C PF4Sulfated Polysaccharide Complexes

PF4 has the highest affinity to heparin among proteins stored within the platelet a-granules. Heparin molecules bind to PF4 by interactions with the positively charged residues on the surface of PF4 (see Chapter 6). Stuckey and coworkers (1992) suggested that heparin is bound to PF4 by being wrapped around the tetramer along the ring of positive charges. A heparin molecule with 16-18 monosaccharides interacts with PF4 by spanning about half of the tetramer. As a consequence, only very long molecules are able to wrap around the complete tetramer. Mayo and coworkers (1995) identified a loop containing Arg-20, Arg-22, His-23, and Thr-25, as well as Lys-46 and Arg-49, which are more relevant for heparin binding than the COOH-terminal lysines. For optimal interaction with PF4, a heparin molecule should consist of at least 12 monosaccharides (Visentin, 1999; Mikhailov et al., 1999). At low concentrations (0.1-1.0 IU/mL) of heparin and high concentrations of PF4, several PF4 tetramers compete for heparin binding. This permits binding of a heparin chain to more than one PF4 tetramer. Particularly, if a heparin molecule is longer than 16 monosaccharides, it is able to bind to and thereby bridge two PF4 tetramers. Thus, at certain concentrations of heparin and PF4, large, multimolecular PF4-heparin complexes are formed. UFH forms larger complexes than LMWH (Rauova et al., 2005; Greinacher et al., 2006). These complexes can be dissociated in the presence of high heparin concentrations (Bock et al., 1980; Greinacher et al., 1994a, 1995).

In vitro, only heparin molecules containing 16 or more monosaccharides completely bind to immobilized PF4, resulting in total neutralization of their antifactor Xa (anti-Xa) and anti-thrombin (anti-IIa) activities, whereas progressively smaller oligosaccharides (without anti-IIa activity) become increasingly

TABLE 1 Main Disaccharide Units of Mammalian Glycosaminoglycans, Arranged by Increasing Affinity to Platelet Factor 4

Glycosaminoglycan

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