Relative efficacy of heparin and related glycosaminoglycans as antithrombotic drugs.
In a standardized animal model, unfractionated heparin (UFH) prevents venous thrombogenesis at a dose of 80 micrograms/kg. Oligosaccharide fragments of heparin, with very high anti-Xa activity both in vitro and in ex vivo plasma samples were less effective than UFH in preventing thrombosis. A decasaccharide fragment was virtually inactive in impairing thrombosis at this dose, although a 20-22 monosaccharide fragment showed some impairment. Dermatan sulfate, which has no anti-factor Xa activity, partially impairs both thrombin generation and stasis thrombosis. However, dermatan sulfate could not suppress thrombin generation below about 35% of control at the doses studied. Neither oligosaccharides nor dermatan sulfate were as effective on a weight basis as UFH in impairing thrombosis, particularly after 20 minutes' stasus. Maximal antithrombotic effects are achieved when both factor Xa and thrombin are inhibited. Drugs which act primarily on factor Xa (oligosaccharides) or thrombin by non-ATIII pathways (dermatan sulfate) are less efficient than UFH as antithrombotic drugs.
Thomas
D P
DP
Department of Haematology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
Merton
R E
RE
Barrowcliffe
T W
TW
D000818:Animals; D003871:Dermatan Sulfate / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa; D006025:Glycosaminoglycans / Q000008:administration & dosage / Q000627:therapeutic use*; D006493:Heparin / Q000008:administration & dosage / Q000627:therapeutic use*; D009844:Oligosaccharides / Q000627:therapeutic use; D010314:Partial Thromboplastin Time; D011817:Rabbits; D015842:Serine Proteinase Inhibitors; D013917:Thrombin / Q000378:metabolism; D013924:Thrombophlebitis / Q000097:blood / Q000188:drug therapy*
D006025:Glycosaminoglycans; D009844:Oligosaccharides; D015842:Serine Proteinase Inhibitors; D003871:Dermatan Sulfate; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa