Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands.

Am J Physiol Cell Physiol 2010 Jul 7;299(1):C97-110. Epub 2010 Apr 7.

Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84132, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00009.2010DOI Listing
July 2010

Publication Analysis

Top Keywords

anticoagulant activity
12
heparin odsh
12
heparin
11
activity heparin
8
advanced glycation
8
leukocyte adhesion
8
heparin-induced thrombocytopenia
8
anti-inflammatory pharmacology
8
odsh
7
anticoagulant
5
anti-inflammatory
5
rage inhibit
4
inhibit ligation
4
receptor advanced
4
cd11b/cd18-mediated leukocyte
4
adhesion receptor
4
ligation rage
4
glycation products
4
products rage
4
ligands including
4

Similar Publications