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aDS, degree of sulfation (sulfate groups per disaccharide unit). bProduced by degradation of unfractionated heparin.

aDS, degree of sulfation (sulfate groups per disaccharide unit). bProduced by degradation of unfractionated heparin.

resistant to neutralization of their anti-Xa activity by PF4 (Denton et al., 1983; Lane et al., 1984). Also in plasma, the anti-IIa activity of LMWHs, which is mediated by molecules with MW > 5400 Da, but not their anti-Xa activity, can be completely neutralized by higher PF4 concentrations (Padilla et al., 1992; Bendetowicz et al., 1994). The reduced sensitivity of LMWHs to inactivation by PF4 also explains why LMWHs are more active than UFH in platelet-rich plasma (Beguin et al., 1989).

Low- as well as high-affinity heparin binds to PF4 with a similar apparent Kd (Loscalzo et al., 1985). The interaction appears to be mediated by electrostatic interactions as shown by studies of heparin oligosaccharides with different charge densities (Maccarana and Lindahl, 1993). Therefore, the complexes are dissociable. Indeed, heparin can be displaced from PF4 by sulfated polysaccharides, such as other GAGs (Handin and Cohen, 1976), dextran sulfate (Loscalzo et al., 1985), or xylan sulfate (Campbell et al., 1987). The molar ratios required for complex formation increase in the order: UFH < LMWH < heparan sulfate < dermatan sulfate < chondroitin-6-O-sulfate < chondroitin-4-O-sulfate (Handin and Cohen, 1976). Besides the degree of sulfation (DS) and MW, other structural parameters, such as the type of the uronic acid and the position of the sulfate groups within the monosaccharide in the case of GAGs, influence the affinity of a polysaccharide to PF4 (Table 1).

In contrast to the earlier findings on a minimum heparin chain length (Visentin, 1999; Mikhailov et al., 1999), heparin molecules as small as the penta-saccharide were recently shown to interact with PF4 as well (Greinacher et al., 2006). By atomic force microscopy and photon correlation spectroscopy, it has been demonstrated that at very high concentrations and in the absence of AT, the pentasaccharide forms clusters in which PF4 tetramers become closely apposed, even though this tendency is much lower than that of UFH and LMWH.

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