Fondaparinux Heparin

AT-dependent Anticoagnlants Heparins, Dana pa roid, and Fondaparinux... 

State at least two potential advantages of the low-molecular-weight heparins and fondaparinux over unfractionated heparin. 

The most extensively studied drugs for the prevention of VTE are unfractionated heparin (UFH), the low-molecular-weight heparins (LMWHs dalteparin, enoxaparin, and tinza-parin), fondaparinux, and warfarin.2 The LMWHs and fondaparinux provide superior protection against VTE when... 

Mechanism of action of unfractionated heparin, low-molecular-weight heparin (LMWH), and fondaparinux. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy ... 

Initiate unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) or fondaparinux by injection (see Table 7-3 for dosing guidelines)... 

The anticoagulant fondaparinux, a synthetic analogue of the terminal fragment of heparin, is synthesized using multiple protection/deprotection steps that result in a route of up to 50 steps. There is, as yet, no enzymatic system that approaches the capability to make such a molecule." As this modified pentasaccharide is a natural product, it should, in theory, be accessible through a series of biotransformations, but we currently lack the biocatalytic tools to achieve more than a few steps and would stiU need to use some protection steps to avoid multiple products. Enzymatic synthesis in vivo depends largely on the levels and selectivities of glycosylating enzymes to achieve multistep reactions, a situation that has been mimicked in vitro for simpler systems." ... 

Spinal/Epidural hematomas When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins (LMWHs), heparinoids, or fondaparinux for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma that can result in long-term or permanent paralysis. 

Heparin-induced thrombocytopenia Use fondaparinux with caution in patients with a history of heparin-induced thrombocytopenia. 

Fondaparinux sodium is the first of a new class of direct-acting antithrombin agents. The anticoagulant activity of heparin depends on the binding of ATIII to a critical pentasaccharide sequence within the heparin molecule. This results in a change in the conformation of AITII. This leads to the inhibitory effect of ATIII on factor Xa, which activates the conversion of prothrombin to thrombin. Fondaparinux is a synthetic pentasaccharide identical to the ATIII-binding site of heparin. 

The following points should be considered in all patients receiving heparin Platelet counts should be performed frequently thrombocytopenia appearing in a time frame consistent with an immune response to heparin should be considered suspicious for HIT and any new thrombus occurring in a patient receiving heparin therapy should raise suspicion of HIT. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor or fondaparinux (see below). 

Primary prevention of venous thrombosis reduces the incidence of and mortality rate from pulmonary emboli. Heparin and warfarin may be used to prevent venous thrombosis. Subcutaneous administration of low-dose unfractionated heparin, low-molecular-weight heparin, or fondaparinux provides effective prophylaxis. Warfarin is also effective but requires laboratory monitoring of the prothrombin time. 

The indirect thrombin inhibitors are so named because their antithrombotic effect is exerted by their interaction with antithrombin. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the synthetic pentasaccharide fondaparinux bind to antithrombin and enhance its inactivation of factor Xa. UFH and to a lesser extent LMWH also enhance antithrombin s inactivation of thrombin (Ha). 

Fondaparinux is a chemically synthesized pentasaccharide that mimics the antithrombin-binding site of heparin and LMWH. Its molecular size (1728Da) is too small to bind to thrombin molecules while it is bound to antithrombin, Therefore, it is a pure anti-Xa inhibitor. It binds very little to platelets, proteins, or endothelium and is excreted in the urine, It does not form a complex with PF4 or other positively charged molecules. It is not neutralizable by protamine sulfate, Recent clinical trials have resulted in FDA approval for prophylaxis of deep vein thrombosis in orthopedic surgery, It has been shown to be effective and safe for the treatment of pulmonary embolism (20,21) and ACS (non-ST-elevation Ml) (OASIS 5—Michelangelo Trial) (17). 

The Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N EnglJ Med 2003 349 1695-1702. 

The most representative example utilizing this approach is the synthesis of the ultralow molecular weight (ULMW) heparin construct 27 (Scheme 9.2), a heptasac-charide that has a very similar structure to the FDA-approved anticoagulant drug fondaparinux. Fondaparinux is currently synthesized chemically through 50 steps... 

Susceptible to inhibition also by low-molecular-weight heparin and fondaparinux... 

Indications. Heparin is used for the prophylaxis and therapy of thrombosis. For the former, low dosages, given subcutaneously, are suf cient. Unfractionated heparin must be injected about three time daily, fractionated heparins and fondaparinux can be administered once daily. For treatment of thrombosis, heparin must be infused intravenously in an increased daily dose. 

Adverse effects. When bleeding is induced by heparin, the heparin action can be instantly reversed by protamine. Against fractionated heparins and fondaparinux, protamine is less or not effective. Heparin-induced thrombocytopenia type II (HIT II) is a dangerous complication. It results from formation of antibodies that precipitate with bound heparin on platelets. The platelets aggregate and give rise to vascular occlusions. Because of the thrombocytopenia, hemorrhages may occur. Fondaparinux is also contraindicated in HIT II. 

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