Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides.
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.
Ma
Qing
Q
Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA. qingma@buffalo.edu
Tobu
Mahmut
M
Schultz
Christopher
C
Jeske
Walter
W
Hoppensteadt
Debra
D
Walenga
Jeanine
J
Cornelli
Umberto
U
Lee
John
J
Linhardt
Robert
R
Hanin
Israel
I
Fareed
Jawed
J
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
D008074:Lipoproteins; D009844:Oligosaccharides; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin