Inhibition of Factor Xa : a potential target for the development of new anticoagulants.
Anticoagulant therapy plays an important role in the prevention and treatment of pathologic arterial and venous thrombosis. There is increasing enthusiasm in the inhibition of Factor Xa as a target to achieve therapeutic anticoagulation because of its central and 'upstream' position in the coagulation process. The indirect, selective, parenteral Factor Xa inhibitor fondaparinux sodium (synthetic pentasaccharide) has been studied extensively in the prevention and treatment of venous thromboembolism. In an overview of four studies in patients undergoing major orthopedic surgery, fondaparinux sodium was associated with a 55% reduction in recurrent thromboembolism, albeit with a modest increase in bleeding. Preliminary results from phase II studies of fondaparinux sodium in patients with ST-elevation and non-ST-elevation acute coronary syndromes have been promising and have led to the initiation of two large phase III trials, which are currently underway. Idraparinux sodium, a long-acting synthetic pentasaccharide, is currently being investigated as a once-weekly alternative to other long-term anticoagulants. DX-9065a and razaxaban are two of many direct selective Factor Xa inhibitors currently in development. DX-9065a has been studied in phase II trials in patients undergoing percutaneous coronary intervention and in those with non-ST-elevation acute coronary syndromes. Razaxaban has been studied in a phase II trial in patients who have undergone orthopedic surgery. Data from these trials, although preliminary and based on small numbers of patients, suggest that direct selective Factor Xa inhibition may provide effective anticoagulation, perhaps without excessive bleeding. Inhibition of Factor Xa is a promising target for the prevention and treatment of thrombosis in both the venous and arterial circulation. Ongoing investigation with numerous oral and parenteral inhibitors of Factor Xa will establish the potential of Factor Xa as a target for therapeutic anticoagulation.
Alexander
John H
JH
Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina 27710, USA. john.h.alexander@duke.edu
Singh
Kanwar P
KP
D000595:Amino Acid Sequence; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D000990:Antithrombin III / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation; D015195:Drug Design; D000077425:Fondaparinux; D006801:Humans; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000627:therapeutic use; D011134:Polysaccharides / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000188:drug therapy
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D009281:Naphthalenes; D011134:Polysaccharides; D011422:Propionates; D000990:Antithrombin III; D000077425:Fondaparinux