Fundamental to the development of HIT is the binding of (anionic) sulfated polysaccharides (UFH or LMWH) to (cationic) PF4, resulting in an allosteric modulation of PF4 structure that presents neoantigens to the immune system. One motivation for the development of pentasaccharide anticoagulants was the inference that these comparatively small (~1700 Da) compounds might not associate significantly with PF4, potentially avoiding or minimizing risk of HIT (Petitou et al., 1999; see also Chapter 7). There is growing evidence supporting this thesis, including numerous in vitro studies, and (more importantly) early favorable experience with fondaparinux in the treatment of HIT (Table 3). The rationale for the use of fondaparinux in treating HIT derives from its efficacy in numerous (non-HIT) clinical settings and the evidence that pentasaccharide anticoagulants do not cross-react significantly with anti-PF4/heparin antibodies.

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