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Title: In_uence of Sulfation on Platelet Aggregation andActivation with Differentially Sulfated Hyaluronic Acids
Authors: Barbucci, Rolando
Lamponi, Stefania 
Magnani, Agnese 
Lawrence F., Poletti
Nick P., Rhodes
Michael, Sobel
David F., Williams
Keywords: sulphated hyaluronic acid derivatives; platelet aggregation; platelet activation; heparin-like
Issue Date: 1998
Project: None 
A number of sulfated hyaluronic acid derivatives(HyalS2.5, HyalS3, and HyalS4) were prepared by sulfation ofthe -OH groups present on hyaluronic acid and were generi-cally termed HyalSx. The anticoagulant properties of thisseries of compounds has previously been shown to be goodin terms of their whole blood clotting inhibition and factorXa and thrombin inactivation. The purpose of the presentstudy was to investigate whether the use of these com-pounds would be bene~cial to patients who would normallybe given heparin, and to perform some preliminary investi-gations into their effects on platelets. The three compoundswere thus studied by investigating their ability to inhibitvon Willebrand factor–dependent platelet agglutination incomparison with unfractionated heparin. Agglutination wasdetermined turbidometrically after the addition of risto-cetin to stirred formaldehyde-~xed platelets and was dem-onstrated to be dependent on the presence of sulfategroups on the polysaccharide chain and correlated with thedegree of HyalSx sulfation. Interactions possibly importantin low shear environments were investigated by measuringthe pharmacological action of the HyalSx on spontaneousplatelet activation and aggregate formation by _ow cy-tometry. The data indicate that platelet activation is notcorrelated with the number of sulfate or hydroxyl groups onHyalSx, suggesting that activation occurs not via electro-static interactions or H bonding, but via some other mecha-nism. A differentiation between low and high glycosamino-glycan sulfation densities is observed with respect toplatelet aggregation, which is correlated with the number ofsulfated groups per disaccharide unit. The ability of HyalSxto inhibit platelet aggregation induced by ADP and throm-bin was measured by aggregometry. HyalS4resisted throm-bin stimulation to a similar extent as heparin. All Hyalderivatives, however, were better at inhibiting ADP-inducedaggregation than was heparin. We conclude, therefore, thatclinical use of HyalSx in place of heparin may be bene~cialbecause ristocetin-dependent agglutination, and thereforeresistance to platelet aggregation in high shear environ-ments, in addition to resistance to stimulation by ADP, hasbeen shown to be superior to heparin. Spontaneous plateletactivation and aggregation are induced at an overall lowlevel, even at high HyalSx concentrations, and are compara-ble with that of heparin.
ISSN: 0929-5305
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