title: Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides.
abstract: Heparin and low molecular weight heparins exert their vascular effects by mobilizing tissue factor pathway inhibitor (TFPI) from the vascular endothelium into the blood circulation. We compared the influence of molecular weight on the TFPI release by heparin and its fractions in a non-human primate model. Primates were treated with unfractionated heparin, a low molecular weight heparin (gammaparin), or a heparin-derived oligosaccharide mixture (C3). Endothelial TFPI release was determined using both immunologic and functional assays. After intravenous administration, all agents significantly increased TFPI levels (p<0.05) in a dose dependent manner. The increase produced by unfractionated heparin and gammaparin was greater than that by C3 at an equal dosage (p<0.05). With subcutaneous injection, all agents produced less TFPI release. Repeated administration of heparin-derived oligosaccharides gradually increased TFPI release. A 1.89 fold increase in TFPI levels was observed 4 days after C3 treatment (2.5 mg/kg). Our findings indicated that TFPI release is dependent on the molecular weight of heparin and its derivatives. Heparin oligosaccharides exert their vascular effects through increased TFPI release after long-term repeated administration.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA. qingma@buffalo.edu
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Mahmut
authors.initials: M
authors.lastname: Tobu
authors.forename: Christopher
authors.initials: C
authors.lastname: Schultz
authors.forename: Walter
authors.initials: W
authors.lastname: Jeske
authors.forename: Debra
authors.initials: D
authors.lastname: Hoppensteadt
authors.forename: Jeanine
authors.initials: J
authors.lastname: Walenga
authors.forename: Umberto
authors.initials: U
authors.lastname: Cornelli
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Linhardt
authors.forename: Israel
authors.initials: I
authors.lastname: Hanin
authors.forename: Jawed
authors.initials: J
authors.lastname: Fareed
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000008:administration & dosage* / Q000031:analogs & derivatives; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008074:Lipoproteins / Q000097:blood*; D008253:Macaca mulatta; D008297:Male; D008970:Molecular Weight; D009844:Oligosaccharides / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D008074:Lipoproteins; D009844:Oligosaccharides; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin