Pentasaccharides

Within the scope of developing new carbohydrate-based antithrombotics, fonda-parinux, a fully synthetic, chemically defined pentasaccharide (formerly named Org31540/SR90107A, MW = 1728 Da; DS = 1.6; 700 anti-Xa U/mg), has been developed, which corresponds to the AT-binding site of heparin (Petitou et al., 1997) (Fig. 5; see also Chapter 17). By its highly specific binding to AT, fondapar-inux selectively inhibits factor Xa and thus prevents thrombin generation (Bauer et al., 2002). Fondaparinux is approved for thrombosis prophylaxis and treatment (see Chapters 1 and 17).

Fondaparinux does not cross-react with HIT antibodies in any concentration tested, either in the PF4-H-EIA or in the serotonin-release assay (Amiral et al., 1997; Greinacher et al., 1995; Ahmad et al., 1999). Immune thrombocytopenia attributable to fondaparinux has not been observed in any of the clinical studies. However, patients treated with fondaparinux in clinical trials generated anti-PF4/heparin antibodies at a similar frequency as observed in patients treated with LMWH (enoxaparin). These antibodies tested positive in a PF4-dependent EIA and caused platelet activation in vitro in the presence of added heparin, although no cross-reactivity with fondaparinux itself could be shown (Warkentin et al., 2005a). It has

FIGURE 5 Chemical structure of the synthetically produced pentasaccharide, fondaparinux (formerly, Org31540/SR90107A; MW = 1728 Da; DS = 1.6; 864 anti-Xa U/mg), with eight sulfate groups corresponding to the natural antithrombin-binding site. Abbreviations: DS, degree of sulfation; MW, molecular weight.

FIGURE 5 Chemical structure of the synthetically produced pentasaccharide, fondaparinux (formerly, Org31540/SR90107A; MW = 1728 Da; DS = 1.6; 864 anti-Xa U/mg), with eight sulfate groups corresponding to the natural antithrombin-binding site. Abbreviations: DS, degree of sulfation; MW, molecular weight.

been hypothesized that PF4 forms only few and potentially relatively unstable multimolecular complexes in the presence of fondaparinux. These few complexes can trigger the immunization but are too sparse to mediate relevant platelet activation (Greinacher et al., 2006).

In support of this concept, we have observed in our laboratory that a more highly sulfated pentasaccharide, Org 32701 (MW = 1991 Da; DS = 2. 0) (Herbert et al., 1996) (Fig. 6), induces platelet activation in the presence of HIT antibodies. This demonstrates that certain highly sulfated oligosaccharides are indeed able to bind to PF4 and thus to form the HIT neoantigen. But, whether such a highly sulfated pentasaccharide itself could induce clinical HIT cannot yet be answered.

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