Oversulfated chondroitin sulfate interaction with heparin-binding proteins: new insights into adverse reactions from contaminated heparins.
An oversulfated chondroitin sulfate (OSCS) was identified as a contaminant to pharmaceutical heparin and severe anaphylactoid reactions were ascribed to this contaminant. An examination of the biochemistry underlying both the anticoagulant activity and the toxic effects of oversulfated chondroitin sulfate was undertaken. This study demonstrates that the anticoagulant activity of this oversulfated chondroitin sulfate is primarily dependent on heparin cofactor II mediated inhibition of thrombin. Heparin and oversulfated chondroitin sulfate binding to coagulation, kinin-kallikrein and complement proteins were studied by surface plasmon resonance. While oversulfated chondroitin sulfate binds tightly to antithrombin III, unlike heparin, OSCS does not induce antithrombin III to undergo the conformational change required for its inactivation of thrombin and factor Xa. In contrast to heparin, oversulfated chondroitin sulfate tightly binds factor XIIa suggesting a biochemical mechanism for the factor XIIa-based enhancement of vasoactive bradykinin production.
Li
Boyangzi
B
Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Suwan
Jiraporn
J
Martin
Jeffrey G
JG
Zhang
Fuming
F
Zhang
Zhenqing
Z
Hoppensteadt
Debra
D
Clark
Melanie
M
Fareed
Jawed
J
Linhardt
Robert J
RJ
D000925:Anticoagulants / Q000009:adverse effects*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry*; D002240:Carbohydrate Sequence; D002352:Carrier Proteins / Q000737:chemistry*; D002809:Chondroitin Sulfates / Q000737:chemistry*; D004340:Drug Contamination; D006493:Heparin / Q000009:adverse effects* / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D020349:Surface Plasmon Resonance
C062991:AZU1 protein, human; D000925:Anticoagulants; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D006493:Heparin; D002809:Chondroitin Sulfates