History

Unfractionated heparin (UFH) is comprised of a highly heterogeneous mixture of linear polysaccharide molecules of variable length (mean, 45-50 saccharide units). Seminal studies by Rosenberg in the 1970s and 1980s defined the structure-function relationship of heparin. The pharmacologic activity of UFH was ascribed to a subpopulation of polysaccharides capable of binding AT (Lam et al., 1976; Rosenberg et al., 1978). Anticoagulation resulted from formation of an inhibitory ternary complex among heparin, AT, and any of five clotting factors (factors IIa, Xa, IXa, XIa, and XIIa). Subsequent studies resolved the minimal chemical motif necessary for anticoagulation as a tetrasaccharide sequence (Rosenberg and Lam, 1979). Based on these findings, synthetic polysaccharides with potent anticoagulant activity were prepared (Choay et al., 1983; Grootenhuis et al., 1995; Petitou et al., 1999). One theoretical benefit of the small size of the synthetic heparin mimetics would be the potential not to cause HIT (Petitou et al., 1999).

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