In this study we found that the complement inhibition by OSCS was also dependent on C1inh, as inhibition by OSCS disappeared with the depletion of C1inh from plasma. Surface plasmon resonance assay showed OSCS increased the binding of C1 inhibitor with C1s protease, the initial component of the classical complement pathway. Therefore OSCS inhibits the complement classical pathway by potentiating the interaction of C1inh with C1s. The GAG enhancement of the C1inh – C1s interaction as a direct cause of complement inhibition is consistent with the crystal structure of C1inh that was determined for the serpin domain of recombinant C1inh in its latent form. Based on this structure, surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpinproteinase encounter complex. Beinrohr et al proposed that by binding to C1inh and neutralizing its positively charged surface patches the polyanions facilitate the C1inh-C1s interaction. This can explain how the inhibitory activity of C1 inhibitor toward proteases, such as C1s or activated factor XI, can be greatly enhanced by heparin and other glycosaminoglycans. Our data support this model for the enhancement of C1inh C1s interaction by GAGs that we observed in the current study, as well as in our earlier work. Heparin lots contaminated with OSCS can inhibit complement activity in vitro. However the sustained levels of 10�C20 microgram/ mL are unlikely with intravenous dosing of heparin although subcutaneous administration of contaminated heparin may have allowed for higher local levels of OSCS. A veterinary drug, polysulfated glycosaminoglycan that is very similar in structure to OSCS is still used in animals and administered locally. PSGAG is also a polysulfated chondroitin sulfate with 3 to 4 sulfate groups per disaccharide unit and is considered to be a disease-modifying veterinary drug for osteoarthritis. PSGAG is anti-inflammatory and many mechanisms have been postulated from preservation of joint glycosaminoglycans to inhibition of PGE2 synthesis, toxic oxygen radical generation, and complement activation. Studies have shown an impact of PSGAG at relatively higher doses on complementmediated lysis of red blood cells without a clear mechanism of action. Our in vitro experiments using bacteria as model indicate PSGAG is a very strong inhibitor of complement fixation of bacteria. The potentiation of C1inh interaction with C1s by OSCS can also explain the effect of PSGAG on complement lysis and provide a mechanism for studies suggesting an increased likelihood of Compound Library inhibitor infections with intra-articular injection of PSGAG and low levels of bacteria. Although there was an increase in the absolute numbers of infections reported during the 2007�C2008 timeframe of the OSCS contamination, the relative numbers decreased. It may be of value to further assess GAG related products including PSGAG, for infection related adverse events, although adverse event reporting has many limitations. Based on the concentrations heeded to inhibit complement, there may not be an in vivo effect unless 
high doses are administered locally rather than systemically. There have been suggestions that glycosaminoglycans can be used to inhibit the complement activity in situations such as GANT61 autoimmune diseases.