Histidine-rich glycoprotein (HRG) is a plasma protein that regulates a number of biological processes in the blood including coagulation, through its ability to bind and neutralize heparins. HRG contains a distinctive histidine-rich region that associates with zinc ions (Zn2+) to stimulate HRG-heparin complex formation. Under normal conditions the majority of Zn2+ in plasma associates with serum albumin. However, clinically high levels of free fatty acid (FFA) allosterically disrupt the major Zn2+-binding site on serum albumin and are associated with an increased risk of thrombotic complications. The Stewart group report in the Journal of Thrombosis and Haemostasis that increased levels of circulatory fatty acids are likely to increase the proportion of plasma Zn2+ associated with HRG. In this study the Zn2+-binding properties of HRG and the formation of HRG-heparin complexes in the presence of different Zn2+ concentrations were investigated. Furthermore, the binding of Zn2+ to serum albumin was examined in the presence of various concentrations of myristate by ITC. Speciation modeling of plasma Zn2+ based upon the data obtained from these experiments suggests that FFA-mediated displacement of Zn2+ from serum albumin is likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels – Full text is available online.