HEPARIN AND DERIVATIZED HEPARIN INHIBIT ZYMOSAN AND COBRA VENOM FACTOR ACTIVATION OF COMPLEMENT IN SERUM

Heparin has been shown to inhibit activity of the alternative, classic al and terminal pathways of complement by regulating C1, C1 inhibitor, C4 binding protein, C3b, factor H and S-protein. In vivo, heparin inh ibits cobra venom factor activation of complement in a dose-related ma nner in guinea pigs. However, the ability of heparin and of modified h eparin to inhibit complement activation in serum has not been examined systematically. The present study compared commercial heparin with a modified heparin that has reduced anticoagulant activity (N-desulfated , N-acetylated heparin) for ability to inhibit cobra venom factor and zymosan-induced complement activation in guinea pig and human serum. B oth heparins inhibited cobra venom factor and zymosan-induced consumpt ion of C3 activity in both human and guinea pig serum. In both serum t ypes, commercial heparin was about twice as active as modified heparin on a weight basis for ability to inhibit cobra venom factor-induced c omplement activation. Both heparins also inhibited zymosan-induced com plement activation in human serum. About four times more heparin was r equired to inhibit cobra venom factor-induced complement activation in guinea pig serum than in human serum while heparin was more than ten times more active in human serum than in guinea pig serum when zymosan was used as the activator of complement. This study suggests that hep arin is considerably more effective in regulating complement activity in humans than in guinea pigs, an animal model in which heparin clearl y has in vivo capacity to regulate complement activity. These observat ions represent an important step in the development of new clinically relevant oligosaccharide-derived pharmacologic agents to regulate comp lement activity.