Glycosaminoglycans and the regulation of blood coagulation.

Blood coagulation involves the sequential activation of a series of serine proteinases, which culminates in the generation of thrombin and subsequent thrombin-catalysed conversion of fibrinogen into insoluble fibrin (Furie and Furie, 1988). Inhibitory modulation of this process, of paramount physiological importance, is primarily achieved by two principally different mechanisms (Figure 1). The enzymes may be inactivated by serine proteinase inhibitors (known as 'serpins'), which act by formation ofstable 1 :1 molar complexes with their target enzymes (Travis and Salvesen, 1983). Alternatively, the so-called protein C pathway leads to inactivation of auxiliary coagulation proteins (factors V. and VIII.) by cleavage at distinct sites (Esmon, 1989; Dahlbaick, 1991). The prime site of regulation is the surface of vascular endothelial cells, which have been known to possess anticoagulant properties (Colburn and Buonassisi, 1982). These properties are particularly conspicuous in the microcirculation, with its high wall surface to blood volume ratio (Busch, 1984). The ability of certain sulphated polysaccharides, glycosaminoglycans, to interfere with blood coagulation has a long-standing record, as illustrated by the extensive clinical use of heparin as an antithrombotic agent (see Roden, 1989). The main effect of heparin (and of its relative, heparan sulphate) is to accelerate the inactivation of coagulation enzymes by the serpin antithrombin (Rosenberg, 1977; Bjork and Lindahl, 1982). A more complex picture emerged with the finding of an additional serpin, heparin cofactor II, which is 'activated' not only by heparin, but also by another glycosaminoglycan, dermatan sulphate, and which selectively inactivates thrombin (Tollefsen et al., 1982; Tollefsen, 1989). Remarkably, also the other major regulatory mechanism, the protein C pathway, involves a glycosaminoglycan-containing molecular species, since the protein C activation cofactor, thrombomodulin, turned out to be a proteoglycan with a functionally important, covalently bound glycosaminoglycan chain (Bourin and Lindahl, 1990; Bourin et al., 1990). In this Review we attempt to summarize our current understanding of glycosaminoglycan involvement in the regulation of blood coagulation.