Influence of zinc on glycosaminoglycan neutralisation during coagulation

Heparan sulfate (HS), dermatan sulfate (DS) and heparin are glycosaminoglycans (GAGs) that serve as key natural and pharmacological anticoagulants. During normal clotting such agents require to be inactivated or neutralised. Several proteins have been reported to facilitate their neutralisation, which reside in platelet α-granules and are released following platelet activation. These include histidine-rich-glycoprotein (HRG), fibrinogen and high-molecular-weight kininogen (HMWK). Zinc ions (Zn(2+)) are also present in α-granules at a high concentration and participate in the propagation of coagulation by influencing the binding of neutralising proteins to GAGs. Zn(2+) in many cases increases the affinity of these proteins to GAGs, and is thus an important regulator of GAG neutralisation and haemostasis. Binding of Zn(2+) to HRG, HMWK and fibrinogen is mediated predominantly through coordination to histidine residues but the mechanisms by which Zn(2+) increases the affinity of the proteins for GAGs are not yet completely clear. Here we will review current knowledge of how Zn(2+) binds to and influences the neutralisation of GAGs and describe the importance of this process in both normal and pathogenic clotting.