Low molecular weight heparin is responsible for the anti-Xa activity of Desmin 370.
Dermatan sulphate does not catalyse the inactivation of factor Xa. However, the low molecular weight (LMW) dermatan sulphate Desmin 370 has been shown to generate circulating anti-Xa activity following administration to humans. Using a single batch of Desmin 370, we measured 3 U/mg of anti-Xa activity by amidolytic assay in vitro. The material responsible for this activity had a lower molecular weight range (6000 and 1800 Da) than Desmin 370 and was more highly sulphated than the bulk of the drug. Heparinase digestion of Desmin 370 eliminated 90% of the in vitro anti-Xa activity without significantly interfering with its ability to potentiate inactivation of thrombin by HCII, suggesting that the anti-Xa activity is not due to dermatan sulphate and is probably heparin. When 125I-labelled Desmin 370 together with 40 mg/kg carrier drug was administered intravenously to a rabbit, anti-Xa activity was readily detectable in the plasma for up to 10 h and had a longer half-life than the sulphated radiolabel. Most of this anticoagulant activity was recovered from the plasma by Polybrene affinity chromatography and was probably a sulphated glycosaminoglycan. Administration of the heparinase-digested drug to a rabbit resulted in 70% less anti-Xa activity than the undigested drug. We conclude that Desmin 370 contains detectable quantities of biologically active low molecular weight heparin, which is responsible for persistent anti-Xa activity following intravenous administration.
Brieger
D
D
Applied Research Group, The Heart Research Institute, Sydney, Australia.
Dawes
J
J
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D003871:Dermatan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005260:Female; D019763:Heparin Lyase; D006495:Heparin, Low-Molecular-Weight / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011817:Rabbits
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D003871:Dermatan Sulfate; D011133:Polysaccharide-Lyases; D019763:Heparin Lyase