TY - JOUR
T1 - Structural features of dermatan sulfates and their relationship to anticoagulant and antithrombotic activities
AU - Linhardt, Robert J.
AU - Al-Hakim, Ali
AU - Jian, Liu
AU - Hoppensteadt, Debra
AU - Mascellani, Giuseppe
AU - Bianchini, Pietro
AU - Fareed, Jawed
PY - 1991/9/27
Y1 - 1991/9/27
N2 - Dermatan sulfate is a polydisperse, microheterogeneous sufated copolymer of N-acetyl-d-galactopyranose and idopyranosyluronic acid that is currently under clinical investigation as a new antithrombotic agent. The structure and activity of two pairs of dermatan sulfates, isolated from bovine and porcine mucosa, were studied. One dermatan sulfate from each species demonstrated high in vivo antithrombotic activity in the rat vena cava assay. The in vitro anticoagulant activity of each dermatan sulfate was determined using activated partial thomboplastin time (APTT), thrombin time (TT) (5 units), calcium thrombin time (CaTT ) (5 units), Heptest®, anti-factor Xa and anti-factor IIa antithrombin assays and heparin cofactor II amidolytic assays. The coagulation-based assays gave the best correlation to in vivo antithrombotic activity. The physical and chemical properties of each dermatan sulfate were determined using 1H-NMR and 13C-NMR spectroscopy, molecular weight determination, potentiometric titration, chemical degradative analysis, chondroitin lyase degradative analysis and oligosaccharide mapping. These analyses indicated that the major difference between dermatan sulfates from a particular species having high and low in vivo antithrombotic activity was their iduronic acid content. The relation between increased iduronic acid content and increased in vivo antithrombotic activity may be the result of the conformational flexibility of this residue.
AB - Dermatan sulfate is a polydisperse, microheterogeneous sufated copolymer of N-acetyl-d-galactopyranose and idopyranosyluronic acid that is currently under clinical investigation as a new antithrombotic agent. The structure and activity of two pairs of dermatan sulfates, isolated from bovine and porcine mucosa, were studied. One dermatan sulfate from each species demonstrated high in vivo antithrombotic activity in the rat vena cava assay. The in vitro anticoagulant activity of each dermatan sulfate was determined using activated partial thomboplastin time (APTT), thrombin time (TT) (5 units), calcium thrombin time (CaTT ) (5 units), Heptest®, anti-factor Xa and anti-factor IIa antithrombin assays and heparin cofactor II amidolytic assays. The coagulation-based assays gave the best correlation to in vivo antithrombotic activity. The physical and chemical properties of each dermatan sulfate were determined using 1H-NMR and 13C-NMR spectroscopy, molecular weight determination, potentiometric titration, chemical degradative analysis, chondroitin lyase degradative analysis and oligosaccharide mapping. These analyses indicated that the major difference between dermatan sulfates from a particular species having high and low in vivo antithrombotic activity was their iduronic acid content. The relation between increased iduronic acid content and increased in vivo antithrombotic activity may be the result of the conformational flexibility of this residue.
UR - http://www.scopus.com/inward/record.url?scp=0025834924&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(91)90431-4
DO - 10.1016/0006-2952(91)90431-4
M3 - Article
C2 - 1930287
AN - SCOPUS:0025834924
SN - 0006-2952
VL - 42
SP - 1609
EP - 1619
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -