Effects of heparin oligosaccharides with high affinity for antithrombin III in experimental venous thrombosis.
The in vitro and in vivo characteristics of two oligosaccharide heparin fragments have been compared to those of unfractionated mucosal heparin. A decasaccharide fragment had essentially no activity by APTT or calcium thrombin time assays in vitro, but possessed very high specific activity by anti-Factor Xa assays. When injected into rabbits at doses of up to 80 microgram/kg, this fragment was relatively ineffective in impairing stasis thrombosis despite producing high blood levels by anti-Xa assays. A 16-18 monosaccharide fragment had even higher specific activity (almost 2000 iu/mg) by chromogenic substrate anti-Xa assay, with minimal activity by APTT. When injected in vivo, this fragment gave low blood levels by APTT, very high anti-Xa levels, and was more effective in preventing thrombosis than the decasaccharide fragment. However, in comparison with unfractionated heparin, the 16-18 monosaccharide fragment was only partially effective in preventing thrombosis, despite producing much higher blood levels by anti-Xa assays. It is concluded that the high-affinity binding of a heparin fragment to antithrombin III does not by itself impair venous thrombogenesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential.
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005170:Factor X / Q000037:antagonists & inhibitors; D015951:Factor Xa; D006493:Heparin / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D009844:Oligosaccharides / Q000627:therapeutic use*; D010314:Partial Thromboplastin Time; D011817:Rabbits; D013918:Thrombin Time; D013924:Thrombophlebitis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
D009844:Oligosaccharides; D000990:Antithrombin III; D005170:Factor X; D006493:Heparin; D015951:Factor Xa