Covalent antithrombin-heparin complexes.
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been utilized as primary anticoagulants for thrombosis prophylaxis and treatment. However, a number of biophysical and safety limitations have led to development of new anticoagulants. Covalent antithrombin-heparin (ATH) complexes may address many of these issues. Early ATH products were prepared that had increased intravenous half-lives relative to UFH but lacked any improvement in anti-factor Xa activity or had no catalytic activity or reactivity against thrombin. However, a recent conjugate developed by Chan et al. has displayed a number of superior properties. Chan et al. ATH has an increased direct thrombin inhibition rate and can catalyze coagulant enzyme inhibition by exogenous antithrombin with very high specific activity. Unlike UFH, clot-bound thrombin is readily inhibited by ATH and, at similar antithrombotic efficacy, the ATH has improved bleeding profiles compared to heparins. Given the preclinical findings, Chan et al. ATH may warrant clinical trial testing for control of clot propagation.
Patel
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Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada.
Berry
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LR
Chan
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D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use*; D000991:Antithrombins / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D015951:Factor Xa / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D046911:Macromolecular Substances
D000925:Anticoagulants; D000991:Antithrombins; D046911:Macromolecular Substances; D006493:Heparin; D015951:Factor Xa