Chemically Oversulfated Glycosaminoglycans Are Potent Modulators of Contact System Activation and Different Cell Signaling Pathways

Abstract

Contaminated heparin was associated with adverse reactions by activating the contact system. Chemically oversulfated/modified glycosaminoglycans (GAGs) consisting of heparan sulfate, dermatan sulfate, and chondroitin sulfate have been identified as heparin contaminants. Current studies demonstrated that each component of oversulfated GAGs was comparable with oversulfated chondroitin sulfate in activating the contact system. By testing a series of unrelated negatively charged compounds, we found that the contact system recognized negative charges rather than specific chemical structures. We further tested how oversulfated GAGs and contaminated heparins affect different cell signaling pathways. Our data showed that chemically oversulfated GAGs and contaminated heparin had higher activity than the parent compounds and authentic heparin, indicative of sulfation-dominant and GAG sequencedependent activities in BaF cell-based models of fibroblast growth factor/fibroblast growth factor receptor, glial cell linederived neurotrophic factor/c-Ret, and hepatocyte growth factor/c-Met signaling. In summary, these data indicate that contaminated heparins intended for blood anticoagulation not only activated the contact system but also modified different GAGdependent cell signaling pathways.

Factor XII: a novel target for safe prevention of thrombosis and inflammation

“…Consistently, local dextran sulphate injection into the skin stimulated BK‐dependent vascular leakage in mice . Oversulphated glycosaminoglycans and modified polysaccharides potently triggered FXII contact activation and induced PK activity in human plasma . In 2008, batches of heparin contaminated with synthetically oversulphated chondroitin sulphate (OSCS) triggered severe BK‐mediated hypersensitivity reactions including hypotonic shock and led to death in more than 150 patients .…”

Determination of the degree of acetylation and the distribution of acetyl groups in chitosan by HPLC analysis of nitrous acid degraded and PMP labeled products

“…However, recently published studies demonstrate that 1 H NMR fails to detect up to 50% polysaccharides in chitosan and PEGylated chitosan copolymers [33] It has also been reported that even though the same M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 amount of oversulfated chondroitin sulfate (OSCS) and oversulfated dermatan sulfate (OSDS), two types of highly resembling chemically sulfated animal polysaccharides, possess the same numbers of acetyl groups, the 1 H NMR proton signal intensities reflecting the acetyl groups in OSDS are only half of that observed in OSCS. [34] Furthermore, 1 H NMR could detect 0.1% OSCS in heparin based on the proton signal intensity of the acetyl groups in OSCS but could not detect 30% oversulfated heparan sulfate (OSHS) in heparin because the proton signal of the acetyl groups in OSHS is totally disappeared when mixed with heparin, [35,36] which suggest that 1 H NMR invisible or non-quantitative phenomena might be associated with polysaccharide structural analysis in general. Although 1 H NMR-based chitin/chitosan analysis produces consistent spectra demonstrating great reproducibility towards polysaccharide analysis and has been chosen as a standard method by the American Standard Test Method organization to determining the DA for chitosan, [37] the invisible and un-quantitative phenomena observed in chitosan and other polysaccharides by 1 H NMR analysis raise questions about the reliability of using 1 H NMR analysis alone for chitin/chitosan DA measurement and for comprehensive structure analysis.…”

Competitive Inhibition of Heparinase by Persulfonated Glycosaminoglycans: A Tool to Detect Heparin Contamination

“…7 Nevertheless, the potential for their introduction is possible, especially given that they likely have similar biological activities as OSCS. 8 …”