FIGURE 4 Repeating unit of (-1, 3-glu-can sulfates: The primary OH group in position 6(**) is preferentially sulfated. Glycosidic-branched (-1, 3-glucan sulfates are substituted by a glucose, rham-nose, or arabinose unit, respectively, in position 6.

An increase in the DS results in improved anticoagulant activity and, after binding to PF4, in increased formation of HIT antibody-binding sites. The MW is a second important structural parameter for anticoagulant potency of a sulfated polysaccharide, as well as its capacity to cause platelet activation in the presence of HIT antibodies. Fractions with hydrodynamic volumes between 38 and 60 kDa showed the most prominent effects (Alban and Franz, 1994a; Greinacher et al., 1995) (the hydrodynamic volumes were determined by gel filtration chromatography using neutral pullulans as MW standards; since these have lower hydrodynamic volumes owing to the missing sulfate groups, the measured hydrodynamic volumes are higher than the real MW; e.g., UFH had a mean hydrodynamic volume of 30 kDa). Therefore, this MW range, which corresponds to that of the so-called extra large material of UFH, seems to represent the optimal chain length both for the interaction with proteins involved in the coagulation cascade as well as with PF4 to form HIT antigens. Beyond the optimal chain length, higher concentrations are required to form multimolecular PF4-GluS complexes (Greinacher et al., 1995).

Compared with linear GluS having similar DS and MW, glycosidically branched compounds generally exhibit higher anticoagulant activity than the respective linear derivatives (Alban, 1993, 1997). Glycosidic substitution changes the 3D structure of the polysaccharide chain, resulting in enhanced flexibility, and improved the interaction with proteins (Kindness et al., 1980). In addition, as the side chains are more accessible to sulfation, they represent clusters of negative charges (Alban and Franz, 1994b) facilitating binding to PF4, which results in an increased cross-reactivity with HIT antibodies.

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