Iiiheparan Sulfatecontaining Proteoglycans Heparin And The Endothelium

The expression and anticoagulant function of heparan sulfate-type proteoglycans (HSPGs) by ECs may be central to the pathogenesis of vascular thrombosis in patients with HIT. The biochemistry and function of these GAGs and the proteo-glycans to which they bind have been the subject of extensive study (for review: see Rosenberg et al., 1997; Esko and Lindahl, 2001; Forsberg and Kjellen, 2001). The involvement of heparan sulfate in the development of HIT is considered elsewhere (see Chapter 7). HSPGs expressed by ECs bind antithrombin (AT) in vitro and in vivo, and accelerate the inactivation of thrombin and factor Xa approximately 20-fold, an effect that is biologically equivalent to 0.1-0.5 U/mL of heparin (Marcum and Rosenberg, 1984). Yet less than 1% of the HSPGs isolated from cultured ECs express anticoagulant activity (Marcum and Rosenberg, 1984). Active species are characterized by an approximately twofold enrichment in glucuronyl 3-O-sulfated glucosamine residues, compared with inactive species (Marcum and Rosenberg, 1984). Interestingly, targeted deletion of the murine 3-O-sulfo-transferase-1 enzyme (the enzyme responsible for generating this anticoagulant modification of HSPGs) does not lead to a prothrombotic phenotype (HajMohammadi et al., 2003). The physiological mechanisms that control the synthesis and postsynthetic modifications of HSPG remain an active area of investigation (Forsberg and Kjellen, 2001).

Microheterogeneity in the composition of HSPG in arteries, veins, and capillaries has been noted (Lowe-Krentz and Joyce, 1991), but the significance of these differences is unknown. Expression of HSPG by ECs undergoes developmental changes (David et al., 1992), and its composition varies after the cells are exposed to thrombin (Benezra et al., 1993), homocysteine (Nishinaga et al., 1993), heparin (Nader et al., 1989), wounding and migration (Kinsella and Wight, 1986), and after induction by activated platelets (Yahalom et al., 1984), among other stimuli. ECs also bind heparin (for review: see Patton et al., 1995), which alters their proliferation, matrix composition, and many other vascular functions. It has also been reported that AT is displaced from ECs by heparin, and its binding is inhibited by PF4 (Stern et al., 1985). Whether HIT antibodies promote the capacity of PF4 to neutralize AT activity has not been reported.

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