title: M118, a novel low-molecular weight heparin with decreased polydispersity leads to enhanced anticoagulant activity and thrombotic occlusion in ApoE knockout mice.
abstract: Heparin and low-molecular weight heparin (LMWH) are complex, heterogeneous polysaccharides used in the treatment of arterial and venous thrombosis. M118 is a novel LMWH with low polydispersity and pronounced anti-Xa and anti-thrombin (IIa) activity as compared to current LMWHs. To determine if M118 is effective in preventing thrombosis in the setting of a vascular plaque, apolipoprotein E knockout mice fed a high fat diet were injected with M118, enoxaparin, unfractionated heparin, or saline control and examined for arterial thrombosis using a rose bengal laser induced carotid artery injury model. M118 significantly increased the time to occlusion as compared to control and unfractionated heparin but not compared to enoxaparin although fewer M118 treated animals had any vascular occlusion present at the time of protocol completion. Platelet-neutrophil aggregates were studied by flow cytometry and were found to be decreased with M118 as compared to enoxaparin. This is the first published report examining M118, a novel LMWH designed to have low polydispersity and enhanced anticoagulant activity. In an animal model of vascular plaque, M118 is a potent inhibitor of arterial thrombosis and, despite lower in vivo anti-Xa and anti-IIa activity levels, M118 was superior to UFH in the prevention of arterial thrombosis.
authors.affiliation: Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 715 Albany Street, W507, Boston, MA 02118, USA. subrata@bu.edu
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Lea M
authors.initials: LM
authors.lastname: Beaulieu
authors.forename: Lara A
authors.initials: LA
authors.lastname: Reyelt
authors.forename: Mark D
authors.initials: MD
authors.lastname: Iafrati
authors.forename: Jane E
authors.initials: JE
authors.lastname: Freedman
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013923:Thromboembolism / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control; D014018:Tissue Distribution / Q000187:drug effects / Q000235:genetics
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D006495:Heparin, Low-Molecular-Weight