fondaparinux and Vascular-Diseases

We present the case of a 78 year-old man who developed a spontaneous rupture of the lumbar artery leading to a retroperitoneal hematoma while receiving fondaparinux therapy after a total hip replacement. A selective angiographic embolization stopped the bleeding. Fondaparinux was discontinuated and the patient presented a complete resolution of his medical status. Spontaneous hematomas has been well described during low molecular weight heparin (LMWH) treatment, expecially in elderly patients, but there are no previous reports of hematomas induced by fondaparinux. We reviewed the literature to identify the possible risk-factors of bleeding. Our review shows that even if many works suggest that fondaparinux is a safe and effective alternative to LMWH in the prevention of venous thromboembolism following major orthopaedic surgery, it should carefully be used in elderly people and patients with renal disfunction.

Topics: Aged; Anticoagulants; Arteries; Fondaparinux; Hematoma; Humans; Lumbar Vertebrae; Male; Polysaccharides; Retroperitoneal Space; Rupture, Spontaneous; Vascular Diseases

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

Topics: Clinical Trials as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Thrombin; Treatment Outcome; Vascular Diseases

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

Extracellular histones exert cytotoxic and procoagulant effects which contribute to immunothrombosis in vascular diseases such as sepsis. Heparin has been shown to neutralize the pathologic effects of histones in vitro and in animal models.. To compare the effectiveness of unfractionated heparin (UFH), low-molecularweight heparin (LMWH), Vasoflux (lacks anticoagulant activity), and fondaparinux in neutralizing the cytotoxic and procoagulant activities of histones METHODS: Binding affinities between heparin variants and histone subunits were determined by Bio-layer Interferometry. The ability of heparin variants to diminish the cytotoxic and procoagulant effects of histones was studied by treating endothelial cells or monocytic THP-1 cells with histones ± heparin variants.. Unfractionated heparin, LMWH, and Vasoflux bind histone subunits with high affinities (K. The ability of heparin to neutralize the cytotoxic and procoagulant effects of histones require heparin fragments >1.7 kDa and is independent of the antithrombin-binding pentasaccharide. In contrast, the ability of heparin to neutralize histone-mediated impairment of APC generation is independent of size and anticoagulant activity. These findings suggest that heparin variants may have differential therapeutic potential in vascular diseases associated with elevated levels of histones.

Topics: Animals; Anticoagulants; Endothelial Cells; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Histones; Humans; Vascular Diseases