p = 0.002). The recanalization rates were 11/16 (68.7%) in patients who received AT, and 3/11 (27.3%) in patients who did not receive it. There was a significant difference between the recanalization rates with and without AT (p = 0.03, OR 5.87). No SVT recurrence was registered during follow-up. No treated patient developed haemorrhagic complications after AT. No deaths were recorded, either in the group undergoing AT or in the one that was not. In conclusion, AT in AP-associated SVT appears to be safe and effective; yet prospective clinical trials are needed to confirm our results.

Topics: Adult; Aged; Anticoagulants; Chi-Square Distribution; Female; Fondaparinux; Humans; Italy; Male; Middle Aged; Pancreatitis; Prospective Studies; Retrospective Studies; Splanchnic Circulation; Thrombosis

Topics: Anticoagulants; Fondaparinux; Heparin; Humans; Thrombocytopenia; Thrombosis

Topics: Aged; Aged, 80 and over; Anticoagulants; COVID-19; COVID-19 Drug Treatment; Enoxaparin; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Italy; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Thrombosis; Treatment Outcome; Venous Thromboembolism

The off-label use of fondaparinux in patients with heparin-induced thrombocytopenia with thrombosis (HITT) has historically been controversial. We present a case of successful fondaparinux use to treat HITT confirmed by the serotonin-release assay in the setting of other significant clotting and bleeding risk factors.. We report a 19-year-old male with a history of Factor V Leiden and recent neurosurgery treated with fondaparinux after developing HITT confirmed by the serotonin-release assay (SRA). The patient achieved full platelet recovery on fondaparinux and was successfully transitioned to warfarin therapy without further thrombotic nor bleeding complications.. This case demonstrates a clear example of success of fondaparinux use to treat SRA-confirmed HITT in the setting of complicating factors and adds to the existing literature supporting the use of fondaparinux for HIT.

Topics: Adult; Anticoagulants; Blood Coagulation; Factor V; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Serotonin; Thrombocytopenia; Thrombosis; Young Adult

Maintaining mechanical circulatory support (MCS) device patients in a specified therapeutic range for anticoagulation remains challenging. Subtherapeutic international normalized ratios (INRs) occur frequently while on warfarin therapy. An effective anticoagulant bridge strategy may improve the care of these patients. This retrospective review of MCS patients with subtherapeutic INRs compared an intravenous unfractionated heparin (UFH) strategy with a subcutaneous enoxaparin or fondaparinux strategy. Native thromboelastography (n-TEG) was used to evaluate anticoagulant effect with coagulation index (CI) as the primary outcome measure. Enoxaparin 0.5 mg/kg subcutaneously (SC) every 12 hours or fondaparinux 2.5-5 mg SC daily were compared with an initial UFH rate of 5 units/kg/hr and titrated to stated n-TEG goal range. The anticoagulant groups UFH, enoxaparin, and fondaparinux were found to be statistically similar with regard to frequency in n-TEG goal range, above range (hypercoagulability), or below range (hypocoagulability). Clinical outcomes were similar among groups with three gastrointestinal bleeds in UFH, one in enoxaparin, and one in fondaparinux groups. Device thrombosis occurred in one UFH patient, while UFH and fondaparinux groups had one ischemic cerebrovascular accident event each. These strategies provided comparable n-TEG results and clinical outcomes when compared with intravenous UFH. Low-dose enoxaparin or fondaparinux may provide an alternative anticoagulant bridging option in MCS patients presenting with subtherapeutic INR.

Topics: Anticoagulants; Enoxaparin; Female; Fondaparinux; Heart-Assist Devices; Humans; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Thrombosis

Essentials Spontaneous HIT syndrome clinically/serologically resembles HIT but without proximate heparin. Rarely, spontaneous HIT syndrome complicates total knee arthroplasty surgery. Mesenteric vein thrombosis is a rare presentation of spontaneous HIT syndrome. IVIg rapidly corrects thrombocytopenia by inhibiting heparin-independent platelet activation. SUMMARY: Spontaneous heparin-induced thrombocytopenia (HIT) syndrome is an autoimmune HIT (aHIT) disorder characterized by thrombocytopenia, thrombosis, and HIT antibodies despite no proximate heparin exposure. For unknown reasons, many cases occur after total knee arthroplasty. A 52-year-old woman presented 12 days posttotal knee replacement (aspirin thromboprophylaxis) with gastrointestinal bleeding (superior mesenteric vein thrombosis); the platelet count was 63 × 10

Topics: Anticoagulants; Arginine; Arthroplasty, Replacement, Knee; Female; Fondaparinux; Gastrointestinal Hemorrhage; Heparin; Humans; Immunoglobulins, Intravenous; Middle Aged; Pipecolic Acids; Platelet Activation; Platelet Count; Serotonin; Sulfonamides; Thrombocytopenia; Thrombosis; Venous Thromboembolism

We discuss two patients with antiphospholipid syndrome (APS) who presented with critical ischemia of both lower extremities due to arterial microthrombi. They received multimodality therapy emergently: anticoagulation, immunosuppression, and therapeutic plasma exchange (TPE). Then they were maintained on anticoagulation with fondaparinux and immunosuppression with mycophenolate mofetil (MMF), and were followed for 4 years.. Two patients with APS with ischemia and necrosis of their distal lower extremities were treated emergently with anticoagulation (intravenous heparin), immunosuppression (prednisone), and TPE. They were maintained on anticoagulation with fondaparinux and immunosuppression with MMF.. Neither patient had recurrent microthrombotic disease during a 4-year follow-up.. As described in our small cohort, patients with APS who suffer from microthrombotic arterial disease may benefit from maintenance therapy of anticoagulation with fondaparinux and immunosuppression with MMF, an approach which may be worthy of further trial. Fondaparinux does not require attention to diet, monitoring, and cumbersome bridging that is typical of warfarin therapy. MMF provides immunosuppression while sparing the side effects of steroid treatment.

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Combined Modality Therapy; Female; Follow-Up Studies; Fondaparinux; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Plasma Exchange; Thrombosis; Treatment Outcome

Topics: Adult; Anticoagulants; Antithrombins; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Fondaparinux; Humans; Lung Neoplasms; Male; Recurrence; Thrombophilia; Thrombosis; Venous Thromboembolism

Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants.

Topics: Anticoagulants; Arginine; Blood Coagulation; Child; Drug Monitoring; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombosis; Venous Thromboembolism; Warfarin

The prevalence of medical conditions representing a risk for thromboembolic complications and requiring antithrombotic therapy increases gradually with age. Two cases of fatal noncritical organ bleeding complication that occurred during the conversion period from initial fondaparinux to vitamin K antagonist are presented. An 81-year-old obese female patient (body mass index 43 kg/m(2)) with previous postoperative thrombosis underwent uneventful total knee replacement under spinal anesthesia. She presented with popliteal hematoma during conversion to oral anticoagulant. A 92-year-old female patient (body mass index 33 kg/m(2)) with left lower limb thrombosis was referred to our orthopedics department from her senior citizens' home for right lower limb hematoma and ischemia that occurred during conversion to oral anticoagulant. Thromboembolic and bleeding events in the elderly are real public health problems. Specific guidelines dedicated to this particular population are needed, which will improve the management of anticoagulation and decrease risk of complications.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Fatal Outcome; Female; Fondaparinux; Hemorrhage; Humans; Obesity; Polysaccharides; Risk Factors; Thromboembolism; Thrombosis; Vitamin K

Edoxaban, an oral direct factor Xa inhibitor, was developed and approved for anticoagulant thromboprophylaxis after total knee arthroplasty (TKA). We retrospectively investigated the postoperative anemia by oral administration of edoxaban 30 mg compared with fondaparinux 2.5 mg in TKA patients. Two hundred twenty nine patients who underwent TKA in National Hospital Organization Okayama Medical Center from July 2010 to June 2012 were divided into two groups; pre and post approval of edoxaban: fondaparinux-group (F-group) and edoxaban-group (E-group). As the primary endpoint, the frequency of postoperative anemia was evaluated. Blood coagulation values and relations between these parameters and postoperative anemia were also investigated. The frequency of postoperative anemia was significantly higher in E-group than F-group patients (52.7% vs. 37.8%; p<0.05). Hemoglobin (Hgb) levels were decreased with the peak at postoperative day (POD) 3 in both groups, and the change of Hgb values from POD1 (ΔHgb) was significantly increased in the E-group (p=0.04). At each POD, prothrombin time (PT) and international normalized ratio of PT (PT-INR) prolonged from the preoperative day in E-group were significantly higher than F-group. Additionally, PT and PT-INR in the E-group at POD3 were significantly prolonged in patients with postoperative anemia and the sensitivity of cut-off values to predict postoperative anemia was superior to the activated partial thromboplastin time (APTT). Thus, as the frequency of postoperative anemia tended to be higher in E-group, edoxaban 30 mg might require vigilance, and prolonged PT and PT-INR could potentially predict edoxaban-associated postoperative anemia after TKA.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anemia; Arthroplasty, Replacement, Knee; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Injections, Subcutaneous; International Normalized Ratio; Male; Partial Thromboplastin Time; Polysaccharides; Postoperative Complications; Prothrombin Time; Pyridines; Thiazoles; Thrombosis

The parenteral anticoagulants may cause uncontrolled and life-threatening bleeding. Protamine, the only registered heparin antidote, is partially effective against low-molecular weight heparins, completely ineffective against fondaparinux and may cause unacceptable toxicity. Therefore, we aimed to develop a synthetic compound for safe and efficient neutralization of all parenteral anticoagulants. We synthesized pegylated PMAPTAC block copolymers, and then, we selected a lead heparin-binding copolymer (HBC). We assessed the effectiveness of HBC in the model of arterial thrombosis electrically induced in the carotid artery of rats by measuring thrombus weight, bleeding time, activated partial thromboplastin time, activated clotting time, and anti-factor Xa activity. The intravital tissue distribution, the cardiorespiratory, and organ toxicity were monitored. HBC diminished antithrombotic and anticoagulant effects of unfractionated heparin. Moreover, it stopped bleeding and completely reversed the enhancement of clotting times and anti-factor Xa activity caused by enoxaparin or fondaparinux. We observed slight pulmonary congestion and cell infiltration, but the cardiorespiratory parameters remained unchanged. We found a strong signal of fluorescently-labeled HBC in the urine, and a weaker in the liver and in the kidney. No signs of hepatic or nephrotoxicity were observed in the blood biochemistry or histopathologic examination. We developed a copolymer efficiently neutralizing effects of heparins in the living organism, which shows a very promising efficacy/safety profile and may help in the management of uncontrolled bleeding resulting from an anticoagulant injection. HBC could enable the safe replacement of unfractionated heparin with low-molecular weight heparins in patients undergoing cardiac surgery and complex vascular procedures.

Topics: Adult; Animals; Anticoagulants; Bleeding Time; Cell Survival; Enoxaparin; Fondaparinux; Heparin; Humans; Male; Mice, Nude; Neutralization Tests; Organ Specificity; Partial Thromboplastin Time; Polymers; Polysaccharides; Rats, Wistar; Thrombosis

EP217609 is a new synthetic parenteral dual-action anticoagulant combining a direct thrombin inhibitor (α-NAPAP analog), an indirect factor Xa inhibitor (fondaparinux analog) and a biotin moiety allowing its neutralisation. EP217609 exhibited similar in vitro anticoagulant properties as its parent compounds. On the basis of dose-response curves, we identified low and moderate doses of EP217609 resulting in similar ex vivo prolongation of the APTT as α-NAPAP analog and comparable ex vivo anti-FXa activity as fondaparinux. The effects of EP217609 were compared to those of its parent compounds used alone or in combination in two models of experimental thrombosis induced by FeCl3 injury of the carotid artery or mechanical injury of atherosclerotic plaques in ApoE-deficient mice. When administered at low doses increasing the APTT by only 1.1 fold, EP217609 significantly reduced the thrombus area in both models as compared to α-NAPAP analog or fondaparinux alone, but not to the combination of these drugs. In contrast, at higher doses increasing the APTT 1.5 times, EP217609 was not superior to either parent compound. Low doses of EP217609 did not prolong the tail bleeding time or increase the volume of blood loss, although a tendency towards an increased blood loss was observed in five out of 12 mice. Finally, the effects of EP217609 could be neutralised in vivo by injection of avidin. The pharmacological profile of EP217609, its performance in arterial thrombosis models and its possible neutralisation make it an interesting molecule and a potential candidate as an antithrombotic drug.

Topics: Animals; Anticoagulants; Arteries; Avidin; Biotin; Bleeding Time; Blood Coagulation; Dose-Response Relationship, Drug; Factor Xa; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligosaccharides; Polysaccharides; Prothrombin; Thrombosis

Topics: Aged; Anticoagulants; Female; Fondaparinux; Heparin; Humans; Middle Aged; Multiple Sclerosis; Neuromyelitis Optica; Plasma Exchange; Polysaccharides; Thrombocytopenia; Thrombosis

Current guidelines for heparin-induced thrombocytopenia (HIT) management recommend heparin cessation and switching to a nonheparin anticoagulant (ie, argatroban, danaparoid) upon clinical suspicion. Fondaparinux may be effective but information supporting its use is limited. We retrospectively evaluated 239 patients who received a nonheparin anticoagulant (fondaparinux = 133, danaparoid = 59, and argatroban = 47) for suspected or confirmed HIT. A propensity score was constructed based on age, gender, creatinine, 4T scores, and comorbidity index, and used to match 133 patients to 60 controls. Outcomes were thrombosis or thrombosis-related death and major bleeding. In the matched population there were 22 (16.5%) episodes of thromboses in the fondaparinux group and 13 (21.4%) in the control group (χ(2) P = .424). Bleeding was observed in 28 (21.1%) patients in the fondaparinux group compared with 12 (20%) in the control group (χ(2) P = .867). Survival analysis, and subgroup and unmatched analyses showed similar results. In the fondaparinux group, 60% of patients received prophylactic doses. Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected HIT. Prophylactic fondaparinux doses seem to be effective if no indication for full anticoagulation exists.

Topics: Aged; Anticoagulants; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Propensity Score; Retrospective Studies; Thrombocytopenia; Thrombosis; Treatment Outcome

Topics: Biological Availability; Drug Approval; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Thrombosis

Cancer cells may alter the efficiency of the antithrombotic agents. To explore this possibility, the present study compared the capacity of the LMWH enoxaparin and the specific inhibitors of Xa (apixaban and fondaparinux) to inhibit thrombin generation triggered by pancreas adenocarcinoma cells (BXPC3) and human breast carcinoma cells (MCF7).. Samples of platelet poor (PPP) or platelet rich plasma (PRP) spiked with apixaban, fondaparinux or enoxaparin were added in micro wells carrying cancer cells and assessed for thrombin generation. In the control experiment thrombin generation was triggered with tissue factor reagent.. The three antithrombotics inhibited thrombin generation in a concentration dependent manner. The BXPC3 and MCF7 cells reversed in a different intensity the effect of the studied agents. According to the histological type of the cancer the antithrombotic efficiency of apixaban was preserved or partially reversed. Fondaparinux, was more vulnerable to the presence of cancer cells as compared to apixaban. The effect of BXCP3 or MCF7 cells on the antithrombotic potency of enoxaparin was of similar magnitude as that on apixaban.. The type of cancer cells is determinant for the antithrombotic efficiency of the specific factor Xa inhibitors. In contrast it does not significantly influence the potency of enoxaparin. The present study shows that the impact of the type of cancer cells on the antithrombotic activity of the specific Xa inhibitors should not be neglected. This has to be taken into consideration for the design of dose-finding studies of the direct orally active FXa inhibitors in patients with different histological types of cancer.

Topics: Anticoagulants; Blood Platelets; Breast Neoplasms; Cell Line, Tumor; Enoxaparin; Factor Xa; Female; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Inhibitory Concentration 50; MCF-7 Cells; Pancreatic Neoplasms; Polysaccharides; Pyrazoles; Pyridones; Thrombin; Thrombosis

Topics: Anticoagulants; Cardiomyopathies; Follow-Up Studies; Fondaparinux; Heart Transplantation; Heart-Assist Devices; Heparin; Humans; Male; Middle Aged; Polysaccharides; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic disorder of heparin treatment that leads to a decline in platelet count and thrombotic complications. If HIT is suspected, then heparin should be stopped and an alternative anticoagulant started. Fondaparinux is a factor Xa-inhibitor that is not FDA-approved for this condition, but preliminary experience in HIT patients has been reported in the literature. The present study describes an experience of anticoagulation management with fondaparinux in postoperative cardiac surgery patients.. Retrospective study.. Tertiary hospital.. Patients who had undergone cardiac surgery from October 2009 to June 2012.. After HIT was suspected clinically, PaGIA and ELISA test were performed in all patients to diagnose HIT. In the patients included, anticoagulation was managed with a low dose of fondaparinux and daily monitoring of platelet count and anti-Xa level.. Of a total of 1,338 postoperative cardiac surgery patients, 15 patients were included (1.1%). Twelve of the 15 patients with HIT presented with renal failure and were under continuous renal replacement therapy. Two major bleeding events occurred during fondaparinux treatment, although platelet count and anti-Xa activity remained within the normal range. No thrombotic episodes were diagnosed.. With daily monitoring of anti-Xa activity, fondaparinux appeared to be a good alternative to heparin in the study group; however, randomized clinical trials are needed to establish the safety and efficacy of this drug in critically ill, previously HIT patients.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Cardiac Surgical Procedures; Dose-Response Relationship, Drug; Factor X; Female; Follow-Up Studies; Fondaparinux; Heart Diseases; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Platelet Count; Polysaccharides; Postoperative Complications; Retrospective Studies; Thrombocytopenia; Thrombosis; Treatment Outcome

Fondaparinux, indirect factor Xa (FXa) inhibitor, is recommended for thromboprophylaxis for high-risk patients undergoing major orthopedic surgery. We evaluated the prothrombotic state and anticoagulant intensity of fondaparinux (2.5 mg daily) after total hip replacement (THR). Twenty patients underwent THR - seven bilateral and 13 unilateral. Blood samples were collected preoperatively and at 6 h, 8 h (2 h after fondaparinux), 1 day (12-14 h after fondaparinux), and 4 weeks (12-14 h after fondaparinux) postoperatively. Antithrombin (AT), fibrinogen, factor VIII activity, coagulation times, thrombin-AT (TAT) complex, D-dimer, C-reactive protein, prothrombinase-induced clotting time (PiCT) and anti-Xa activity were measured. The latter two were also tested after plasma spiking with fondaparinux 0-1.25 μg/ml. In spiked prophylactic fondaparinux samples (0-0.25 μg/ml), PiCT and anti-Xa activity correlated (r = 0.84) better than in the patient samples (r = 0.35). On the first day, anti-Xa activity and PiCT dissociated, and PiCT lost sensitivity for fondaparinux. AT decreased but stayed within the normal range, whereas TAT complex and D-dimer peaked at 6 h as signs of thrombin generation. On the first postoperative day, TAT and D-dimer halved. Bilateral THR associated with higher TAT and D-dimer levels up to 4 weeks. Perioperative FVIII levels were not affected, but were elevated in both groups (range 191-211%) after 4 weeks. Anti-Xa activity detected prophylactic fondaparinux with higher sensitivity than PiCT in vitro, but even more so in vivo. Thus, PiCT is not the method of choice to assess fondaparinux at least in association with THR. THR, bilateral more than unilateral, increased thrombin generation and D-dimer 7-11-fold early after surgery. Factor VIII activity and D-dimer remained elevated even after 4 weeks despite the compliant thromboprophylaxis with fondaparinux.

Topics: Adult; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Blood Coagulation; Blood Coagulation Tests; C-Reactive Protein; Factor VIII; Factor Xa; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fondaparinux; Hip Joint; Humans; Male; Middle Aged; Polysaccharides; Thrombin; Thromboplastin; Thrombosis

In a model of acute inflammation, Factor Xa inhibitors have been reported not only to suppress the coagulation system but also to exert anti-inflammatory effects. However, this has not been experimentally demonstrated in a model of chronic inflammation. Recent studies demonstrated that vascular inflammation in the metabolic syndrome plays major roles in the development of thrombotic diseases. Therefore, we examined the anti-inflammatory effects of fondaparinux, a Factor Xa inhibitor, in a mouse model of the metabolic syndrome, looking at both leukocyte adhesion on the vascular endothelium and thrombus formation.. Following clamping of the mesenteric vein for 20 min in the KK-A(y) mouse, mice were administered by subcutaneous injection either low-dose or high-dose fondaparinux or placebo (n = 10 in each group. Microscopic observation of the intestinal microcirculation was carried out. In another series, blood samples were taken and measured for blood cell counts and organ damage markers (n = 6 in each).. Both leukocyte adherence and thrombus formation were inhibited by treatment with fondaparinux. Red blood cell and white blood cell counts were maintained better in high-dose group. Levels of alanine aminotransferase (ALT) were significantly reduced in both low-dose and high-dose groups (P < 0.05 and 0.01, compared with control, respectively).. Factor Xa inhibitor attenuates leukocyte adhesion and leukocyte-platelet conjugate formation in a mouse model of the metabolic syndrome. These effects appeared to be related to both inhibition of thrombus formation and reduction in markers of organ damage.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Blood Cell Count; Cell Adhesion; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Fondaparinux; Leukocytes; Metabolic Syndrome; Mice; Polysaccharides; Thrombosis

Topics: Aged, 80 and over; Female; Fibrinolytic Agents; Fondaparinux; Heparin; Humans; Off-Label Use; Polysaccharides; Thrombocytopenia; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition that can develop after exposure to unfractionated or low-molecular-weight heparins. Treatment options appear to be limited in patients on concurrent intermittent hemodialysis. We report the case of an 88-year-old man newly initiated on high-flux hemodialysis who developed HIT and extracorporeal circuit thrombosis after 3 weeks of exposure to unfractionated heparin. Our patient was successfully treated with fondaparinux 2.5 mg subcutaneously three times per week and citrate during dialysis sessions. Antifactor Xa levels were measured on several occasions while receiving fondaparinux.

Topics: Aged, 80 and over; Anticoagulants; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Male; Polysaccharides; Renal Dialysis; Thrombocytopenia; Thrombosis

The pentasaccharide fondaparinux is widely approved for prophylaxis and treatment of thromboembolic diseases and therapy of acute coronary syndrome. It is also used off-label in patients with acute, suspected or antecedent heparin-induced thrombocytopenia (HIT). The aim of this prospective observational cohort study was to document fondaparinux' prescription practice, tolerance and therapy safety in a representative mixed German single-centre patient cohort.. Between 09/2008 - 04/2009, 231 consecutive patients treated with fondaparinux were enrolled. Medical data were obtained from patient's records. The patients were clinically screened for thrombosis (Wells score), sequelae of HIT (4T's score), and bleeding complications (ISTH-criteria) and subjected to further assessment (i.e. sonography, HIT-diagnostics), if necessary. The mortality rate was assessed 30 days after therapy start.. Overall, 153/231 patients had a prophylactic, 74/231 patients a therapeutic, and 4/231 patients a successive prophylactic/therapeutic indication. In 11/231 patients fondaparinux was used due to suspected/antecedent HIT, in 5/231 patients due to a previous cutaneous delayed-type hypersensitivity to heparins. Other indications were rare. Three new/progressive thromboses were detected. No cases of HIT, major bleedings, or fatalities occurred.. Fondaparinux was well tolerated and was safe in prophylaxis and therapy; prescriptions mostly followed the current approval guidelines and were rarely related to HIT-associated indications (<5% of prescriptions), which is in contrast to previous study results in the U.S. (>94% of prescriptions were HIT-associated). A trend towards an individualised fondaparinux use based on the compound's inherent properties and the patients' risk profiles, i.e., antecedent HIT, bone fractures, heparin allergy, was observed.

Topics: Adult; Aged; Anticoagulants; Drug Hypersensitivity; Drug Prescriptions; Female; Fondaparinux; Germany; Hemorrhage; Heparin; Hospitals, University; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Risk Assessment; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

Catheters initiate coagulation by activating factor (f) XII, which can lead to catheter thrombosis. Fondaparinux, which only targets activated fX (fXa), is associated with more catheter thrombosis than heparin, which targets fXa and thrombin. To render catheters less thrombogenic and fondaparinux more effective, we examined whether coating catheters with corn trypsin inhibitor (CTI), which blocks fXIIa, attenuates catheter-induced clotting and promotes fondaparinux activity. Compared with unmodified catheters, CTI-coated catheters demonstrated (a) decreased adsorption of fibrinogen and fXII, (b) greater inhibition of fXIIa generated by catheter-induced autoactivation, (c) attenuated fXIIa-mediated activation of fXI and (d) longer plasma clotting times in the absence or presence of fondaparinux. In an accelerated catheter thrombosis model in rabbits, (a) the time to catheter occlusion was longer with CTI-coated catheters than with unmodified catheters and (b) an intravenous dose of fondaparinux that had no effect on the time to occlusion of unmodified catheters extended the time to occlusion of CTI-coated catheters. These findings support the concept that the prothrombotic activity of catheters reflects their capacity to activate fXII and identify CTI immobilization as a novel approach for rendering catheters and other blood-contacting medical devices less thrombogenic.

Topics: Adsorption; Animals; Blood Coagulation; Catheters; Coated Materials, Biocompatible; Factor XII; Fondaparinux; Humans; Percutaneous Coronary Intervention; Photoelectron Spectroscopy; Plant Proteins; Polysaccharides; Protein Binding; Rabbits; Surface Properties; Thrombosis; Water

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin administration. As HIT may occur during the thrombolysis of prosthetic heart valve thrombosis (PVHT) due to the administration of heparin, this entity should be considered during and after sessions of this regimen. The study aim was to investigate the development, diagnosis, and management of HIT during thrombolytic therapy (TT) of PHVT.. A diagnosis of HIT was made on a clinical basis and laboratory confirmation based on a particle immunofiltration assay. Serial transthoracic echocardiography and two-dimensional transesophageal echocardiography were used to detect thrombus morphology and hemodynamic changes before and after TT sessions in 214 patients.. Four patients (1.9%) who underwent TT for PHVT were diagnosed with HIT. The mean period of onset of HIT after heparin exposure was 8.7 +/- 3.9 days, while mean platelet levels before and after heparin infusion were 308,000/mm3 and 77,250/mm3, respectively. Fondaparinux was employed as bridging therapy in three patients. TT resulted in a successful outcome in two patients, while two other patients underwent surgery for increased valve gradients (due to progression of obstructive PHVT during TT in one case, and obstructive PHVT resulting in a cerebrovascular accident in the other case).. Details are presented of the development of HIT during TT for PHVT, which resulted in an increased thrombus size immediately after successful TT. Fondaparinux may be considered as an effective bridging treatment in this regimen.

Topics: Adult; Anticoagulants; Aortic Valve; Fondaparinux; Heart Valve Diseases; Heart Valve Prosthesis; Heparin; Humans; Male; Middle Aged; Mitral Valve; Polysaccharides; Thrombocytopenia; Thrombolytic Therapy; Thrombosis

As a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg-1] and saline), PCC (fondaparinux and PCC [40 UI.kg-1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelastometric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Carotid Arteries; Disease Models, Animal; Fondaparinux; Hemorrhage; Polysaccharides; Rabbits; Regional Blood Flow; Thrombosis; Treatment Outcome

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.

Topics: Animals; Anticoagulants; Antithrombin Proteins; Factor Xa Inhibitors; Fondaparinux; Humans; Liver Diseases; Polysaccharides; Rabbits; Thrombosis

We present a case of a 54 years old female patient after anterior wall left ventricular myocardial infarction in 2005 who underwent coronary artery bypass graft (CABG) surgery requiring cannulation of the right internal jugular vein (IJV). She was admitted to a Department of Pulmonary Diseases with left bronchopneumonia (BPN) following 7 day treatment, with hemoptysis, dyspnoea and fevers. Duplex ultrasound (DUS) was used to diagnose flapping thrombus in the right IJV, severe thrombocytopenia and, in addition, progressing multiple infiltrates on X-ray a few days later. We empirically adjusted the treatment initiated in primary care and observed deterioration of the severe thrombocytopenia during treatment with low molecular weight heparine. We diagnosed heparin-induced thrombocytopenia (HIT) and, even though this indication was not included in our drug formulary, we initiated treatment with Arixtra (fondaparinux) 2.5 mg s.c. daily. Intensive conservative treatment was associated with significant clinical and laboratory improvement of the condition, significant regression of the IJV thrombus as well as the finding on X-ray. The final effective antibiotic treatment lasted 20 (amoxicillin + clavulanate) and 10 (clindamycin) days, respectively. Treatment with Arixtra (fondaparinux) continued in primary care and lasted a total of 65 days until normal thrombocyte levels were achieved, with gradual transition to oral anticoagulation treatment. The patient was discharged to primary care on the 23rd day of hospitalization when she was stabilized, a febrile and her cardiopulmonary functions were compensated. We did not identify any case of treatment of jugular thrombosis and concurrent HIT with fondaparin anywhere in the international literature.

Topics: Anticoagulants; Bronchopneumonia; Catheterization, Central Venous; Coronary Artery Bypass; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Jugular Veins; Middle Aged; Polysaccharides; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Fondaparinux; Heart Valve Prosthesis; Humans; Intracranial Hemorrhages; Middle Aged; Polysaccharides; Prosthesis Failure; Risk Factors; Thrombosis; Time Factors

In patients undergoing percutaneous coronary intervention, catheter thrombosis is more frequent with fondaparinux than heparin. This study was undertaken to identify the responsible mechanism and to develop strategies for its prevention. Percutaneous coronary intervention catheter segments shortened plasma clotting times from 971 ± 92 to 352 ± 22 seconds. This activity is factor XII (fXII) dependent because it was attenuated with corn trypsin inhibitor and was abolished in fXII-deficient plasma. Heparin and enoxaparin blocked catheter-induced clotting at 0.5 and 2 anti-Xa U/mL, respectively, whereas fondaparinux had no effect. Addition of fondaparinux to bivalirudin or low-dose heparin attenuated catheter-induced clotting more than either agent alone. In a rabbit model of catheter thrombosis, a 70 anti-Xa U/kg intravenous bolus of heparin or enoxaparin prolonged the time to catheter occlusion by 4.6- and 2.5-fold, respectively, compared with saline, whereas the same dose of fondaparinux had no effect. Although 15 anti-Xa U/kg heparin had no effect on its own, when given in conjunction with 70 anti-Xa U/kg fondaparinux, the time to catheter occlusion was prolonged 2.9-fold. These findings indicate that (1) catheters are prothrombotic because they trigger fXII activation, and (2) fondaparinux does not prevent catheter-induced clotting unless supplemented with low-dose heparin or bivalirudin.

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Catheters; Disease Models, Animal; Drug Synergism; Enoxaparin; Factor XII; Fondaparinux; Heparin; Humans; Male; Polysaccharides; Rabbits; Thrombosis

Edoxaban is an oral, direct factor Xa (FXa) inhibitor under late-phase clinical development. This study compared the antithrombotic efficacy of edoxaban with that of an indirect FXa inhibitor, fondaparinux, in in vivo venous and arterial thrombosis models and in ex vivo perfusion chamber thrombosis model under low and high shear rates in rats. Venous and arterial thrombi were induced by platinum wire insertion into the inferior vena cava and by application of FeCl₃ to the carotid artery, respectively. The perfusion chamber thrombus was formed by blood perfusion into a collagen-coated capillary at 150 s⁻¹ (low shear rate) and 1,600 s⁻¹ (high shear rate). Effective doses of edoxaban that reduced thrombus formation by 50% (ED₅₀) in venous and arterial thrombosis models were 0.076 and 0.093 mg/kg/h, respectively. In contrast, ED₅₀ of fondaparinux in the arterial thrombosis model (>10 mg/kg/h) was markedly higher compared to ED₅₀ in the venous thrombosis model (0.021 mg/kg/h). In the perfusion chamber thrombosis model, the ratio of ED₅₀ under high shear rate (1.13 mg/kg/h) to that under low shear rate (0.63 mg/kg/h) for edoxaban was 1.9, whereas that for fondaparinux was more than 66. While the efficacy of fondaparinux markedly decreased in arterial thrombosis and in a high-shear state, edoxaban exerted consistent antithrombotic effects regardless of flow conditions. These results suggest that shear rate is a key factor in different antithrombotic effects between edoxaban and fondaparinux.

Topics: Animals; Anticoagulants; Antithrombins; Blood Flow Velocity; Carotid Arteries; Disease Models, Animal; Factor Xa Inhibitors; Fondaparinux; Humans; Male; Polysaccharides; Pyridines; Rats; Rats, Wistar; Thiazoles; Thrombosis; Vena Cava, Inferior

Interruption of oral anticoagulation is discussed often, particularly in the outpatient setting. We present a 66- year-old woman who developed a thrombus in the left atrial appendage under bridging therapy with fondaparinux. With this case report we would like to emphasize that off-label use of fondaparinux should not be administered to patients at high risk for systemic embolism.

Topics: Aged; Anticoagulants; Atrial Appendage; Atrial Flutter; Female; Fondaparinux; Humans; Off-Label Use; Polysaccharides; Thrombosis

Venous thromboembolism (VTE) remains a great challenge because of its frequency and of its potential severity. However, VTE treatment can also lead to iatrogenic complications. We report a case of thigh haematoma by a 83-year-old woman under fondaparinux for a solear thrombosis. Then we discuss the indications of Unfractionated Heparin (UFH), Low-Molecular-Weight Heparins (LMWH) and Fondaparinux, which are the three classes of rapidly acting anticoagulant treatments nowadays available. As their efficacy is comparable, the choice between these classes relies on the risk of adverse effects, which depends on some patient's characteristics. LMWH and fondaparinux are contra-indicated by the patients with a renal clearance under 30 ml/min. Only UFH are authorized during the whole pregnancy even though LMWH are more and more used. Fondaparinux has proven its safety by patients over 100 kg. UFH requires a daily biological management whereas it is optional for LMWH and fondaparinux, as long as their contra-indications are taken into account. No Heparin-induced-thrombocytopenia Syndrome (HIT-Sd) has been proven yet under fondaparinux so that platelets management seems not necessary, contrary to UFH and LMWH which require a twice-weekly platelets count. The accuracy of the therapeutic indication should result in the best benefit/risk assessment.

Topics: Aged, 80 and over; Anticoagulants; Female; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Thrombosis

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Anticoagulants; Fondaparinux; Hemoglobinuria, Paroxysmal; Humans; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Polypharmacy; Polysaccharides; Recurrence; Thrombosis; Treatment Outcome

Heparin-induced thrombocytopenia is an antibody-mediated disorder exhibiting variable frequency in different clinical settings. Antibodies recognize PF4/heparin complexes formed at optimal stoichiometric molar ratios.. To identify clinical factors influencing risk of anti-PF4/heparin immunization.. We performed observational studies and exploratory analyses of the frequency of anti-PF4/heparin antibody formation in 6324 patients who received enoxaparin or fondaparinux in four randomized controlled trials of postorthopedic surgery thromboprophylaxis. Variables included surgery type (knee vs. hip), timing of first anticoagulant dose (pre- vs. postsurgery), circumstances of surgery (elective vs. hip fracture), anticoagulant (enoxaparin vs. fondaparinux) and body-mass index (BMI). We applied a stoichiometry-based model that predicts immunization risk based on expected differences in PF4/anticoagulant ratios in different settings, and specifically used this model to predict the effect of increasing BMI quartiles upon relative risk (RR) of immunization for fondaparinux vs. enoxaparin.. Anti-PF4/heparin immunization was more frequent after knee vs. hip surgery (particularly for enoxaparin), and when enoxaparin was given post- rather than pre-elective surgery; however, the opposite occurred with hip fracture surgery, that is, antibody formation was more frequent when enoxaparin or fondaparinux was given presurgery. The RR of immunization for fondaparinux vs. enoxaparin decreased significantly for increasing BMI quartiles, an effect predominantly because of increasing immunization with enoxaparin at increasing BMI quartiles.. Several non-drug factors--including type and circumstances of surgery, timing of first anticoagulant dose and BMI--influence risk of anti-PF4/heparin antibody formation, consistent with a stoichiometry-based immunization model of PF4 and anticoagulant ratios occurring during the early peri-operative period.

Topics: Antibodies; Anticoagulants; Body Mass Index; Drug Administration Schedule; Enoxaparin; Evidence-Based Medicine; Fondaparinux; Humans; Models, Statistical; Orthopedic Procedures; Platelet Factor 4; Polysaccharides; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thrombocytopenia; Thrombosis

Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Four anticoagulant agents are currently commercially available for ACS, namely unfractionated heparin (UFH), enoxaparin, bivalirudin and fondaparinux. We describe the advantages of fondaparinux and the reasons that have hampered its uptake into routine management of ACS. Fondaparinux was shown to be efficacious in the prevention of deep vein thrombosis vs low-molecular-weight heparins, while in the setting of venous thrombo-embolic disease, it was shown to be noninferior to enoxaparin and UFH. Two pivotal studies have demonstrated the efficacy of fondaparinux as an anticoagulant in the setting of ACS, namely OASIS-5 in non-ST elevation ACS, and OASIS-6 in ST elevation myocardial infarction (MI). In OASIS-5, fondaparinux was shown to be noninferior to enoxaparin in terms of death, MI or refractory ischemia at 9 days. Furthermore, a 50% reduction in bleeding complications was obtained with fondaparinux vs enoxaparin, leading to a risk reduction for death. In OASIS-6, fondaparinux was shown to be superior to the comparator (UFH or placebo). European and North American guidelines give fondaparinux a Grade 1A and 1B recommendation respectively, but uptake of fondaparinux in routine practice has been slow. We explore reasons for this, such as prevailing doubts about the efficacy of fondaparinux in the setting of angioplasty, the problem of catheter thrombosis, and the lack of antidote in case of bleeding complications. With the exception of primary angioplasty, fondaparinux is as effective as enoxaparin or UFH, but is also associated with a considerable reduction in bleeding complications, and thus, an undeniable net clinical benefit.

Topics: Acute Coronary Syndrome; Anticoagulants; Catheterization; Enoxaparin; Fondaparinux; Hirudins; Humans; Peptide Fragments; Polysaccharides; Recombinant Proteins; Thrombosis

Topics: Aged; Antibodies; Anticoagulants; Arthroplasty, Replacement, Knee; Fondaparinux; Heparin; Humans; Infarction, Middle Cerebral Artery; Male; Platelet Factor 4; Polysaccharides; Stroke; Thrombocytopenia; Thrombosis

Topics: Anesthesia, Epidural; Anesthesia, Spinal; Anticoagulants; Arthroplasty, Replacement, Hip; Catheterization; Fondaparinux; Humans; Lumbosacral Plexus; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thrombosis

Previous surveys in the Netherlands have revealed that guidelines regarding orthopedic thromboprophylaxis were not followed and that a wide variation in protocols exists. This survey was performed to assess the current use of thromboprophylactic modalities and to compare it with the results of a previous survey.. All departments of orthopedic surgery in the Netherlands were sent a follow-up survey on venous thromboprophylaxis, and the data obtained were compared to the results of a survey performed 5 years earlier.. All departments used pharmacological thromboprophylaxis following arthroplasties of the hip and knee. Low-molecular-weight heparin (LMWH) was used most frequently (79%) of the departments, followed by fondaparinux (13%). 5 years earlier, coumarin treatment was the predominant prophylaxis (79%). All departments prescribed pharmacological prophylaxis after femoral and tibial fractures; 78% used LMWH. Prophylaxis was continued for 6 weeks in 85% of cases. LMWH treatment was initiated on the day before surgery in 31% of cases (65% in the previous survey), perioperatively in 55%, and in the evening following surgery in 24%. In general, for daycare surgery and arthroscopies either no prophylaxis was given or a LMWH was given for 1 day. After anterior cruciate ligament reconstruction, 94% of departments prescribed some form of pharmacological prophylaxis.. The use of pharmacological prophylaxis after arthroplasty of the hip and knee and also after fracture surgery around the hip and knee is common practice in the Netherlands. In 5 years, the widely used coumarin derivates have been largely replaced with LMWH.

Topics: Anterior Cruciate Ligament; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Coumarins; Follow-Up Studies; Fondaparinux; Fracture Fixation, Internal; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Netherlands; Polysaccharides; Practice Patterns, Physicians'; Stockings, Compression; Surveys and Questionnaires; Thrombosis

An 11-year-old female developed heparin induced thrombocytopenia (HIT) with thrombosis during therapy for lower extremity deep vein thrombosis and pulmonary embolism. Transition from bivalirudin, a direct thrombin inhibitor (DTI), to warfarin resulted in extensive re-thrombosis, and fondaparinux therapy similarly failed. She was then treated with argatroban, and transitioned successfully to warfarin after 9 weeks. The risk of re-thrombosis was ultimately reduced by allowing time for the thrombogenic potential to abate. The argatroban/warfarin transition was monitored with chromogenic factor X levels. This case highlights several difficult problems in pediatric thrombosis.

Topics: Anticoagulants; Child; Female; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombocytopenia; Thrombosis; Warfarin

Heparin is the most commonly used anticoagulant drug for prevention and treatment of thromboembolic diseases. Heparin-induced thrombocytopenia (HIT) is a well-known and potentially fatal side-effect of heparin therapy. HIT type 1 (HIT-1) is transient and relatively common; it usually develops within 1-7 days of initial heparin exposure. Type 2 HIT (HIT-2) is more severe and is associated with thrombocytopenia and thrombosis. HIT-2 usually develops 5 or more days after initial heparin exposure. It is an immune-mediated disorder that is presumably caused by development of platelet activating antibody against platelet factor 4 (PF4)/heparin complex. Fondaparinux (Arixtra) is a fast-acting selective inhibitor of factor Xa believed to be non-reactive to HIT sera and therefore may be used as prophylaxis for thrombosis in patients with a history of HIT-1 or HIT-2. Development of HIT-2 in patients currently taking fondaparinux prophylaxis is rare. Here we present a fatal case of delayed-onset HIT-2 (1 year after heparin exposure) manifesting while on fondaparinux prophylaxis.

Topics: Aged; Anticoagulants; Fatal Outcome; Fondaparinux; Heparin; Humans; Male; Polysaccharides; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Female; Fondaparinux; Gastroenteritis; Humans; Infant; Polysaccharides; Thrombosis

The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Blood Coagulation Tests; Chondroitin Sulfates; Citrates; Critical Care; Dermatan Sulfate; Diagnostic Errors; Dose-Response Relationship, Drug; Epoprostenol; Fondaparinux; Hemofiltration; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Iloprost; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sodium Citrate; Sulfonamides; Thrombocytopenia; Thrombosis

The Organization to Assess Strategies in Acute Ischemic Syndromes trials showed that fondaparinux (fonda) is at least as effective and safe as unfractionated heparin (UFH) and enoxaparin (enoxa) in acute coronary syndromes. Unexpectedly, there was an increase in catheter-related thrombus formation during percutaneous coronary interventions in fonda-treated patients.. Ten healthy male volunteers were pretreated with aspirin 500 mg 2 h before venesection of 50 ml of blood. Eight groups of anticoagulant (combinations) were tested and volunteers donated blood eight times, thus, acting as their own controls. The groups were UFH, UFH+eptifibatide, enoxa, enoxa+eptifibatide, fonda, fonda+eptifibatide, fonda+(half-therapeutic) UFH, and fonda+eptifibatide+(half-therapeutic) UFH. The blood/anticoagulant mix was kept at 37 degrees C and continuously circulated through a guiding catheter for 60 min or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy of the catheter lining was used to quantify the degree of erythrocyte and fibrin deposition.. Despite fonda anticoagulation, catheters were invariably occluded by thrombus before the 60 min perfusion period had elapsed. Thrombotic catheter occlusion occurred even with higher fonda concentrations and combined fonda/eptifibatide use. All other combinations (including fonda and half-therapeutic UFH) ensured catheter patency for 60 min. Furthermore, thrombus weight and the cell/fibrinogen counts were significantly increased in fonda and fonda+eptifibatide compared with other treatment groups.. Treatment with fonda, even in combination with eptifibatide, was not sufficient to prevent cardiac catheter thrombus development in our in-vitro study. However, the combination of fonda with 'half' therapeutic dosages of UFH were as efficient as other treatment strategies in preventing thrombus formation.

Topics: Cardiac Catheterization; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heparin; Humans; In Vitro Techniques; Male; Microscopy, Electron; Polysaccharides; Thrombosis

Deep vein thrombosis (DVT) remains a major burden and fondaparinux represents a new option for DVT therapy. We sought to determine if fondaparinux offered financial advantages over low-molecular weight heparin since it is given as a fixed dose over a wide range of patient weights rather then dosed directly on weight and because fondaparinux is not associated with heparin-induced thrombocytopenia (HIT).. We conducted a cost-minimization analysis comparing fondaparinux to enoxaparin for acute anticoagulation in DVT. We modeled a cohort of 1,000 hypothetical subjects and drew estimates for model inputs from the published literature. We completed multiple sensitivity analyses to asses the significance of our assumptions and used Monte Carlo simulation to estimate the 95% confidence intervals (CIs) around our estimation of the cost differential for the two agents.. In the base case, total disease management costs per patient with fondaparinux are US 472 dollars compared to 769 dollars with enoxaparin. The 95% CI around this difference ranges from US 48 dollars to US 401 dollars. The model was mildly sensitive to the pharmacy acquisition costs of fondaparinux and enoxaparin which was the major driver of overall costs. Neither the rates of nor costs associated with DVT recurrence, major bleeding, nor HIT substantially affected our observations. Breakeven analysis indicated our findings to be robust over a wide range of likely clinical scenarios.. From the perspective of a healthcare system, fondaparinux use offers an attractive economic alternative to other agents for initial DVT therapy. Expanded reliance on fondaparinux could potentially result in savings.

Topics: Body Weight; Costs and Cost Analysis; Enoxaparin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Models, Economic; Polysaccharides; Recurrence; Thrombosis; Venous Thrombosis

To describe the clinical characteristics, management, and outcomes of patients with heparin-induced thrombocytopenia with thrombosis (HITTS) or without thrombosis (HIT) who also had an elevated baseline activated partial thromboplastin time (aPTT) due to antiphospholipid antibody syndrome (APS).. Four patients with HIT/HITTS and an elevated baseline aPTT due to APS were identified. Two patients had venous thrombosis, 1 had limb ischemia, and 1 had isolated HIT. All 4 were managed with a weight-based fixed dose of argatroban without laboratory monitoring. None of the patients had thrombotic or bleeding complications once therapy was initiated.. Management of patients with HIT/HITTS and an abnormal baseline aPTT due to APS is problematic. We review alternative management strategies, such as monitoring direct thrombin inhibitors with the ecarin clotting time or thrombin inhibition time or using an alternative anticoagulant, such as fondaparinux. As of March 13, 2006, none of these management strategies has been evaluated in a clinical trial for this patient population. We report the successful use of weight-based, fixed-dose argatroban without laboratory monitoring in patients with APS.. Use of a fixed-dose argatroban regimen without laboratory monitoring is a potential management strategy for patients with HIT/HITTS and an elevated baseline aPTT due to APS.

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Arginine; Female; Fondaparinux; Heparin; Humans; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Polysaccharides; Sulfonamides; Thrombocytopenia; Thrombosis

Topics: Anticoagulants; Enoxaparin; Fondaparinux; Humans; Leg; Polysaccharides; Thrombosis

The study aim was to investigate the efficacy of three different anticoagulants in preventing thrombus formation on mechanical heart valves, using an in-vitro system.. Blood samples (470 ml) were taken from young and healthy male volunteers and anticoagulated with unfractionated heparin (UFH; n=18), low molecular-weight heparin (LMWH; n=18) or fondaparinux (n=16). Bileaflet mechanical heart valves were placed in a new device--the 'Thrombosis Tester'--and exposed in a continuous circulation at a rate of 80 beats per min to the anticoagulated blood samples for a total exposure time of 60 min. Results for thrombus weight were skewed distributed and presented as log-transformed values.. The weight of each valve was measured before and after 1 h of perfusion; subsequent mean (+/-SD) thrombus weights were 0.739 +/- 0.573 g for UFH, 0.789 +/- 0.099 g for LMWH, and 0.934 +/- 0.145 g for fondaparinux (p = 0.397 for comparison of all groups by ANOVA). Electron microscopy showed concordant results with regard to thrombus formation on heart valve surfaces.. Fondaparinux and LMWH were as effective as UFH in preventing thrombus formation on mechanical heart valves in vitro. The 'Thrombosis Tester' proved to be a new, unique instrument for investigating the ability of anticoagulants to prevent valve thrombosis on mechanical heart valves under in-vitro conditions.

Topics: Anticoagulants; Blood Coagulation; Equipment Failure Analysis; Fondaparinux; Heart Valve Prosthesis; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Polysaccharides; Prosthesis Failure; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Fondaparinux; Heparin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polysaccharides; Thrombocytopenia; Thrombosis; Treatment Outcome

Topics: Aged; Anticoagulants; Female; Fondaparinux; Heparin; Humans; Middle Aged; Platelet Count; Polysaccharides; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome; Warfarin

Topics: Anticoagulants; Fondaparinux; Hip Fractures; Humans; Polysaccharides; Postoperative Complications; Thrombosis

Unfractionated heparin reduces metastasis in many murine models. Multiple mechanisms are proposed, particularly anticoagulation and/or inhibition of P-selectin and L-selectin. However, the doses used are not clinically tolerable and other heparins are now commonly used. We studied metastasis inhibition by clinically relevant levels of various heparins and investigated the structural basis for selectin inhibition differences.. Five clinically approved heparins were evaluated for inhibition of P-selectin and L-selectin binding to carcinoma cells. Pharmacokinetic studies determined optimal dosing for clinically relevant anticoagulant levels in mice. Experimental metastasis assays using carcinoma and melanoma cells investigated effects of a single injection of various heparins. Heparins were compared for structural relationships to selectin inhibition.. One (Tinzaparin) of three low molecular weight heparins showed increased selectin inhibitory activity, and the synthetic pentasaccharide, Fondaparinux, showed none when normalized to anticoagulant activity. Experimental metastasis models showed attenuation with unfractionated heparin and Tinzaparin, but not Fondaparinux, at clinically relevant anticoagulation levels. Tinzaparin has a small population of high molecular weight fragments not present in other low molecular weight heparins, enriched for selectin inhibitory activity.. Heparin can attenuate metastasis at clinically relevant doses, likely by inhibiting selectins. Equivalent anticoagulation alone with Fondaparinux is ineffective. Clinically approved heparins have differing abilities to inhibit selectins, likely explained by size distribution. It should be possible to size fractionate heparins and inhibit selectins at concentrations that do not have a large effect on coagulation. Caution is also raised about the current preference for smaller heparins. Despite equivalent anticoagulation, hitherto unsuspected benefits of selectin inhibition in various clinical circumstances may be unwittingly discarded.

Topics: Animals; Anticoagulants; Cell Line, Tumor; Disaccharides; Factor Xa; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Kinetics; L-Selectin; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Oligosaccharides; P-Selectin; Polysaccharides; Protein Binding; Selectins; Sialyl Lewis X Antigen; Temperature; Thrombosis; Time Factors; Tinzaparin

The activity of SanOrg123781A, a new synthetic antithrombotic drug inhibiting both factor Xa and thrombin through antithrombin (AT), was compared to that of unfractionated heparin (UFH) and of the synthetic pentasaccharide (fondaparinux, SP) in an ex vivo arterial thrombosis model in the pig. Six groups of four pigs were administered intravenously with SanOrg123781A (1, 3, 10 and 30 nmol kg(-1)), UFH (30 nmol kg(-1)) or SP (30 nmol kg(-1)). In this arterial model in which platelet thrombus was formed on a thrombogenic surface under a constant high shear rate, UFH and SP had moderate antithrombotic effects while SanOrg123781A exhibited a strong, dose-dependent inhibitory activity on platelet adhesion and platelet thrombus formation. In contrast to UFH, SanOrg123781A did not modify the activated partial thromboplastin time (aPTT) even at 30 nmol kg(-1), but strongly inhibited thrombin generation. At the same dose, despite a lower antithrombotic activity than SanOrg123781A, UFH significantly affected all the coagulation parameters. Taken together, these results show that SanOrg123781A, due to its potent and selective antifactor Xa and antifactor IIa activities is a promising new antithrombotic agent even in arterial setting.

Topics: Animals; Blood Platelets; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Fondaparinux; Heparin; Partial Thromboplastin Time; Polysaccharides; Prothrombin; Swine; Thrombosis

New developments--in the form of emerging clinical settings for regional anesthesia as well as problems arising with the concomitant use of regional techniques and hemostasis-altering drugs--require the ongoing revision of safety guidelines. The annual meeting of ESRA held in Spain in 2003 saw the discussion and clarification of a variety of issues of current concern, including conclusions reached on the estimated risk of spinal hematoma when published safety guidelines are followed or not, precautions to take in epidural anesthesia during cardiac surgery, guidelines for using fondaparinux for thromboprophylaxis, the circumstances under which neuroaxial techniques can be used safely in patients under the effects of platelet aggregation inhibitors such as thienopyridine, and the application of epidural anesthesia in parturients with eclampsia who have received platelet aggregation inhibitors. Conclusions drawn at the meeting enrich and clarify certain important safety issues related to local and regional anesthesia in patients receiving antiplatelet drugs and/or anticoagulants.

Topics: Anesthesia, Conduction; Anesthesia, Epidural; Anesthesia, Obstetrical; Anesthesia, Spinal; Anesthetics; Anticoagulants; Contraindications; Extracorporeal Circulation; Female; Fibrinolytic Agents; Fondaparinux; Hematoma; Hemostasis; Humans; Intraoperative Complications; Platelet Aggregation Inhibitors; Polysaccharides; Postoperative Complications; Practice Guidelines as Topic; Pregnancy; Risk Factors; Safety; Spinal Diseases; Thrombosis

Heparin and Vitamin K antagonists have been the only available anticoagulants for several decades. Their use has lead to significant achievements in all fields of medicine despite various shortcomings and bleeding complications. With the objective of an improved benefit-/risk ratio selective inhibitors of factor Xa (Fondaparinux) and factor IIa (Ximelagatran) have been developed. Ximelagatran can also be orally administered. The results obtained from various clinical trials with these compounds are extremely encouraging. Thus, a significant improvement of antithrombotic treatment may be expected by their future use in the clinical and out-patient setting.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Meta-Analysis as Topic; Polysaccharides; Prodrugs; Risk Factors; Stroke; Thrombosis

The aim of the present study was to investigate the efficacy of three different parenterally administered anticoagulants for the prevention of thrombus formation on artificial heart valves in an experimental rabbit model. Unfractionated heparin was administered intravenously in group I (n = 10), Enoxaparin subcutaneously in group II (n = 10), fondaparinux intravenously in group III (n = 10), and no medication was administered to group IV (n = 9). Leaflets from Sulzer Carbomedics bileaflet mechanical heart valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein. In group IV the flow chamber was clotted after a median of 15 minutes of circulation. Weight analysis before and after 1 h of perfusion showed that the median thrombus weight was 18.0 mg in group I, 17.7 mg in group II, 20.3 mg in group III, and 30.8 mg in group IV. Further analysis by electron microscopy showed similar results regarding deposition of fibrin, platelets, and erythrocytes on leaflet surfaces. Fondaparinux and subcutaneously administered enoxaparin were as effective as intravenously administered unfractionated heparin in preventing thrombus formation on artificial heart valve leaflets in our investigation. This rabbit model, in which the heart valve leaflets were exposed to rabbit blood for a short time under laminar flow, should be further evaluated with respect to whether it can provide information about anti-thrombotic regimens in patients after mechanical heart valve replacement.

Topics: Animals; Anticoagulants; Blood Coagulation Tests; Enoxaparin; Fondaparinux; Heart Valve Prosthesis; Heparin; Male; Microscopy, Electron; Polysaccharides; Rabbits; Thrombosis

Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man.

Topics: Animals; Antithrombin III; Arginine; Blood Coagulation Tests; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Half-Life; Hemorrhage; Heparin; Male; Molecular Structure; Oligosaccharides; Pipecolic Acids; Polysaccharides; Rabbits; Rats; Rats, Wistar; Sulfonamides; Thrombin; Thrombolytic Therapy; Thrombosis

On a previous model using Wessler's principle in the rat, we have demonstrated that a partial ligature of the inferior vena cava leading to a 40% increase in up-stream venous pressure was thrombogenic only in association with the infusion of low dose of thromboplastin (90 microg/kg). In these thrombogenic conditions, the infusion of pentasaccharide (Arixtra, fondaparinux) should lead to a strong inhibition of thrombus formation. Therefore, we performed on five groups of 10 rats: stasis alone (group S) with a 40% increase in up-stream venous pressure; stasis and thromboplastin (group ST90); and stasis, thromboplastin and pentasaccharide (groups SPT50, SPT100 and SPT250) at three different dosages (50, 100 and 250 microg/kg). The efficacy of pentasaccharide was measured according to the variations in up-stream venous pressure, thrombus weight and thrombin-antithrombin complexes levels. Only 250 microl/kg pentasaccharide significantly reduced the thrombus weight in comparison with group ST90 (5 mg versus 23.8 mg, P = 0.01) but it was not sufficient to induce a return to the basic state (5 mg versus 0.2 mg in group S, P = 0.049). Thrombin-antithrombin complex levels measured at the end of the experiment were significantly reduced in comparison with group ST90 (16.7 versus 57.8 mg, P = 0.01) and were not statistically different from group S (16.1 versus 16.6 mg, P = 0.65). In conclusion, in a very borderline model toward thrombogenesis, pentasaccharide was able to reduce thrombus weight and abolished biological hypercoagulability.

Topics: Animals; Antithrombin III; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Fondaparinux; Hemostasis; Male; Peptide Hydrolases; Polysaccharides; Rats; Rats, Sprague-Dawley; Thrombophilia; Thromboplastin; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Azetidines; Benzylamines; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin; History, 20th Century; Humans; Polysaccharides; Prodrugs; Thrombosis; Warfarin

During the last decade, new anticoagulant drugs with anti-factor-Xa properties have been described (1, 2). Among them is fondaparinux that has been licensed recently. It is a pentasaccharide mimicking the site where heparin binds to antithrombin III (1). This new drug has produced very promising clinical results in the prophylaxis of venous thrombosis after orthopedic surgery (3). Here we report two different clinical situations in which fondaparinux has yielded a successful outcome: first, a patient with repeated cutaneus reaction to several different low molecular weight heparins (LMWH), and second, a patient with severe heparin-induced thrombocytopenia (HIT). We decided to use fondaparinux in both cases since it is commercially available in Spain and mostly because the absence of in vitro cross-reaction with heparins, as discussed later.

Topics: Abortion, Induced; Acute Kidney Injury; Adenocarcinoma; Adult; Aged; Autoimmune Diseases; Combined Modality Therapy; Drug Eruptions; Drug Hypersensitivity; Endometrial Neoplasms; Female; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Lupus Erythematosus, Systemic; Polysaccharides; Postoperative Complications; Pregnancy; Thrombophilia; Thrombosis

Topics: Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Hospitalization; Humans; Immobilization; Middle Aged; Placebos; Polysaccharides; Risk Factors; Thrombosis

Topics: Antineoplastic Agents; Azetidines; Benzylamines; Blood Coagulation Factors; Clinical Trials as Topic; Endothelium, Vascular; Fibrinolytic Agents; Fondaparinux; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Polysaccharides; Stilbenes; Thrombosis