title: Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands.
abstract: While heparin has been used almost exclusively as a blood anticoagulant, important literature demonstrates that it also has broad anti-inflammatory activity. Herein, using low anti-coagulant 2-O,3-O-desulfated heparin (ODSH), we demonstrate that most of the anti-inflammatory pharmacology of heparin is unrelated to anticoagulant activity. ODSH has low affinity for anti-thrombin III, low anti-Xa, and anti-IIa anticoagulant activities and does not activate Hageman factor (factor XII). Unlike heparin, ODSH does not interact with heparin-platelet factor-4 antibodies present in patients with heparin-induced thrombocytopenia and even suppresses platelet activation in the presence of activating concentrations of heparin. Like heparin, ODSH inhibits complement activation, binding to the leukocyte adhesion molecule P-selectin, and the leukocyte cationic granular proteins azurocidin, human leukocyte elastase, and cathepsin G. In addition, ODSH and heparin disrupt Mac-1 (CD11b/CD18)-mediated leukocyte adhesion to the receptor for advanced glycation end products (RAGE) and inhibit ligation of RAGE by its many proinflammatory ligands, including the advanced glycation end-product carboxymethyl lysine-bovine serum albumin, the nuclear protein high mobility group box protein-1 (HMGB-1), and S100 calgranulins. In mice, ODSH is more effective than heparin in reducing selectin-mediated lung metastasis from melanoma and inhibits RAGE-mediated airway inflammation from intratracheal HMGB-1. In humans, 50% inhibitory concentrations of ODSH for these anti-inflammatory activities can be achieved in the blood without anticoagulation. These results demonstrate that the anticoagulant activity of heparin is distinct from its anti-inflammatory actions and indicate that 2-O and 3-O sulfate groups can be removed to reduce anticoagulant activity of heparin without impairing its anti-inflammatory pharmacology.
authors.affiliation: Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84132, USA. Narayanam.Rao@hsc.utah.edu
authors.forename: Narayanam V
authors.initials: NV
authors.lastname: Rao
authors.forename: Brian
authors.initials: B
authors.lastname: Argyle
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: Walenga
authors.forename: Margaret
authors.initials: M
authors.lastname: Prechel
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Robert B
authors.initials: RB
authors.lastname: MacArthur
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Walters
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015956:Factor XIIa / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008024:Ligands; D008175:Lung Neoplasms / Q000097:blood / Q000517:prevention & control / Q000556:secondary; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D008024:Ligands; D016177:Macrophage-1 Antigen; C520325:N-desulfated,2-O,3-O-desulfated heparin; D009414:Nerve Growth Factors; D019007:P-Selectin; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D000990:Antithrombin III; D006493:Heparin; D015956:Factor XIIa